US 7,169,904 B2Grant

Immunocytokine sequences and uses thereof

Issue Date:2007-01-30

•5 Claims

•11 Drawing Sheets

Abstract

The invention provides a family of antibodies that specifically bind the human cell surface glycosphingolipid GD2. The antibodies comprise modified variable regions, more specially, modified framework regions, which reduce their immunogenicity when administered to a human. The antibodies may be coupled to a therapeutic agent and used in the treatment of cancer.

Metadata

Assignee

EMD Lexigen Research Center Corp.

Inventors

Stephen D. Gillies
Kin-Ming Lo
Susan X. Qian

Application Information

Application Number:US 10/737,208

Filing Date:2003-12-16

Priority Date:2002-12-17

Art Unit:1646

Classifications

IPC:

C07K16/00

Patent Drawings (11 sheets)

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This incorporates by reference, and claims priority to and the benefit of, U.S. provisional patent application 60/433,945, which was filed on Dec. 17, 2002.

FIELD OF THE INVENTION

[0002] This invention relates generally to modified antibodies. More particularly, the invention relates to modified antibodies with reduced immunogenicity that specifically bind the human cell surface glycosphingolipid GD2, and their use as therapeutic agents.

BACKGROUND OF THE INVENTION

[0003] There has been significant progress in the development of antibody-based therapies over the years. For example, investigators have identified not only a variety of cancer-specific markers but also a variety of antibodies that specifically bind to those markers. Antibodies can be used to deliver certain molecules, for example, a toxin or an immune stimulatory moiety, for example, a cytokine, to a cancer cell expressing the marker so as to selectively kill the cancer cell.

[0004] The 14.18 antibody is a mouse-derived monoclonal antibody directed against the cell surface glycosphingolipid GD2. GD2 is a disialoganglioside that is normally only expressed at a significant level on the outer surface membranes of neuronal cells, where its exposure to the immune system is limited by the blood brain barrier.

[0005] Many tumor cells, in contrast, have abnormal levels of glycosphingolipid cell surface expression. For example, GD2 is expressed on the surfaces of a wide range of tumor cells including neuroblastomas, medulloblastomas, astrocytomas, melanomas, small-cell lung cancer, osteosarcomas and other soft tissue sarcomas. Thus, GD2 is a convenient tumor-specific marker for targeting immune-stimulatory protein domains to tumor cells for the purpose of raising an effective immune response against the tumor cells to destroy them. While the 14.18 mouse antibody (m14.18 antibody) may assist the targeting of these protein domains to tumor cells, its mouse-derived amino acid sequences can impair the desired therapeutic effect.

[0006] When administered to a patient, antibodies can have an associated immunogenicity in the host mammal. This is more likely to occur when the antibodies are not autologous. Consequently, the effectiveness of antibody-based therapies often is limited by an immunogenic response directed against the therapeutic antibody. This immunogenic response typically is increased when the antibody is derived in whole or in part from a mammal different than the host mammal, e.g., when the antibody is derived from a mouse and the recipient is a human.

[0007] For clinical use in humans, it may be helpful to modify mouse-derived antibodies to more closely resemble human antibodies, so as to reduce or minimize the immunogenicity of the mouse-derived antibody. The immunogenicity of the mouse-derived antibody can be reduced by the creation of a chimeric antibody in which the constant regions of a human antibody are fused to mouse variable domains. However, the remaining mouse variable domains are generally still immunogenic in humans, and can thus impair the efficacy of an antibody-based therapy.

[0008] Some approaches to reducing immunogenicity, such as “veneering” and “humanization” involve the introduction of many amino acid substitutions and may disrupt the binding of an antibody to an antigen. The m14.18 antibody binds to GD2 with moderate affinity. Therefore, mutations that significantly lower the affinity of m14.18 for GD2 are expected to make it less effective for therapeutic purposes in humans. Accordingly, there is a need in the art for therapeutic antibodies that can effectively target GD2 and have reduced immunogenicity when administered to a human.

SUMMARY OF THE INVENTION

[0009] Generally, the present invention provides a modified form of the m14.18 antibody that is less immunogenic in humans, but still maintains the binding affinity of m14.18 for human GD2.

[0010] More particularly, the invention provides a humanized form of the m14.18 antibody (hu14.18 antibody) in which several mouse-specific amino acids in one or more of the framework regions have been substituted with different amino acids to reduce their immunogenicity in humans. The invention also provides fusions of the hu14.18 antibody to one or more non-immunoglobulin moieties for enhancing the effects of targeted immune therapy.

[0011] In one aspect, the present invention provides an antibody variable region including the amino acid sequence set forth in SEQ ID NO: 1, which defines an immunoglobulin light chain variable region (V_Lregion). In another aspect, the invention relates to an antibody variable region including the amino acid sequence set forth in SEQ ID NO: 2, which defines an immunoglobulin heavy chain variable region (V_Hregion). In one embodiment, the invention provides an antibody variable region in which the amino acid sequence of SEQ ID NO: 1 is linked to the amino acid sequence set forth in SEQ ID NO: 2. The amino acid sequences can be linked, such as by a disulfide bond or a peptide bond.

[0012] In another aspect, the invention relates to an antibody variable region that specifically binds to GD2 and includes at least amino acids 1–23 of SEQ ID NO: 1, amino acids 1–25 of SEQ ID NO: 2, or amino acids 67–98 of SEQ ID NO: 2. These sequences define framework regions in the immunoglobulin variable regions of the hu14.18 antibody. Framework regions are described in greater detail below.

[0013] One aspect of the invention relates to a method for targeting a cell with GD2 on its surface and includes administering an antibody variable region of the present invention to a patient. In one embodiment, the targeted cell is a tumor cell. Further aspects of the invention include a nucleic acid encoding the antibody variable region or a cell that includes this nucleic acid, either of which can be administered to a patient or used for in vitro protein production.

[0014] The invention also provides a polypeptide that includes an antibody variable region of the invention and an Fc portion comprising at least a CH2 domain, nucleic acids encoding the polypeptide, cells including the nucleic acids, and methods for targeting a cell with GD2 on its surface by administering the polypeptide, nucleic acid, or cell to a patient. In some embodiments of the invention, the Fc portion is derived from IgG1.

[0015] The antibody variable region can be linked, with or without an intervening Fc portion, to a non-immunoglobulin moiety. Specifically, the non-immunoglobulin moiety can be a cytokine, such as an interleukin, a hematopoietic factor, a lymphokine, an interferon, or a chemokine. The interleukin can be, for example, interleukin-2 or interleukin-12. The hematopoietic factor and lymphokine can be, for example, granulocyte-macrophage colony stimulating factor (GM-CSF) and a lymphotoxin, respectively. The interferon can be, for example, interferon-α, interferon-β, or interferon-γ. In some embodiments of the invention, the fusion protein includes a second non-immunologlobulin moiety, such as a second cytokine. In a particular embodiment, the fusion protein includes the antibody variable region, IL-2, and IL-12.

[0016] It is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.

DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A shows the amino acid sequence of an immunoglobulin light chain variable region in accordance with the invention.

[0018] FIG. 1B shows the amino acid sequence of an immunoglobulin heavy chain variable region in accordance with the invention.

[0019] FIGS. 2A–G show the nucleotide sequence of a vector for expression of an immunoglobulin light chain and an immunoglobulin heavy chain-IL-2 fusion protein in accordance with the invention. The nucleotide sequence is presented in 5′ to 3′ direction from left to right and top to bottom, spanning FIGS. 2A–2G, and is SEQ ID NO: 4.

[0020] FIG. 3A shows the amino acid sequence of an immunoglobulin light chain in accordance with the invention.

[0021] FIG. 3B shows the amino acid sequence of an immunoglobulin heavy chain in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0022] The present invention provides a modified form of the m14.18 antibody that is less immunogenic in humans, but is still able to specifically bind human GD2. The reduced immunogenicity is provided by one or more altered amino acid sequences in the immunoglobulin variable domains. The antibody is useful for treating GD2-positive tumors, particularly when fused to a cytokine or other immune modulator.

[0023] As used herein, the terms “antibody” and “immunoglobulin” are understood to mean (i) an intact antibody (for example, a monoclonal antibody or polyclonal antibody), (ii) antigen binding portions thereof, including, for example, an Fab fragment, an Fab′ fragment, an (Fab′)₂fragment, an Fv fragment, a single chain antibody binding site, an sFv, (iii) bi-specific antibodies and antigen binding portions thereof, and (iv) multi-specific antibodies and antigen binding portions thereof.

[0024] As used herein, the terms “bind specifically,” “specifically bind” and “specific binding” are understood to mean that the antibody has a binding affinity for a particular antigen of at least about 10⁶M⁻¹, more preferably, at least about 10⁷M⁻¹, more preferably at least about 10⁸M⁻¹, and most preferably at least about 10¹⁰M⁻¹.

[0025] As used herein, the terms “Framework Regions” and “FRs” are understood to mean the regions of an immunoglobulin variable region adjacent to the Complementarity-Determining Regions (CDRs). CDRs are the portions of an immunoglobulin variable region that interact primarily with an antigen. As shown in FIG. 1, the V_Hand V_Lregions both contain four FRs and are located within the boxed portions of the amino acid sequences.

[0026] In particular, with reference to the amino acid sequence shown in FIG. 1A (SEQ ID NO: 1), the light chain FRs are defined by the amino acid sequences from Asp1 to Cys23 (huV_LFR1), from His39 to His54 (huV_LFR2), from Gly62 to Cys93 (huV_LFR3), and from Phe104 to Lys113 (huV_LFR4). With reference to the amino acid sequence shown in FIG. 1B (SEQ ID NO: 2), the heavy chain FRs are defined by the amino acid sequences from Glu1 to Ser25 (huV_HFR1), from Trp36 to Gly49 (huV_HFR2), from Arg67 to Ser98 (huV_HFR3), and from Trp103 to Ser113 (huV_HFR4).

Protein Sequences of the Invention

[0027] The present invention features antibodies that bind, preferably specifically, to the human cell surface glycosphingolipid GD2 and have modified regions derived from the m14.18 antibody. The V_Hor V_Lamino acid sequences (or both) are modified or humanized to reduce their immunogenicity when administered to a human. In accordance with the invention, the m14.18 antibody can be humanized, for example, by using deimmunization methods in which potential T cell epitopes are eliminated or weakened by introduction of mutations that reduce binding of a peptide epitope to an MHC Class II molecule (see, for example, WO98/52976 and WO00/34317). Alternatively, non-human T cell epitopes are mutated so that they correspond to human self epitopes that are present in human antibodies (see, for example, U.S. Pat. No. 5,712,120). The present invention provides GD2 antibodies having V_Land V_Hregions that include at least one humanized FR sequence, thereby reducing immunogenicity when administered to a human.

I. Heavy and Light Chains Variable Regions

[0028] As mentioned above, the hu14.18 includes humanized variable regions derived from the m14.18 antibody that maintain specific binding of human GD2 antigen. In some embodiments of the invention, the V_Lregion of the hu14.18 antibody includes the following polypeptide:

[0029]

D-V-V-M-T-Q-T-P-L-S-L-P-V-T-P-G-E-P-A-S-I-S-C-R-S-S-Q-S-L-V-H-R-N-G-N-T-	(SEQ ID NO: 1)

Y-L-H-W-Y-L-Q-K-P-G-Q-S-P-K-L-L-I-H-K-V-S-N-R-F-S-G-V-P-D-R-F-S-G-S-G-S-

G-T-D-F-T-L-K-I-S-R-V-E-A-E-D-L-G-V-Y-F-C-S-Q-S-T-H-V-P-P-L-T-F-G-A-G-T-

K-L-E-L-K.

[0030] In particular embodiments, the hu14.18 antibody includes a light chain FR1 that is defined by residues 1 to 23 of SEQ ID NO: 1, namely, D-V-V-M-T-Q-T-P-L-S-L-P-V-T-P-G-E-P-A-S-I-S-C (huV_LFR1).

[0031] In other embodiments of the invention, the V_Hregion of the hu14.18 antibody includes the following polypeptide:

[0032]

E-V-Q-L-V-Q-S-G-A-E-V-E-K-P-G-A-S-V-K-I-S-C-K-A-S-G-S-S-F-T-G-Y-N-M-N-	(SEQ ID NO: 2)

W-V-R-Q-N-I-G-K-S-L-E-W-I-G-A-I-D-P-Y-Y-G-G-T-S-Y-N-Q-K-F-K-G-R-A-T-L-T-

V-D-K-S-T-S-T-A-Y-M-H-L-K-S-L-R-S-E-D-T-A-V-Y-Y-C-V-S-G-M-E-Y-W-G-Q-G-

T-S-V-T-V-S-S.

[0033] In particular embodiments, the hu14.18 antibody includes a heavy chain FR1 that is defined by residues 1 to 25 of SEQ ID NO: 2, namely E-V-Q-L-V-Q-S-G-A-E-V-E-K-P-G-A-S-V-K-I-S-C-K-A-S (huV_HFR1).

[0034] In further embodiments of the invention, the hu14.18 antibody includes a heavy chain FR3 that is represented by residues 67 to 98 of SEQ ID NO: 2, namely R-A-T-L-T-V-D-K-S-T-S-T-A-Y-M-H-L-K-S-L-R-S-E-D-T-A-V-Y-Y-C-V-S (huV_HFR3).

[0035] Various combinations of the foregoing embodiments are also within the scope of the present invention. For example, the hu14.18 antibody may include the V_Lsequence set forth in SEQ ID NO: 1 and the V_Hsequence set forth in SEQ ID NO: 2. The V_Land V_Hregions can be linked by a disulfide bond or a peptide bond, depending on how their nucleic acid sequences are constructed. In general, V regions are linked by a disulfide bond when their sequences are encoded on separate DNA constructs. In contrast, the V regions are typically linked by a peptide bond when their sequences are encoded on a single-chain DNA construct.

[0036] The present invention also contemplates an antibody that specifically binds GD2 and includes at least a portion of the humanized V regions. For example, the hu14.18 antibody can include a V_Lregion as defined by SEQ ID NO:1 and a V_Hregion having at least one humanized FR, such as huV_HFR1 or huV_HFR2. Alternatively, the antibody of the present invention can include a V_Hregion as defined by SEQ ID NO: 2 and a V_Lregion having at least one humanized FR, such as huV_LFR1. The hu14.18 antibody can also include a V_Hregion having at least one humanized FR and/or a V_Lregion having at least one humanized FR.

[0037] In certain embodiments of the invention, the light chain variable region and the heavy chain variable region can be coupled, respectively, to a light chain constant region and a heavy chain constant region of an immunoglobulin. The immunoglobulin light chains have constant regions that are designated as either kappa or lambda chains. In a particular embodiment of the invention, the light chain constant region is a kappa chain. The heavy chain constant regions, and various modification and combinations thereof are discussed below in detail.

II. Fc Portion

[0038] The antibody variable domains of the present invention are optionally fused to an Fc portion. As used herein, the Fc portion encompasses domains derived from the heavy chain constant region of an immunoglobulin, preferably a human immunoglobulin, including a fragment, analog, variant, mutant or derivative of the constant region. The constant region of an immunoglobulin heavy chain is defined as a naturally-occurring or synthetically produced polypeptide homologous to at least a portion of the C-terminal region of the heavy chain, including the CH1, hinge, CH2, CH3, and, for some heavy chain classes, CH4 domains. The “hinge” region joins the CH1 domain to the CH2–CH3 region of an Fc portion. The constant region of the heavy chains of all mammalian immunoglobulins exhibit extensive amino acid sequence similarity. DNA sequences for these immunoglobulin regions are well known in the art. (See, e.g., Gillies et al. (1989) J. Immunol. Meth. 125:191).

[0039] In the present invention, the Fc portion typically includes at least a CH2 domain. For example, the Fc portion can include the entire immunoglobulin heavy chain constant region (CH1-hinge-CH2–CH3). Alternatively, the Fc portion can include all or a portion of the hinge region, the CH2 domain and the CH3 domain.

[0040] The constant region of an immunoglobulin is responsible for many important antibody effector functions, including Fc receptor (FcR) binding and complement fixation. There are five major classes of the heavy chain constant region, classified as IgA, IgG, IgD, IgE, and IgM, each with characteristic effector functions designated by isotype.

[0041] IgG, for example, is separated into four γ isotypes: γ1, γ2, γ3, and γ4, also known as IgG1, IgG2, IgG3, and IgG4, respectively. IgG molecules can interact with multiple classes of cellular receptors including three classes of Fcγ receptors (FcγR) specific for the IgG class of antibody, namely FcγRI, FcγRII, and FcγRIII. The sequences important for the binding of IgG to the FcγR receptors have been reported to be in the CH2 and CH3 domains.

[0042] The serum half-life of an antibody is influenced by the ability of that antibody to bind to an Fc receptor (FcR). Similarly, the serum half-life of immunoglobulin fusion proteins is also influenced by the inability to bind to such receptors (Gillies et al., Cancer Research (1999) 59:2159–66). The CH2 and CH3 domains of IgG2 and IgG4 have undetectable or reduced binding affinity to Fc receptors compared to those of IgG1. Accordingly, the serum half-life of the featured antibody can be increased by using the CH2 and/or CH3 domain from IgG2 or IgG4 isotypes. Alternatively, the antibody can include a CH2 and/or CH3 domain from IgG1 or IgG3 with modification in one or more amino acids in these domains to reduce the binding affinity for Fc receptors (see, e.g., U.S. patent application Ser. No. 09/256,156, published as U.S. patent application publication 2003-0105294-A1).

[0043] The hinge region of the Fc portion normally adjoins the C-terminus of the CH1 domain of the heavy chain constant region. When included in the proteins of the present invention, the hinge is homologous to a naturally-occurring immunoglobulin region and typically includes cysteine residues linking two heavy chains via disulfide bonds as in natural immunoglobulins. Representative sequences of hinge regions for human and mouse immunoglobulin can be found in ANTIBODY ENGINEERING, a PRACTICAL GUIDE, (Borrebaeck, ed., W. H. Freeman and Co., 1992).

[0044] Suitable hinge regions for the present invention can be derived from IgG1, IgG2, IgG3, IgG4, and other immunoglobulin isotypes. The IgG1 isotype has two disulfide bonds in the hinge region permitting efficient and consistent disulfide bonding formation. Therefore, a preferred hinge region of the present invention is derived from IgG1. Optionally, the first, most N-terminal cysteine of an IgG1 hinge is mutated to enhance the expression and assembly of antibodies or antibody fusion proteins of the invention (see, e.g., U.S. patent application Ser. No. 10/093,958, published as U.S. patent application publication 2003-0044423-A1).

[0045] In contrast to IgG1, the hinge region of IgG4 is known to form interchain disulfide bonds inefficiently (Angal et al., (1993), Mol. Immunol. 30:105–8). Also, the IgG2 hinge region has four disulfide bonds that tend to promote oligomerization and possibly incorrect disulfide bonding during secretion in recombinant systems. One suitable hinge region for the present invention can be derived from the IgG4 hinge region, preferentially containing a mutation that enhances correct formation of disulfide bonds between heavy chain-derived moieties (Angal et al., (1993), Mol. Immunol. 30(1):105–8). Another preferred hinge region is derived from an IgG2 hinge in which the first two cysteines are each mutated to another amino acid, such as, in order of general preference, serine, alanine, threonine, proline, glutamic acid, glutamine, lysine, histidine, arginine, asparagine, aspartic acid, glycine, methionine, valine, isoleucine, leucine, tyrosine, phenylalanine, tryptophan or selenocysteine (see, e.g., U.S. patent application publication 2003-0044423-A1).

[0046] An Fc portion fused to an antibody variable region of the invention can contain CH2 and/or CH3 domains and a hinge region that are derived from different antibody isotypes. For example, the Fc portion can contain CH2 and/or CH3 domains of IgG2 or IgG4 and a hinge region of IgG1. Assembly of such hybrid Fc portions has been described in U.S. patent application publication 2003-0044423-A1.

[0047] When fused to an antibody variable region of the invention, the Fc portion preferably contains one or more amino acid modifications that generally extend the serum half-life of an Fc fusion protein. Such amino acid modifications include mutations substantially decreasing or eliminating Fc receptor binding or complement fixing activity. For example, one type of such mutation removes the glycosylation site of the Fc portion of an immunoglobulin heavy chain. In IgG1, the glycosylation site is Asn297 (see, for example, U.S. patent application Ser. No. 10/310,719, published as U.S. patent application publication 2003-0166163-A1).

III. Fusion Junction Region

[0048] The antibody variable regions of the present invention can optionally be linked or fused to a non-immunoglobulin moiety directly or indirectly, such as through a linker peptide (e.g., (Gly₄-Ser)₃(SEQ ID NO: 3)). The immunogenicity of the disclosed fusion proteins can be reduced by impairing the ability of the fusion junction or junctional epitope to interact with a T-cell receptor, as described in U.S. patent application publication 2003-0166877-A1. Even in a fusion between two human proteins, e.g., human Fc and human IL-2, the region surrounding the fusion junction or junctional epitope includes a peptide sequence that is not normally present in the human body and, thus, that can be immunogenic. The immunogenicity of the junctional epitope can be reduced, for example, by introducing one or more glycosylation sites near the fusion junction, or by identifying a candidate T-cell epitope spanning the junction as described in U.S. patent application publication 2003-0166877-A1 and changing an amino acid near the junction to reduce the ability of the candidate T-cell epitope to interact with a T-cell receptor.

[0049] The serum half-life of the protein can also be increased by introducing mutations into the fusion junction region. For example, in a protein including a CH3 domain fused to a non-immunoglobulin moiety, the C-terminal lysine of the CH3 domain can be changed to another amino acid, such as alanine, which can provide a substantial increase in serum half-life of the resulting fusion protein.

[0050] In certain embodiments, proteolytic cleavage of the fusion junction is desirable. Accordingly, the intergenic region can include a nucleotide sequence encoding a proteolytic cleavage site. This site, interposed between the immunoglobulin and the cytokine, can be designed to provide for proteolytic release of the cytokine at the target site. For example, it is well known that plasmin and trypsin cleave after lysine and arginine residues at sites that are accessible to the proteases. Other site-specific endoproteases and the amino acid sequences they recognize are well-known.

IV. Treatment of Human Disease with hu14.18 Antibody Fusion Proteins

[0051] The antibody variable regions of the invention can be attached to a diagnostic and/or a therapeutic agent. The agent can be fused to the antibody to produce a fusion protein. Alternatively, the agent can be chemically coupled to the antibody to produce an immuno-conjugate. The agent can be, for example, a toxin, radiolabel, imaging agent, immunostimulatory moiety or the like.

[0052] The antibody variable region of the invention can be attached to a cytokine. Preferred cytokines include interleukins such as interleukin-2 (IL-2), IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16 and IL-18, hematopoietic factors such as granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF) and erythropoeitin, tumor necrosis factors (TNF) such as TNFα, lymphokines such as lymphotoxin, regulators of metabolic processes such as leptin, interferons such as interferon α, interferon β, and interferon γ, and chemokines. Preferably, the antibody-cytokine fusion protein or immunoconjugate displays cytokine biological activity. In one embodiment, the antibody variable domain is fused to IL-2. Preferably, several amino acids within the IL-2 moiety are mutated to reduce toxicity, as described in U.S. patent application publication 2003-0166163-A1.

[0053] For example, FIGS. 3A and 3B show the amino acid sequences of a particular embodiment of an antibody fusion protein in accordance with the invention. Specifically, FIG. 3A shows the peptide sequence of a humanized immunoglobulin light chain that includes a variable and constant region. FIG. 3B shows the peptide sequence of a humanized immunoglobulin heavy chain linked to IL-2. The polypeptides provide a humanized antibody fusion protein capable of specifically binding to GD2 and stimulating the immune system.

[0054] Optionally, the protein complexes can further include a second agent, such as a second cytokine. In one embodiment, a hu14.18 antibody fusion protein includes IL-12 and IL-2. The construction of protein complexes containing an immunoglobulin domain and two, different cytokines is described in detail in U.S. Pat. No. 6,617,135.

[0055] Fusion proteins of the present invention are useful in treating human disease, such as cancer. When treating human tumors, it is particularly useful to administer an antibody-IL-2 fusion protein comprising the V regions of the invention by infusion or subcutaneous injection, using doses of 0.1 to 100 milligrams/meter²/patient. In a preferred embodiment, it is particularly useful to administer an antibody-IL-2 fusion protein comprising the V regions of the invention by infusion or subcutaneous injection, using doses of 1 to 10 milligrams/meter²/patient, and more preferably about 3 to 6 milligrams/meter²/patient.

[0056] Clinical studies have shown that following administration of hu14.18-IL-2, the fusion protein retains its ability to activate IL-2 responsive cells through the IL-2 receptor and retains its ability to bind to GD2-positive tumor cells and to deliver IL-2 to their surface. Furthermore, administration of hu14.18-IL-2 fusion protein to a cancer patients resulted in stabilization of disease progression in a surprisingly large number of patients (see Example 1).

[0057] Pharmaceutical compositions of the invention may be used in the form of solid, semisolid, or liquid dosage forms, such as, for example, pills, capsules, powders, liquids, suspensions, or the like, preferably in unit dosage forms suitable for administration of precise dosages. The compositions include a conventional pharmaceutical carrier or excipient and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Such excipients may include other proteins, such as, for example, human serum albumin or plasma proteins. Actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art. The composition or formulation to be administered will, in any event, contain a quantity of the active component(s) in an amount effective to achieve the desired effect in the subject being treated.

[0058] Administration of the compositions hereof can be via any of the accepted modes of administration for agents that exhibit such activity. These methods include oral, parenteral, or topical administration and otherwise systemic forms. Intravenous injection in a pharmaceutically acceptable carrier is a preferred method of administration (see Example 1).

[0059] The amount of active compound administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

Nucleic Acids of the Invention

I. hu14.18 Antibody Constructs

[0060] The invention also features nucleic acids capable of expressing each of the above types of proteins. These include, for example, nucleic acids encoding the amino acid sequence set forth in SEQ ID NO: 1; the amino acid sequence set forth in SEQ ID NO: 2; a hu14.18 antibody V_Lregion that includes the huV_LFR1 amino acid sequence; a hu14.18 antibody V_Hregion that includes the huV_HFR1 amino acid sequence; a hu14.18 antibody V_Hregion that includes hUV_HFR3 amino acid sequence; and fusion proteins comprising a hu14.18 antibody including at least one of the foregoing humanized FR sequences and one or more therapeutic agents.

[0061] The hu14.18 antibodies of this invention can be produced by genetic engineering techniques; i.e., by forming a nucleic acid construct encoding an GD2 specific antibody containing the desired FRs of the present invention. In one embodiment, the gene construct encoding the featured antibody includes, in 5′ to 3′ orientation, a DNA segment which encodes a heavy chain variable region including at least one humanized FR therein and a DNA segment encoding a heavy chain constant region. In another embodiment, another DNA segment encoding a cytokine is fused to the 3′ end of the DNA segment encoding the heavy chain constant region. In a different embodiment, the gene construct includes, in 5′ to 3′ orientation, a DNA segment encoding a heavy chain variable region including at least one humanized FR and a DNA segment encoding a cytokine. Alternatively, a nucleic acid of the invention can include, in 5′ to 3′ orientation, a DNA segment encoding a light chain variable region including at least one humanized FR therein and a DNA segment encoding a cytokine. In some embodiments, a nucleic acid encoding a cytokine is joined in frame to the 3′ end of a gene encoding a constant region (e.g., CH3 exon), either directly or through an intergenic region (e.g., by appropriate linkers, such as by DNA encoding (Gly₄-Ser)₃(SEQ ID NO: 3)).

II. Expression of hu14.18 Antibody Constructs

[0062] Nucleic acid encoding proteins of the present invention can be assembled or inserted into one or more expression vectors for introduction into an appropriate recipient cell where it is expressed. The introduction of nucleic acids into expression vectors can be accomplished by standard molecular biology techniques. Preferred expression vectors include those from which the encoded protein can be expressed in either bacteria or mammalian cells.

[0063] In accordance with the invention, a heavy chain of an antibody variable region is preferably co-expressed in the same cell with a corresponding light chain. For fusion proteins that comprise multiple polypeptide chains, more than one expression vector can be used. Co-transfection methods using, for example, two expression vectors, frequently result in both vectors being delivered to a target cell. Alternatively, it is sometimes useful to use a single vector encoding a plurality of polypeptides for co-expression in the same cell.

[0064] For example, FIGS. 2A–G show the nucleic acid sequence of a single vector encoding both the heavy and light chains of an immunoglobulin in accordance with the invention. The vector also includes a nucleic acid encoding IL-2 fused to the 3′ end of the immunoglobulin heavy chain. Thus, when introduced into a cell, this vector alone can provide a humanized antibody-IL-2 fusion protein that specifically binds GD2 and stimulates immune function.

[0065] Furthermore, it can be convenient to express the proteins of the present invention as single-chain molecules. For example, an antibody variable region can be expressed as a single chain antibody or sFv optionally fused to a non-immunoglobulin protein. In another embodiment, a heavy chain (with or without a fused cytokine) is combined with a light (or heavy) chain counterpart (with or without a fused cytokine) to form monovalent and divalent immunoconjugates.

[0066] Recipient cell lines are preferably lymphoid cells, such as a myeloma (or hybridoma). Myelomas can synthesize, assemble, and secrete immunoglobulins encoded by transfected genes and can glycosylate proteins. A particularly preferred recipient cell is the Sp2/0 myeloma, which normally does not produce endogenous immunoglobulin. When transfected, the cell will produce only immunoglobulins encoded by the transfected gene constructs. Transfected myelomas can be grown in culture or in the peritonea of mice where secreted immunoconjugates can be recovered from ascites fluid. Other lymphoid cells such as B lymphocytes can also be used as recipient cells.

[0067] There are several methods for transfecting lymphoid cells with vectors containing the nucleic acid constructs encoding the chimeric Ig chain. A preferred way of introducing a vector into lymphoid cells is by spheroblast fusion. (see, e.g., Gillies et al. (1989) Biotechnol. 7:798–804). Alternative methods include electroporation or calcium phosphate precipitation. Other useful methods of producing the immunoconjugates include the preparation of an RNA sequence encoding the construct and its translation in an appropriate in vivo or in vitro system. Once expressed, the proteins of the invention can be harvested by standard protein purification procedures (see, e.g., U.S. Pat. No. 5,650,150).

III. Treatment of Cancer by Gene Therapy

[0068] The nucleic acids of the invention can be used as gene therapy agents for treatment of cancer and other diseases in which it is desirable to target the immune system to a specific cell type. For example, cells can be withdrawn from a human or animal, and one or more nucleic acids encoding an antibody of the present invention can be transfected into the cells. The cells are then reintroduced into the human or animal. The transfected cells can be normal or cancer cells. Alternatively, a nucleic acid can be introduced into cells in situ. The human or animal then mounts an immune response to the cancer cells, which can cure or lessen the severity of the cancer. An antibody variable region of the invention, coupled to appropriate regulatory elements to promote expression in mammalian cells, can be transfected into the cells by any of a variety of techniques, including via calcium phosphate, a “gene gun”, adenovirus vectors, cationic liposomes, retroviral vectors, or any other efficient transfection method.

[0069] In a particular embodiment of the invention, a hu14.18 antibody is used to selectively deliver a cytokine to a target cell in vivo so that the cytokine can exert a localized biological effect such as a local inflammatory response, stimulation of T cell growth and activation, or ADCC activity. A therapeutically effective amount of the antibody is administered into the circulatory system of a subject harboring the target cell.

[0070] The invention is illustrated further by the non-limiting examples.

EXAMPLES

Example 1

Purification and Formulation of hu14.18-IL2

[0071] In one study, hu14.18-IL2 was expressed from NS/0 cells, tissue culture supernatant was harvested, and the hu14.18-IL2 protein was purified using, in sequence, Abx Mixed Resin column chromatography, recombinant Protein A chromatography, and Q Sepharose column chromatography, followed by Pellicon 2 tangential flow diafiltration for buffer exchange into formulation buffer. Details of these purification steps are described below. Virus inactivation and removal steps were interdigitated into these steps as described below. The virus inactivation and removal steps were not necessary for purification per se, but were used to satisfy regulatory considerations.

[0072] Two liters of NS/0 tissue culture supernatant containing hu14.18-IL2 was pH-adjusted to 5.9 with 1M acetic acid and was applied to an Abx column (J. T. Baker); washed with 10 mM MES, 100 mM sodium acetate pH 6.2; and eluted with 500 mM sodium acetate pH 7. This material was loaded onto a recombinant Protein A column (Pharmacia); washed with 100 mM sodium phosphate, 150 mM NaCl pH 7; washed with 100 mM sodium phosphate, 150 mM NaCl pH 6; washed with 10 mM sodium phosphate pH 7; and eluted with 100 mM sodium phosphate, 150 mM NaCl pH 3.5. The pH of the eluted material was 4.2. To promote virus inactivation, this pH was reduced to 3.8 and the preparation was incubated for 30 minutes, after which the pH was neutralized to 7 with 1M NaOH. To remove nucleic acid, this material was loaded onto a Q sepharose column (Pharmacia) and washed with 100 mM sodium phosphate, 150 mM NaCl pH 7. Nucleic acid bound to the column, while the protein was found in the flow through and washes, which were repeated until the A280 returned to baseline. Pellicon 2 diafiltration (Millipore) was performed according to the manufacturer's instructions, so that the final hu14.18-IL2 material was placed in the following formulation.

[0073]


	1. Mannitol	4%
	2. Arginine Hydrochloride USP/NF	100 mM
	3. Citric Acid USP-FCC	5 mM
	4. Polysorbate 80	0.01% (w.v)

The pH of the formulation buffer was adjusted to 7 with 1 M NaOH.

[0074] As a final step, the preparation was filtered through a Viresolve 180 membrane (Millipore), which has a molecular weight cutoff of 180,000 Daltons. This had the effect of ‘polishing’ the material so that as a result, aggregated dimers and higher-order oligomers were removed.

Example 2

Anti-Tumor Activity of the hu14.18-IL-2 Fusion Protein Observed in Phase I Clinical Trials

[0075] To evaluate the safety and efficacy of hu14.18-IL-2, a Phase I clinical trial was performed. Eligible patients had histologically confirmed melanoma that was considered surgically and medically incurable. These patients could have either measurable or evaluable metastatic disease, or they could have no evidence of disease following surgical resection of either distant metastases or regionally recurrent disease. Patients with multiple (two or more) local or regional recurrences were included only if they had prior evidence of lymph node involvement and if each recurrence was separated in time by at least 2 months. All patients needed to have adequate bone marrow function (defined by total white blood cells (WBC ) >3,500/ml, or total granulocytes >2000/ml, platelets >100,000/ml, and hemoglobin >10.0 g/dl), adequate liver function [defined by an aspartate aminotransferase (AST) <3× normal and a total bilirubin <2.0 mg/dl], and adequate renal function (defined by a serum creatinine <2.0 mg/dl or a creatinine clearance of >60 ml/minute). All patients had an electrocorticography (ECOG) performance status of 0 or 1 and a life expectancy of at least 12 weeks. Patients who had previously received chemotherapy, radiation therapy, or other immunosuppressive therapy within 4 weeks prior to study were excluded. Patients could have prior central nervous system (CNS) metastases if treated and stable for at least 4 weeks prior to starting the study. Informed consent was obtained from all patients.

[0076] This phase I trial was designed as an open-label, nonrandomized dose escalation study in which groups of 3 to 6 patients received hu14.18-IL-2 at one of the following dose levels: 0.8, 1.6, 3.2, 4.8, 6.0 or 7.5 mg/m²/day. The hu14.18-IL-2 was administered on an inpatient basis as a 4-hour intravenous (IV) infusion over 3 consecutive days during the first week of each course. The hu14.18-IL-2 fusion protein was administered to patients in a formulation comprising 4% Mannitol; Arginine HCl, 100 mM; Citrate, 5 mM; and 0.01% Tween 80, at pH 7. Patients were discharged from the hospital, if stable, approximately 24 hours following the completion of the third infusion. Adverse events and toxicities were graded as per NCI Common Toxicity Criteria (version 2.0) and the University of Wisconsin Comprehensive Cancer Center Toxicity Grading Scale for IL-2 (performance status, weight gain, and temperature). Dose-limiting toxicity (DLT) was defined as the occurrence of grade 3 or 4 toxicity other than grade 3 lymphopenia, hyperbilirubinemia, hypophosphatemia or hyperglycemia. The maximal tolerated dose (MTD) was defined as the dose level at which two of six patients had DLT during course 1. Patients with grade 3 treatment-related toxicities were required to recover to at least grade 1 before they could resume treatment at a 50% dose reduction for course 2. Patients with ≧25% disease progression were removed from the study. Patients with stable disease were administered course 2.

[0077] The pharmacokinetic properties of hu14.18-IL-2 were evaluated in the patients. When hu14.18-IL-2 levels were evaluated in serial samples from all 33 patients immediately following the first 4-hour infusion (day 1, course 1), the half-life was found to be 3.7 hours (+/−SD of 0.9 h). This is intermediate between the half-lives of its 2 components (approximately 45 minutes for IL-2 and 3 days for the chimeric m14.18 antibody), and comparable to that which was observed for the half-life of chimeric m14.18-IL-2 in mice. Following the clearance of hu14.18-IL-2 from the serum of these patients, neither the IL-2 nor hu14.18 antibody components could be detected. The peak serum and area under the curve (AUC) during course 1 showed a significant dose-dependent increase (p<0.001).

[0078] Thirty-three patients were treated in this study. Table 1 lists clinical outcomes. Two patients (6%) completed only the first 2 of 3 days for course 1. One of these patients (dose level 3) had a grade 3 hyperbilirubinemia on day 2 of treatment, and the other patient (dose level 6) had grade 3 hypoxia and hypotension requiring treatment to be held. Both of these patients had progression of disease and did not receive a second course of therapy. Nineteen patients (58%) had stable disease following the first course of therapy and received a second course of therapy. Five patients (15% of all patients) required a 50% dose reduction for course 2 secondary to adverse events in course 1. Seventeen patients (52% of all patients) completed course 2. One patient (dose level 4) declined to receive the final infusion during course 2, and one patient (dose level 6) had the final infusion during course 2 held due to hypotension. Eight patients (24% of all patients) had stable disease following the second course of treatment. The results indicate that hu14.18-IL-2 caused stabilization of disease progression in a surprisingly large number of patients.

[0079] Eight of the 33 patients maintained stable disease after 2 courses of therapy, and 4 of these 8 patients continue with no evidence of progressive disease (1 with stable disease and 3 with no evidence of disease) for 20–52 months since completing protocol therapy.

[0080] Five of the 33 patients entered the study with no measurable disease following surgical resection of recurrences or metastases. Two of these five patients had disease progression, while the remaining 3 patients continued with no evidence of disease (20–52 months). These findings are consistent with the hypothesis that clinical benefit from an immunotherapeutic intervention is most likely in a patient with a low tumor burden. One additional patient had an objective decrease in a lung nodule following two courses of therapy, but the overall disease response was scored as disease progression due to growth in a distant node. The node was resected following hu14.18-IL-2 therapy and the patient remained free from disease progression for over 3 years.

[0081]

TABLE 1

Clinical Outcomes
	Number of
	Patients

	Patients completing course 1	31
	Stable disease following course 1	19
	50% dose reduction for course 2	5
	Patients completing course 2	17
	Stable disease following course 2	8

Example 3

Immune Stimulation in vivo by hu14.18-IL-2 in a Phase I Clinical Trial

[0082] Patients treated with hu14.18-IL-2 were also examined for indications of immune stimulation. A peripheral blood lymphopenia occurred on days 2–4, and this was followed by a rebound lymphocytosis on days 5–22. Both of these changes were dose-dependent (p<0.01 and p<0.05, respectively). The lymphocyte counts on days 5, 8, 15 and 22 were significantly greater than baseline for course 1. The baseline lymphocyte count for course 2 (day 29 of course 1) was increased over the baseline lymphocyte count for course 1, indicating that effects of the first course of treatment are still present on day 29. In addition, the lymphocyte counts during course 2 on days 5, 8 and 15 are greater than the corresponding values for days 5, 8, and 15 during course 1 for these 12 patients. Lymphocyte cell surface phenotype showed an expansion of CD16+ and CD56+ lymphocytes (natural killer (NK) cell markers) following the first week of hu14.18-IL-2 therapy. This effect was still present on day 29 of course 1 (day 1, course 2). For patients 19–33 (receiving 4.8–7.5 mg/m²/day), lymphocyte cell surface phenotype was determined on days 15 and 22 in addition to days 1 and 8. This analysis demonstrated that the augmentation of CD56 and CD56/CD16 co-expressing cells remained significantly elevated (p<0.01) on days 8, 15 and 22.

[0083] As a measure of immune activation, C-reactive protein (CRP) levels for patients 13–33 and soluble IL-2 receptor (sIL-2R) levels for the 31 patients completing course 1, were obtained. A significant increase in mean CRP was present on treatment days 3–5 in both course 1 and course 2 compared to baseline for each course. This increase in CRP returned to baseline levels by day 8 of each treatment course. The sIL-2R level was significantly increased over baseline starting 24 hours after the hu14.18-IL-2 infusion during both course 1 and course 2, which persisted through day 8. The increase in sIL-2R was found to be dose dependent (p=0.014). sIL-2R values for course 2 were increased compared to corresponding values in course 1 for days 1–5 for patients receiving the same dose in both courses (p<0.05).

[0084] The LA-N-5 neuroblastoma cell line that expresses GD2 and binds hu14.18-IL-2 was used to evaluate IL-2 activated NK function and antibody dependent cellular cytotoxicity (ADCC) on peripheral blood mononuclear cells (PBMC) from 31 patients completing course 1. There was a significant increase in killing mediated by lymphocytes from day 8 when compared with day 1 for these two assays. The 12 patients that received course 2 at the same dose as in course 1, showed ADCC results that were very similar to those obtained during course 1. The only parameter that was found to be different for course 2 from course 1 was increased killing in the presence of IL-2 on day 1, indicating that augmented killing in this assay remained elevated on day 29 (day 1, course 2).

[0085] Because the LA-N-5 target is relatively resistant to fresh NK cells, it is useful for measuring IL-2 augmented killing, and ADCC. However, the weak killing of LA-N-5 mediated by fresh PBMC in medium (without supplemental IL-2 in vitro) was not significantly greater on day 8 than on day 1.

[0086] For patients 19–33, standard NK assays were performed on days 1, 8, 15 and 22, using the NK susceptible K562 target cell line. A significant increase in NK lysis of K562 target cells, when tested either in medium or in the presence of IL-2, was observed on days 8 and 22 when compared with day 1. Serum samples from selected patients were also evaluated to determine functional IL-2 activity and functional anti-GD2 antibody.

[0087] The IL-2 responsive Tf-1b cell line demonstrated IL-2-induced proliferation with patient serum obtained following infusion of hu14.18-IL-2. A progressive increase in proliferation was seen during the first 4 hours following the 4-hour infusion. Values returned to baseline by 16 hours after this infusion, consistent with the serum half-life for hu14.18-IL-2 of approximately 4 hours. Serum samples from these time-points were also examined by flow cytometry for the presence of intact hu14.18-IL-2 immunocytokine (IC) that retains its IL-2 component and its anti-GD2 antibody activity. hu14.18-IL-2 capable of binding to the M21 cell line (GD2 positive) was detectable in patient serum samples following an infusion of IC. The amount of IC able to bind to M21 progressively increased during the first 4 hours following the 4-hour infusion, and decreased after that, again consistent with the half-life of approximately 4 hours.

[0088] Finally, in vitro assays were performed with specimens from patients to determine whether administration of hu14.18-IL-2 results in conditions in vivo consistent with those needed to achieve ADCC. PBMCs from day 8 show augmented ADCC on GD2+ target cells when hu14.18-IL-2 is added to the cytotoxic assay. This same ADCC assay was performed with PBMC from day 8, however instead of adding hu14.18-IL-2 to the assay, serum from the patient, obtained before or after hu14.18-IL-2 administration, was added. PBMC obtained from patients on day 8 of course 2 were able to mediate augmented killing of the LA-N-5 cell line in the presence of serum obtained following hu14.18-IL-2 administration, compared to that observed with serum obtained prior to infusion. Thus the hu14.18-IL-2 circulating in patients after IV administration is able to facilitate ADCC with PBMCs activated in vivo by hu14.18-IL-2 from that same patient.

[0089] In summary, these results indicate that there were immunological changes associated with this hu14.18-IL-2 therapy including an increase in lymphocyte count, an increase in the percentage of CD16+ and CD56+ PBMC, an increase in NK lysis, and an increase in ADCC. Additional evidence for immune activation included an increase in serum levels of CRP and of sIL-2R. Laboratory analyses of serum and PBMC showed that the hu14.18-IL-2 molecule circulating in patient serum following IV administration retained its ability to activate IL-2 responsive cells through the IL-2 receptor and retained its ability to bind to GD2 positive tumor cells, and deliver IL-2 to their surface, as detected by flow cytometry. NK cells were activated in vivo based on their ability to mediate NK and ADCC function in vitro. Furthermore, the NK cells activated in vivo by the hu14.18-IL-2 administered to these patients were able to mediate ADCC facilitated by the hu14.18-IL-2 circulating in the serum of those same patients. Thus, conditions to achieve immune activation were achieved in all patients in this study.

INCORPORATION BY REFERENCE

[0090] The disclosures of each of the patent documents and scientific publications disclosed herein are incorporated by reference into this application in their entireties.

Claims

We claim:

1. An antibody variable region comprising the amino acid sequence set forth in SEQ ID NO: 1.

2. An antibody variable region comprising the amino acid sequence set forth in SEQ ID NO: 2.

3. The antibody variable region of claim 2 further comprising the amino acid sequence set forth in SEQ ID NO: 1.

4. The antibody variable region of claim 3, wherein the amino acid sequences are linked by a disulfide bond.

5. The antibody variable region of claim 3, wherein the amino acid sequences are linked by a peptide bond.

Patent Citations (252)

Patent	Date	Inventor	Cited By
US4196265(A)	1980-04-01	Koprowski et al.	Applicant
US4469797(A)	1984-09-01	Albarella	Applicant
US4522811(A)	1985-06-01	Eppstein et al.	Applicant
US4667016(A)	1987-05-01	Lai et al.	Applicant
US4676980(A)	1987-06-01	Segal et al.	Applicant
US4703008(A)	1987-10-01	Lin	Applicant
US4732683(A)	1988-03-01	Georgiades et al.	Applicant
US4737462(A)	1988-04-01	Mark et al.	Applicant
US4816567(A)	1989-03-01	Cabilly et al.	Applicant
US4946778(A)	1990-08-01	Ladner et al.	Applicant
US4975369(A)	1990-12-01	Beavers et al.	Applicant
US5019368(A)	1991-05-01	Epstein et al.	Applicant
US5073627(A)	1991-12-01	Curtis et al.	Applicant
US5082658(A)	1992-01-01	Palladino	Applicant
US5091513(A)	1992-02-01	Huston et al.	Applicant
US5114711(A)	1992-05-01	Bell et al.	Applicant
US5116964(A)	1992-05-01	Capon et al.	Applicant
US5196320(A)	1993-03-01	Gillies	Examiner
US5199942(A)	1993-04-01	Gillis	Applicant
US5225538(A)	1993-07-01	Capon et al.	Applicant
US5225539(A)	1993-07-01	Winter	Applicant
US5258498(A)	1993-11-01	Huston et al.	Applicant
US5314995(A)	1994-05-01	Fell, Jr. et al.	Applicant
US5349053(A)	1994-09-01	Landolfi	Applicant
US5359035(A)	1994-10-01	Habermann	Applicant
US5399346(A)	1995-03-01	Anderson et al.	Applicant
US5428130(A)	1995-06-01	Capon et al.	Applicant
US5441868(A)	1995-08-01	Lin	Applicant
US5457038(A)	1995-10-01	Trinchieri et al.	Applicant
US5480981(A)	1996-01-01	Goodwin et al.	Applicant
US5514582(A)	1996-05-01	Capon et al.	Applicant
US5538866(A)	1996-07-01	Israeli et al.	Applicant
US5541087(A)	1996-07-01	Lo et al.	Applicant
US5543297(A)	1996-08-01	Cromlish et al.	Applicant
US5547933(A)	1996-08-01	Lin	Applicant
US5552524(A)	1996-09-01	Basinski et al.	Applicant
US5585089(A)	1996-12-01	Queen et al.	Applicant
US5589466(A)	1996-12-01	Felgner et al.	Applicant
US5601819(A)	1997-02-01	Wong et al.	Applicant
US5609846(A)	1997-03-01	Goldenberg	Applicant
US5614184(A)	1997-03-01	Sytkowski et al.	Applicant
US5618698(A)	1997-04-01	Lin	Applicant
US5624821(A)	1997-04-01	Winter et al.	Applicant
US5639725(A)	1997-06-01	O'Reilly et al.	Applicant
US5645835(A)	1997-07-01	Fell, Jr. et al.	Applicant
US5650150(A)	1997-07-01	Gillies	Applicant
US5650492(A)	1997-07-01	Gately et al.	Applicant
US5667776(A)	1997-09-01	Zimmerman et al.	Applicant
US5679543(A)	1997-10-01	Lawlis	Applicant
US5688679(A)	1997-11-01	Powell	Applicant
US5691309(A)	1997-11-01	Basinski et al.	Applicant
US5709859(A)	1998-01-01	Aruffo et al.	Applicant
US5712120(A)	1998-01-01	Rodriguez et al.	Applicant
US5719266(A)	1998-02-01	DiMarchi et al.	Applicant
US5723125(A)	1998-03-01	Chang et al.	Applicant
US5726044(A)	1998-03-01	Lo et al.	Applicant
US5728552(A)	1998-03-01	Fujisawa et al.	Applicant
US5733876(A)	1998-03-01	O'Reilly et al.	Applicant
US5738852(A)	1998-04-01	Robinson et al.	Applicant
US5756349(A)	1998-05-01	Lin	Applicant
US5756461(A)	1998-05-01	Stephens	Applicant
US5759551(A)	1998-06-01	Ladd et al.	Applicant
US5770195(A)	1998-06-01	Hudziak et al.	Applicant
US5795779(A)	1998-08-01	McCormick	Applicant
US5800810(A)	1998-09-01	Doyle et al.	Applicant
US5807715(A)	1998-09-01	Morrison et al.	Applicant
US5827516(A)	1998-10-01	Urban et al.	Applicant
US5827703(A)	1998-10-01	Debs et al.	Applicant
US5837682(A)	1998-11-01	Folkman et al.	Applicant
US5837821(A)	1998-11-01	Wu et al.	Applicant
US5843423(A)	1998-12-01	Lyman et al.	Applicant
US5854205(A)	1998-12-01	O'Reilly et al.	Applicant
US5856298(A)	1999-01-01	Strickland	Applicant
US5858347(A)	1999-01-01	Bauer et al.	Applicant
US5885795(A)	1999-03-01	O'Reilly et al.	Applicant
US5886178(A)	1999-03-01	Allen et al.	Applicant
US5888772(A)	1999-03-01	Okasinski et al.	Applicant
US5891680(A)	1999-04-01	Lieschke et al.	Applicant
US5908626(A)	1999-06-01	Chang et al.	Applicant
US5922685(A)	1999-07-01	Rakhmilevich et al.	Applicant
US5955422(A)	1999-09-01	Lin	Applicant
US5994104(A)	1999-11-01	Anderson et al.	Applicant
US5994126(A)	1999-11-01	Steinman et al.	Applicant
US6080409(A)	2000-06-01	Laus et al.	Applicant
US6086875(A)	2000-07-01	Blumberg et al.	Applicant
US6100387(A)	2000-08-01	Herrmann et al.	Applicant
US6169070(B1)	2001-01-01	Chen et al.	Applicant
US6171588(B1)	2001-01-01	Carron et al.	Applicant
US6231536(B1)	2001-05-01	Lentz	Applicant
US6277375(B1)	2001-08-01	Ward	Applicant
US6281010(B1)	2001-08-01	Gao et al.	Applicant
US6284536(B1)	2001-09-01	Morrison et al.	Applicant
US6291158(B1)	2001-09-01	Winter et al.	Applicant
US6309636(B1)	2001-10-01	do Couto et al.	Examiner
US6335176(B1)	2002-01-01	Inglese et al.	Applicant
US6340742(B1)	2002-01-01	Burg et al.	Applicant
US6348192(B1)	2002-02-01	Chan et al.	Applicant
US6406689(B1)	2002-06-01	Falkenberg et al.	Applicant
US6429199(B1)	2002-08-01	Krieg et al.	Applicant
US6444792(B1)	2002-09-01	Gray et al.	Applicant
US6475717(B1)	2002-11-01	Enssle et al.	Applicant
US6485726(B1)	2002-11-01	Blumberg et al.	Applicant
US6500641(B1)	2002-12-01	Chen et al.	Applicant
US6506405(B1)	2003-01-01	Desai et al.	Applicant
US6551592(B2)	2003-04-01	Lindhofer et al.	Applicant
US6583272(B1)	2003-06-01	Bailon	Applicant
US6586398(B1)	2003-07-01	Kinstler et al.	Applicant
US6617135(B1)	2003-09-01	Gillies et al.	Applicant
US6627615(B1)	2003-09-01	Debs et al.	Applicant
US6646113(B1)	2003-11-01	Dreyfuss et al.	Applicant
US6777540(B1)	2004-08-01	Okumura et al.	Examiner
US2001/0053539(A1)	2001-12-01	Lauffer et al.	Applicant
US2002/0037558(A1)	2002-03-01	Lo et al.	Applicant
US2002/0081664(A1)	2002-06-01	Lo et al.	Applicant
US2002/0142374(A1)	2002-10-01	Gallo et al.	Applicant
US2002/0146388(A1)	2002-10-01	Gillies	Applicant
US2002/0147311(A1)	2002-10-01	Gillies et al.	Applicant
US2002/0192222(A1)	2002-12-01	Blumberg et al.	Applicant
US2002/0193570(A1)	2002-12-01	Gillies et al.	Applicant
US2003/0003529(A1)	2003-01-01	Bayer	Applicant
US2003/0012789(A1)	2003-01-01	Blumberg et al.	Applicant
US2003/0044423(A1)	2003-03-01	Gillies et al.	Applicant
US2003/0049227(A1)	2003-03-01	Gillies et al.	Applicant
US2003/0105294(A1)	2003-06-01	Gillies et al.	Applicant
US2003/0139365(A1)	2003-07-01	Lo et al.	Applicant
US2003/0139575(A1)	2003-07-01	Gillies	Applicant
US2003/0157054(A1)	2003-08-01	Gillies et al.	Applicant
US2003/0166163(A1)	2003-09-01	Gillies	Applicant
US2003/0166877(A1)	2003-09-01	Gillies et al.	Applicant
US2004/0013640(A1)	2004-01-01	Zardi et al.	Applicant
US2004/0033210(A1)	2004-02-01	Gillies	Applicant
US2004/0043457(A1)	2004-03-01	Schumacher et al.	Applicant
US2004/0053366(A1)	2004-03-01	Lo et al.	Applicant
US2004/0072299(A1)	2004-04-01	Gillies et al.	Applicant
US2004/0082039(A1)	2004-04-01	Gillies et al.	Applicant
AU21725/88	1989-03-01		Applicant
CN93100115.3	1993-07-01		Applicant
DE3712985	1988-11-01		Applicant
EP158198(A1)	1985-10-01		Applicant
EP211769(A2)	1987-02-01		Applicant
EP237019(A2)	1987-09-01		Applicant
EP256714(A2)	1988-02-01		Applicant
EP294703(A2)	1988-12-01		Applicant
EP308936(B1)	1989-03-01		Applicant
EP314317(B1)	1989-05-01		Applicant
EP318554(B1)	1989-06-01		Applicant
EP319012(A2)	1989-06-01		Applicant
EP326120(B1)	1989-08-01		Applicant
EP350230(A2)	1990-01-01		Applicant
EP375562(B1)	1990-06-01		Applicant
EP396387(A2)	1990-11-01		Applicant
EP439095(A2)	1991-07-01		Applicant
EP511747(A1)	1992-11-01		Applicant
EP519596(A1)	1992-12-01		Applicant
EP601043(B1)	1994-06-01		Applicant
EP640619(A1)	1995-03-01		Applicant
EP668353(A1)	1995-08-01		Applicant
EP699755(A2)	1996-03-01		Applicant
EP428596(B1)	1996-04-01		Applicant
EP706799(A2)	1996-04-01		Applicant
EP428267(B1)	1996-12-01		Applicant
EP790309(A1)	1997-08-01		Applicant
EP433827(B1)	1998-03-01		Applicant
EP668351(B1)	1999-09-01		Applicant
EP1088888(A1)	2001-04-01		Applicant
GB2188638	1987-10-01		Applicant
GB2292382(A)	1996-02-01		Applicant
JP63-267278	1988-11-01		Applicant
JP63-267296	1988-11-01		Applicant
WO86/01533	1986-03-01		Applicant
WO88/00052	1988-01-01		Applicant
WO88/09344	1988-12-01		Applicant
WO89/02922	1989-04-01		Applicant
WO89/09620	1989-10-01		Applicant
WO90/03801	1990-04-01		Applicant
WO91/00360	1991-01-01		Applicant
WO91/04329	1991-04-01		Applicant
WO91/08298	1991-06-01		Applicant
WO91/13166	1991-09-01		Applicant
WO91/14438	1991-10-01		Applicant
WO92/02240	1992-02-01		Applicant
WO92/08801	1992-05-01		Applicant
WO95/08495	1992-05-01		Applicant
WO92/10755	1992-06-01		Applicant
WO92/16562	1992-10-01		Applicant
WO93/03157	1993-02-01		Applicant
WO93/10229	1993-05-01		Applicant
WO93/20185	1993-10-01		Applicant
WO94/24160	1994-10-01		Applicant
WO94/25055	1994-11-01		Applicant
WO94/25609	1994-11-01		Applicant
WO95/05468	1995-02-01		Applicant
WO95/21258	1995-08-01		Applicant
WO95/28427	1995-10-01		Applicant
WO95/31483	1995-11-01		Applicant
WO96/04388	1996-02-01		Applicant
WO96/05309	1996-02-01		Applicant
WO96/08570	1996-03-01		Applicant
WO96/18412	1996-06-01		Applicant
WO96/31526	1996-10-01		Applicant
WO96/40792	1996-12-01		Applicant
WO97/00317	1997-01-01		Applicant
WO97/00319	1997-01-01		Applicant
WO97/15666	1997-05-01		Applicant
WO97/20062	1997-06-01		Applicant
WO97/24137	1997-07-01		Applicant
WO97/24440	1997-07-01		Applicant
WO97/26335	1997-07-01		Applicant
WO97/30089	1997-08-01		Applicant
WO97/33617	1997-09-01		Applicant
WO97/33619	1997-09-01		Applicant
WO97/34631	1997-09-01		Applicant
WO97/43316	1997-11-01		Applicant
WO98/00127	1998-01-01		Applicant
WO98/06752	1998-02-01		Applicant
WO98/28427	1998-07-01		Applicant
WO98/30706	1998-07-01		Applicant
WO98/46257	1998-10-01		Applicant
WO98/52796	1998-11-01		Applicant
WO98/59244	1998-12-01		Applicant
WO99/02709	1999-01-01		Applicant
WO99/03887	1999-01-01		Applicant
WO99/29732	1999-06-01		Applicant
WO99/43713	1999-09-01		Applicant
WO99/52562	1999-10-01		Applicant
WO99/53958	1999-10-01		Applicant
WO99/60128	1999-11-01		Applicant
WO99/62944	1999-12-01		Applicant
WO99/66054	1999-12-01		Applicant
WO/01822	2000-01-01		Applicant
WO/11033	2000-03-01		Applicant
WO/24893	2000-05-01		Applicant
WO/34317	2000-06-01		Applicant
WO/40615	2000-07-01		Applicant
WO/68376	2000-11-01		Applicant
WO/69913	2000-11-01		Applicant
WO/78334	2000-12-01		Applicant
WO1/07081	2001-02-01		Applicant
WO1/10912	2001-02-01		Applicant
WO1/36489	2001-05-01		Applicant
WO1/58957	2001-08-01		Applicant
WO2/02143	2002-01-01		Applicant
WO2/066514	2002-08-01		Applicant
WO2/069232	2002-09-01		Applicant
WO2/072605	2002-09-01		Applicant
WO2/074783	2002-09-01		Applicant
WO2/079232	2002-10-01		Applicant
WO2/079415	2002-10-01		Applicant
WO2/090566	2002-11-01		Applicant
WO3/015697	2003-02-01		Applicant
WO3/048334	2003-06-01		Applicant
WO3/077834	2003-09-01		Applicant

Non-Patent Literature (429)

Alberts et al., The Cell 2002, Garland Science, 4th edition, esp. p. 161: Figure 3-42.Examiner
Demirci and Li, 2004, Cell Mol. Immunol., 1(2):123-128 (abstract).Examiner
U.S. Appl. No. 07/348,237, May 5, 1989, Rosenblum et al.Applicant
Abaza et al., (1992), “Effects of Amino Acid Substitutions Outside an Antigenic Site on Protein Binding to Monoclonal Antibodies of Predetermined Specificity Obtained by Peptide Immunization: Demonstration with Region 94-100 (Antigenic Site 3) of Myoglobin,” Journal of Protein Chemistry, 11(5):433-444.Applicant
Abstract XP-002116766, Lupulescu, (1996), “Prostaglandins, Their Inhibitors and Cancer,” Prostaglandins, Leukotrienes and Essential Fatty Acids, 54(2):83-94.Applicant
Afonso et al., (1994), “The Adjuvant Effect of Interleukin-12 in a Vaccine Against Leishmania Major,” Science, 263:235-237.Applicant
Angal et al., (1993), “A Single Amino Acid Substitution Abolishes the Heterogeneity of Chimeric Mouse/Human (IgG4) Antibody,” Molecular Immunology, 30(1):105-108.Applicant
Arenberg et al., (1996), “Interferon-γ-inducible Protein 10 (IP-10) is an Angiostatic Factor that Inhibits Human Non-small Cell Lung Cancer (NSCLC) Tumorigenesis and Spontaneous Metastases,” J. Exp. Med., 184:981-992.Applicant
Bacha et al., (1988), “Interleukin 2 Receptor-Targeted Cytotoxicity: Interleukin 2 Receptor-mediated Action of a Diphtheria Toxin-related Interleukin 2 Fusion Protein,” J. Exp. Med., 167:612-622.Applicant
Bachelot et al., (1998), “Retrovirus-Mediated Gene Tranfer of an Angiostatin-Endostatin Fusion Protein with Enhanced Anti-Tumor Properties In Vivo,” Proceedings of the Annual Meeting of the American Association for Cancer Research, 39:271, Abstract #1856 (XP-002089298).Applicant
Barnett et al., (1994), “Purification, Characterization and Selective Inhibition of Human Prostaglandin G/H Synthase 1 and 2 Expressed in the Baculovirus System,” Biochimica et Biophysica Acta, 1209:130-139.Applicant
Baselga et al., (1998), “Recombinant Humanized Anti-HER2 Antibody (Herceptin ™) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER3/neu Overexpressing Human Breast Cancer Xenogratfs,” Cancer Research, 58:2825-2831.Applicant
Batova et al., (1999), “The Ch14.18-GM-CSF Fusion Protein Is Effective at Mediating Antibody-dependent Cellular Cytotoxicity and Complement-dependent Cytotoxicity in Vitro,” Clinical Cancer Research, 5:4259-4263.Applicant
Batra et al., (1993), “Insertion of Constant Region Domains of Human IgG1 into CD4-PE40 Increases Its Plasma Half-Life,” Molecular Immunology, 30(4):379-386.Applicant
Becker et al., (1996), “An Antibody-Interleukin 2 Fusion Protein Overcomes Tumor Heterogeneity by Induction of a Cellular Immune Response,” Proc. Natl. Acad. Sci. USA, 93:7826-7831.Applicant
Becker et al., (1996), “Eradication of Human Hepatic and Pulmonary Melanoma Metastases in SCID Mice by Antibody-interleukin 2 Fusion Proteins,” Proc. Natl. Acad. Sci. USA, 93:2702-2707.Applicant
Becker et al., (1996), “Long-lived and Transferable Tumor Immunity in Mice after Targeted Interleukin-2 Therapy,” J. Clin. Invest., 98(12):2801-2804.Applicant
Becker et al., (1996), “T Cell-mediated Eradication of Murine Metastatic Melanoma Induced by Targeted Interleukin-2 Therapy,” J. Exp. Med., 183(50):2361-2366.Applicant
Beutler et al., (1988), “Tumor Necrosis, Cachexia, Shock, and Inflammation: A Common Mediator,” Annual Rev. Biochem., 57:505-518.Applicant
Bissery et al., (1997), “The Taxoids,” in Cancer Therapeutics: Experimental and Clinical Agents, Teicher (ed.), pp. 175-193.Applicant
Bitonti et al., (2002), “Transepithelial Absorption of an Erythropoietin-Fc Fusion Protein After Delivery to the Central Airways,” Respiratory Drug Delivery, 8:309-312.Applicant
Bjorn et al., (1985), “Evaluation of Monoclonal Antibodies for the Development of Breast Cancer Immunotoxins,” Cancer Research, 45:1214-1221.Applicant
Boehm et al., (1997), “Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance,” Nature, 390:404-407.Applicant
Boehm et al., (1998), “Zinc-Binding of Endostatin Is Essential for Its Antiangiogenic Activity,” Biochemical and Biophysical Research Communications, 252:190-194.Applicant
Boissel et al., (1993), “Erythropoietin Structure-Function Relationships: Mutant Proteins that Test a Model of Tertiary Structure,” The Journal of Biological Chemistry, 268(21):15983-15993.Applicant
Briggs et al., (1974), “Hepatic Clearance of Intact and Desialylated Erythropoietin,” American Journal of Physiology, 227(6):1385-1388.Applicant
Brooks et al., (1994), “Integrin ανβ3 Antagonists Promote Tumor Regression by Inducing Apoptosis of Angiogenic Blood Vessels,” Cell, 79:1157-1164.Applicant
Buchli et al., (1993), “Structural and Biologic Properties of a Human Aspartic Acid-126 Interleukin-2 Analog,” Archives of Biochemistry and Biophysics, 307(2):411-415.Applicant
Burgess et al., (1990), “Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-Binding (Acidic Fibroblast) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single Lysine Residue,” Journal of Cell Biology, 111:2129-2138.Applicant
Canfield et al., (1991), “The Binding Affinity of Human IgG for its High Affinity Fc Receptor is Determined by Multiple Amino Acids in the CH2 Domain and Is Modulated by the Hinge Region,” J. Exp. Med., 173(6):1483-1491.Applicant
Cao et al., (1996), “Kringle Domains of Human Angiostatin: Characterization of the Anti-Proliferative Activity of Endothelial Cells,” The Journal of Biological Chemistry, 271(46):29461-29467.Applicant
Cao et al., (1997), “Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth,” The Journal of Biological Chemistry, 272(36):22924-22928.Applicant
Capon et al., (1989), “Designing CD4 Immunoadhesins for AIDS Therapy,” Nature, 337:525-531.Applicant
Caton et al., (1986), “Structural and Functional Implications of a Restricted Antibody Response to a Defined Antigenic Region on the Influenza Virus Hemagglutinin,” The EMBO Journal, 5(7):1577-1587.Applicant
Chan et al., (1991), “Induction of Interferon γ Production by Natural Killer Cell Stimulatory Factor: Characterization of the Responder Cells and Synergy with Other Inducers,” J. Exp. Med., 173: 869-879.Applicant
Chang et al., (1989), “Overview of Interleukin-2 as an Immunotherapeutic Agent,” Seminars in Surgical Oncology, 5:385-390.Applicant
Chang et al., (1996), “A Point Mutation in Interleukin-2 that Alters Ligand Internalization,” Journal of Biological Chemistry, 271(23):13349-13355.Applicant
Chapman et al., (1994), “Mapping Effector Functions of a Monoclonal Antibody to GD3 by Characterization of a Mouse-Human Chimeric Antibody,” Cancer Immuno. Immunother., 39:198-204.Applicant
Chaudhary et al., (1988), “Selective Killing of HIV-infected Cells by Recombinant Human CD4-Pseudomonas Exotoxin Hybrid Protein,” Nature, 335:370-372.Applicant
Chaudhary et al., (1989), “A Recombinant Immunotoxin Consisting of Two Antibody Variable Domains Fused to Pseudomonas Exotoxin,” Nature, 339:394-397.Applicant
Chen et al., (1997),“Eradication of Murine Bladder Carcinoma by Intratumor Injection of a Bicistronic Adenoviral Vector Carrying cDNAs for the IL-12 Heterodimer and Its Inhibition by the IL-12 p40 Subunit Homodiner,” Journal of Immunology, 159(1):351-358.Applicant
Cheon et al., (1994), “High-affinity Binding Sites for Related Fibroblast Growth Factor Ligands Reside Within Different Receptor Immunoglobulin-like Domains,” Proc. Natl. Acad. Sci. USA, 91: 989-993.Applicant
Chuang et al., (1993), “Effect of New Investigational Drug Taxol on Oncolytic Activity and Stimulation of Human Lymphocytes,” Gynecologic Oncology, 49:291-298.Applicant
Chuang et al., (1994), “Alteration of Lymphocyte Microtubule Assembly, Cytotoxicity, and Activation by the Anticancer Drug Taxol,” Cancer Research, 54:1286-1291.Applicant
Cohen et al., (1996), “Human Leptin Characterization,” Nature, 382:589.Applicant
Cole et al., (1997), “Human IgG2 Variants of Chimeric Anti-CD3 Are Nonmitogenic to T Cells,” Journal of Immunology, 159:3613-3621.Applicant
Collins et al., (1988), “Identification of Specific Residues of Human Interleukin 2 That Affect Binding to the 70-kDa Subunit (p70) of the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 85:7709-7713.Applicant
Colombo et al., (1996), “Amount of Interleukin 12 Available at the Tumor Site is Critical for Tumor Regression,” Cancer Research, 56:2531-2534.Applicant
Conner et al., (2004), “Ex vivo Evaluation of Anti-EpCAM Immunocytokine huKS-IL2 in Ovarian Cancer,” J. Immunotherapy, 27:211-219.Applicant
Cruse et al., (eds.), (1995), Illustrated Dictionary of Immunology, pp. 156-158, CRC Press, NY.Applicant
D'Amato et al., (1994), “Thalidomide is an Inhibitor of Angiogenesis,” Proc. Natl. Acad. Sci. USA, 91:4082-4085.Applicant
D'Andrea et al., (1992), “Production of Natural Killer Cell Stimulatory Factor (Interleukin 12) by Peripheral Blood Mononuclear Cells,” J. Exp. Med., 176:1387-1398.Applicant
Darling et al., (2002), “Glycosylation of Erythropoietin Affects Receptor Binding Kinetics: Role of Electrostatic Interactions,” Biochemistry, 41:14524-14531.Applicant
Davis et al., (2003), “Immunocytokines: Amplification of Anti-cancer Immunity,” Cancer Immunol. Immunother., 52:297-308.Applicant
de la Salle et al., (1996), “FcγR on Human Dendritic Cells,” in Human IgG Receptors, pp. 39-55, van de Winkel et al. (eds.), R.G. Landes Co.Applicant
Ding et al., (1988), “Zinc-Dependent Dimers Observed in Crystals of Human Endostatin,” Proc. Natl. Acad. Sci. USA, 95:10443-10448.Applicant
Dolman et al., (1998), “Suppression of Human Prostate Carcinoma Metastases in Severe Combined Immunodeficient Mice by Interleukin 2 Immunocytokine Therapy,” Clin. Cancer Research., 4(10):2551-2557.Applicant
Dorai et al., (1991), “Agylcosylated Chimeric Mouse/Human IgG1 Antibody Retains Some Effector Function,” Hybridoma, 10(2):211-217.Applicant
Dorai et al., (1992), “Role of Inter-Heavy and Light Chain Disulfide Bonds in the Effector Functions of Human IgG1,” Molecular Immunology, 29(12):1487-1491.Applicant
Duncan et al., (1988), “The Binding Site for Clq on IgG,” Nature, 332:738-740.Applicant
Earnest et al., (1992), “Piroxicam and Other Cyclooxygenase Inhibitors: Potential for Cancer Chemoprevention,” J. Cell. Biochem., Supp., 161:156-166.Applicant
Egrie et al., (2001), “Development and Characterization of Novel Erythropoiesis Stimulating Protein (NESP),” Nephrol. Dial. Transplant., 16(Supp 3):3-13.Applicant
Eisenthal, (1990), “Indomethacin Up-regulates the Generation of Lymphokine-Activated Killer-cell Activity and Antibody-dependent Cellular Cytotoxicity Mediated by Interleukin-2,” Cancer Immunol. Immunother., 31:342-348.Applicant
Elliott et al., (1996), “Fine-Structure Epitope Mapping of Antierythropoietin Monoclonal Antibodies Reveals a Model of Recombinant Human Erythropoietin Structure,” Blood, 87(7):2702-2713.Applicant
Elliott et al., (1997), “Mapping of the Active Site of Recombinant Human Erythropoietin,” Blood, 89(2):493-502.Applicant
Fell et al., (1991), “Genetic Construction and Characterization of A Fusion Protein Consisting of a Chimeric F(ab') with Specificity for Carcinomas and Human IL-2,” J. Immunology, 146(7):2446-2452.Applicant
Fell et al., (1992), “Chimeric L6 Anti-tumor Antibody: Genomic Construction, Expression, and Characterization of the Antigen Binding Site,” J. Biological Chemistry, 267:15552-15558.Applicant
Fibi et al., (1995), “N- and O-Glycosylation Muteins of Recombinant Human Erythropoietin Secreted From BHK-21 Cells,” Blood, 85(5):1229-1236.Applicant
Friedman et al., (1998), “Leptin and the Regulation of Body Weight in Mammals,” Nature, 395:763-770.Applicant
Frost et al., (1997), “A Phase 1/1B Trial of Murine Monoclonal Anti-GD2 Antibody 14.G2a Plus Interleukin-2 in Children with Refractory Neuroblastoma,” Cancer, 80(2):317-333.Applicant
Gan et al., (1999), “Specific Enzyme-linked Immunosorbent Assays for Quantitation of Antibody-cytokine Fusion Proteins,” Clinical and Diagnostic Laboratory Immunology, 6(2):236-42.Applicant
Gasson et al., (1984), “Purified Human Granulocyte Colony-Stimulating Factor: Direct Action on Neutrophils,” Science, 226:1339-1342.Applicant
Gately et al., (1998), “The Interleukin-12/Interleukin-12-Receptor System: Role in Normal and Pathologic Immune Responses,” Annu. Rev. Immunol., 16:495-521.Applicant
Gillessen et al., (1995), “Mouse Interleukin-12 (IL-12) p40 Homodimer: A Potent IL-12 Antagonist,” Eur. J. Immunol., 25:200-206.Applicant
Gillies et al., (1989), “Expression of Human Anti-Tetanus Toxoid Antibody in Transfected Murine Myeloma Cells,” Bio/Technology, 7:799-804.Applicant
Gillies et al., (1989), “High-Level Expression of Chimeric Antibodies Using Adapted cDNA Variable Region Cassettes,” J. Immunol. Methods, 125:191-202.Applicant
Gillies et al., (1990), “Antigen Binding and Biological Activities of Engineered Mutant Chimeric Antibodies with Human Tumor Specificities,” Hum. Antibod. Hybridomas, 1(1):47-54.Applicant
Gillies et al., (1991), “Expression of Genetically Engineered Immunoconjugates of Lymphotoxin and a Chimeric Anti-ganglioside GD2 Antibody,” Hybridoma., 10(3):347-56.Applicant
Gillies et al., (1991), “Targeting Human Cytotoxic T Lymphocytes to Kill Heterologous Epidermal Growth Factor Receptor-Bearing Tumor Cells: Tumor-Infiltrating Lymphocyte/Hormone Receptor/Recombinant Antibody,” J. Immunology, 146(3):1067-1071.Applicant
Gillies et al., (1992), “Antibody-Targeted Interleukin 2 Stimulates T-Cell Killing of Autologous Tumor Cells,” Proc. Natl. Acad. Sci. USA , 89:1428-1432.Applicant
Gillies et al., (1993), “Biological Activity and In Vivo Clearance of Antitumor Antibody/Cytokine Fusion Proteins,” Bioconjugate Chem., 4(3):230-235.Applicant
Gillies et al., (1998), “Antibody-IL-12 Fusion Proteins are Effective in SCID Mouse Models of Prostate and Colon Carcinoma Metastases,” J. Immunology, 160:6195-6203.Applicant
Gillies et al., (1999), “Improving the Efficacy of Antibody-Interleukin 2 Fusion Proteins by Reducing Their Interaction with Fc Receptors,” Cancer Research, 59:2159-2166.Applicant
Gillies et al., (2002), “Bi-functional Cytokine Fusion Proteins for Gene Therapy and Antibody-targeted Treatment of Cancer,” Cancer Immunol. Immunother., 51(8):449-60.Applicant
Gillies et al., (2002), “Improved Circulating Half-life and Efficacy of an Antibody-interleukin 2 Immunocytokine Based on Reduced Intracellular Proteolysis,” Clin. Cancer Research, 8(1):210-216.Applicant
Gillis et al., (1978), “T Cell Growth Factor: Parameters of Production And A Quantitative Microassay for Activity,” J. Immunology, 120(6):2027-2032.Applicant
Goeddel et al., (1986), “Tumor Necrosis Factors: Gene Stucture and Biological Activities,” Cold Spring Harb. Symp. Quant. Biol., 51:597-609.Applicant
Greene et al., (1975), “Neuronal Properties of Hybrid Neuroblastoma X Sympathetic Ganglion Cells,” Proc. Natl. Acad. Sci. USA, 72(12):4923-4927.Applicant
Gren et al., (1983), “A New Type of Leukocytic Interferon,” English Translation of Dokl. Akad. Nauk. SSSR., 269(4):986-990.Applicant
Griffon-Etienne et al., (1999), “Taxane-induced Apoptosis Decompresses Blood Vessels and Lowers Interstitial Fluid Pressure in Solid Tumors: Clinical Implications,” Cancer Research, 59:3776-3782.Applicant
Grimaldi et al., (1989), “The t(5;14) Chromosomal Translocation in a Case of Acute Lymphocytic Leukemia Joins the Interleukin-3 Gene to the Immunoglobulin Heavy Chain Gene,” Blood, 73(8):2081-2085.Applicant
Guyre et al., (1997), “Increased Potency of Fc-receptor-targeted Antigens,” Cancer Immunol. Immunother., 45:146-148.Applicant
Hammerling et al., (1996), “In Vitro Bioassay for Human Erythropoietin Based on Proliferative Stimulation of an Erythroid Cell Line and Analysis of Carbohydrate-dependent Microheterogeneity,” Journal of Pharmaceutical and Biomedical Analysis, 14:1455-1469.Applicant
Handgretinger et al., (1995), “A Phase I Study of Human/Mouse Chimeric Anti-ganglioside GD2 Antibody ch14.18 in Patients with Neuroblastoma,” European J. Cancer, 31A(2):261-267.Applicant
Hank et al., (1996), “Activation of Human Effector Cells by a Tumor Reactive Recombinant Anti-ganglioside GD2 Interleukin-2 Fusion Protein (ch14.18-IL2),” Clin Cancer Research, 2(12):1951-1959.Applicant
Hank et al., (2003), “Determination of Peak Serum Levels and Immune Response to the Humanized Anti-ganglioside Antibody-interleukin-2 Immunocytokine,” in Methods in Molecular Medicine, vol. 85: Novel Anticancer Drug Protocols, Buolamwini et al., (eds.), pp. 123-131, Humana Press Inc., Totowana, NJ.Applicant
Haraguchi, (1994), “Isolation of GD3 Synthase Gene by Expression Cloning of GM3 α-2,8-sialyltransferase cDNA using anti-GD2 Monoclonal Antibody,” Proc. Natl. Acad. Sci. USA, 91(22):10455-10459.Applicant
Harris et al., (1993), “Therapeutic Antibodies—the Coming of Age,” Trends in Biotechnology, 11:42-44.Applicant
Harris, (1995), “Processing of C-terminal Lysine and Arginine Residues of Proteins Isolated from Mammalian Cell Culture,” J. Chromatography A, 705:129-134.Applicant
Harvill et al., (1995), “An IgG3-IL2 Fusion Protein Activates Complement, Binds FcγRI, Generates LAK Activity and Shows Enhanced Binding to the High Affinity IL-2R,” Immunotechnology, 1:95-105.Applicant
Harvill et al., (1996), “In Vivo Properties of an IgG3-IL-2 Fusion Protein: A General Strategy for Immune Potentiation,” J. Immunology, 157(7):3165-3170.Applicant
Hazama et al., (1993), “Adjuvant-Independent Enhanced Immune Responses to Recombinant Herpes Simplex Virus Type 1 Glycoprotein D by Fusion with Biologically Active Interleukin-2,” Vaccine, 11(6):629-636.Applicant
He et al., (1998), “Humanization and Pharmacokinetics of a Monoclonal Antibody with Specificity for Both E- and P-Selectin,” J. Immunology, 160:1029-1035.Applicant
Heijnen et al., (1996), “Antigen Targeting to Myeloid-specific Human FcγRI/CD64 Triggers Enhanced Antibody Responses in Transgenic Mice,” J. Clin. Invest., 97(2):331-338.Applicant
Heinzel et al., (1997), “In Vivo Production and Function of IL-12 p40 Homodimers,” J. Immunology, 158:4381-4388.Applicant
Hellstrom et al., (1986), “Antitumor Effects of L6, an IgG2a Antibody that Reacts with Most Human Carcinomas,” Proc. Natl. Acad. Sci. USA, 83: 7059-7063.Applicant
Henkart, (1985), “Mechanism of Lymphocyte-Mediated Cytotoxicity,” Ann. Rev. Immunol., 3:31-58.Applicant
Herrmann et al., (1989), “Hematopoietic Responses With Advanced Malignancy Treated With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor,” Journal of Clinical Oncology, 7(2):159-167.Applicant
Hezareh et al., (2001), “Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1,” J. Virology, 75(24):12161-12168.Applicant
Hohenester et al., (1998), “Crystal Structure of the Angiogenesis Inhibitor Endostatin at 1.5 Å Resolution,” EMBO Journal, 17(6):1656-1664.Applicant
Holden et al., (2001), “Augmentation of Anti-Tumor Activity of KS-IL2 Immunocytokine with Chemotherapeutic Agents,” Proceedings of the American Association for Cancer Research, 42:683, Abstract No. 3675 (XP-002195344).Applicant
Holden et al., (2001), “Augmentation of Antitumor Activity of an Antibody-Interleukin 2 Immunocytokine with Chemotherapeutic Agents,” Clinical Cancer Research, 7:2862-2869.Applicant
Hoogenboom et al., (1991), “Construction and Expression of Antibody-tumor Necrosis Factor Fusion Proteins,” Molecular Immunology, 28(9):1027-1037.Applicant
Hoogenboom et al., (1991), “Targeting of Tumor Necrosis Factor to Tumor Cells Secretion by Myeloma Cells of a Genetically Engineered Antibody-Tumor Necrosis Factor Hybrid Molecule,” Biochim. and Biophys. Acta, 1096(4):345-354 (Abstract).Applicant
Hornick et al., (1999), “Pretreatment with a Monoclonal Antibody/Interleukin-2 Fusion Protein Directed Against DNA Enhances the Delivery of Therapeutic Molecules to Solid Tumors,” Clin. Cancer Research, 5:51-60.Applicant
Hu et al., (1996), “A Chimeric Lym-1/Interleukin 2 Fusion for Increasing Tumor Vascular Permeability and Enhancing Antibody Uptake,” Cancer Research, 56:4998-5004.Applicant
Huck et al., (1986), “Sequence of a Human Immunoglobulin Gamma 3 Heavy Chain Constant Region Gene: Comparison With the Other Human Cγ genes,” Nucleic Acids Research, 14(4):1779-1789.Applicant
Hurn et al., (1980), “Production of Reagent Antibodies,” Methods in Enzymology, 70: 104-142.Applicant
Huse et al., (1989), “Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda,” Science, 246:1275-1281.Applicant
Idusogie et al., (2000), “Mapping of the Clq Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc,” J. Immunology, 164(8):4178-4184.Applicant
Imboden et al., (2001), “The Level of MHC Class 1 Expression on Murine Adenocarcinoma Can Change the Antitumor Effector Mechanism of Immunocytokine Therapy,” Cancer Research,61(4):1500-7.Applicant
Ingber et al., (1990), “Synthetic Analogues of Fumagillin that Inhibit Angiogenesis and Suppress Tumour Growth,” Nature, 348:555-557.Applicant
Isenman et al., (1975), “The Structure and Function of Immunoglobulin Domains: II. The Importance of Interchain Disulfide Bonds and the Possible Role of Molecular Flexibility in the Interaction between Immunoglobulin G and Complement,” J. Immunology, 114(6):1726-1729.Applicant
Jones et al., (1986), “Replacing the Complementarity-determining Regions in a Human Antibody with Those from a Mouse,” Nature, 321:522-525.Applicant
Ju et al., (1987), “Structure-Function Analysis of Human Interleukin-2: Identification of Amino Acid Residues for Biological Activity,” Journal of Biological Chemistry, 262(12):5723-5731.Applicant
Jung et al., (1986), “Activation of Human Peripheral Blood Mononuclear Cells by Anti-T3: Killing of Tumor Target Cells Coated with Anti-target-anti-T3 Conjugates,” Proc. Natl. Acad. Sci. USA, 83:4479-4483.Applicant
Junghans et al., (1996), “The Protection Receptor IgG Catabolism is the B2-microglobulin-containing Neonatal Intestinal Transport Receptor,” Proc. Natl. Acad. Sci. USA, 93(11):5512-5516.Applicant
Kang et al., (1991), “Antibody Redesign by Chain Shuffling from Random Combinatorial Immunoglobulin Libraries,” Proc. Natl. Acad. Sci. USA, 88:11120-11123.Applicant
Kappel et al., (1992), “Regulating Gene Expression in Transgenic Animals,” Current Opinion in Biotechnology, 3:548-553.Applicant
Kato et al., (1997), “Mechanism for the Nonlinear Pharmacokinetics of Erythropoietin in Rats,” The Journal of Pharmacology and Experimental Therapeutics, 283:520-527.Applicant
Kato et al., (1998), “Pharmacokinetics of Erythopoietin in Genetically Anemic Mice,” Drug Metabolism and Disposition, 26(2):126-131.Applicant
Karpovsky et al., (1984), “Production of Target-Specific Effector Cells using Hetero-Cross Linked Aggregate Containing Anti-Target Cell and AntiFcγ Receptor Antibodies,” Journal of Experimental Medicine, 1609(6):1686-1701.Applicant
Kendra et al., (1999),“Pharmacokinetics and Stability of the ch14.18-Interleukin-2 Fusion Protein in Mice,” Cancer Immunol. Immunother., 48:219-229.Applicant
Kim et al., (1997),“An Ovalbumin-IL-12 Fusion Protein is More Effective than Ovalbumin Plus Free Recombinant IL-12 in Inducing a T Helper Cell Type 1-dominated Immune Response and Inhibiting Antigen-Specific IgE Production,” J. Immunology, 158(9):4137-4144.Applicant
Kim et al., (1999), “Cytokine Molecular Adjuvants Modulate Immune Responses Induced by DNA Vaccine Constructs for HIV-1 and SIV,” Journal of Interferon and Cytokine Research, 19:77-84.Applicant
Kitamura et al., (1989), “Establishment and Characterization of a Unique Human Cell Line that Proliferates Dependently on GM-CSF, IL-3, or Erythropoietin,” Journal of Cellular Physiology, 140:323-334.Applicant
Ko et al., (2004), “Safety, Pharmacokinetics, and Biological Pharmacodynamics of the Immunocytokine EMD 273066 (huKS-IL2),” J. Immunotherapy, 27:232-239.Applicant
Kranz et al., (1984), “Attachment of an Anti-receptor Antibody to Non-target Cells Renders Them Susceptible to Lysis by a Clone of Cytotoxic T Lymphocytes,” Proc. Natl. Acad. Sci. USA, 81:7922-7926.Applicant
Kuo et al., (2001), “Oligomerization-dependent Regulation of Motility and Morphogenesis by the Collagen XVIII NC1/Endostatin Domain,” Journal of Cell Biology, 152(6):1233-1246.Applicant
Kushner et al., (2001), “Phase II Trial of the Anti-GD2 Monoclonal Antibody 3F8 and Granulocyte-Macrophage Colony-Stimulating Factor for Neuroblastoma,” J. Clinical Oncology, 19(22):4189-94.Applicant
LaVallie et al., (1993), “Cloning and Functional Expression of a cDNA Encoding the Catalytic Subunit of Bovine Enterokinase,” Journal of Biological Chemistry, 268(31):23311-23317.Applicant
Lazar et al., (1988), “Transforming Growth Factor α: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities,” Molecular and Cellular Biology, 8(3):1247-1252.Applicant
LeBerthon et al., (1991), “Enhanced Tumor Uptake of Macromolecules Induced by a Novel Vasoactive Interleukin 2 Immunoconjugate,” Cancer Research, 51:2694-2698.Applicant
Lieschke, et al., (1997), “Bioactive Murine and Human Interleukin-12 Fusion Proteins which Retain Antitumor Activity In Vivo,” Nature Biotechnology, 15(1):35-40.Applicant
Linsley et al., (1991), “CTLA-4 is a Second Receptor for B Cell Activation B7,” J. Exp. Med., 174(3):561-569.Applicant
Liu et al., (1985), “Heteroantibody Duplexes Target Cells for Lysis by Cytotoxic T Lymphocytes,” Proc. Natl. Acad. Sci. USA, 82:8648-8652.Applicant
Liu et al., (1988), “Hormone Conjugated with Antibody to CD3 Mediates Cytotoxic T Cell Lysis of Human Melanoma Cells,” Science, 239:395-398.Applicant
Liu et al., (1998), “Immunostimulatory CpG Oligodeoxynucleotides Enhance the Immune Response to Vaccine Strategies Involving Granulocyte-Macrophage Colony-Stimulating Factor,” Blood, 92(10):3730-3736.Applicant
Lo et al., (1992), “Expression and Secretion of an Assembled Tetrameric CH2-deleted Antibody in E. coli, ” Hum. Antibod. Hybridomas, 3:123-128.Applicant
Lo et al., (1998), “High Level Expression and Secretion of Fc-X Fusion Proteins in Mammalian Cells,” Protein Engineering, 11(6):495-500.Applicant
Locatelli et al., (2001), “Darbepoetin alfa Amgen,” Current Opinion in Investigational Drugs, 2:1097-1104.Applicant
Lode et al., (1997), “Targeted Interleukin-2 Therapy for Spontaneous Neuroblastoma Metastases to Bone Marrow,” J. Natl. Cancer Inst., 89(21):1586-94.Applicant
Lode et al., (1998), “Immunocytokines: A Promising Approach to Cancer Immunotherapy,” Pharmacol. Ther., 80(3):277-292.Applicant
Lode et al., (1998), “Natural Killer Cell-Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy,” Blood, 91(5):1706-1715.Applicant
Lode et al., (1999), “Synergy Between an Antiangiogenic Integrin αν Antagonist and an Antibody-cytokine Fusion Protein Eradicates Spontaneous Tumor Metastases,” Proc. Natl. Acad. Sci. USA, 96:1591-1596.Applicant
Lode et al., (1999), “Tumor-targeted IL-2 Amplifies T Cell-mediated Immune Response Induced by Gene Therapy with Single-chain Il-12,” Proc. Natl. Acad. Sci. USA, 96:8591-8596.Applicant
Lode et al., (2000), “Amplification of T Cell Mediated Immune Responses by Antibody-Cytokine Fusion Proteins,” Immunological Investigations, 29(2):117-120.Applicant
Lode et al., (2000), “What To Do With Targeted IL-2,” Drugs of Today, 36(5):321-336.Applicant
Lode et al., (2000), “Melanoma Immunotherapy for Targeted IL-2 Depends on CD4(+) T-cell Help Mediated by CD40/CD40L Interaction,” J. Clin. Invest., 105(11):1623-30.Applicant
Macdougall, (2002), “Optimizing the Use of Erythropoietic Agents—Pharmacokinetics and Pharmacodynamic Considerations,” Nephrol. Dial. Transplant., 17 (Supp 5):66-70.Applicant
Maecker et al., (1997), “DNA Vaccination with Cytokine Fusion Constructs Biases the Immune Response to Ovalbumin,” Vaccine, 15(15):1687-1696.Applicant
Maloney et al., (1994), “Phase I Clinical Trial Using Escalating Single-Dose Infusion of Chimeric Anti-CD20 Monoclonal Antibody (IDEC-C2B8) in Patients with Recurrent B-Cell Lymphoma,” Blood, 84(8):2457-2466.Applicant
Mark et al., (1992), “Expression and Characterization of Hepatocyte Growth Factor Receptor-IgG Fusion Proteins,” Journal of Biological Chemistry, 267(36):26166-26171.Applicant
Martinotti et al., (1995), “CD4 T Cells Inhibit In Vivo the CD8-Mediated Immune Response Against Murine Colon Carcinoma Cells Transduced with Interleukin-12 Genes,” Eur. J. Immunol. 25:137-146.Applicant
Medesan et al., (1997), “Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1,” J. Immunology, 158(5):2211-2217.Applicant
Metelitsa et al., (2002), “Antidisialoganglioside/granulocyte Macrophage-colony-stimulating Factor Fusion Protein Facilitates Neutrophil Antibody-dependent Cellular Cytotoxicity and Depends on FcγRII (CD32) and Mac-1 (CD11b/CD18) for Enhanced Effector Cell Adhesion and Azurophil Granule Exocytosis,” Blood, 99(11):4166-73.Applicant
Mestre et al., (1997), “Retinoids Suppress Epidermal Growth Factor-induced Transcription of Cyclooxygenase-2 in Human Oral Squamous Carcinoma Cells,” Cancer Research, 57:2890-2895.Applicant
Mosmann et al., (1989), “TH1 and TH2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties,” Ann. Rev. Immunol., 7:145-173.Applicant
Mott et al., (1995), “The Solution Structure of the F42A Mutant of Human Interleukin 2,” J. Mol. Biol., 247:979-994.Applicant
Mueller et al., (1990), “Enhancement of Antibody-Dependent Cytotoxicity With A Chimeric Anti-GD2 Antibody,” J. Immunology, 144(4):1382-1386.Applicant
Mueller et al., (1990), “Serum Half-Life and Tumor Localization of a Chimeric Antibody Deleted of the CH2 Domain and Directed Against the Disialoganglioside GD2,” Proc. Natl. Acad. Sci. USA., 87:5702-5705.Applicant
Mueller et al., (1997), “Humanized Porcine VCAM-specific Monoclonal Antibodies with Chimeric IgG2/G4 Constant Regions Block Human Leukocyte Binding to Porcine Endothelial Cells,” Molecular Immunology, 34(6):441-452.Applicant
Mullins et al., (1997), “Taxol-mediated Changes in Fibrosarcoma-induced Immune Cell Function: Modulation of Antitumor Activities,” Cancer Immunol. Immunother. 45:20-28.Applicant
Mullins et al., (1998), “Interleukin-12 Overcomes Paclitaxel-mediated Suppression of T-cell Proliferation,” Immunopharmacol. Immunotoxicol., 20(4):473-492.Applicant
Murphy et al., (1986), “Genetic Construction, Expression, and Melanoma-selective Cytotoxicity of a Diphtheria Toxin-related α-melanocyte-stimulating Hormone Fusion Protein,” Proc. Natl. Acad. Sci. USA, 83:8258-8262.Applicant
Murphy, (1988), “Diphtheria-related Peptide Hormone Gene Fusions: A Molecular Gene Approach to Chimeric Toxin Development,” in Immunotoxins, pp. 123-140, Frankel (ed.), Kluwer Acad. Pub.Applicant
Naramura et al., (1993), “Therapeutic Potential of Chimeric and Murine Anti-(Epidermal Growth Factor Receptor) Antibodies in a Metastasis Model for Human Melanoma,” Cancer Immuno. Immunother., 37:343-349.Applicant
Naramura et al., (1994), “Mechanisms of Cellular Cytotoxicity Mediated by a Recombinant Antibody-IL2 Fusion Protein Against Human Melanoma Cells,” Immunology Letters, 39:91-99.Applicant
Neal et al., (2003), “NXS2 Murine Neuroblastomas Express Increased Levels of MHC Class I Antigens upon Recurrence Following NK-dependent Immunotherapy,” Cancer Immunol. Immunother., 53:41-52.Applicant
Nedwin et al., (1985), “Human Lymphotoxin and Tumor Necrosis Factor Genes: Structure, Homology and Chromosomal Localization,” Nucleic Acids Research, 13(17):6361-6373.Applicant
Netti et al., (1995), “Time-dependent Behavior of Interstitial Fluid Pressure in Solid Tumors: Implications for Drug Delivery,” Cancer Research, 55:5451-5458.Applicant
Netti et al., (1999), “Enhancement of Fluid Filtration Across Tumor Vessels: Implication for Delivery of Macromolecules,” Proc. Nat. Acad. Sci.USA, 96:3137-3142.Applicant
Neuberger et al., (1984), “Recombinant Antibodies Possessing Novel Effector Functions,” Nature, 312:604-608.Applicant
Ngo et al., (1994), “Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox,” in The Protein Folding Problem and Tertiary Structure Prediction, Merz et al. (eds.), pp. 433-440 and 492-495, Birkhauser, Boston, MA.Applicant
Niethammer et al., (2002) “An Oral DNA Vaccine Against Human Carcinoembryonic Antigen (CEA) Prevents Growth and Dissemination of Lewis Lung Carcinoma in CEA Transgenic Mice,” Vaccine, 20:421-429.Applicant
Niethammer et al., (2001), “Targeted Interleukin 2 Therapy Enhances Protective Immunity Induced by an Autologous Oral DNA Vaccine Against Murine Melanoma,” Cancer Research, 61(16):6178-84.Applicant
Nimtz et al., (1993), “Structures of Sialylated Oligosaccharides of Human Erythropoietin Expressed in Recombinant BHK-21 Cells,” Eur. J. Biochem., 213:39-56.Applicant
O'Reilly et al., (1994), “Angiostatin: A Novel Angiogenesis Inhibitor That Mediates the Suppression of Metastases by a Lewis Lung Carcinoma,” Cell, 79:315-328.Applicant
O'Reilly et al., (1996), “Angiostatin Induces and Sustains Dormancy of Human Primary Tumors in Mice,” Nature Medicine, 2(6):689-692.Applicant
O'Reilly et al., (1997), “Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth,” Cell, 88:277-285.Applicant
Pancook et al., (1996), “Eradication of Established Hepatic Human Neuroblastoma Metastases in Mice with Severe Combined Immunodeficiency by Antibody-targeted Interleukin-2,” Cancer Immunol. Immunother., 42(2):88-92.Applicant
Park et al., (2000), “Efficiency of Promoter and Cell Line in High-level Expression of Erythropoietin,” Biotechnol. Appl. Biochem., 32:167-172.Applicant
Pastan et al., (1989), “Pseudomonas Exotoxin: Chimeric Toxins,” Journal of Biological Chemistry, 264(26):15157-15160.Applicant
Paul et al., (1988), “Lymphotoxin,” Ann. Rev. Immunol., 6:407-438.Applicant
Perez et al., (1986), “Specific Targeting of Human Peripheral Blood T Cells by Heteroaggregates Containing Anti-T3 Crosslinked to Anti-Target Cell Antibodies,” J. Exp. Med., 163:166-178.Applicant
Perez et al., (1989), “Isolation and Characterization of a cDNA Encoding the KS1/4 Epithelial Carcinoma Marker,” J. Immunology, 142(10):3662-3667.Applicant
Pertl et al., (2003), “Immunotherapy with a Posttranscriptionally Modified DNA Vaccine Induces Complete Protection Against Metastatic Neuroblastoma,” Blood, 101(2):649-654.Applicant
Polizzi et al., (1999), “A Novel Taxane with Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts,” Cancer Research, 59:1036-1040.Applicant
Putzer et al., (1997), “Interleukin 12 and B7-1 Costimulatory Molecule Expressed by an Adenovirus Vector Act Synergistically to Facilitate Tumor Regression,” Proc. Natl. Acad. Sci. USA, 94(20):10889-10894.Applicant
Reisfeld et al., (1994), “Potential of Genetically Engineered Anti-Ganglioside GD2 Antibodies for Cancer Immunotherapy,” Prog. Brain Res., 101:201-212.Applicant
Reisfeld et al., (1996), “Antibody-interleukin 2 Fusion Proteins: A New Approach to Cancer Therapy,” J. Clin. Lab. Anal., 10:160-166.Applicant
Reisfeld et al., (1996), “Involvement of B Lymphocytes in the Growth Inhibition of Human Pulmonary Melanoma Metastases in Athymic nu/nu Mice by an Antibody-lymphotoxin Fusion Protein,” Cancer Research, 56(8):1707-1712.Applicant
Reisfeld et al., (1996), “Recombinant Antibody Fusion Proteins for Cancer Immunotherapy,” Current Topics in Microbiology and Immunology, 213:27-53.Applicant
Reisfeld et al., (1997), “Immunocytokines: A New Approach to Immunotherapy of Melanoma,” Melanoma Research, 7(Supp2):S99-S106.Applicant
Riethmuller et al., (1994), “Randomised Trial of Monoclonal Antibody for Adjuvant Therapy of Resected Dukes' C Colorectal Carcinoma,” The Lancet, 343:1177-1183.Applicant
Roessler et al., (1994), “Cooperative Interactions Between the Interleukin 2 Receptor α and β Chains Alter the Interleukin 2-binding Affinity of the Receptor Subunits,” Proc. Natl. Acad. Sci. USA, 91:3344-3347.Applicant
Roitt et al., (1993), “The Role of TH Cells in the Selection of Effector Mechanisms Directed Against Target Antigens,” Immunology, 3rd Ed., pp. 8.3-8.4.Applicant
Rosenberg, (1988), “Immunotherapy of Cancer Using Interleukin 2: Current Status and Future Prospects,” Immunology Today, 9(2):58-62.Applicant
Rozwarski et al., (1994), “Structural Comparisons Among the Short-chain Helical Cytokines,” Structure, 2(3):159-173.Applicant
Ruehlmann et al., (2001), “MIG (CIXCL9) Chemokine Gene Therapy Combines with Antibody-cytokine Fusion Protein to Suppress Growth and Dissemination of Murine Colon Carcinoma,” Cancer Research, 61(23):8498-503.Applicant
Sabzevari et al., (1994), “A Recombinant Antibody-interleukin 2 Fusion Protein Suppresses Growth of Hepatic Human Severe Combined Immunodeficiency Mice,” Proc. Natl. Acad. Sci. USA, 91(20):9626-30.Applicant
Saleh et al., (1992), “Phase 1 Trial of the Chimeric Anti-GD2 Monoclonal Antibody ch14.18 in Patients With Malignant Melanoma,” Hum. Antiob. Hybridomas, 3:19-24.Applicant
Sallusto et al., (1994), “Efficient Presentation of Soluble Antigen by Cultured Human Dendritic Cells Is Maintained by Granulocyte/Macrophage Colony-stimulating Factor Plus Interleukin 4 and Downregulated by Tumor Necrosis Factor α,” J. Exp. Med., 179:1109-1118.Applicant
Santon et al., (1986), “Effects of Epidermal Growth Factor Receptor Concentration on Tumorigenicity of A431 Cells in Nude Mice,” Cancer Research, 46:4701-4705.Applicant
Sasaki et al., (1998), “Structure, Function and Tissue Forms of the C-terminal Globular Domain of Collagen XVIII Containing the Angiogenesis Inhibitor Endostatin,” EMBO Journal, 17(15):4249-4256.Applicant
Sauve et al., (1991), “Localization in Human Interleukin 2 of the Binding Site to the α-chain (p55) of the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 88:4636-4640.Applicant
Schlom (1991), “Monoclonal Antibodies: They're More and Less Than You Think,” in Molecular Foundations of Oncology, pp. 95-133.Applicant
Schnee et al., (1987), “Construction and Expression of a Recombinant Antibody-targeted Plasminogen Activator,” Proc. Natl. Acad. Sci. USA, 84:6904-6908.Applicant
Schoenhaut et al., (1992), “Cloning and Expression of Murine IL-12,” J. Immunology, 148(11):3433-3340.Applicant
Seidenfeld et al., (2001), “Epoietin Treatment of Anemia Associated with Cancer Therapy: A Systematic Review and Meta-analysis of Controlled Clinical Trials,” Journal of National Cancer Institute, 93(16):1204-1214.Applicant
Senter et al., (1988), “Anti-tumor Effects of Antibody-alkaline Phosphatase Conjugates in Combination with Etoposide Phosphate,” Proc. Natl. Acad. Sci. USA, 85(13):4842-4846.Applicant
Shanafelt et al., (2000), “A T-cell-Selective Interleukin 2 Mutein Exhibits Potent Antitumor Activity and is Well Tolerated In Vivo,” Nature Biotechnology, 18:1197-1202.Applicant
Sharma et al., (1999), “T cell-derived IL-10 Promotes Lung Cancer Growth by Suppressing Both T cell and APC Function,” Journal of Immunology, 163:5020-5028.Applicant
Shen et al., (1986), “Heteroantibody-Mediated Cytotoxicity: Antibody to the High Affinity Fc Receptor for IgG Mediates Cytotoxicity by Human Monocytes That is Enhanced by Interferon-γ and is Not Blocked by Human IgG,” J. Immunology,137(11):3378-3382.Applicant
Shiff et al., (1995), “Sulindac Sulfide, an Asprin-like Compound, Inhibits Proliferation, Causes Cell Cycle Quiescence, and Induces Apoptosis in HT-29 Colon Adenocarcinoma Cells,” Journal of Clinical Investigation, 96:491-503.Applicant
Shin et al., (1990), “Expression and Characterization of an Antibody Binding Specificity Joined to Insulin-like Growth Factor 1: Potential Applications for Cellular Targeting,” Proc. Natl. Acad. Sci. USA, 87:5322-5326.Applicant
Shinkawa et al., (2003), “The Absence of Fucose But Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity,” J. Biol. Chem., 278:3466-3473.Applicant
Sim et al., (1997), “A Recombinant Human Angiostatin Protein Inhibits Experimental Primary and Metastatic Cancer,” Cancer Research, 57:1329-1334.Applicant
Spiekermann et al., (2002), “Receptor-mediated Immunoglobulin G Transport Across Mucosal Barriers in Adult-Life: Functional Expression of FcRn in the Mammalian Lung,” J. Exp. Med., 196:303-310.Applicant
Stevenson et al., (1997), “Conjugation of Human Fcγ in Closed-Hinge or Open-Hinge Configuration to Fab'γ and Analogous Ligands,” J. Immunology, 158:2242-2250.Applicant
Strom et al., (1996), “Therapeutic Approach to Organ Transplantation,” Chapter 36, pp. 451-456, in Therapeutic Immunology, Austen et al., (eds.), Blackwell Science.Applicant
Sulitzeanu, (1993), “Immunosuppressive Factors in Human Cancer,” pp. 247-266 in Advances in Cancer Research, vol. 60, Vande Woude et al. (eds.), Academic Press, Inc.Applicant
Syed et al., (1998), “Efficiency of Signaling Through Cytokine Receptors Depends Critically on Receptor Orientation,” Nature, 395:511-516.Applicant
Taniguchi et al., (1983), “Structure and Expression of a Cloned cDNA for Human Interleukin-2,” Nature, 302:305-309.Applicant
Tao et al., (1989), “Studies of Aglycosylated Chimeric Mouse IgG: Role of Carbohydrate in the Structure and Effector Functions Mediated by the Human IgG Constant Region,” J. Immunology, 143(8):2595-2601.Applicant
Tao et al., (1993), “Structural Features of Human Immunoglobulin G that Determine Isotype-Differences in Complement Activation,” J. Exp. Med., 178(2):661-667.Applicant
Teicher et al., (1994), “Potentiation of Cytotoxic Cancer Therapies by TNP-470 Alone and With Other Anti-Angiogenic Agents,” Int. J. Cancer, 57:920-925.Applicant
The Merck Manual of Diagnosis and Therapy, 17th Ed., (1999) pp. 990-993 and 1278-1283.Applicant
Thommesen et al., (2000), “Lysine 322 in the Human IgG3 Ch2 Domain is Crucial for Antibody Dependent Complement Activation,” Mol. Immunol., 37(16):995-1004.Applicant
Till et al., (1988), “An Assay that Predicts the Ability of Monoclonal Antibodies to Form Potent Ricin A Chain-containing Immunotoxins,” Cancer Research, 48(5):1119-1123.Applicant
Till et al., (1988), “HIV-Infected Cells are Killed by rCD4-Ricin A Chain,” Science, 242:1166-1168.Applicant
Trinchieri, (1994), “Interleukin-12: A Cytokine Produced by Antigen-Presenting Cells With Immunoregulatory Functions in the Generation of T-Helper Cells Type 1 and Cytotoxic Lymphocytes,” Blood, 84:4008-4027.Applicant
Vagliani et al., (1996), “Interleukin 12 Potentiates that Curative Effect of a Vaccine Based on Interleukin 2-transduced Tumor Cells,” Cancer Research, 56:467-470.Applicant
Varki et al., (1984), “Antigens Associated with a Human Lung Adenocarcinoma Defined by Monoclonal Antibodies,” Cancer Research, 44:681-687.Applicant
Verhoeyen et al., (1988), “Reshaping Human Antibodies: Grafting an Antilysozyme Activity,” Science, 239:1534-1536.Applicant
Villunger et al., (1997), “Constitutive Expression of Fas (Apo-1/CD95) Ligand on Multiple Myeloma Cells: A Potential Mechanism of Tumor-induced Suppression of Immune Surveillance,” Blood, 90(1):12-20.Applicant
Watanabe et al., (1997), “Long-term Depletion of Naive T cells in Patients Treated for Hodgkin's Disease,” Blood, 90(9):3662-3672.Applicant
Weber et al., (2001), “Phase I Trial of huKS-IL2 Immunocytokine in Patients with Prostate Carcinoma: Clinical, PK, and Biological PD Results (Abstract),” American Society of Clinical Oncology Program/Proceedings, 20(Part 1):259a.Applicant
Wells, (1990), “Addivity of Mutational Effect in Proteins,” Biochemistry, 29(37):8509-8517.Applicant
Wen et al., (1993), “Erythropoietin Structure-Function Relationships: High Degree of Sequence Homology Among Mammals,” Blood, 82(5):1507-1516.Applicant
Wen et al., (1994), “Erythropoietin Structure-Function Relationships: Identification of Functionally Important Domains,” J. Biological Chemistry, 269(36):22839-22846.Applicant
Williams et al., (1986), “Production of Antibody-tagged Enzymes by Myeloma Cells: Application to DNA Polymerase I Klenow Fragment,” Gene, 43:319-324.Applicant
Williams et al., (1987), “Diphtheria Toxin Receptor Binding Domain Substitution with Interleukin-2: Genetic Construction and Properties of a Diptheria Toxin-related Interleukin-2 Fusion Protein,” Protein Engineering, 1(6):493-498.Applicant
Wooley et al., (1993), “Influence of a Recombinant Human Soluble Tumor Necrosis Factor Receptor Fc Fusion Protein on Type II Collagen-Induced Arthritis in Mice,” J. Immunology, 151:6602-6607.Applicant
Wu et al., (1997), “Suppression of Tumor Growth with Recombinant Murine Angiostatin,” Biochemical and Biophysical Research Communications, 236:651-654.Applicant
Xiang et al., (1997), “Elimination of Established Murine Colon Carcinoma Metastases by Antibody-Interleukin 2 Fusion Protein Therapy,” Cancer Research, 57:4948-4955.Applicant
Xiang et al., (1998), “Induction of Persistant Tumor-protective Immunity in Mice Cured of Established Colon Carcinoma Metastases,” Cancer Research, 58(17):3918-3925.Applicant
Xiang et al., (1999) “T Cell Memory against Colon Carcinoma is Long-lived in the Absence of Antigen,” J. Immunology, 163(7):3676-83.Applicant
Xiang et al., (2001), “A Dual Function DNA Vaccine Encoding Carcinoembryonic Antigen and CD40 Ligand Trimer Induces T Cell-mediated Protective Immunity Against Colon Cancer Carcinoembryonic Antigen-Transgenic Mice,” J. Immunology, 167(8):4560-5.Applicant
Xiang et al., (2001), “Protective Immunity Against Human Carcinoembryonic Antigen (CEA) Induced by an Oral DNA Vaccine in CEA-transgenic Mice,” Clinical Cancer Research, 7(3 Supp):S856-S864.Applicant
Xu et al., (1994), “Residue at Position 331 in the IgG1 and IgG4 CH2 Domains Contributes to Their Differential Ability to Bind and Activate Complement,” J. Biol. Chem., 269(5):3469-3474.Applicant
Yu et al., (1998), “Phase I Trial of a Human-Mouse Chimeric Anti-Disaloganglioside Monoclonal Antibody ch14.18 in Patients with Refractory Neuroblastoma and Osteosarcoma,” J. Clinical Oncology, 16(6):2169-80.Applicant
Zagozdzon et al., (1999), “Potentiation of Antitumor Effects of IL-12 in Combination with Paclitaxel in Murine Melanoma Model In Vivo,” International Journal of Molecular Medicine, 4:645-648.Applicant
Zheng et al., (1995), “Administration of Noncytolytic IL-10/Fc in Murine Models of Lipopolysaccharide-induced Septic Shock and Allogenic Islet Transplantation,” J. Immunology, 154:5590-5600.Applicant
Aichele et al., (1994), “Peptide-Induced T-Cell Tolerance to Prevent Autoimmune Diabetes in a Transgenic Mouse Model,” Proc. Natl. Acad. Sci. USA, 91:444-448.Applicant
Altschul et al., (1990), “Basic Local Alignment Search Tool,” J. Mol. Biol., 215:403-10.Applicant
Altschul et al., (1997), “Gapped BLAST and PSI-BLAST: A New Generation of Protein Database Search Programs,” Nucleic Acids Res., 25(17):3389-3402.Applicant
Anderson et al., (1980), “Characterization of the Fc Receptor for IgG on a Human Macrophage Cell Line U937,” J. Immunol., 125(6):2735-41.Applicant
Anderson et al., (1994), “Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2,” Clin. Pharmacokinet., 27(1):19-31.Applicant
Baici et al., (1980), “Kinetics of the Different Susceptibilities of the Four Human Immunoglobulin G Subclasses to Proteolysis by Human Lysosomal Elastase,” Scand. J. Immunol. 12(1):41-50.Applicant
Barbulescu et al., (1998), “IL-12 and IL-18 Differentially Regulate the Transcriptional Activity of the Human IFN-γ Promoter in Primary CD4+ T Lymphocytes,” J. Immunol., 160:3642-7.Applicant
Bednarek et al., (1991), “Soluble HLA-A2.1 Restricted Peptides that are Recognized by Influenza Virus Specific Cytotoxic T Lymphocytes,” J. Immunol. Methods, 139:41-47.Applicant
Benacerraf et al., (1959), “The Clearance of Antigen Antibody Complexes from the Blood by the Reticulo-Endothelial System,” J. Immunol., 82:131-7.Applicant
Böhm, (1994), “On the Use of LUDI to Search the Fine Chemicals Directory for Ligands of Proteins of Known Three-Dimensional Structure,” J. Comput. Aided Mol. Des., 8:623-32.Applicant
Böhm, (1994), “The Development of a Simple Empirical Scoring Function to Estimate the Binding Constant for a Protein-Ligand Complex of Known Three-Dimensional Structure,” J. Comput. Aided Mol. Des., 8(3):243-56.Applicant
Böhm, (1998), “Prediction of Binding Constants of Protein Ligands: A Fast Method for the Priorization of Hits Obtained from De Novo Design or 3D Database Search Programs,” J. Comput. Aided Mol. Des., 12(4):309-23.Applicant
Boshart et al., (1985), “A Very Strong Enhancer is Located Upstream of an Immediate Early Gene of Human Cytomegalovirus,” Cell, 41:521-530.Applicant
Boulianne et al., (1984), “Production of Functional Chimeric Mouse/Human Antibody,” Nature, 312:643-6.Applicant
Bourgois et al., (1974), “Determination of the Primary Structure of a Mouse IgG2a Immunoglobulin Amino Acid Sequence of the Fc Fragment: Implications for the Evolution of Immunoglobulin Structure and Function,” Eur. J. Biochem., 43:423-45.Applicant
Brambell et al., (1964), “A Theoretical Model of γ-Globulin Catabolism,” Nature, 203:1352-55.Applicant
Brazolot Millan et al., (1998), “Cpg DNA Can Induce Strong TH1 Humoral and Cell-Mediated Immune Responses against Hepatitis B Surface Antigen in Young Mice,” Proc. Natl. Acad. Sci. USA, 95:15553-8.Applicant
Brekke et al., (1994), “Human IgG Isotype-Specific Amino Acid Residues Affecting Complement-Mediated Cell Lysis and Phagocytosis,” Eur. J. Immunol., 24:2542-2547.Applicant
Brem et al., (1993), “The Combination of Antiangiogenic Agents to Inhibit Primary Tumor Growth and Metastasis,” J. Pediatr. Surg., 28(10):1253-7.Applicant
Brocklebank et al., (2001), “Enumeration of CD34+ Cells in Cord Blood: A Variation of a Single-Platform Flow Cytometric Method Based on the ISHAGE Gating Strategy,” Cytometry, 46:254-261.Applicant
Brooks et al., (1983), “CHARMM: A Program for Macromolecular Energy Minimization and Dynamics Calculations,” J. Comput. Chemistry, 4:187-217.Applicant
Broudy et al., (1988), “Recombinant Human Erythropoietin: Purification and Analysis of Carbohydrate Linkage,” Arch. Biochem. Biophys., 265:329-36.Applicant
Bubenik et al., (1995), “Interleukin-2 Gene Therapy of Residual EL-4 Leukaemia Potentiates the Effect of Cyclophosphamide Pretreatment,” J. Cancer Res. Clin. Oncol., 121:39-43.Applicant
Bumol et al., (1982), “Unique Glycoprotein-Proteoglycan Complex Defined By Monoclonal Antibody on Human Melanoma Cells,” Proc. Natl. Acad. Sci. USA, 79:1245-9.Applicant
Carnemolla et al., (1989), “A Tumor-Associated Fibronectin Isoform Generated by Alternative Splicing of Messenger RNA Precursors,” J. Cell. Biol., 108:1139-1148.Applicant
Carnemolla et al., (1992), “The Inclusion of the Type III Repeat ED-B in the Fibronectin Molecule Generates Conformational Modifications that Unmask a Cryptic Sequence,” J. Biol. Chem., 267(34):24689-24692.Applicant
Casadevall et al., (2002) “Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin,” The New Eng. School of Medicine, 346:469-75.Applicant
Cazzola et al., (1998), “Red Blood Cell Precursor Mass as an Independent Determinant of Serum Erythropoietin Level,” Blood, 91:2139-45.Applicant
Chan et al., (1992), “Mechanisms of IFN-γ Induction by Natural Killer Cell Stimulatory Factor (NKSF/IL-12). Role of Transcription and mRNA Stability in the Synergistic Interaction Between NKSF and Il-2,” J. Immunol., 148:92-98.Applicant
Chappel et al., (1991), “Identification of the Fc Gamma Receptor Class I Binding Site In Human IgG Through Use of Recombinant IgG1/IgG2 Hybrid and Point-Mutated Antibodies,” Proc. Natl. Acad. Sci. USA, 88(20):9036-40.Applicant
Cheetham, (1998), “NMR Structure of Human Erythropoietin and a Comparison with its Receptor Bound Conformation,” Nat. Struct. Biol., 5:861-6.Applicant
Ciardiello et al., (1996), “Antitumor Activity of Combined Blockade of Epidermal Growth Factor Receptor anf Protein Kinase A,” J. Natl. Cancer Inst., 88:1770-6.Applicant
Cirulli et al., (1998), “KSA Antigen Ep-CAM Mediates Cell-Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development,” J. Cell Biol., 140:1519-34.Applicant
Cohen et al., (1998), “An Artificial Cell-Cycle Inhibitor Isolated from a Combinatorial Library,” Proc. Natl. Acad. Sci. USA, 95:14272-7.Applicant
Congote et al., (1984), “The Erthrotropins, New Erythroid Cell Stimulate Factors Extracted From Human and Bovine Fetal Tissues,” Abstract 364, “Proceedings 7th Intl. Congress of Endocrinology,” Quebec City, Quebec, Jul. 1-7, 1984.Applicant
Congote, (1983), “Isolation of Two Biologically Active Peptides, Erythrotropin I and Erythrotropin II from Fetal Calf Intestine,” Biochem. Biophys. Res. Commun., 115(2):477-83.Applicant
Congote, (1984), “Extraction from Fetal Bovine Serum of Erythrotropin, an Erythroid Cell-Stimulating Factor,” Anal. Biochem., 140:428-33.Applicant
Connor et al., (2004), “Ex vivo Evaluation of Anti-EpCAM Immunocytokine huKS-IL2 in Ovarian Cancer,” J. Immunotherapy, 27:211-219.Applicant
Cosenza et al., (1997), “Disulfide Bond Assignment in Human Interleukin-7 by Matrix-Assisted Laser Desorption/Ionization Mass Spectroscopy and Site-Directed Cysteine to Serine Mutational Analysis,” J. Biol. Chem., 272:32995-3000.Applicant
Cunningham et al., (1989), “High-Resolution Epitope Mapping of hGH-Receptor Interactions by Alanine-Scanning Mutagenesis,” Science, 244:1081-85.Applicant
Curiel et al., (1991), “Adenovirus Enhancement of Transferrin-Polylysine-Mediated Gene Delivery,” Proc. Natl. Acad. Sci. USA, 88:8850-4.Applicant
Dauber-Osguthorpe et al., (1988), “Structure and Energetics of Ligand Binding to Proteins: Escherichia coli Dihydrofolate Reductase-Trimethoprim, A Drug-Receptor System,” Proteins, 4:31-47.Applicant
Daugherty et al., (1991), “Polymerase Chain Reaction Facilities the Cloning, CDR-Grafting, and Rapid Expression of a Murine Monoclonal Antibody Directed Against the CD18 Component of Leukocyte Integrins,” Nucleic Acid Res., 19:2471-2476.Applicant
De Bruijn et al., (1995), “Phagocyte-Induced Antigen-Specific Activation of Unprimed CD8+ T Cells in Vitro,” Eur. J. Immunol., 25:1274-85.Applicant
Delorme et al., (1992), “Role of Glycosylation on the Secretion and Biological Activity of Erythropoietin,” Biochemistry, 31:9871-6.Applicant
Desai et al., (1992), “IL-12 Receptor. II. Distribution and Regulation of Receptor Expression,” J. Immunol., 148:3125-32.Applicant
Dillman et al., (1994), “Human Anti-Mouse Antibody Response in Cancer Patients Following Single Low-Dose Injections of Radiolabeled Murine Monoclonal Antibodies,” Cancer Biotherapy, 9:17-28.Applicant
Donnelly et al., (1993), “Targeted Delivery of Peptide Epitopes to Class I Major Histocompatibility Molecules by a Modified Pseudomonas Exotoxin,” Proc. Natl. Acad. Sci. USA, 90:3530-4.Applicant
Donnelly et al., (1997), “DNA Vaccines,” Annu. Rev. Immunol., 15:617-48.Applicant
Dube et al., (1988), “Glycosylation at Specific Sites of Erythropoietin is Essential for Biosynthesis, Secretion, and Biological Function,” J. Biol. Chem., 263:17516-21.Applicant
Ellison et al., (1982), “The Nucleotide Sequence of a Human Immunoglobulin C γ1 Gene,” Nucleic Acids Res., 10:4071-9.Applicant
Faas et al., (1993), “Phenotypically Diverse Mouse Thymic Stromal Cell Lines which Induce Proliferation and Differentiation of Hematopoietic Cells,” Eur. J. Immunol., 23:1201-14.Applicant
Famer et al., (1995), “Distinction Between γc C Detection and Function in YT Lymphoid Cells and in the Granulocyte-Macrophage Colony-Stimulating Factor-Responsive Human Myeloid Cell Line, Tf-1,” Blood, 86:4568-78.Applicant
Fawell et al., (1994), “Tat-Mediated Delivery of Heterologous Protein in Cells,” Proc. Natl. Acad. Sci. USA, 91:664-8.Applicant
Fu et al., (1993), “The Sheep Erythropoietin Gene: Molecular Cloning and Effect of Hemorrhage on Plasma Erythropoietin and Renal/Liver Messenger RNA in Adult Sheep,” Mol. Cell. Endocrinol., 93:107-16.Applicant
Gainsford et al., (1996), “Leptin Can Induce Proliferation, Differentiation, and Functional Activation of Hemopoietic Cells,” Proc. Natl. Acad. Sci. USA, 93:14564-14568.Applicant
Gammon et al., (1992), “Endogenous Loading of HLA-A2 Molecules with an Analog of the Influenza Virus Matrix Protein-Derived Peptide and Its Inhibition By An Exogenous Peptide Antagonist,” J. Immunol., 148:7-12.Applicant
Ghetie et al., (1990), “Disseminated or Localized Growth of a Human B-Cell Tumor (Daudi) in SCID Mice,” Intl. J. Cancer, 45:485.Applicant
Ghetie et al., (1997), “FcRn: The MHC Class 1-Related Receptor that is More Than an IgG Transporter,” Immunology Today, 18(12):592-598.Applicant
Goldwasser et al., (1971), “Purification of Erythropoietin,” Proc. Natl. Acad. Sci. USA, 68:697-8.Applicant
Goldwasser et al., (1975), “Erythropoietin: Assay and Study of its Mode of Action,” Methods Enzymol., 37(PtB):109-21.Applicant
Gurewich et al., (1988), “Characterization of the Intrinsic Fibrinolytic Properties of Pro-Urokinase Through a Study of Plasmin-Resistant Mutant Forms Produced by Site-Specific Mutagenesis of Lysine,” J. Clin. Invest., 82:1956-1962.Applicant
Halin et al., (2002), “Enhancement of the Antitumor Activity of Interleukin-12 by Targeted Delivery to Neovasculature,” Nature Biotechnology, 20:264-269.Applicant
Handgretinger et al., “Immunological Aspects of Haploidentical Stem Cell Transplantation in Children,” Annals New York Academy of Sciences, 340-(Date not known).Applicant
Hashimoto et al., (1999), “Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively,” J. Immunol., 163:583-9.Applicant
Henikoff et al., (1992), “Amino Acid Substitution Matrices from Protein Blocks,” Proc. Natl. Acad. Sci. USA, 89:10915-10919.Applicant
Hilgers et al., (1999), “Sulfolipo-Cyclodextrin in Squalane-In-Water as a Novel and Safe Vaccine Adjuvant,” Vaccine, 17:219-28.Applicant
Hori et al., (1987), “Establishment of an Interleukin 2-Dependent Human T Cell Line from a Patient with T Cell Lymphocytic Leukemia Who is Not Infected with Human T Cell Leukemia/Lymphoma Virus,” Blood, 70:1069-72.Applicant
Hulett et al., (1994), “Molecular Basis of Fc Receptor Function,” Adv. Immunol., 57:1127.Applicant
Huston et al., (1988), “Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli,” Proc. Natl. Acad. Sci. USA, 85:5879-5883.Applicant
Investigator's Brochure 2004, pp. 6-10, 34 and 35.Applicant
Jacobs et al., (1985), “Isolation and Characterization of Genomic And cDNA Clones of Human Erythropoietin,” Nature, 313:806-10.Applicant
Jefferis et al., (1990), “Molcular Definition of Interaction Sites on Human IgG for Fc Receptors huFcγR,” Mol. Immunol., 27(12):1237-1240.Applicant
Karlin et al., (1990), “Methods for Assessing the Statistical Significance of Molecular Sequence Features by Using General Scoring Schemes,” Proc. Natl. Acad. Sci. USA, 87:2264-8.Applicant
Karlin et al., (1993), “Applications and Statistics for Multiple High-Scoring Segments in Molecular Sequences,” Proc. Natl. Acad. Sci. USA, 90:5873-7.Applicant
Karpusas et al., (1997), “The Crystal Structure of Human Interferon β at 2.2-A Resolution,” Proc. Natl. Acad. Sci. USA, 94:11813-11818.Applicant
Kelner et al., (1994), “Lymphotactin: A Cytokine that Represents a New Class of Chemokine,” Science, 266:1395-9.Applicant
Kirkman et al., (1989), “Prolongation of Cardiac Allograft Survival in Murine Recipients Treated with a Diphtheria Toxin-Related Interleukin-2 Fusion Protein,” Transplantation, 47(2):327-330.Applicant
King et al., (2004), “Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients,” J. Clin. Oncol., 22(22):4463-73.Applicant
Klinman et al., (1997), “Contribution of CpG Motifs to the Immunogenicity of DNA Vaccines,” J. Immunol., 158:3635-9.Applicant
Kuntz et al., (1982), “A Geometric Approach to Macromolecule-Ligand Interactions,” J. Mol. Biol., 161:269-88.Applicant
Kurtz, (1982), “A New Candidate for the Regulation of Erythropoiesis. Insulin-Like Growth Factor I,” FEBLAL., 149(1):105-8.Applicant
Lai et al., (1986), “Structural Characterization of Human Erythropoietin,” J. Biol. Chem., 261:3116-21.Applicant
Lai et al., (1998), “DNA Vaccines,” Crit. Rev. Immunol., 18:449-84.Applicant
Lanza et al., (1993), “Active Immunity against the CD4 Receptor by Using an Antibody Antigenized with Residues 41-55 of the First Extracellular Domain,” Proc. Natl. Acad. Sci. USA, 90:11683-7.Applicant
Lawn et al., (1981), “DNA Sequence of a Major Human Leukocyte Interferon Gene,” Proc. Natl. Acad. Sci. USA, 78:5435-9.Applicant
Lin et al., (1985), “Cloning and Expression of the Human Erythropoietin Gene,” Proc. Natl. Acad. Sci. USA, 82:7580-4.Applicant
Lin et al., (1986), “Monkey Erythropoietin Gene: Cloning, Expression and Comparison with the Human Erythropoietin Gene,” Gene, 44:201-9.Applicant
Lode et al., (1998), “Gene Therapy with a Single Chain Interleukin 12 Fusion Protein Induces T Cell-Dependent Protective Immunity in a Syngeneic Model of Murine Neuroblastoma,” Proc. Natl. Acad. Sci. USA, 95:2475-80.Applicant
Lorenz et al., (1999), “Induction of Anti-Tumor Immunity Elicited by Tumor Cells Expressing a Murine LFA-3 Analog Via a Recombinant Vaccinia Virus,” Hum. Gene Ther., 10:623-31.Applicant
Lotze et al., (1996), “Cytokine Gene Therapy of Cancer Using Interleukin-12: Murine and Clinical Trials,” Ann. NY Acad. Sci., 795:440-54.Applicant
Macdougall, et al., (2002), “Optimizing the Use of Erythropoietic Agents—Pharmacokinetics and Pharmacodynamic Considerations,” Nephol. Dial. Transplant. 17(5):66-70.Applicant
MacLean et al., (1996), “Enhancing the Effect of Theratope STn-KLH Cancer Vaccine in Patients with Metastatic Breast Cancer by Pretreatment with Low-Dose Intravenous Cyclophosphamide,” J. Immunother., 19(4):309-316.Applicant
Maghazachi et al., (1997), “Interferon-Inducible Protein-10 and Lymphotactin Induce the Chemotaxis and Mobilization of Intracellular Calcium in Natural Killer Cells through Pertussis Toxin Sensitive and—Insensitive Heterotrimeric G-Proteins,” FASEB J., 11:765-74.Applicant
Maloy et al., (2001), “Regulatory T Cells in the Control of Immune Pathology,” 2(9):816-822.Applicant
Mariani et al., (1997), “Tumor Targeting Potential of the Monoclonal Antibody BC-1 against Oncofetal Fibronectin in Nude Mice Bearing Human Tumor Implants,” Cancer, 80:2378-84.Applicant
Marshall et al., (1994), “Role of the Polymorphic Residues in HLA-DR Molecules in Allele-Specific Binding of Peptide Ligands,” J. Immunol., 15:4946-57.Applicant
Marshall et al., (1995), “Prediction of Peptide Affinity to HLA-DR Molecules,” Biomed. Pept. Proteins Nucleic Acids, 1(3):157-62.Applicant
Martin et al., (2001), “Crystal Structure at 2.8 A of an FcRn/Heterodimeric Fc Complex: Mechanism of pH Dependent Binding,” Molecular Cell, 7:867-877.Applicant
McDonald, (1986), “Cloning, Sequencing, and Evolutionary Analysis of the Mouse Erythropoietin Gene,” Mol. Cell. Biol., 6:842-8.Applicant
McGonigle et al., (1984), “Erythropoietin Deficiency and Inhibition of Erythropoiesis in Renal Insufficiency,” Kidney Int., 25(2):437-44.Applicant
McMahan et al., (1991), “A Novel IL-1 Receptor, Cloned From B-Cells by Mammalian Expression is Expressed in Many Cell Types,” EMBO J., 10:2821-32.Applicant
McMahon et al., (1990), “Pharmacokinetics and Effects of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Injections in Healthy Volunteers,” Blood, 76:1718-22.Applicant
Mehrotra et al., (1993), “Effects of IL-12 on the Generation of Cytotoxic Activity in Human CD8+ T Lymphocytes,” J. Immunol., 151:2444-52.Applicant
Menard et al., (1983), “Generation of Monoclonal Antibodies Reacting with Normal and Cancer Cells of Human Breast,” Cancer Res., 43:1295-300.Applicant
Miyake et al., (1977), “Purification of Human Erythropoietin,” J. Biol. Chem., 252:5558-64.Applicant
Miyake et al., (1988), “Synthesis of Recombinant Human Single-Chain Urokinase-Type Plasminogen Activator Variants Resistant to Plasmin and Thrombin,” J. Biochem., 104:643-647.Applicant
Morrison et al., (1984), “Chimeric Human Antibody Molecules: Mouse Antigen-Binding Domains with Human Constant Region Domains,” Proc. Natl. Acad. Sci. USA, 81:6851-5.Applicant
Nagao et al., (1992), “Nucleotide Sequence of Rat Erythropoietin,” Biochim. Biophys. Acta, 1171(1):99-102.Applicant
Nastala et al., (1994), “Recombinant IL-12 Administration Induces Tumor Regression in Association with IFN-γ Production,” J. Immunol., 153:1697-706.Applicant
Naughton et al., (1983), “Evidence for an Erythropoietin-Stimulating Factor in Patients with Renal and Hepatic Disease,” Acta. Haemat., 69:171-9.Applicant
Neal et al., (2004), “Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin-2 Therapy,” Clin. Cancer. Res., 10:4839-4847.Applicant
Nelles et al., (1987), “Characterization of Recombinant Human Single Chain Urokinase-Type Plaminogen Activtor Mutants Produced by Site-Specific Mutagenesis of Lysine 158,” J. Biol. Chem., 262(12):5682-5689.Applicant
Noguchi et al., (1994), “A Mouse Mutant P53 Product Recognized by CD4+ and CD8+ T Cells,” Proc. Natl. Acad. Sci. USA, 91:3171-5.Applicant
Orlandi et al., (1989), “Cloning Immunoglobulin Variable Domains for Expression by the Polymerase Chain Reaction,” Proc. Natl. Acad. Sci. USA, 86:3833-7.Applicant
Palmer et al., (2001), “Phase I Study of the BLP 25 (MUCI Peptide) Liposomal Vaccine for Active Specific Immunotherapy in Stage IIIB/IV Non-Small-Cell Lung Cancer,” Clinical Lung Cancer, 3(1):49-57.Applicant
Palucka et al., (1998), “Dendritic Cells as the Terminal Stage of Monocyte Differentiation,” J. Immunol., 160:4587-95.Applicant
Panina-Bordignon et al., (1989), “Universally Immunogenic T Cell Epitopes: Promiscuous Binding to Human MHC Class II and Promiscuous Recognition by T Cells,” Eur. J. Immunol., 19:2237-42.Applicant
Pavlović-Kentera et al., (1980), “Effects of Prostaglandin Synthetase Inhibitors, Salt Overload and Renomedullary Dissection on the Hypoxia Stimulated Erythropoietin Production in Rats,” Exp. Hematol., 8(Supp. 8):283-92.Applicant
Pedley et al. (1999), “Enhancement of Antibody-Directed Enzyme Prodrug Therapy in Colorectal Xenografts by an Antivascular Agent,” Cancer Res., 59:3998-4003.Applicant
Perussia et al., (1992), “Natural Killer (NK) Cell Stimulatory Factor or IL-12 Has Differential Effects on the Proliferaton of TCR-αβ+, TCR-γδ+ T Lymphocytes, and NK Cells,” J. Immunol., 149:3495-502.Applicant
Pluschke et al., (1996), “Molecular Cloning of a Human Melanoma-Associated Chondroitin Sulfate Proteoglycan,” Proc. Natl. Acad. Sci. USA, 93:9710-5.Applicant
Poon et al., (1995), “Structure and Function of Several Anti-Dansyl Chimeric Antibodies Formed by Domain Interchanges Between Human IgM and Mouse IgG2b,” J. Biol. Chem., 270:8571-7.Applicant
Queen et al., (1989), “A Humanized Antibody that Binds to the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 86:10029-33.Applicant
Radhakrishnan et al., (1996), “Zinc Mediated Dimer of Human Inteferon-α2b Revealed by X-Ray Crystallography,” Structure 4(12):1453-63.Applicant
Ramachandran et al., (1968)“Conformation of Polypeptides and Proteins,” Adv. Prot. Chem., 23:283-294.Applicant
Rarey et al., (1995), “Time-Efficient Docking of Flexible Ligands into Active Sites Of Proteins,” Proc. Int. Conf. Intell. Syst. Mol. Biol. 3:300-8.Applicant
Resegotti et al., (1981), “Treatment of Aplastic Anaemia with Methenolone, Stanozolol and Nandrolone. A Report of 130 Cases,” Pan. Med., 23:243-8.Applicant
Riechmann et al., (1988), “Reshaping Human Antibodies for Therapy,” Nature, 332:323-7.Applicant
Robinson et al., (1998), “Optimizing the Stability of Single-Chain Proteins by Linker Length and Composition Mutagenesis,” Proc. Natl. Acad. Sci. USA, 95:5929-34.Applicant
Rothmann et al., (1982), “Erythropoietin-Dependent Erythrocytosis associated with Hepatic Angiosarcoma,” J. Surg. Oncol., 20:105-8.Applicant
Runkel et al., (1998), “Structural and Functional Differences Between Glycosylated and Non-Glycosylated Forms of Human Interferon-β (IFN-β),” Pharmaceutical Res., 15:641-649.Applicant
Sakano et al., (1980), “Two Types of Somatic Recombination are Necessary for the Generation of Complete Immunoglobin Heavy-Chain Genes,” Nature, 286:676-683.Applicant
Säli et al., (1993), “Comparative Protein Modelling by Satisfaction of Spatial Restraints,” J. Mol. Biol., 234:779-815.Applicant
Schecter et al., (1997), “Tissue Factor is Induced by Monocyte Chemoattractant Protein-1 in Human Aortic Smooth Muscle And THP-1 Cells,” J. Biol. Chem., 272:28568-73.Applicant
Senior et al., (2000), “Cleavage of a Recombinant Human Immunoglobulin A2 (igA2)-IgA1 Hybrid Antibody by Certain Bacterial IgA1 Proteases,” Infect. Immun., 68(2):463-9.Applicant
Sharp et al., (1988), “Codon Usage Patterns in Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens; a Review of the Consdierable Within-Species Diversity,” Nucleic Acids Res., 16(17):8207-8211.Applicant
Simonsen et al., (1983), “Isolation and Expression of an Altered Mouse Dihydrofolate Reductase cDNA,” Proc. Natl. Acad. Sci. USA, 80:2495-2499.Applicant
Smith et al., (1981), “Identification of Common Molecular Subsequences,” J. Mol. Biol., 147:195-197.Applicant
Soligo et al., (1998), “Expansion of Dendritic Cells Derived from Human CD34+ Cells in Static And Continuous Perfusion Cultures,” Br. J. Haematol., 101:352-63.Applicant
Spivak et al., (1989), “The In Vivo Metabolism of Recombinant Human Erythropoietin in the Rat,” Blood, 73:90-9.Applicant
Stumiolo et al., (1999), “Generation of Tissue-Specific and Promiscuous HLA Ligand Databases Using DNA Microarrays and Virtual HLA Class II Matrices,” Nat. Biotech., 17(6):555-61.Applicant
Suliman et al., (1996), “Cloning of a cDNA Encoding Bovine Erythropoietin and Analysis of Its Transcription in Selected Tissues,” Gene, 171:275-80.Applicant
Takahashi et al., (2000), “Immunologic Self-Tolerance Maintained by CD25+ CD+ Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte-Associated Antigen 4,” J. Exp. Med., 192(2):303-309.Applicant
Takai, (2002), “Roles of Fc Receptors in Autoimmunity,” Nature, 2:580-592.Applicant
Taniguchi et al., (1980), “Expression of the Human Fibroblast Interferon Gene in Escherichia coli,” Proc. Natl. Acad. Sci. USA, 77:5230-5233.Applicant
Thumer, (1999), “Generation of Large Numbers of Fully Mature and Stable Dendritic Cells from Leukapheresis Products for Clinical Application,” J. Immunol. Methods, 223:1-15.Applicant
Tiruppathi et al., (1996), “Isolation and Characterization of a Cell Surface Albumin-Binding Protein from Vascular Endothelial Cells,” Proc. Nat. Acad. Sci. USA, 93:250-4.Applicant
Van Den Eynde et al., (1989), “Presence on a Human Melanoma of Multiple Antigens Recognized By Autologous CTL,” Int. J. Cancer, 44:634-40.Applicant
Van Der Bruggen et al., (1991), “A Gene Encoding an Antigen Recognized by Cytolytic T Lymphocytes on a Human Melanoma,” Science, 254:1643-7.Applicant
Van Heyningen et al., (1982), “Human MHC Class II Molecules as Differentiation Markers,” Immunogenetics, 16:459-69.Applicant
Voest et al., (1995), “Inhibition of Angiogenesis in Vivo by Interleukin 12,” J. Natl. Canc. Inst., 87:581-6.Applicant
Von Heijne et al., (1986), “A New Method for Predicting Signal Sequence Cleavage Sites,” Nucleic Acid Res., 14:4683-4690.Applicant
Ward et al., (1995), “The Effector Functions of Immunoglobulins: Implications for Therapy,” Therapeutic. Immunology, 2:77-94.Applicant
Watson et al., (1984), “Compilation of Published Signal Sequences,” Nucleic Acid Res., 12:5145-5164.Applicant
Weitkamp et al., (1973), “Additional Data on the Population Distribution of Human Serum Albumin Genes; Three New Variants,” Ann. Hum. Genet., 37:219-26.Applicant
Wetzel et al., (2001), “BAY50-4798, an Interleukin-2 (IL-2) Variant, Demonstrates Selective Activation of Human and Chipanzee T Cells Relative to NK Cells but Shows Less Selectivity for T Cells from Monkeys and Rodents,” 2001 ASCO Annual Meeting.Applicant
Woof et al., (1986), “Localisation of the Monocyte-Binding Region on Human Immunoglobulin G,” Mol. Immunol., 23:319-30.Applicant
Wyatt et al., (1998), “The Antigenic Structure of the HIV gp120 Envelope Glycoprotein,” Nature, 393:705-11.Applicant
Wysocka et al., (1995), “Interleukin-12 is Required for Interferon-γ Production and Lethality in Lipopolysaccharide-Induced Shock in Mice,” Eur. J. Immunol., 25:672-6.Applicant
Yan et al., (1996), “Characterization of an Ig VH Idiotope that Results in Specific Homophilic Binding and Increased Avidity for Antigen,” J. Immunol., 157:1582-8.Applicant
Yeh et al., (1992), “Design of Yeast-Secreted Albumin Derivatives for Human Therapy: Biological and Antiviral Properties of a Serum Albumin-CD4 Genetic Conjugate,” Proc. Natl. Acad. Sci. USA, 89:1904-8.Applicant
Zhang et al., (1994), “Structure/Activity Analysis of Human Monocyte Chemoattractant Protein-1 (MCP-1) by Mutagenesis,” J. Biol. Chem., 269:15918-24.Applicant
Zhu et al., (2001), “MHC Class I-Related Neonatal Fc Receptor for IgG Is Functionally Expressed in Monocytes, Intestinal Macrophages, and Dendritic Cells,” J. Immunol., 166:3266-3276.Applicant
Zuckier et al., (1998), “Chimeric Human-Mouse IgG Antibodies with Shuffled Constant Region Exons Demonstrate that Multiple Domains Contribute to In Vivo Half-Life,” Cancer Res., 58(17):3905-8.Applicant

Abstract

Description

CROSS REFERENCE TO RELATED APPLICATION

[0001] This incorporates by reference, and claims priority to and the benefit of, U.S. provisional patent application 60/433,945, which was filed on Dec. 17, 2002.

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

[0009] Generally, the present invention provides a modified form of the m14.18 antibody that is less immunogenic in humans, but still maintains the binding affinity of m14.18 for human GD2.

[0016] It is to be understood that the features of the various embodiments described herein are not mutually exclusive and can exist in various combinations and permutations.

DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1A shows the amino acid sequence of an immunoglobulin light chain variable region in accordance with the invention.

[0018] FIG. 1B shows the amino acid sequence of an immunoglobulin heavy chain variable region in accordance with the invention.

[0020] FIG. 3A shows the amino acid sequence of an immunoglobulin light chain in accordance with the invention.

[0021] FIG. 3B shows the amino acid sequence of an immunoglobulin heavy chain in accordance with the invention.

DETAILED DESCRIPTION OF THE INVENTION

Protein Sequences of the Invention

I. Heavy and Light Chains Variable Regions

[0029]

D-V-V-M-T-Q-T-P-L-S-L-P-V-T-P-G-E-P-A-S-I-S-C-R-S-S-Q-S-L-V-H-R-N-G-N-T-	(SEQ ID NO: 1)

Y-L-H-W-Y-L-Q-K-P-G-Q-S-P-K-L-L-I-H-K-V-S-N-R-F-S-G-V-P-D-R-F-S-G-S-G-S-

G-T-D-F-T-L-K-I-S-R-V-E-A-E-D-L-G-V-Y-F-C-S-Q-S-T-H-V-P-P-L-T-F-G-A-G-T-

K-L-E-L-K.

[0031] In other embodiments of the invention, the V_Hregion of the hu14.18 antibody includes the following polypeptide:

[0032]

E-V-Q-L-V-Q-S-G-A-E-V-E-K-P-G-A-S-V-K-I-S-C-K-A-S-G-S-S-F-T-G-Y-N-M-N-	(SEQ ID NO: 2)

W-V-R-Q-N-I-G-K-S-L-E-W-I-G-A-I-D-P-Y-Y-G-G-T-S-Y-N-Q-K-F-K-G-R-A-T-L-T-

V-D-K-S-T-S-T-A-Y-M-H-L-K-S-L-R-S-E-D-T-A-V-Y-Y-C-V-S-G-M-E-Y-W-G-Q-G-

T-S-V-T-V-S-S.

II. Fc Portion

III. Fusion Junction Region

IV. Treatment of Human Disease with hu14.18 Antibody Fusion Proteins

Nucleic Acids of the Invention

I. hu14.18 Antibody Constructs

II. Expression of hu14.18 Antibody Constructs

III. Treatment of Cancer by Gene Therapy

[0070] The invention is illustrated further by the non-limiting examples.

EXAMPLES

Example 1

Purification and Formulation of hu14.18-IL2

[0073]


	1. Mannitol	4%
	2. Arginine Hydrochloride USP/NF	100 mM
	3. Citric Acid USP-FCC	5 mM
	4. Polysorbate 80	0.01% (w.v)

The pH of the formulation buffer was adjusted to 7 with 1 M NaOH.

Example 2

Anti-Tumor Activity of the hu14.18-IL-2 Fusion Protein Observed in Phase I Clinical Trials

[0081]

TABLE 1

Clinical Outcomes
	Number of
	Patients

	Patients completing course 1	31
	Stable disease following course 1	19
	50% dose reduction for course 2	5
	Patients completing course 2	17
	Stable disease following course 2	8

Example 3

Immune Stimulation in vivo by hu14.18-IL-2 in a Phase I Clinical Trial

INCORPORATION BY REFERENCE

[0090] The disclosures of each of the patent documents and scientific publications disclosed herein are incorporated by reference into this application in their entireties.

Claims

We claim:

1. An antibody variable region comprising the amino acid sequence set forth in SEQ ID NO: 1.

2. An antibody variable region comprising the amino acid sequence set forth in SEQ ID NO: 2.

3. The antibody variable region of claim 2 further comprising the amino acid sequence set forth in SEQ ID NO: 1.

4. The antibody variable region of claim 3, wherein the amino acid sequences are linked by a disulfide bond.

5. The antibody variable region of claim 3, wherein the amino acid sequences are linked by a peptide bond.

Patent Citations (252)

Patent	Date	Inventor	Cited By
US4196265(A)	1980-04-01	Koprowski et al.	Applicant
US4469797(A)	1984-09-01	Albarella	Applicant
US4522811(A)	1985-06-01	Eppstein et al.	Applicant
US4667016(A)	1987-05-01	Lai et al.	Applicant
US4676980(A)	1987-06-01	Segal et al.	Applicant
US4703008(A)	1987-10-01	Lin	Applicant
US4732683(A)	1988-03-01	Georgiades et al.	Applicant
US4737462(A)	1988-04-01	Mark et al.	Applicant
US4816567(A)	1989-03-01	Cabilly et al.	Applicant
US4946778(A)	1990-08-01	Ladner et al.	Applicant
US4975369(A)	1990-12-01	Beavers et al.	Applicant
US5019368(A)	1991-05-01	Epstein et al.	Applicant
US5073627(A)	1991-12-01	Curtis et al.	Applicant
US5082658(A)	1992-01-01	Palladino	Applicant
US5091513(A)	1992-02-01	Huston et al.	Applicant
US5114711(A)	1992-05-01	Bell et al.	Applicant
US5116964(A)	1992-05-01	Capon et al.	Applicant
US5196320(A)	1993-03-01	Gillies	Examiner
US5199942(A)	1993-04-01	Gillis	Applicant
US5225538(A)	1993-07-01	Capon et al.	Applicant
US5225539(A)	1993-07-01	Winter	Applicant
US5258498(A)	1993-11-01	Huston et al.	Applicant
US5314995(A)	1994-05-01	Fell, Jr. et al.	Applicant
US5349053(A)	1994-09-01	Landolfi	Applicant
US5359035(A)	1994-10-01	Habermann	Applicant
US5399346(A)	1995-03-01	Anderson et al.	Applicant
US5428130(A)	1995-06-01	Capon et al.	Applicant
US5441868(A)	1995-08-01	Lin	Applicant
US5457038(A)	1995-10-01	Trinchieri et al.	Applicant
US5480981(A)	1996-01-01	Goodwin et al.	Applicant
US5514582(A)	1996-05-01	Capon et al.	Applicant
US5538866(A)	1996-07-01	Israeli et al.	Applicant
US5541087(A)	1996-07-01	Lo et al.	Applicant
US5543297(A)	1996-08-01	Cromlish et al.	Applicant
US5547933(A)	1996-08-01	Lin	Applicant
US5552524(A)	1996-09-01	Basinski et al.	Applicant
US5585089(A)	1996-12-01	Queen et al.	Applicant
US5589466(A)	1996-12-01	Felgner et al.	Applicant
US5601819(A)	1997-02-01	Wong et al.	Applicant
US5609846(A)	1997-03-01	Goldenberg	Applicant
US5614184(A)	1997-03-01	Sytkowski et al.	Applicant
US5618698(A)	1997-04-01	Lin	Applicant
US5624821(A)	1997-04-01	Winter et al.	Applicant
US5639725(A)	1997-06-01	O'Reilly et al.	Applicant
US5645835(A)	1997-07-01	Fell, Jr. et al.	Applicant
US5650150(A)	1997-07-01	Gillies	Applicant
US5650492(A)	1997-07-01	Gately et al.	Applicant
US5667776(A)	1997-09-01	Zimmerman et al.	Applicant
US5679543(A)	1997-10-01	Lawlis	Applicant
US5688679(A)	1997-11-01	Powell	Applicant
US5691309(A)	1997-11-01	Basinski et al.	Applicant
US5709859(A)	1998-01-01	Aruffo et al.	Applicant
US5712120(A)	1998-01-01	Rodriguez et al.	Applicant
US5719266(A)	1998-02-01	DiMarchi et al.	Applicant
US5723125(A)	1998-03-01	Chang et al.	Applicant
US5726044(A)	1998-03-01	Lo et al.	Applicant
US5728552(A)	1998-03-01	Fujisawa et al.	Applicant
US5733876(A)	1998-03-01	O'Reilly et al.	Applicant
US5738852(A)	1998-04-01	Robinson et al.	Applicant
US5756349(A)	1998-05-01	Lin	Applicant
US5756461(A)	1998-05-01	Stephens	Applicant
US5759551(A)	1998-06-01	Ladd et al.	Applicant
US5770195(A)	1998-06-01	Hudziak et al.	Applicant
US5795779(A)	1998-08-01	McCormick	Applicant
US5800810(A)	1998-09-01	Doyle et al.	Applicant
US5807715(A)	1998-09-01	Morrison et al.	Applicant
US5827516(A)	1998-10-01	Urban et al.	Applicant
US5827703(A)	1998-10-01	Debs et al.	Applicant
US5837682(A)	1998-11-01	Folkman et al.	Applicant
US5837821(A)	1998-11-01	Wu et al.	Applicant
US5843423(A)	1998-12-01	Lyman et al.	Applicant
US5854205(A)	1998-12-01	O'Reilly et al.	Applicant
US5856298(A)	1999-01-01	Strickland	Applicant
US5858347(A)	1999-01-01	Bauer et al.	Applicant
US5885795(A)	1999-03-01	O'Reilly et al.	Applicant
US5886178(A)	1999-03-01	Allen et al.	Applicant
US5888772(A)	1999-03-01	Okasinski et al.	Applicant
US5891680(A)	1999-04-01	Lieschke et al.	Applicant
US5908626(A)	1999-06-01	Chang et al.	Applicant
US5922685(A)	1999-07-01	Rakhmilevich et al.	Applicant
US5955422(A)	1999-09-01	Lin	Applicant
US5994104(A)	1999-11-01	Anderson et al.	Applicant
US5994126(A)	1999-11-01	Steinman et al.	Applicant
US6080409(A)	2000-06-01	Laus et al.	Applicant
US6086875(A)	2000-07-01	Blumberg et al.	Applicant
US6100387(A)	2000-08-01	Herrmann et al.	Applicant
US6169070(B1)	2001-01-01	Chen et al.	Applicant
US6171588(B1)	2001-01-01	Carron et al.	Applicant
US6231536(B1)	2001-05-01	Lentz	Applicant
US6277375(B1)	2001-08-01	Ward	Applicant
US6281010(B1)	2001-08-01	Gao et al.	Applicant
US6284536(B1)	2001-09-01	Morrison et al.	Applicant
US6291158(B1)	2001-09-01	Winter et al.	Applicant
US6309636(B1)	2001-10-01	do Couto et al.	Examiner
US6335176(B1)	2002-01-01	Inglese et al.	Applicant
US6340742(B1)	2002-01-01	Burg et al.	Applicant
US6348192(B1)	2002-02-01	Chan et al.	Applicant
US6406689(B1)	2002-06-01	Falkenberg et al.	Applicant
US6429199(B1)	2002-08-01	Krieg et al.	Applicant
US6444792(B1)	2002-09-01	Gray et al.	Applicant
US6475717(B1)	2002-11-01	Enssle et al.	Applicant
US6485726(B1)	2002-11-01	Blumberg et al.	Applicant
US6500641(B1)	2002-12-01	Chen et al.	Applicant
US6506405(B1)	2003-01-01	Desai et al.	Applicant
US6551592(B2)	2003-04-01	Lindhofer et al.	Applicant
US6583272(B1)	2003-06-01	Bailon	Applicant
US6586398(B1)	2003-07-01	Kinstler et al.	Applicant
US6617135(B1)	2003-09-01	Gillies et al.	Applicant
US6627615(B1)	2003-09-01	Debs et al.	Applicant
US6646113(B1)	2003-11-01	Dreyfuss et al.	Applicant
US6777540(B1)	2004-08-01	Okumura et al.	Examiner
US2001/0053539(A1)	2001-12-01	Lauffer et al.	Applicant
US2002/0037558(A1)	2002-03-01	Lo et al.	Applicant
US2002/0081664(A1)	2002-06-01	Lo et al.	Applicant
US2002/0142374(A1)	2002-10-01	Gallo et al.	Applicant
US2002/0146388(A1)	2002-10-01	Gillies	Applicant
US2002/0147311(A1)	2002-10-01	Gillies et al.	Applicant
US2002/0192222(A1)	2002-12-01	Blumberg et al.	Applicant
US2002/0193570(A1)	2002-12-01	Gillies et al.	Applicant
US2003/0003529(A1)	2003-01-01	Bayer	Applicant
US2003/0012789(A1)	2003-01-01	Blumberg et al.	Applicant
US2003/0044423(A1)	2003-03-01	Gillies et al.	Applicant
US2003/0049227(A1)	2003-03-01	Gillies et al.	Applicant
US2003/0105294(A1)	2003-06-01	Gillies et al.	Applicant
US2003/0139365(A1)	2003-07-01	Lo et al.	Applicant
US2003/0139575(A1)	2003-07-01	Gillies	Applicant
US2003/0157054(A1)	2003-08-01	Gillies et al.	Applicant
US2003/0166163(A1)	2003-09-01	Gillies	Applicant
US2003/0166877(A1)	2003-09-01	Gillies et al.	Applicant
US2004/0013640(A1)	2004-01-01	Zardi et al.	Applicant
US2004/0033210(A1)	2004-02-01	Gillies	Applicant
US2004/0043457(A1)	2004-03-01	Schumacher et al.	Applicant
US2004/0053366(A1)	2004-03-01	Lo et al.	Applicant
US2004/0072299(A1)	2004-04-01	Gillies et al.	Applicant
US2004/0082039(A1)	2004-04-01	Gillies et al.	Applicant
AU21725/88	1989-03-01		Applicant
CN93100115.3	1993-07-01		Applicant
DE3712985	1988-11-01		Applicant
EP158198(A1)	1985-10-01		Applicant
EP211769(A2)	1987-02-01		Applicant
EP237019(A2)	1987-09-01		Applicant
EP256714(A2)	1988-02-01		Applicant
EP294703(A2)	1988-12-01		Applicant
EP308936(B1)	1989-03-01		Applicant
EP314317(B1)	1989-05-01		Applicant
EP318554(B1)	1989-06-01		Applicant
EP319012(A2)	1989-06-01		Applicant
EP326120(B1)	1989-08-01		Applicant
EP350230(A2)	1990-01-01		Applicant
EP375562(B1)	1990-06-01		Applicant
EP396387(A2)	1990-11-01		Applicant
EP439095(A2)	1991-07-01		Applicant
EP511747(A1)	1992-11-01		Applicant
EP519596(A1)	1992-12-01		Applicant
EP601043(B1)	1994-06-01		Applicant
EP640619(A1)	1995-03-01		Applicant
EP668353(A1)	1995-08-01		Applicant
EP699755(A2)	1996-03-01		Applicant
EP428596(B1)	1996-04-01		Applicant
EP706799(A2)	1996-04-01		Applicant
EP428267(B1)	1996-12-01		Applicant
EP790309(A1)	1997-08-01		Applicant
EP433827(B1)	1998-03-01		Applicant
EP668351(B1)	1999-09-01		Applicant
EP1088888(A1)	2001-04-01		Applicant
GB2188638	1987-10-01		Applicant
GB2292382(A)	1996-02-01		Applicant
JP63-267278	1988-11-01		Applicant
JP63-267296	1988-11-01		Applicant
WO86/01533	1986-03-01		Applicant
WO88/00052	1988-01-01		Applicant
WO88/09344	1988-12-01		Applicant
WO89/02922	1989-04-01		Applicant
WO89/09620	1989-10-01		Applicant
WO90/03801	1990-04-01		Applicant
WO91/00360	1991-01-01		Applicant
WO91/04329	1991-04-01		Applicant
WO91/08298	1991-06-01		Applicant
WO91/13166	1991-09-01		Applicant
WO91/14438	1991-10-01		Applicant
WO92/02240	1992-02-01		Applicant
WO92/08801	1992-05-01		Applicant
WO95/08495	1992-05-01		Applicant
WO92/10755	1992-06-01		Applicant
WO92/16562	1992-10-01		Applicant
WO93/03157	1993-02-01		Applicant
WO93/10229	1993-05-01		Applicant
WO93/20185	1993-10-01		Applicant
WO94/24160	1994-10-01		Applicant
WO94/25055	1994-11-01		Applicant
WO94/25609	1994-11-01		Applicant
WO95/05468	1995-02-01		Applicant
WO95/21258	1995-08-01		Applicant
WO95/28427	1995-10-01		Applicant
WO95/31483	1995-11-01		Applicant
WO96/04388	1996-02-01		Applicant
WO96/05309	1996-02-01		Applicant
WO96/08570	1996-03-01		Applicant
WO96/18412	1996-06-01		Applicant
WO96/31526	1996-10-01		Applicant
WO96/40792	1996-12-01		Applicant
WO97/00317	1997-01-01		Applicant
WO97/00319	1997-01-01		Applicant
WO97/15666	1997-05-01		Applicant
WO97/20062	1997-06-01		Applicant
WO97/24137	1997-07-01		Applicant
WO97/24440	1997-07-01		Applicant
WO97/26335	1997-07-01		Applicant
WO97/30089	1997-08-01		Applicant
WO97/33617	1997-09-01		Applicant
WO97/33619	1997-09-01		Applicant
WO97/34631	1997-09-01		Applicant
WO97/43316	1997-11-01		Applicant
WO98/00127	1998-01-01		Applicant
WO98/06752	1998-02-01		Applicant
WO98/28427	1998-07-01		Applicant
WO98/30706	1998-07-01		Applicant
WO98/46257	1998-10-01		Applicant
WO98/52796	1998-11-01		Applicant
WO98/59244	1998-12-01		Applicant
WO99/02709	1999-01-01		Applicant
WO99/03887	1999-01-01		Applicant
WO99/29732	1999-06-01		Applicant
WO99/43713	1999-09-01		Applicant
WO99/52562	1999-10-01		Applicant
WO99/53958	1999-10-01		Applicant
WO99/60128	1999-11-01		Applicant
WO99/62944	1999-12-01		Applicant
WO99/66054	1999-12-01		Applicant
WO/01822	2000-01-01		Applicant
WO/11033	2000-03-01		Applicant
WO/24893	2000-05-01		Applicant
WO/34317	2000-06-01		Applicant
WO/40615	2000-07-01		Applicant
WO/68376	2000-11-01		Applicant
WO/69913	2000-11-01		Applicant
WO/78334	2000-12-01		Applicant
WO1/07081	2001-02-01		Applicant
WO1/10912	2001-02-01		Applicant
WO1/36489	2001-05-01		Applicant
WO1/58957	2001-08-01		Applicant
WO2/02143	2002-01-01		Applicant
WO2/066514	2002-08-01		Applicant
WO2/069232	2002-09-01		Applicant
WO2/072605	2002-09-01		Applicant
WO2/074783	2002-09-01		Applicant
WO2/079232	2002-10-01		Applicant
WO2/079415	2002-10-01		Applicant
WO2/090566	2002-11-01		Applicant
WO3/015697	2003-02-01		Applicant
WO3/048334	2003-06-01		Applicant
WO3/077834	2003-09-01		Applicant

Non-Patent Literature (429)

Alberts et al., The Cell 2002, Garland Science, 4th edition, esp. p. 161: Figure 3-42.Examiner

Demirci and Li, 2004, Cell Mol. Immunol., 1(2):123-128 (abstract).Examiner

U.S. Appl. No. 07/348,237, May 5, 1989, Rosenblum et al.Applicant

Abaza et al., (1992), “Effects of Amino Acid Substitutions Outside an Antigenic Site on Protein Binding to Monoclonal Antibodies of Predetermined Specificity Obtained by Peptide Immunization: Demonstration with Region 94-100 (Antigenic Site 3) of Myoglobin,” Journal of Protein Chemistry, 11(5):433-444.Applicant

Abstract XP-002116766, Lupulescu, (1996), “Prostaglandins, Their Inhibitors and Cancer,” Prostaglandins, Leukotrienes and Essential Fatty Acids, 54(2):83-94.Applicant

Afonso et al., (1994), “The Adjuvant Effect of Interleukin-12 in a Vaccine Against Leishmania Major,” Science, 263:235-237.Applicant

Angal et al., (1993), “A Single Amino Acid Substitution Abolishes the Heterogeneity of Chimeric Mouse/Human (IgG4) Antibody,” Molecular Immunology, 30(1):105-108.Applicant

Arenberg et al., (1996), “Interferon-γ-inducible Protein 10 (IP-10) is an Angiostatic Factor that Inhibits Human Non-small Cell Lung Cancer (NSCLC) Tumorigenesis and Spontaneous Metastases,” J. Exp. Med., 184:981-992.Applicant

Bacha et al., (1988), “Interleukin 2 Receptor-Targeted Cytotoxicity: Interleukin 2 Receptor-mediated Action of a Diphtheria Toxin-related Interleukin 2 Fusion Protein,” J. Exp. Med., 167:612-622.Applicant

Bachelot et al., (1998), “Retrovirus-Mediated Gene Tranfer of an Angiostatin-Endostatin Fusion Protein with Enhanced Anti-Tumor Properties In Vivo,” Proceedings of the Annual Meeting of the American Association for Cancer Research, 39:271, Abstract #1856 (XP-002089298).Applicant

Barnett et al., (1994), “Purification, Characterization and Selective Inhibition of Human Prostaglandin G/H Synthase 1 and 2 Expressed in the Baculovirus System,” Biochimica et Biophysica Acta, 1209:130-139.Applicant

Baselga et al., (1998), “Recombinant Humanized Anti-HER2 Antibody (Herceptin ™) Enhances the Antitumor Activity of Paclitaxel and Doxorubicin against HER3/neu Overexpressing Human Breast Cancer Xenogratfs,” Cancer Research, 58:2825-2831.Applicant

Batova et al., (1999), “The Ch14.18-GM-CSF Fusion Protein Is Effective at Mediating Antibody-dependent Cellular Cytotoxicity and Complement-dependent Cytotoxicity in Vitro,” Clinical Cancer Research, 5:4259-4263.Applicant

Batra et al., (1993), “Insertion of Constant Region Domains of Human IgG1 into CD4-PE40 Increases Its Plasma Half-Life,” Molecular Immunology, 30(4):379-386.Applicant

Becker et al., (1996), “An Antibody-Interleukin 2 Fusion Protein Overcomes Tumor Heterogeneity by Induction of a Cellular Immune Response,” Proc. Natl. Acad. Sci. USA, 93:7826-7831.Applicant

Becker et al., (1996), “Eradication of Human Hepatic and Pulmonary Melanoma Metastases in SCID Mice by Antibody-interleukin 2 Fusion Proteins,” Proc. Natl. Acad. Sci. USA, 93:2702-2707.Applicant

Becker et al., (1996), “Long-lived and Transferable Tumor Immunity in Mice after Targeted Interleukin-2 Therapy,” J. Clin. Invest., 98(12):2801-2804.Applicant

Becker et al., (1996), “T Cell-mediated Eradication of Murine Metastatic Melanoma Induced by Targeted Interleukin-2 Therapy,” J. Exp. Med., 183(50):2361-2366.Applicant

Beutler et al., (1988), “Tumor Necrosis, Cachexia, Shock, and Inflammation: A Common Mediator,” Annual Rev. Biochem., 57:505-518.Applicant

Bissery et al., (1997), “The Taxoids,” in Cancer Therapeutics: Experimental and Clinical Agents, Teicher (ed.), pp. 175-193.Applicant

Bitonti et al., (2002), “Transepithelial Absorption of an Erythropoietin-Fc Fusion Protein After Delivery to the Central Airways,” Respiratory Drug Delivery, 8:309-312.Applicant

Bjorn et al., (1985), “Evaluation of Monoclonal Antibodies for the Development of Breast Cancer Immunotoxins,” Cancer Research, 45:1214-1221.Applicant

Boehm et al., (1997), “Antiangiogenic Therapy of Experimental Cancer Does Not Induce Acquired Drug Resistance,” Nature, 390:404-407.Applicant

Boehm et al., (1998), “Zinc-Binding of Endostatin Is Essential for Its Antiangiogenic Activity,” Biochemical and Biophysical Research Communications, 252:190-194.Applicant

Boissel et al., (1993), “Erythropoietin Structure-Function Relationships: Mutant Proteins that Test a Model of Tertiary Structure,” The Journal of Biological Chemistry, 268(21):15983-15993.Applicant

Briggs et al., (1974), “Hepatic Clearance of Intact and Desialylated Erythropoietin,” American Journal of Physiology, 227(6):1385-1388.Applicant

Brooks et al., (1994), “Integrin ανβ3 Antagonists Promote Tumor Regression by Inducing Apoptosis of Angiogenic Blood Vessels,” Cell, 79:1157-1164.Applicant

Buchli et al., (1993), “Structural and Biologic Properties of a Human Aspartic Acid-126 Interleukin-2 Analog,” Archives of Biochemistry and Biophysics, 307(2):411-415.Applicant

Burgess et al., (1990), “Possible Dissociation of the Heparin-binding and Mitogenic Activities of Heparin-Binding (Acidic Fibroblast) Growth Factor-1 from Its Receptor-binding Activities by Site-directed Mutagenesis of a Single Lysine Residue,” Journal of Cell Biology, 111:2129-2138.Applicant

Canfield et al., (1991), “The Binding Affinity of Human IgG for its High Affinity Fc Receptor is Determined by Multiple Amino Acids in the CH2 Domain and Is Modulated by the Hinge Region,” J. Exp. Med., 173(6):1483-1491.Applicant

Cao et al., (1996), “Kringle Domains of Human Angiostatin: Characterization of the Anti-Proliferative Activity of Endothelial Cells,” The Journal of Biological Chemistry, 271(46):29461-29467.Applicant

Cao et al., (1997), “Kringle 5 of Plasminogen is a Novel Inhibitor of Endothelial Cell Growth,” The Journal of Biological Chemistry, 272(36):22924-22928.Applicant

Capon et al., (1989), “Designing CD4 Immunoadhesins for AIDS Therapy,” Nature, 337:525-531.Applicant

Caton et al., (1986), “Structural and Functional Implications of a Restricted Antibody Response to a Defined Antigenic Region on the Influenza Virus Hemagglutinin,” The EMBO Journal, 5(7):1577-1587.Applicant

Chan et al., (1991), “Induction of Interferon γ Production by Natural Killer Cell Stimulatory Factor: Characterization of the Responder Cells and Synergy with Other Inducers,” J. Exp. Med., 173: 869-879.Applicant

Chang et al., (1989), “Overview of Interleukin-2 as an Immunotherapeutic Agent,” Seminars in Surgical Oncology, 5:385-390.Applicant

Chang et al., (1996), “A Point Mutation in Interleukin-2 that Alters Ligand Internalization,” Journal of Biological Chemistry, 271(23):13349-13355.Applicant

Chapman et al., (1994), “Mapping Effector Functions of a Monoclonal Antibody to GD3 by Characterization of a Mouse-Human Chimeric Antibody,” Cancer Immuno. Immunother., 39:198-204.Applicant

Chaudhary et al., (1988), “Selective Killing of HIV-infected Cells by Recombinant Human CD4-Pseudomonas Exotoxin Hybrid Protein,” Nature, 335:370-372.Applicant

Chaudhary et al., (1989), “A Recombinant Immunotoxin Consisting of Two Antibody Variable Domains Fused to Pseudomonas Exotoxin,” Nature, 339:394-397.Applicant

Chen et al., (1997),“Eradication of Murine Bladder Carcinoma by Intratumor Injection of a Bicistronic Adenoviral Vector Carrying cDNAs for the IL-12 Heterodimer and Its Inhibition by the IL-12 p40 Subunit Homodiner,” Journal of Immunology, 159(1):351-358.Applicant

Cheon et al., (1994), “High-affinity Binding Sites for Related Fibroblast Growth Factor Ligands Reside Within Different Receptor Immunoglobulin-like Domains,” Proc. Natl. Acad. Sci. USA, 91: 989-993.Applicant

Chuang et al., (1993), “Effect of New Investigational Drug Taxol on Oncolytic Activity and Stimulation of Human Lymphocytes,” Gynecologic Oncology, 49:291-298.Applicant

Chuang et al., (1994), “Alteration of Lymphocyte Microtubule Assembly, Cytotoxicity, and Activation by the Anticancer Drug Taxol,” Cancer Research, 54:1286-1291.Applicant

Cohen et al., (1996), “Human Leptin Characterization,” Nature, 382:589.Applicant

Cole et al., (1997), “Human IgG2 Variants of Chimeric Anti-CD3 Are Nonmitogenic to T Cells,” Journal of Immunology, 159:3613-3621.Applicant

Collins et al., (1988), “Identification of Specific Residues of Human Interleukin 2 That Affect Binding to the 70-kDa Subunit (p70) of the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 85:7709-7713.Applicant

Colombo et al., (1996), “Amount of Interleukin 12 Available at the Tumor Site is Critical for Tumor Regression,” Cancer Research, 56:2531-2534.Applicant

Conner et al., (2004), “Ex vivo Evaluation of Anti-EpCAM Immunocytokine huKS-IL2 in Ovarian Cancer,” J. Immunotherapy, 27:211-219.Applicant

Cruse et al., (eds.), (1995), Illustrated Dictionary of Immunology, pp. 156-158, CRC Press, NY.Applicant

D'Amato et al., (1994), “Thalidomide is an Inhibitor of Angiogenesis,” Proc. Natl. Acad. Sci. USA, 91:4082-4085.Applicant

D'Andrea et al., (1992), “Production of Natural Killer Cell Stimulatory Factor (Interleukin 12) by Peripheral Blood Mononuclear Cells,” J. Exp. Med., 176:1387-1398.Applicant

Darling et al., (2002), “Glycosylation of Erythropoietin Affects Receptor Binding Kinetics: Role of Electrostatic Interactions,” Biochemistry, 41:14524-14531.Applicant

Davis et al., (2003), “Immunocytokines: Amplification of Anti-cancer Immunity,” Cancer Immunol. Immunother., 52:297-308.Applicant

de la Salle et al., (1996), “FcγR on Human Dendritic Cells,” in Human IgG Receptors, pp. 39-55, van de Winkel et al. (eds.), R.G. Landes Co.Applicant

Ding et al., (1988), “Zinc-Dependent Dimers Observed in Crystals of Human Endostatin,” Proc. Natl. Acad. Sci. USA, 95:10443-10448.Applicant

Dolman et al., (1998), “Suppression of Human Prostate Carcinoma Metastases in Severe Combined Immunodeficient Mice by Interleukin 2 Immunocytokine Therapy,” Clin. Cancer Research., 4(10):2551-2557.Applicant

Dorai et al., (1991), “Agylcosylated Chimeric Mouse/Human IgG1 Antibody Retains Some Effector Function,” Hybridoma, 10(2):211-217.Applicant

Dorai et al., (1992), “Role of Inter-Heavy and Light Chain Disulfide Bonds in the Effector Functions of Human IgG1,” Molecular Immunology, 29(12):1487-1491.Applicant

Duncan et al., (1988), “The Binding Site for Clq on IgG,” Nature, 332:738-740.Applicant

Earnest et al., (1992), “Piroxicam and Other Cyclooxygenase Inhibitors: Potential for Cancer Chemoprevention,” J. Cell. Biochem., Supp., 161:156-166.Applicant

Egrie et al., (2001), “Development and Characterization of Novel Erythropoiesis Stimulating Protein (NESP),” Nephrol. Dial. Transplant., 16(Supp 3):3-13.Applicant

Eisenthal, (1990), “Indomethacin Up-regulates the Generation of Lymphokine-Activated Killer-cell Activity and Antibody-dependent Cellular Cytotoxicity Mediated by Interleukin-2,” Cancer Immunol. Immunother., 31:342-348.Applicant

Elliott et al., (1996), “Fine-Structure Epitope Mapping of Antierythropoietin Monoclonal Antibodies Reveals a Model of Recombinant Human Erythropoietin Structure,” Blood, 87(7):2702-2713.Applicant

Elliott et al., (1997), “Mapping of the Active Site of Recombinant Human Erythropoietin,” Blood, 89(2):493-502.Applicant

Fell et al., (1991), “Genetic Construction and Characterization of A Fusion Protein Consisting of a Chimeric F(ab') with Specificity for Carcinomas and Human IL-2,” J. Immunology, 146(7):2446-2452.Applicant

Fell et al., (1992), “Chimeric L6 Anti-tumor Antibody: Genomic Construction, Expression, and Characterization of the Antigen Binding Site,” J. Biological Chemistry, 267:15552-15558.Applicant

Fibi et al., (1995), “N- and O-Glycosylation Muteins of Recombinant Human Erythropoietin Secreted From BHK-21 Cells,” Blood, 85(5):1229-1236.Applicant

Friedman et al., (1998), “Leptin and the Regulation of Body Weight in Mammals,” Nature, 395:763-770.Applicant

Frost et al., (1997), “A Phase 1/1B Trial of Murine Monoclonal Anti-GD2 Antibody 14.G2a Plus Interleukin-2 in Children with Refractory Neuroblastoma,” Cancer, 80(2):317-333.Applicant

Gan et al., (1999), “Specific Enzyme-linked Immunosorbent Assays for Quantitation of Antibody-cytokine Fusion Proteins,” Clinical and Diagnostic Laboratory Immunology, 6(2):236-42.Applicant

Gasson et al., (1984), “Purified Human Granulocyte Colony-Stimulating Factor: Direct Action on Neutrophils,” Science, 226:1339-1342.Applicant

Gately et al., (1998), “The Interleukin-12/Interleukin-12-Receptor System: Role in Normal and Pathologic Immune Responses,” Annu. Rev. Immunol., 16:495-521.Applicant

Gillessen et al., (1995), “Mouse Interleukin-12 (IL-12) p40 Homodimer: A Potent IL-12 Antagonist,” Eur. J. Immunol., 25:200-206.Applicant

Gillies et al., (1989), “Expression of Human Anti-Tetanus Toxoid Antibody in Transfected Murine Myeloma Cells,” Bio/Technology, 7:799-804.Applicant

Gillies et al., (1989), “High-Level Expression of Chimeric Antibodies Using Adapted cDNA Variable Region Cassettes,” J. Immunol. Methods, 125:191-202.Applicant

Gillies et al., (1990), “Antigen Binding and Biological Activities of Engineered Mutant Chimeric Antibodies with Human Tumor Specificities,” Hum. Antibod. Hybridomas, 1(1):47-54.Applicant

Gillies et al., (1991), “Expression of Genetically Engineered Immunoconjugates of Lymphotoxin and a Chimeric Anti-ganglioside GD2 Antibody,” Hybridoma., 10(3):347-56.Applicant

Gillies et al., (1991), “Targeting Human Cytotoxic T Lymphocytes to Kill Heterologous Epidermal Growth Factor Receptor-Bearing Tumor Cells: Tumor-Infiltrating Lymphocyte/Hormone Receptor/Recombinant Antibody,” J. Immunology, 146(3):1067-1071.Applicant

Gillies et al., (1992), “Antibody-Targeted Interleukin 2 Stimulates T-Cell Killing of Autologous Tumor Cells,” Proc. Natl. Acad. Sci. USA , 89:1428-1432.Applicant

Gillies et al., (1993), “Biological Activity and In Vivo Clearance of Antitumor Antibody/Cytokine Fusion Proteins,” Bioconjugate Chem., 4(3):230-235.Applicant

Gillies et al., (1998), “Antibody-IL-12 Fusion Proteins are Effective in SCID Mouse Models of Prostate and Colon Carcinoma Metastases,” J. Immunology, 160:6195-6203.Applicant

Gillies et al., (1999), “Improving the Efficacy of Antibody-Interleukin 2 Fusion Proteins by Reducing Their Interaction with Fc Receptors,” Cancer Research, 59:2159-2166.Applicant

Gillies et al., (2002), “Bi-functional Cytokine Fusion Proteins for Gene Therapy and Antibody-targeted Treatment of Cancer,” Cancer Immunol. Immunother., 51(8):449-60.Applicant

Gillies et al., (2002), “Improved Circulating Half-life and Efficacy of an Antibody-interleukin 2 Immunocytokine Based on Reduced Intracellular Proteolysis,” Clin. Cancer Research, 8(1):210-216.Applicant

Gillis et al., (1978), “T Cell Growth Factor: Parameters of Production And A Quantitative Microassay for Activity,” J. Immunology, 120(6):2027-2032.Applicant

Goeddel et al., (1986), “Tumor Necrosis Factors: Gene Stucture and Biological Activities,” Cold Spring Harb. Symp. Quant. Biol., 51:597-609.Applicant

Greene et al., (1975), “Neuronal Properties of Hybrid Neuroblastoma X Sympathetic Ganglion Cells,” Proc. Natl. Acad. Sci. USA, 72(12):4923-4927.Applicant

Gren et al., (1983), “A New Type of Leukocytic Interferon,” English Translation of Dokl. Akad. Nauk. SSSR., 269(4):986-990.Applicant

Griffon-Etienne et al., (1999), “Taxane-induced Apoptosis Decompresses Blood Vessels and Lowers Interstitial Fluid Pressure in Solid Tumors: Clinical Implications,” Cancer Research, 59:3776-3782.Applicant

Grimaldi et al., (1989), “The t(5;14) Chromosomal Translocation in a Case of Acute Lymphocytic Leukemia Joins the Interleukin-3 Gene to the Immunoglobulin Heavy Chain Gene,” Blood, 73(8):2081-2085.Applicant

Guyre et al., (1997), “Increased Potency of Fc-receptor-targeted Antigens,” Cancer Immunol. Immunother., 45:146-148.Applicant

Hammerling et al., (1996), “In Vitro Bioassay for Human Erythropoietin Based on Proliferative Stimulation of an Erythroid Cell Line and Analysis of Carbohydrate-dependent Microheterogeneity,” Journal of Pharmaceutical and Biomedical Analysis, 14:1455-1469.Applicant

Handgretinger et al., (1995), “A Phase I Study of Human/Mouse Chimeric Anti-ganglioside GD2 Antibody ch14.18 in Patients with Neuroblastoma,” European J. Cancer, 31A(2):261-267.Applicant

Hank et al., (1996), “Activation of Human Effector Cells by a Tumor Reactive Recombinant Anti-ganglioside GD2 Interleukin-2 Fusion Protein (ch14.18-IL2),” Clin Cancer Research, 2(12):1951-1959.Applicant

Hank et al., (2003), “Determination of Peak Serum Levels and Immune Response to the Humanized Anti-ganglioside Antibody-interleukin-2 Immunocytokine,” in Methods in Molecular Medicine, vol. 85: Novel Anticancer Drug Protocols, Buolamwini et al., (eds.), pp. 123-131, Humana Press Inc., Totowana, NJ.Applicant

Haraguchi, (1994), “Isolation of GD3 Synthase Gene by Expression Cloning of GM3 α-2,8-sialyltransferase cDNA using anti-GD2 Monoclonal Antibody,” Proc. Natl. Acad. Sci. USA, 91(22):10455-10459.Applicant

Harris et al., (1993), “Therapeutic Antibodies—the Coming of Age,” Trends in Biotechnology, 11:42-44.Applicant

Harris, (1995), “Processing of C-terminal Lysine and Arginine Residues of Proteins Isolated from Mammalian Cell Culture,” J. Chromatography A, 705:129-134.Applicant

Harvill et al., (1995), “An IgG3-IL2 Fusion Protein Activates Complement, Binds FcγRI, Generates LAK Activity and Shows Enhanced Binding to the High Affinity IL-2R,” Immunotechnology, 1:95-105.Applicant

Harvill et al., (1996), “In Vivo Properties of an IgG3-IL-2 Fusion Protein: A General Strategy for Immune Potentiation,” J. Immunology, 157(7):3165-3170.Applicant

Hazama et al., (1993), “Adjuvant-Independent Enhanced Immune Responses to Recombinant Herpes Simplex Virus Type 1 Glycoprotein D by Fusion with Biologically Active Interleukin-2,” Vaccine, 11(6):629-636.Applicant

He et al., (1998), “Humanization and Pharmacokinetics of a Monoclonal Antibody with Specificity for Both E- and P-Selectin,” J. Immunology, 160:1029-1035.Applicant

Heijnen et al., (1996), “Antigen Targeting to Myeloid-specific Human FcγRI/CD64 Triggers Enhanced Antibody Responses in Transgenic Mice,” J. Clin. Invest., 97(2):331-338.Applicant

Heinzel et al., (1997), “In Vivo Production and Function of IL-12 p40 Homodimers,” J. Immunology, 158:4381-4388.Applicant

Hellstrom et al., (1986), “Antitumor Effects of L6, an IgG2a Antibody that Reacts with Most Human Carcinomas,” Proc. Natl. Acad. Sci. USA, 83: 7059-7063.Applicant

Henkart, (1985), “Mechanism of Lymphocyte-Mediated Cytotoxicity,” Ann. Rev. Immunol., 3:31-58.Applicant

Herrmann et al., (1989), “Hematopoietic Responses With Advanced Malignancy Treated With Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor,” Journal of Clinical Oncology, 7(2):159-167.Applicant

Hezareh et al., (2001), “Effector Function Activities of a Panel of Mutants of a Broadly Neutralizing Antibody against Human Immunodeficiency Virus Type 1,” J. Virology, 75(24):12161-12168.Applicant

Hohenester et al., (1998), “Crystal Structure of the Angiogenesis Inhibitor Endostatin at 1.5 Å Resolution,” EMBO Journal, 17(6):1656-1664.Applicant

Holden et al., (2001), “Augmentation of Anti-Tumor Activity of KS-IL2 Immunocytokine with Chemotherapeutic Agents,” Proceedings of the American Association for Cancer Research, 42:683, Abstract No. 3675 (XP-002195344).Applicant

Holden et al., (2001), “Augmentation of Antitumor Activity of an Antibody-Interleukin 2 Immunocytokine with Chemotherapeutic Agents,” Clinical Cancer Research, 7:2862-2869.Applicant

Hoogenboom et al., (1991), “Construction and Expression of Antibody-tumor Necrosis Factor Fusion Proteins,” Molecular Immunology, 28(9):1027-1037.Applicant

Hoogenboom et al., (1991), “Targeting of Tumor Necrosis Factor to Tumor Cells Secretion by Myeloma Cells of a Genetically Engineered Antibody-Tumor Necrosis Factor Hybrid Molecule,” Biochim. and Biophys. Acta, 1096(4):345-354 (Abstract).Applicant

Hornick et al., (1999), “Pretreatment with a Monoclonal Antibody/Interleukin-2 Fusion Protein Directed Against DNA Enhances the Delivery of Therapeutic Molecules to Solid Tumors,” Clin. Cancer Research, 5:51-60.Applicant

Hu et al., (1996), “A Chimeric Lym-1/Interleukin 2 Fusion for Increasing Tumor Vascular Permeability and Enhancing Antibody Uptake,” Cancer Research, 56:4998-5004.Applicant

Huck et al., (1986), “Sequence of a Human Immunoglobulin Gamma 3 Heavy Chain Constant Region Gene: Comparison With the Other Human Cγ genes,” Nucleic Acids Research, 14(4):1779-1789.Applicant

Hurn et al., (1980), “Production of Reagent Antibodies,” Methods in Enzymology, 70: 104-142.Applicant

Huse et al., (1989), “Generation of a Large Combinatorial Library of the Immunoglobulin Repertoire in Phage Lambda,” Science, 246:1275-1281.Applicant

Idusogie et al., (2000), “Mapping of the Clq Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc,” J. Immunology, 164(8):4178-4184.Applicant

Imboden et al., (2001), “The Level of MHC Class 1 Expression on Murine Adenocarcinoma Can Change the Antitumor Effector Mechanism of Immunocytokine Therapy,” Cancer Research,61(4):1500-7.Applicant

Ingber et al., (1990), “Synthetic Analogues of Fumagillin that Inhibit Angiogenesis and Suppress Tumour Growth,” Nature, 348:555-557.Applicant

Isenman et al., (1975), “The Structure and Function of Immunoglobulin Domains: II. The Importance of Interchain Disulfide Bonds and the Possible Role of Molecular Flexibility in the Interaction between Immunoglobulin G and Complement,” J. Immunology, 114(6):1726-1729.Applicant

Jones et al., (1986), “Replacing the Complementarity-determining Regions in a Human Antibody with Those from a Mouse,” Nature, 321:522-525.Applicant

Ju et al., (1987), “Structure-Function Analysis of Human Interleukin-2: Identification of Amino Acid Residues for Biological Activity,” Journal of Biological Chemistry, 262(12):5723-5731.Applicant

Jung et al., (1986), “Activation of Human Peripheral Blood Mononuclear Cells by Anti-T3: Killing of Tumor Target Cells Coated with Anti-target-anti-T3 Conjugates,” Proc. Natl. Acad. Sci. USA, 83:4479-4483.Applicant

Junghans et al., (1996), “The Protection Receptor IgG Catabolism is the B2-microglobulin-containing Neonatal Intestinal Transport Receptor,” Proc. Natl. Acad. Sci. USA, 93(11):5512-5516.Applicant

Kang et al., (1991), “Antibody Redesign by Chain Shuffling from Random Combinatorial Immunoglobulin Libraries,” Proc. Natl. Acad. Sci. USA, 88:11120-11123.Applicant

Kappel et al., (1992), “Regulating Gene Expression in Transgenic Animals,” Current Opinion in Biotechnology, 3:548-553.Applicant

Kato et al., (1997), “Mechanism for the Nonlinear Pharmacokinetics of Erythropoietin in Rats,” The Journal of Pharmacology and Experimental Therapeutics, 283:520-527.Applicant

Kato et al., (1998), “Pharmacokinetics of Erythopoietin in Genetically Anemic Mice,” Drug Metabolism and Disposition, 26(2):126-131.Applicant

Karpovsky et al., (1984), “Production of Target-Specific Effector Cells using Hetero-Cross Linked Aggregate Containing Anti-Target Cell and AntiFcγ Receptor Antibodies,” Journal of Experimental Medicine, 1609(6):1686-1701.Applicant

Kendra et al., (1999),“Pharmacokinetics and Stability of the ch14.18-Interleukin-2 Fusion Protein in Mice,” Cancer Immunol. Immunother., 48:219-229.Applicant

Kim et al., (1997),“An Ovalbumin-IL-12 Fusion Protein is More Effective than Ovalbumin Plus Free Recombinant IL-12 in Inducing a T Helper Cell Type 1-dominated Immune Response and Inhibiting Antigen-Specific IgE Production,” J. Immunology, 158(9):4137-4144.Applicant

Kim et al., (1999), “Cytokine Molecular Adjuvants Modulate Immune Responses Induced by DNA Vaccine Constructs for HIV-1 and SIV,” Journal of Interferon and Cytokine Research, 19:77-84.Applicant

Kitamura et al., (1989), “Establishment and Characterization of a Unique Human Cell Line that Proliferates Dependently on GM-CSF, IL-3, or Erythropoietin,” Journal of Cellular Physiology, 140:323-334.Applicant

Ko et al., (2004), “Safety, Pharmacokinetics, and Biological Pharmacodynamics of the Immunocytokine EMD 273066 (huKS-IL2),” J. Immunotherapy, 27:232-239.Applicant

Kranz et al., (1984), “Attachment of an Anti-receptor Antibody to Non-target Cells Renders Them Susceptible to Lysis by a Clone of Cytotoxic T Lymphocytes,” Proc. Natl. Acad. Sci. USA, 81:7922-7926.Applicant

Kuo et al., (2001), “Oligomerization-dependent Regulation of Motility and Morphogenesis by the Collagen XVIII NC1/Endostatin Domain,” Journal of Cell Biology, 152(6):1233-1246.Applicant

Kushner et al., (2001), “Phase II Trial of the Anti-GD2 Monoclonal Antibody 3F8 and Granulocyte-Macrophage Colony-Stimulating Factor for Neuroblastoma,” J. Clinical Oncology, 19(22):4189-94.Applicant

LaVallie et al., (1993), “Cloning and Functional Expression of a cDNA Encoding the Catalytic Subunit of Bovine Enterokinase,” Journal of Biological Chemistry, 268(31):23311-23317.Applicant

Lazar et al., (1988), “Transforming Growth Factor α: Mutation of Aspartic Acid 47 and Leucine 48 Results in Different Biological Activities,” Molecular and Cellular Biology, 8(3):1247-1252.Applicant

LeBerthon et al., (1991), “Enhanced Tumor Uptake of Macromolecules Induced by a Novel Vasoactive Interleukin 2 Immunoconjugate,” Cancer Research, 51:2694-2698.Applicant

Lieschke, et al., (1997), “Bioactive Murine and Human Interleukin-12 Fusion Proteins which Retain Antitumor Activity In Vivo,” Nature Biotechnology, 15(1):35-40.Applicant

Linsley et al., (1991), “CTLA-4 is a Second Receptor for B Cell Activation B7,” J. Exp. Med., 174(3):561-569.Applicant

Liu et al., (1985), “Heteroantibody Duplexes Target Cells for Lysis by Cytotoxic T Lymphocytes,” Proc. Natl. Acad. Sci. USA, 82:8648-8652.Applicant

Liu et al., (1988), “Hormone Conjugated with Antibody to CD3 Mediates Cytotoxic T Cell Lysis of Human Melanoma Cells,” Science, 239:395-398.Applicant

Liu et al., (1998), “Immunostimulatory CpG Oligodeoxynucleotides Enhance the Immune Response to Vaccine Strategies Involving Granulocyte-Macrophage Colony-Stimulating Factor,” Blood, 92(10):3730-3736.Applicant

Lo et al., (1992), “Expression and Secretion of an Assembled Tetrameric CH2-deleted Antibody in E. coli, ” Hum. Antibod. Hybridomas, 3:123-128.Applicant

Lo et al., (1998), “High Level Expression and Secretion of Fc-X Fusion Proteins in Mammalian Cells,” Protein Engineering, 11(6):495-500.Applicant

Locatelli et al., (2001), “Darbepoetin alfa Amgen,” Current Opinion in Investigational Drugs, 2:1097-1104.Applicant

Lode et al., (1997), “Targeted Interleukin-2 Therapy for Spontaneous Neuroblastoma Metastases to Bone Marrow,” J. Natl. Cancer Inst., 89(21):1586-94.Applicant

Lode et al., (1998), “Immunocytokines: A Promising Approach to Cancer Immunotherapy,” Pharmacol. Ther., 80(3):277-292.Applicant

Lode et al., (1998), “Natural Killer Cell-Mediated Eradication of Neuroblastoma Metastases to Bone Marrow by Targeted Interleukin-2 Therapy,” Blood, 91(5):1706-1715.Applicant

Lode et al., (1999), “Synergy Between an Antiangiogenic Integrin αν Antagonist and an Antibody-cytokine Fusion Protein Eradicates Spontaneous Tumor Metastases,” Proc. Natl. Acad. Sci. USA, 96:1591-1596.Applicant

Lode et al., (1999), “Tumor-targeted IL-2 Amplifies T Cell-mediated Immune Response Induced by Gene Therapy with Single-chain Il-12,” Proc. Natl. Acad. Sci. USA, 96:8591-8596.Applicant

Lode et al., (2000), “Amplification of T Cell Mediated Immune Responses by Antibody-Cytokine Fusion Proteins,” Immunological Investigations, 29(2):117-120.Applicant

Lode et al., (2000), “What To Do With Targeted IL-2,” Drugs of Today, 36(5):321-336.Applicant

Lode et al., (2000), “Melanoma Immunotherapy for Targeted IL-2 Depends on CD4(+) T-cell Help Mediated by CD40/CD40L Interaction,” J. Clin. Invest., 105(11):1623-30.Applicant

Macdougall, (2002), “Optimizing the Use of Erythropoietic Agents—Pharmacokinetics and Pharmacodynamic Considerations,” Nephrol. Dial. Transplant., 17 (Supp 5):66-70.Applicant

Maecker et al., (1997), “DNA Vaccination with Cytokine Fusion Constructs Biases the Immune Response to Ovalbumin,” Vaccine, 15(15):1687-1696.Applicant

Maloney et al., (1994), “Phase I Clinical Trial Using Escalating Single-Dose Infusion of Chimeric Anti-CD20 Monoclonal Antibody (IDEC-C2B8) in Patients with Recurrent B-Cell Lymphoma,” Blood, 84(8):2457-2466.Applicant

Mark et al., (1992), “Expression and Characterization of Hepatocyte Growth Factor Receptor-IgG Fusion Proteins,” Journal of Biological Chemistry, 267(36):26166-26171.Applicant

Martinotti et al., (1995), “CD4 T Cells Inhibit In Vivo the CD8-Mediated Immune Response Against Murine Colon Carcinoma Cells Transduced with Interleukin-12 Genes,” Eur. J. Immunol. 25:137-146.Applicant

Medesan et al., (1997), “Delineation of the Amino Acid Residues Involved in Transcytosis and Catabolism of Mouse IgG1,” J. Immunology, 158(5):2211-2217.Applicant

Metelitsa et al., (2002), “Antidisialoganglioside/granulocyte Macrophage-colony-stimulating Factor Fusion Protein Facilitates Neutrophil Antibody-dependent Cellular Cytotoxicity and Depends on FcγRII (CD32) and Mac-1 (CD11b/CD18) for Enhanced Effector Cell Adhesion and Azurophil Granule Exocytosis,” Blood, 99(11):4166-73.Applicant

Mestre et al., (1997), “Retinoids Suppress Epidermal Growth Factor-induced Transcription of Cyclooxygenase-2 in Human Oral Squamous Carcinoma Cells,” Cancer Research, 57:2890-2895.Applicant

Mosmann et al., (1989), “TH1 and TH2 Cells: Different Patterns of Lymphokine Secretion Lead to Different Functional Properties,” Ann. Rev. Immunol., 7:145-173.Applicant

Mott et al., (1995), “The Solution Structure of the F42A Mutant of Human Interleukin 2,” J. Mol. Biol., 247:979-994.Applicant

Mueller et al., (1990), “Enhancement of Antibody-Dependent Cytotoxicity With A Chimeric Anti-GD2 Antibody,” J. Immunology, 144(4):1382-1386.Applicant

Mueller et al., (1990), “Serum Half-Life and Tumor Localization of a Chimeric Antibody Deleted of the CH2 Domain and Directed Against the Disialoganglioside GD2,” Proc. Natl. Acad. Sci. USA., 87:5702-5705.Applicant

Mueller et al., (1997), “Humanized Porcine VCAM-specific Monoclonal Antibodies with Chimeric IgG2/G4 Constant Regions Block Human Leukocyte Binding to Porcine Endothelial Cells,” Molecular Immunology, 34(6):441-452.Applicant

Mullins et al., (1997), “Taxol-mediated Changes in Fibrosarcoma-induced Immune Cell Function: Modulation of Antitumor Activities,” Cancer Immunol. Immunother. 45:20-28.Applicant

Mullins et al., (1998), “Interleukin-12 Overcomes Paclitaxel-mediated Suppression of T-cell Proliferation,” Immunopharmacol. Immunotoxicol., 20(4):473-492.Applicant

Murphy et al., (1986), “Genetic Construction, Expression, and Melanoma-selective Cytotoxicity of a Diphtheria Toxin-related α-melanocyte-stimulating Hormone Fusion Protein,” Proc. Natl. Acad. Sci. USA, 83:8258-8262.Applicant

Murphy, (1988), “Diphtheria-related Peptide Hormone Gene Fusions: A Molecular Gene Approach to Chimeric Toxin Development,” in Immunotoxins, pp. 123-140, Frankel (ed.), Kluwer Acad. Pub.Applicant

Naramura et al., (1993), “Therapeutic Potential of Chimeric and Murine Anti-(Epidermal Growth Factor Receptor) Antibodies in a Metastasis Model for Human Melanoma,” Cancer Immuno. Immunother., 37:343-349.Applicant

Naramura et al., (1994), “Mechanisms of Cellular Cytotoxicity Mediated by a Recombinant Antibody-IL2 Fusion Protein Against Human Melanoma Cells,” Immunology Letters, 39:91-99.Applicant

Neal et al., (2003), “NXS2 Murine Neuroblastomas Express Increased Levels of MHC Class I Antigens upon Recurrence Following NK-dependent Immunotherapy,” Cancer Immunol. Immunother., 53:41-52.Applicant

Nedwin et al., (1985), “Human Lymphotoxin and Tumor Necrosis Factor Genes: Structure, Homology and Chromosomal Localization,” Nucleic Acids Research, 13(17):6361-6373.Applicant

Netti et al., (1995), “Time-dependent Behavior of Interstitial Fluid Pressure in Solid Tumors: Implications for Drug Delivery,” Cancer Research, 55:5451-5458.Applicant

Netti et al., (1999), “Enhancement of Fluid Filtration Across Tumor Vessels: Implication for Delivery of Macromolecules,” Proc. Nat. Acad. Sci.USA, 96:3137-3142.Applicant

Neuberger et al., (1984), “Recombinant Antibodies Possessing Novel Effector Functions,” Nature, 312:604-608.Applicant

Ngo et al., (1994), “Computational Complexity, Protein Structure Prediction, and the Levinthal Paradox,” in The Protein Folding Problem and Tertiary Structure Prediction, Merz et al. (eds.), pp. 433-440 and 492-495, Birkhauser, Boston, MA.Applicant

Niethammer et al., (2002) “An Oral DNA Vaccine Against Human Carcinoembryonic Antigen (CEA) Prevents Growth and Dissemination of Lewis Lung Carcinoma in CEA Transgenic Mice,” Vaccine, 20:421-429.Applicant

Niethammer et al., (2001), “Targeted Interleukin 2 Therapy Enhances Protective Immunity Induced by an Autologous Oral DNA Vaccine Against Murine Melanoma,” Cancer Research, 61(16):6178-84.Applicant

Nimtz et al., (1993), “Structures of Sialylated Oligosaccharides of Human Erythropoietin Expressed in Recombinant BHK-21 Cells,” Eur. J. Biochem., 213:39-56.Applicant

O'Reilly et al., (1994), “Angiostatin: A Novel Angiogenesis Inhibitor That Mediates the Suppression of Metastases by a Lewis Lung Carcinoma,” Cell, 79:315-328.Applicant

O'Reilly et al., (1996), “Angiostatin Induces and Sustains Dormancy of Human Primary Tumors in Mice,” Nature Medicine, 2(6):689-692.Applicant

O'Reilly et al., (1997), “Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth,” Cell, 88:277-285.Applicant

Pancook et al., (1996), “Eradication of Established Hepatic Human Neuroblastoma Metastases in Mice with Severe Combined Immunodeficiency by Antibody-targeted Interleukin-2,” Cancer Immunol. Immunother., 42(2):88-92.Applicant

Park et al., (2000), “Efficiency of Promoter and Cell Line in High-level Expression of Erythropoietin,” Biotechnol. Appl. Biochem., 32:167-172.Applicant

Pastan et al., (1989), “Pseudomonas Exotoxin: Chimeric Toxins,” Journal of Biological Chemistry, 264(26):15157-15160.Applicant

Paul et al., (1988), “Lymphotoxin,” Ann. Rev. Immunol., 6:407-438.Applicant

Perez et al., (1986), “Specific Targeting of Human Peripheral Blood T Cells by Heteroaggregates Containing Anti-T3 Crosslinked to Anti-Target Cell Antibodies,” J. Exp. Med., 163:166-178.Applicant

Perez et al., (1989), “Isolation and Characterization of a cDNA Encoding the KS1/4 Epithelial Carcinoma Marker,” J. Immunology, 142(10):3662-3667.Applicant

Pertl et al., (2003), “Immunotherapy with a Posttranscriptionally Modified DNA Vaccine Induces Complete Protection Against Metastatic Neuroblastoma,” Blood, 101(2):649-654.Applicant

Polizzi et al., (1999), “A Novel Taxane with Improved Tolerability and Therapeutic Activity in a Panel of Human Tumor Xenografts,” Cancer Research, 59:1036-1040.Applicant

Putzer et al., (1997), “Interleukin 12 and B7-1 Costimulatory Molecule Expressed by an Adenovirus Vector Act Synergistically to Facilitate Tumor Regression,” Proc. Natl. Acad. Sci. USA, 94(20):10889-10894.Applicant

Reisfeld et al., (1994), “Potential of Genetically Engineered Anti-Ganglioside GD2 Antibodies for Cancer Immunotherapy,” Prog. Brain Res., 101:201-212.Applicant

Reisfeld et al., (1996), “Antibody-interleukin 2 Fusion Proteins: A New Approach to Cancer Therapy,” J. Clin. Lab. Anal., 10:160-166.Applicant

Reisfeld et al., (1996), “Involvement of B Lymphocytes in the Growth Inhibition of Human Pulmonary Melanoma Metastases in Athymic nu/nu Mice by an Antibody-lymphotoxin Fusion Protein,” Cancer Research, 56(8):1707-1712.Applicant

Reisfeld et al., (1996), “Recombinant Antibody Fusion Proteins for Cancer Immunotherapy,” Current Topics in Microbiology and Immunology, 213:27-53.Applicant

Reisfeld et al., (1997), “Immunocytokines: A New Approach to Immunotherapy of Melanoma,” Melanoma Research, 7(Supp2):S99-S106.Applicant

Riethmuller et al., (1994), “Randomised Trial of Monoclonal Antibody for Adjuvant Therapy of Resected Dukes' C Colorectal Carcinoma,” The Lancet, 343:1177-1183.Applicant

Roessler et al., (1994), “Cooperative Interactions Between the Interleukin 2 Receptor α and β Chains Alter the Interleukin 2-binding Affinity of the Receptor Subunits,” Proc. Natl. Acad. Sci. USA, 91:3344-3347.Applicant

Roitt et al., (1993), “The Role of TH Cells in the Selection of Effector Mechanisms Directed Against Target Antigens,” Immunology, 3rd Ed., pp. 8.3-8.4.Applicant

Rosenberg, (1988), “Immunotherapy of Cancer Using Interleukin 2: Current Status and Future Prospects,” Immunology Today, 9(2):58-62.Applicant

Rozwarski et al., (1994), “Structural Comparisons Among the Short-chain Helical Cytokines,” Structure, 2(3):159-173.Applicant

Ruehlmann et al., (2001), “MIG (CIXCL9) Chemokine Gene Therapy Combines with Antibody-cytokine Fusion Protein to Suppress Growth and Dissemination of Murine Colon Carcinoma,” Cancer Research, 61(23):8498-503.Applicant

Sabzevari et al., (1994), “A Recombinant Antibody-interleukin 2 Fusion Protein Suppresses Growth of Hepatic Human Severe Combined Immunodeficiency Mice,” Proc. Natl. Acad. Sci. USA, 91(20):9626-30.Applicant

Saleh et al., (1992), “Phase 1 Trial of the Chimeric Anti-GD2 Monoclonal Antibody ch14.18 in Patients With Malignant Melanoma,” Hum. Antiob. Hybridomas, 3:19-24.Applicant

Sallusto et al., (1994), “Efficient Presentation of Soluble Antigen by Cultured Human Dendritic Cells Is Maintained by Granulocyte/Macrophage Colony-stimulating Factor Plus Interleukin 4 and Downregulated by Tumor Necrosis Factor α,” J. Exp. Med., 179:1109-1118.Applicant

Santon et al., (1986), “Effects of Epidermal Growth Factor Receptor Concentration on Tumorigenicity of A431 Cells in Nude Mice,” Cancer Research, 46:4701-4705.Applicant

Sasaki et al., (1998), “Structure, Function and Tissue Forms of the C-terminal Globular Domain of Collagen XVIII Containing the Angiogenesis Inhibitor Endostatin,” EMBO Journal, 17(15):4249-4256.Applicant

Sauve et al., (1991), “Localization in Human Interleukin 2 of the Binding Site to the α-chain (p55) of the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 88:4636-4640.Applicant

Schlom (1991), “Monoclonal Antibodies: They're More and Less Than You Think,” in Molecular Foundations of Oncology, pp. 95-133.Applicant

Schnee et al., (1987), “Construction and Expression of a Recombinant Antibody-targeted Plasminogen Activator,” Proc. Natl. Acad. Sci. USA, 84:6904-6908.Applicant

Schoenhaut et al., (1992), “Cloning and Expression of Murine IL-12,” J. Immunology, 148(11):3433-3340.Applicant

Seidenfeld et al., (2001), “Epoietin Treatment of Anemia Associated with Cancer Therapy: A Systematic Review and Meta-analysis of Controlled Clinical Trials,” Journal of National Cancer Institute, 93(16):1204-1214.Applicant

Senter et al., (1988), “Anti-tumor Effects of Antibody-alkaline Phosphatase Conjugates in Combination with Etoposide Phosphate,” Proc. Natl. Acad. Sci. USA, 85(13):4842-4846.Applicant

Shanafelt et al., (2000), “A T-cell-Selective Interleukin 2 Mutein Exhibits Potent Antitumor Activity and is Well Tolerated In Vivo,” Nature Biotechnology, 18:1197-1202.Applicant

Sharma et al., (1999), “T cell-derived IL-10 Promotes Lung Cancer Growth by Suppressing Both T cell and APC Function,” Journal of Immunology, 163:5020-5028.Applicant

Shen et al., (1986), “Heteroantibody-Mediated Cytotoxicity: Antibody to the High Affinity Fc Receptor for IgG Mediates Cytotoxicity by Human Monocytes That is Enhanced by Interferon-γ and is Not Blocked by Human IgG,” J. Immunology,137(11):3378-3382.Applicant

Shiff et al., (1995), “Sulindac Sulfide, an Asprin-like Compound, Inhibits Proliferation, Causes Cell Cycle Quiescence, and Induces Apoptosis in HT-29 Colon Adenocarcinoma Cells,” Journal of Clinical Investigation, 96:491-503.Applicant

Shin et al., (1990), “Expression and Characterization of an Antibody Binding Specificity Joined to Insulin-like Growth Factor 1: Potential Applications for Cellular Targeting,” Proc. Natl. Acad. Sci. USA, 87:5322-5326.Applicant

Shinkawa et al., (2003), “The Absence of Fucose But Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human IgG1 Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity,” J. Biol. Chem., 278:3466-3473.Applicant

Sim et al., (1997), “A Recombinant Human Angiostatin Protein Inhibits Experimental Primary and Metastatic Cancer,” Cancer Research, 57:1329-1334.Applicant

Spiekermann et al., (2002), “Receptor-mediated Immunoglobulin G Transport Across Mucosal Barriers in Adult-Life: Functional Expression of FcRn in the Mammalian Lung,” J. Exp. Med., 196:303-310.Applicant

Stevenson et al., (1997), “Conjugation of Human Fcγ in Closed-Hinge or Open-Hinge Configuration to Fab'γ and Analogous Ligands,” J. Immunology, 158:2242-2250.Applicant

Strom et al., (1996), “Therapeutic Approach to Organ Transplantation,” Chapter 36, pp. 451-456, in Therapeutic Immunology, Austen et al., (eds.), Blackwell Science.Applicant

Sulitzeanu, (1993), “Immunosuppressive Factors in Human Cancer,” pp. 247-266 in Advances in Cancer Research, vol. 60, Vande Woude et al. (eds.), Academic Press, Inc.Applicant

Syed et al., (1998), “Efficiency of Signaling Through Cytokine Receptors Depends Critically on Receptor Orientation,” Nature, 395:511-516.Applicant

Taniguchi et al., (1983), “Structure and Expression of a Cloned cDNA for Human Interleukin-2,” Nature, 302:305-309.Applicant

Tao et al., (1989), “Studies of Aglycosylated Chimeric Mouse IgG: Role of Carbohydrate in the Structure and Effector Functions Mediated by the Human IgG Constant Region,” J. Immunology, 143(8):2595-2601.Applicant

Tao et al., (1993), “Structural Features of Human Immunoglobulin G that Determine Isotype-Differences in Complement Activation,” J. Exp. Med., 178(2):661-667.Applicant

Teicher et al., (1994), “Potentiation of Cytotoxic Cancer Therapies by TNP-470 Alone and With Other Anti-Angiogenic Agents,” Int. J. Cancer, 57:920-925.Applicant

The Merck Manual of Diagnosis and Therapy, 17th Ed., (1999) pp. 990-993 and 1278-1283.Applicant

Thommesen et al., (2000), “Lysine 322 in the Human IgG3 Ch2 Domain is Crucial for Antibody Dependent Complement Activation,” Mol. Immunol., 37(16):995-1004.Applicant

Till et al., (1988), “An Assay that Predicts the Ability of Monoclonal Antibodies to Form Potent Ricin A Chain-containing Immunotoxins,” Cancer Research, 48(5):1119-1123.Applicant

Till et al., (1988), “HIV-Infected Cells are Killed by rCD4-Ricin A Chain,” Science, 242:1166-1168.Applicant

Trinchieri, (1994), “Interleukin-12: A Cytokine Produced by Antigen-Presenting Cells With Immunoregulatory Functions in the Generation of T-Helper Cells Type 1 and Cytotoxic Lymphocytes,” Blood, 84:4008-4027.Applicant

Vagliani et al., (1996), “Interleukin 12 Potentiates that Curative Effect of a Vaccine Based on Interleukin 2-transduced Tumor Cells,” Cancer Research, 56:467-470.Applicant

Varki et al., (1984), “Antigens Associated with a Human Lung Adenocarcinoma Defined by Monoclonal Antibodies,” Cancer Research, 44:681-687.Applicant

Verhoeyen et al., (1988), “Reshaping Human Antibodies: Grafting an Antilysozyme Activity,” Science, 239:1534-1536.Applicant

Villunger et al., (1997), “Constitutive Expression of Fas (Apo-1/CD95) Ligand on Multiple Myeloma Cells: A Potential Mechanism of Tumor-induced Suppression of Immune Surveillance,” Blood, 90(1):12-20.Applicant

Watanabe et al., (1997), “Long-term Depletion of Naive T cells in Patients Treated for Hodgkin's Disease,” Blood, 90(9):3662-3672.Applicant

Weber et al., (2001), “Phase I Trial of huKS-IL2 Immunocytokine in Patients with Prostate Carcinoma: Clinical, PK, and Biological PD Results (Abstract),” American Society of Clinical Oncology Program/Proceedings, 20(Part 1):259a.Applicant

Wells, (1990), “Addivity of Mutational Effect in Proteins,” Biochemistry, 29(37):8509-8517.Applicant

Wen et al., (1993), “Erythropoietin Structure-Function Relationships: High Degree of Sequence Homology Among Mammals,” Blood, 82(5):1507-1516.Applicant

Wen et al., (1994), “Erythropoietin Structure-Function Relationships: Identification of Functionally Important Domains,” J. Biological Chemistry, 269(36):22839-22846.Applicant

Williams et al., (1986), “Production of Antibody-tagged Enzymes by Myeloma Cells: Application to DNA Polymerase I Klenow Fragment,” Gene, 43:319-324.Applicant

Williams et al., (1987), “Diphtheria Toxin Receptor Binding Domain Substitution with Interleukin-2: Genetic Construction and Properties of a Diptheria Toxin-related Interleukin-2 Fusion Protein,” Protein Engineering, 1(6):493-498.Applicant

Wooley et al., (1993), “Influence of a Recombinant Human Soluble Tumor Necrosis Factor Receptor Fc Fusion Protein on Type II Collagen-Induced Arthritis in Mice,” J. Immunology, 151:6602-6607.Applicant

Wu et al., (1997), “Suppression of Tumor Growth with Recombinant Murine Angiostatin,” Biochemical and Biophysical Research Communications, 236:651-654.Applicant

Xiang et al., (1997), “Elimination of Established Murine Colon Carcinoma Metastases by Antibody-Interleukin 2 Fusion Protein Therapy,” Cancer Research, 57:4948-4955.Applicant

Xiang et al., (1998), “Induction of Persistant Tumor-protective Immunity in Mice Cured of Established Colon Carcinoma Metastases,” Cancer Research, 58(17):3918-3925.Applicant

Xiang et al., (1999) “T Cell Memory against Colon Carcinoma is Long-lived in the Absence of Antigen,” J. Immunology, 163(7):3676-83.Applicant

Xiang et al., (2001), “A Dual Function DNA Vaccine Encoding Carcinoembryonic Antigen and CD40 Ligand Trimer Induces T Cell-mediated Protective Immunity Against Colon Cancer Carcinoembryonic Antigen-Transgenic Mice,” J. Immunology, 167(8):4560-5.Applicant

Xiang et al., (2001), “Protective Immunity Against Human Carcinoembryonic Antigen (CEA) Induced by an Oral DNA Vaccine in CEA-transgenic Mice,” Clinical Cancer Research, 7(3 Supp):S856-S864.Applicant

Xu et al., (1994), “Residue at Position 331 in the IgG1 and IgG4 CH2 Domains Contributes to Their Differential Ability to Bind and Activate Complement,” J. Biol. Chem., 269(5):3469-3474.Applicant

Yu et al., (1998), “Phase I Trial of a Human-Mouse Chimeric Anti-Disaloganglioside Monoclonal Antibody ch14.18 in Patients with Refractory Neuroblastoma and Osteosarcoma,” J. Clinical Oncology, 16(6):2169-80.Applicant

Zagozdzon et al., (1999), “Potentiation of Antitumor Effects of IL-12 in Combination with Paclitaxel in Murine Melanoma Model In Vivo,” International Journal of Molecular Medicine, 4:645-648.Applicant

Zheng et al., (1995), “Administration of Noncytolytic IL-10/Fc in Murine Models of Lipopolysaccharide-induced Septic Shock and Allogenic Islet Transplantation,” J. Immunology, 154:5590-5600.Applicant

Aichele et al., (1994), “Peptide-Induced T-Cell Tolerance to Prevent Autoimmune Diabetes in a Transgenic Mouse Model,” Proc. Natl. Acad. Sci. USA, 91:444-448.Applicant

Altschul et al., (1990), “Basic Local Alignment Search Tool,” J. Mol. Biol., 215:403-10.Applicant

Altschul et al., (1997), “Gapped BLAST and PSI-BLAST: A New Generation of Protein Database Search Programs,” Nucleic Acids Res., 25(17):3389-3402.Applicant

Anderson et al., (1980), “Characterization of the Fc Receptor for IgG on a Human Macrophage Cell Line U937,” J. Immunol., 125(6):2735-41.Applicant

Anderson et al., (1994), “Effects of Route and Formulation on Clinical Pharmacokinetics of Interleukin-2,” Clin. Pharmacokinet., 27(1):19-31.Applicant

Baici et al., (1980), “Kinetics of the Different Susceptibilities of the Four Human Immunoglobulin G Subclasses to Proteolysis by Human Lysosomal Elastase,” Scand. J. Immunol. 12(1):41-50.Applicant

Barbulescu et al., (1998), “IL-12 and IL-18 Differentially Regulate the Transcriptional Activity of the Human IFN-γ Promoter in Primary CD4+ T Lymphocytes,” J. Immunol., 160:3642-7.Applicant

Bednarek et al., (1991), “Soluble HLA-A2.1 Restricted Peptides that are Recognized by Influenza Virus Specific Cytotoxic T Lymphocytes,” J. Immunol. Methods, 139:41-47.Applicant

Benacerraf et al., (1959), “The Clearance of Antigen Antibody Complexes from the Blood by the Reticulo-Endothelial System,” J. Immunol., 82:131-7.Applicant

Böhm, (1994), “On the Use of LUDI to Search the Fine Chemicals Directory for Ligands of Proteins of Known Three-Dimensional Structure,” J. Comput. Aided Mol. Des., 8:623-32.Applicant

Böhm, (1994), “The Development of a Simple Empirical Scoring Function to Estimate the Binding Constant for a Protein-Ligand Complex of Known Three-Dimensional Structure,” J. Comput. Aided Mol. Des., 8(3):243-56.Applicant

Böhm, (1998), “Prediction of Binding Constants of Protein Ligands: A Fast Method for the Priorization of Hits Obtained from De Novo Design or 3D Database Search Programs,” J. Comput. Aided Mol. Des., 12(4):309-23.Applicant

Boshart et al., (1985), “A Very Strong Enhancer is Located Upstream of an Immediate Early Gene of Human Cytomegalovirus,” Cell, 41:521-530.Applicant

Boulianne et al., (1984), “Production of Functional Chimeric Mouse/Human Antibody,” Nature, 312:643-6.Applicant

Bourgois et al., (1974), “Determination of the Primary Structure of a Mouse IgG2a Immunoglobulin Amino Acid Sequence of the Fc Fragment: Implications for the Evolution of Immunoglobulin Structure and Function,” Eur. J. Biochem., 43:423-45.Applicant

Brambell et al., (1964), “A Theoretical Model of γ-Globulin Catabolism,” Nature, 203:1352-55.Applicant

Brazolot Millan et al., (1998), “Cpg DNA Can Induce Strong TH1 Humoral and Cell-Mediated Immune Responses against Hepatitis B Surface Antigen in Young Mice,” Proc. Natl. Acad. Sci. USA, 95:15553-8.Applicant

Brekke et al., (1994), “Human IgG Isotype-Specific Amino Acid Residues Affecting Complement-Mediated Cell Lysis and Phagocytosis,” Eur. J. Immunol., 24:2542-2547.Applicant

Brem et al., (1993), “The Combination of Antiangiogenic Agents to Inhibit Primary Tumor Growth and Metastasis,” J. Pediatr. Surg., 28(10):1253-7.Applicant

Brocklebank et al., (2001), “Enumeration of CD34+ Cells in Cord Blood: A Variation of a Single-Platform Flow Cytometric Method Based on the ISHAGE Gating Strategy,” Cytometry, 46:254-261.Applicant

Brooks et al., (1983), “CHARMM: A Program for Macromolecular Energy Minimization and Dynamics Calculations,” J. Comput. Chemistry, 4:187-217.Applicant

Broudy et al., (1988), “Recombinant Human Erythropoietin: Purification and Analysis of Carbohydrate Linkage,” Arch. Biochem. Biophys., 265:329-36.Applicant

Bubenik et al., (1995), “Interleukin-2 Gene Therapy of Residual EL-4 Leukaemia Potentiates the Effect of Cyclophosphamide Pretreatment,” J. Cancer Res. Clin. Oncol., 121:39-43.Applicant

Bumol et al., (1982), “Unique Glycoprotein-Proteoglycan Complex Defined By Monoclonal Antibody on Human Melanoma Cells,” Proc. Natl. Acad. Sci. USA, 79:1245-9.Applicant

Carnemolla et al., (1989), “A Tumor-Associated Fibronectin Isoform Generated by Alternative Splicing of Messenger RNA Precursors,” J. Cell. Biol., 108:1139-1148.Applicant

Carnemolla et al., (1992), “The Inclusion of the Type III Repeat ED-B in the Fibronectin Molecule Generates Conformational Modifications that Unmask a Cryptic Sequence,” J. Biol. Chem., 267(34):24689-24692.Applicant

Casadevall et al., (2002) “Pure Red-Cell Aplasia and Antierythropoietin Antibodies in Patients Treated with Recombinant Erythropoietin,” The New Eng. School of Medicine, 346:469-75.Applicant

Cazzola et al., (1998), “Red Blood Cell Precursor Mass as an Independent Determinant of Serum Erythropoietin Level,” Blood, 91:2139-45.Applicant

Chan et al., (1992), “Mechanisms of IFN-γ Induction by Natural Killer Cell Stimulatory Factor (NKSF/IL-12). Role of Transcription and mRNA Stability in the Synergistic Interaction Between NKSF and Il-2,” J. Immunol., 148:92-98.Applicant

Chappel et al., (1991), “Identification of the Fc Gamma Receptor Class I Binding Site In Human IgG Through Use of Recombinant IgG1/IgG2 Hybrid and Point-Mutated Antibodies,” Proc. Natl. Acad. Sci. USA, 88(20):9036-40.Applicant

Cheetham, (1998), “NMR Structure of Human Erythropoietin and a Comparison with its Receptor Bound Conformation,” Nat. Struct. Biol., 5:861-6.Applicant

Ciardiello et al., (1996), “Antitumor Activity of Combined Blockade of Epidermal Growth Factor Receptor anf Protein Kinase A,” J. Natl. Cancer Inst., 88:1770-6.Applicant

Cirulli et al., (1998), “KSA Antigen Ep-CAM Mediates Cell-Cell Adhesion of Pancreatic Epithelial Cells: Morphoregulatory Roles in Pancreatic Islet Development,” J. Cell Biol., 140:1519-34.Applicant

Cohen et al., (1998), “An Artificial Cell-Cycle Inhibitor Isolated from a Combinatorial Library,” Proc. Natl. Acad. Sci. USA, 95:14272-7.Applicant

Congote et al., (1984), “The Erthrotropins, New Erythroid Cell Stimulate Factors Extracted From Human and Bovine Fetal Tissues,” Abstract 364, “Proceedings 7th Intl. Congress of Endocrinology,” Quebec City, Quebec, Jul. 1-7, 1984.Applicant

Congote, (1983), “Isolation of Two Biologically Active Peptides, Erythrotropin I and Erythrotropin II from Fetal Calf Intestine,” Biochem. Biophys. Res. Commun., 115(2):477-83.Applicant

Congote, (1984), “Extraction from Fetal Bovine Serum of Erythrotropin, an Erythroid Cell-Stimulating Factor,” Anal. Biochem., 140:428-33.Applicant

Connor et al., (2004), “Ex vivo Evaluation of Anti-EpCAM Immunocytokine huKS-IL2 in Ovarian Cancer,” J. Immunotherapy, 27:211-219.Applicant

Cosenza et al., (1997), “Disulfide Bond Assignment in Human Interleukin-7 by Matrix-Assisted Laser Desorption/Ionization Mass Spectroscopy and Site-Directed Cysteine to Serine Mutational Analysis,” J. Biol. Chem., 272:32995-3000.Applicant

Cunningham et al., (1989), “High-Resolution Epitope Mapping of hGH-Receptor Interactions by Alanine-Scanning Mutagenesis,” Science, 244:1081-85.Applicant

Curiel et al., (1991), “Adenovirus Enhancement of Transferrin-Polylysine-Mediated Gene Delivery,” Proc. Natl. Acad. Sci. USA, 88:8850-4.Applicant

Dauber-Osguthorpe et al., (1988), “Structure and Energetics of Ligand Binding to Proteins: Escherichia coli Dihydrofolate Reductase-Trimethoprim, A Drug-Receptor System,” Proteins, 4:31-47.Applicant

Daugherty et al., (1991), “Polymerase Chain Reaction Facilities the Cloning, CDR-Grafting, and Rapid Expression of a Murine Monoclonal Antibody Directed Against the CD18 Component of Leukocyte Integrins,” Nucleic Acid Res., 19:2471-2476.Applicant

De Bruijn et al., (1995), “Phagocyte-Induced Antigen-Specific Activation of Unprimed CD8+ T Cells in Vitro,” Eur. J. Immunol., 25:1274-85.Applicant

Delorme et al., (1992), “Role of Glycosylation on the Secretion and Biological Activity of Erythropoietin,” Biochemistry, 31:9871-6.Applicant

Desai et al., (1992), “IL-12 Receptor. II. Distribution and Regulation of Receptor Expression,” J. Immunol., 148:3125-32.Applicant

Dillman et al., (1994), “Human Anti-Mouse Antibody Response in Cancer Patients Following Single Low-Dose Injections of Radiolabeled Murine Monoclonal Antibodies,” Cancer Biotherapy, 9:17-28.Applicant

Donnelly et al., (1993), “Targeted Delivery of Peptide Epitopes to Class I Major Histocompatibility Molecules by a Modified Pseudomonas Exotoxin,” Proc. Natl. Acad. Sci. USA, 90:3530-4.Applicant

Donnelly et al., (1997), “DNA Vaccines,” Annu. Rev. Immunol., 15:617-48.Applicant

Dube et al., (1988), “Glycosylation at Specific Sites of Erythropoietin is Essential for Biosynthesis, Secretion, and Biological Function,” J. Biol. Chem., 263:17516-21.Applicant

Ellison et al., (1982), “The Nucleotide Sequence of a Human Immunoglobulin C γ1 Gene,” Nucleic Acids Res., 10:4071-9.Applicant

Faas et al., (1993), “Phenotypically Diverse Mouse Thymic Stromal Cell Lines which Induce Proliferation and Differentiation of Hematopoietic Cells,” Eur. J. Immunol., 23:1201-14.Applicant

Famer et al., (1995), “Distinction Between γc C Detection and Function in YT Lymphoid Cells and in the Granulocyte-Macrophage Colony-Stimulating Factor-Responsive Human Myeloid Cell Line, Tf-1,” Blood, 86:4568-78.Applicant

Fawell et al., (1994), “Tat-Mediated Delivery of Heterologous Protein in Cells,” Proc. Natl. Acad. Sci. USA, 91:664-8.Applicant

Fu et al., (1993), “The Sheep Erythropoietin Gene: Molecular Cloning and Effect of Hemorrhage on Plasma Erythropoietin and Renal/Liver Messenger RNA in Adult Sheep,” Mol. Cell. Endocrinol., 93:107-16.Applicant

Gainsford et al., (1996), “Leptin Can Induce Proliferation, Differentiation, and Functional Activation of Hemopoietic Cells,” Proc. Natl. Acad. Sci. USA, 93:14564-14568.Applicant

Gammon et al., (1992), “Endogenous Loading of HLA-A2 Molecules with an Analog of the Influenza Virus Matrix Protein-Derived Peptide and Its Inhibition By An Exogenous Peptide Antagonist,” J. Immunol., 148:7-12.Applicant

Ghetie et al., (1990), “Disseminated or Localized Growth of a Human B-Cell Tumor (Daudi) in SCID Mice,” Intl. J. Cancer, 45:485.Applicant

Ghetie et al., (1997), “FcRn: The MHC Class 1-Related Receptor that is More Than an IgG Transporter,” Immunology Today, 18(12):592-598.Applicant

Goldwasser et al., (1971), “Purification of Erythropoietin,” Proc. Natl. Acad. Sci. USA, 68:697-8.Applicant

Goldwasser et al., (1975), “Erythropoietin: Assay and Study of its Mode of Action,” Methods Enzymol., 37(PtB):109-21.Applicant

Gurewich et al., (1988), “Characterization of the Intrinsic Fibrinolytic Properties of Pro-Urokinase Through a Study of Plasmin-Resistant Mutant Forms Produced by Site-Specific Mutagenesis of Lysine,” J. Clin. Invest., 82:1956-1962.Applicant

Halin et al., (2002), “Enhancement of the Antitumor Activity of Interleukin-12 by Targeted Delivery to Neovasculature,” Nature Biotechnology, 20:264-269.Applicant

Handgretinger et al., “Immunological Aspects of Haploidentical Stem Cell Transplantation in Children,” Annals New York Academy of Sciences, 340-(Date not known).Applicant

Hashimoto et al., (1999), “Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively,” J. Immunol., 163:583-9.Applicant

Henikoff et al., (1992), “Amino Acid Substitution Matrices from Protein Blocks,” Proc. Natl. Acad. Sci. USA, 89:10915-10919.Applicant

Hilgers et al., (1999), “Sulfolipo-Cyclodextrin in Squalane-In-Water as a Novel and Safe Vaccine Adjuvant,” Vaccine, 17:219-28.Applicant

Hori et al., (1987), “Establishment of an Interleukin 2-Dependent Human T Cell Line from a Patient with T Cell Lymphocytic Leukemia Who is Not Infected with Human T Cell Leukemia/Lymphoma Virus,” Blood, 70:1069-72.Applicant

Hulett et al., (1994), “Molecular Basis of Fc Receptor Function,” Adv. Immunol., 57:1127.Applicant

Huston et al., (1988), “Protein Engineering of Antibody Binding Sites: Recovery of Specific Activity in an Anti-Digoxin Single-Chain Fv Analogue Produced in Escherichia coli,” Proc. Natl. Acad. Sci. USA, 85:5879-5883.Applicant

Investigator's Brochure 2004, pp. 6-10, 34 and 35.Applicant

Jacobs et al., (1985), “Isolation and Characterization of Genomic And cDNA Clones of Human Erythropoietin,” Nature, 313:806-10.Applicant

Jefferis et al., (1990), “Molcular Definition of Interaction Sites on Human IgG for Fc Receptors huFcγR,” Mol. Immunol., 27(12):1237-1240.Applicant

Karlin et al., (1990), “Methods for Assessing the Statistical Significance of Molecular Sequence Features by Using General Scoring Schemes,” Proc. Natl. Acad. Sci. USA, 87:2264-8.Applicant

Karlin et al., (1993), “Applications and Statistics for Multiple High-Scoring Segments in Molecular Sequences,” Proc. Natl. Acad. Sci. USA, 90:5873-7.Applicant

Karpusas et al., (1997), “The Crystal Structure of Human Interferon β at 2.2-A Resolution,” Proc. Natl. Acad. Sci. USA, 94:11813-11818.Applicant

Kelner et al., (1994), “Lymphotactin: A Cytokine that Represents a New Class of Chemokine,” Science, 266:1395-9.Applicant

Kirkman et al., (1989), “Prolongation of Cardiac Allograft Survival in Murine Recipients Treated with a Diphtheria Toxin-Related Interleukin-2 Fusion Protein,” Transplantation, 47(2):327-330.Applicant

King et al., (2004), “Phase I Clinical Trial of the Immunocytokine EMD 273063 in Melanoma Patients,” J. Clin. Oncol., 22(22):4463-73.Applicant

Klinman et al., (1997), “Contribution of CpG Motifs to the Immunogenicity of DNA Vaccines,” J. Immunol., 158:3635-9.Applicant

Kuntz et al., (1982), “A Geometric Approach to Macromolecule-Ligand Interactions,” J. Mol. Biol., 161:269-88.Applicant

Kurtz, (1982), “A New Candidate for the Regulation of Erythropoiesis. Insulin-Like Growth Factor I,” FEBLAL., 149(1):105-8.Applicant

Lai et al., (1986), “Structural Characterization of Human Erythropoietin,” J. Biol. Chem., 261:3116-21.Applicant

Lai et al., (1998), “DNA Vaccines,” Crit. Rev. Immunol., 18:449-84.Applicant

Lanza et al., (1993), “Active Immunity against the CD4 Receptor by Using an Antibody Antigenized with Residues 41-55 of the First Extracellular Domain,” Proc. Natl. Acad. Sci. USA, 90:11683-7.Applicant

Lawn et al., (1981), “DNA Sequence of a Major Human Leukocyte Interferon Gene,” Proc. Natl. Acad. Sci. USA, 78:5435-9.Applicant

Lin et al., (1985), “Cloning and Expression of the Human Erythropoietin Gene,” Proc. Natl. Acad. Sci. USA, 82:7580-4.Applicant

Lin et al., (1986), “Monkey Erythropoietin Gene: Cloning, Expression and Comparison with the Human Erythropoietin Gene,” Gene, 44:201-9.Applicant

Lode et al., (1998), “Gene Therapy with a Single Chain Interleukin 12 Fusion Protein Induces T Cell-Dependent Protective Immunity in a Syngeneic Model of Murine Neuroblastoma,” Proc. Natl. Acad. Sci. USA, 95:2475-80.Applicant

Lorenz et al., (1999), “Induction of Anti-Tumor Immunity Elicited by Tumor Cells Expressing a Murine LFA-3 Analog Via a Recombinant Vaccinia Virus,” Hum. Gene Ther., 10:623-31.Applicant

Lotze et al., (1996), “Cytokine Gene Therapy of Cancer Using Interleukin-12: Murine and Clinical Trials,” Ann. NY Acad. Sci., 795:440-54.Applicant

Macdougall, et al., (2002), “Optimizing the Use of Erythropoietic Agents—Pharmacokinetics and Pharmacodynamic Considerations,” Nephol. Dial. Transplant. 17(5):66-70.Applicant

MacLean et al., (1996), “Enhancing the Effect of Theratope STn-KLH Cancer Vaccine in Patients with Metastatic Breast Cancer by Pretreatment with Low-Dose Intravenous Cyclophosphamide,” J. Immunother., 19(4):309-316.Applicant

Maghazachi et al., (1997), “Interferon-Inducible Protein-10 and Lymphotactin Induce the Chemotaxis and Mobilization of Intracellular Calcium in Natural Killer Cells through Pertussis Toxin Sensitive and—Insensitive Heterotrimeric G-Proteins,” FASEB J., 11:765-74.Applicant

Maloy et al., (2001), “Regulatory T Cells in the Control of Immune Pathology,” 2(9):816-822.Applicant

Mariani et al., (1997), “Tumor Targeting Potential of the Monoclonal Antibody BC-1 against Oncofetal Fibronectin in Nude Mice Bearing Human Tumor Implants,” Cancer, 80:2378-84.Applicant

Marshall et al., (1994), “Role of the Polymorphic Residues in HLA-DR Molecules in Allele-Specific Binding of Peptide Ligands,” J. Immunol., 15:4946-57.Applicant

Marshall et al., (1995), “Prediction of Peptide Affinity to HLA-DR Molecules,” Biomed. Pept. Proteins Nucleic Acids, 1(3):157-62.Applicant

Martin et al., (2001), “Crystal Structure at 2.8 A of an FcRn/Heterodimeric Fc Complex: Mechanism of pH Dependent Binding,” Molecular Cell, 7:867-877.Applicant

McDonald, (1986), “Cloning, Sequencing, and Evolutionary Analysis of the Mouse Erythropoietin Gene,” Mol. Cell. Biol., 6:842-8.Applicant

McGonigle et al., (1984), “Erythropoietin Deficiency and Inhibition of Erythropoiesis in Renal Insufficiency,” Kidney Int., 25(2):437-44.Applicant

McMahan et al., (1991), “A Novel IL-1 Receptor, Cloned From B-Cells by Mammalian Expression is Expressed in Many Cell Types,” EMBO J., 10:2821-32.Applicant

McMahon et al., (1990), “Pharmacokinetics and Effects of Recombinant Human Erythropoietin after Intravenous and Subcutaneous Injections in Healthy Volunteers,” Blood, 76:1718-22.Applicant

Mehrotra et al., (1993), “Effects of IL-12 on the Generation of Cytotoxic Activity in Human CD8+ T Lymphocytes,” J. Immunol., 151:2444-52.Applicant

Menard et al., (1983), “Generation of Monoclonal Antibodies Reacting with Normal and Cancer Cells of Human Breast,” Cancer Res., 43:1295-300.Applicant

Miyake et al., (1977), “Purification of Human Erythropoietin,” J. Biol. Chem., 252:5558-64.Applicant

Miyake et al., (1988), “Synthesis of Recombinant Human Single-Chain Urokinase-Type Plasminogen Activator Variants Resistant to Plasmin and Thrombin,” J. Biochem., 104:643-647.Applicant

Morrison et al., (1984), “Chimeric Human Antibody Molecules: Mouse Antigen-Binding Domains with Human Constant Region Domains,” Proc. Natl. Acad. Sci. USA, 81:6851-5.Applicant

Nagao et al., (1992), “Nucleotide Sequence of Rat Erythropoietin,” Biochim. Biophys. Acta, 1171(1):99-102.Applicant

Nastala et al., (1994), “Recombinant IL-12 Administration Induces Tumor Regression in Association with IFN-γ Production,” J. Immunol., 153:1697-706.Applicant

Naughton et al., (1983), “Evidence for an Erythropoietin-Stimulating Factor in Patients with Renal and Hepatic Disease,” Acta. Haemat., 69:171-9.Applicant

Neal et al., (2004), “Enhanced Activity of Hu14.18-IL2 Immunocytokine against Murine NXS2 Neuroblastoma when Combined with Interleukin-2 Therapy,” Clin. Cancer. Res., 10:4839-4847.Applicant

Nelles et al., (1987), “Characterization of Recombinant Human Single Chain Urokinase-Type Plaminogen Activtor Mutants Produced by Site-Specific Mutagenesis of Lysine 158,” J. Biol. Chem., 262(12):5682-5689.Applicant

Noguchi et al., (1994), “A Mouse Mutant P53 Product Recognized by CD4+ and CD8+ T Cells,” Proc. Natl. Acad. Sci. USA, 91:3171-5.Applicant

Orlandi et al., (1989), “Cloning Immunoglobulin Variable Domains for Expression by the Polymerase Chain Reaction,” Proc. Natl. Acad. Sci. USA, 86:3833-7.Applicant

Palmer et al., (2001), “Phase I Study of the BLP 25 (MUCI Peptide) Liposomal Vaccine for Active Specific Immunotherapy in Stage IIIB/IV Non-Small-Cell Lung Cancer,” Clinical Lung Cancer, 3(1):49-57.Applicant

Palucka et al., (1998), “Dendritic Cells as the Terminal Stage of Monocyte Differentiation,” J. Immunol., 160:4587-95.Applicant

Panina-Bordignon et al., (1989), “Universally Immunogenic T Cell Epitopes: Promiscuous Binding to Human MHC Class II and Promiscuous Recognition by T Cells,” Eur. J. Immunol., 19:2237-42.Applicant

Pavlović-Kentera et al., (1980), “Effects of Prostaglandin Synthetase Inhibitors, Salt Overload and Renomedullary Dissection on the Hypoxia Stimulated Erythropoietin Production in Rats,” Exp. Hematol., 8(Supp. 8):283-92.Applicant

Pedley et al. (1999), “Enhancement of Antibody-Directed Enzyme Prodrug Therapy in Colorectal Xenografts by an Antivascular Agent,” Cancer Res., 59:3998-4003.Applicant

Perussia et al., (1992), “Natural Killer (NK) Cell Stimulatory Factor or IL-12 Has Differential Effects on the Proliferaton of TCR-αβ+, TCR-γδ+ T Lymphocytes, and NK Cells,” J. Immunol., 149:3495-502.Applicant

Pluschke et al., (1996), “Molecular Cloning of a Human Melanoma-Associated Chondroitin Sulfate Proteoglycan,” Proc. Natl. Acad. Sci. USA, 93:9710-5.Applicant

Poon et al., (1995), “Structure and Function of Several Anti-Dansyl Chimeric Antibodies Formed by Domain Interchanges Between Human IgM and Mouse IgG2b,” J. Biol. Chem., 270:8571-7.Applicant

Queen et al., (1989), “A Humanized Antibody that Binds to the Interleukin 2 Receptor,” Proc. Natl. Acad. Sci. USA, 86:10029-33.Applicant

Radhakrishnan et al., (1996), “Zinc Mediated Dimer of Human Inteferon-α2b Revealed by X-Ray Crystallography,” Structure 4(12):1453-63.Applicant

Ramachandran et al., (1968)“Conformation of Polypeptides and Proteins,” Adv. Prot. Chem., 23:283-294.Applicant

Rarey et al., (1995), “Time-Efficient Docking of Flexible Ligands into Active Sites Of Proteins,” Proc. Int. Conf. Intell. Syst. Mol. Biol. 3:300-8.Applicant

Resegotti et al., (1981), “Treatment of Aplastic Anaemia with Methenolone, Stanozolol and Nandrolone. A Report of 130 Cases,” Pan. Med., 23:243-8.Applicant

Riechmann et al., (1988), “Reshaping Human Antibodies for Therapy,” Nature, 332:323-7.Applicant

Robinson et al., (1998), “Optimizing the Stability of Single-Chain Proteins by Linker Length and Composition Mutagenesis,” Proc. Natl. Acad. Sci. USA, 95:5929-34.Applicant

Rothmann et al., (1982), “Erythropoietin-Dependent Erythrocytosis associated with Hepatic Angiosarcoma,” J. Surg. Oncol., 20:105-8.Applicant

Runkel et al., (1998), “Structural and Functional Differences Between Glycosylated and Non-Glycosylated Forms of Human Interferon-β (IFN-β),” Pharmaceutical Res., 15:641-649.Applicant

Sakano et al., (1980), “Two Types of Somatic Recombination are Necessary for the Generation of Complete Immunoglobin Heavy-Chain Genes,” Nature, 286:676-683.Applicant

Säli et al., (1993), “Comparative Protein Modelling by Satisfaction of Spatial Restraints,” J. Mol. Biol., 234:779-815.Applicant

Schecter et al., (1997), “Tissue Factor is Induced by Monocyte Chemoattractant Protein-1 in Human Aortic Smooth Muscle And THP-1 Cells,” J. Biol. Chem., 272:28568-73.Applicant

Senior et al., (2000), “Cleavage of a Recombinant Human Immunoglobulin A2 (igA2)-IgA1 Hybrid Antibody by Certain Bacterial IgA1 Proteases,” Infect. Immun., 68(2):463-9.Applicant

Sharp et al., (1988), “Codon Usage Patterns in Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Drosophila melanogaster and Homo sapiens; a Review of the Consdierable Within-Species Diversity,” Nucleic Acids Res., 16(17):8207-8211.Applicant

Simonsen et al., (1983), “Isolation and Expression of an Altered Mouse Dihydrofolate Reductase cDNA,” Proc. Natl. Acad. Sci. USA, 80:2495-2499.Applicant

Smith et al., (1981), “Identification of Common Molecular Subsequences,” J. Mol. Biol., 147:195-197.Applicant

Soligo et al., (1998), “Expansion of Dendritic Cells Derived from Human CD34+ Cells in Static And Continuous Perfusion Cultures,” Br. J. Haematol., 101:352-63.Applicant

Spivak et al., (1989), “The In Vivo Metabolism of Recombinant Human Erythropoietin in the Rat,” Blood, 73:90-9.Applicant

Stumiolo et al., (1999), “Generation of Tissue-Specific and Promiscuous HLA Ligand Databases Using DNA Microarrays and Virtual HLA Class II Matrices,” Nat. Biotech., 17(6):555-61.Applicant

Suliman et al., (1996), “Cloning of a cDNA Encoding Bovine Erythropoietin and Analysis of Its Transcription in Selected Tissues,” Gene, 171:275-80.Applicant

Takahashi et al., (2000), “Immunologic Self-Tolerance Maintained by CD25+ CD+ Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte-Associated Antigen 4,” J. Exp. Med., 192(2):303-309.Applicant

Takai, (2002), “Roles of Fc Receptors in Autoimmunity,” Nature, 2:580-592.Applicant

Taniguchi et al., (1980), “Expression of the Human Fibroblast Interferon Gene in Escherichia coli,” Proc. Natl. Acad. Sci. USA, 77:5230-5233.Applicant

Thumer, (1999), “Generation of Large Numbers of Fully Mature and Stable Dendritic Cells from Leukapheresis Products for Clinical Application,” J. Immunol. Methods, 223:1-15.Applicant

Tiruppathi et al., (1996), “Isolation and Characterization of a Cell Surface Albumin-Binding Protein from Vascular Endothelial Cells,” Proc. Nat. Acad. Sci. USA, 93:250-4.Applicant

Van Den Eynde et al., (1989), “Presence on a Human Melanoma of Multiple Antigens Recognized By Autologous CTL,” Int. J. Cancer, 44:634-40.Applicant

Van Der Bruggen et al., (1991), “A Gene Encoding an Antigen Recognized by Cytolytic T Lymphocytes on a Human Melanoma,” Science, 254:1643-7.Applicant

Van Heyningen et al., (1982), “Human MHC Class II Molecules as Differentiation Markers,” Immunogenetics, 16:459-69.Applicant

Voest et al., (1995), “Inhibition of Angiogenesis in Vivo by Interleukin 12,” J. Natl. Canc. Inst., 87:581-6.Applicant

Von Heijne et al., (1986), “A New Method for Predicting Signal Sequence Cleavage Sites,” Nucleic Acid Res., 14:4683-4690.Applicant

Ward et al., (1995), “The Effector Functions of Immunoglobulins: Implications for Therapy,” Therapeutic. Immunology, 2:77-94.Applicant

Watson et al., (1984), “Compilation of Published Signal Sequences,” Nucleic Acid Res., 12:5145-5164.Applicant

Weitkamp et al., (1973), “Additional Data on the Population Distribution of Human Serum Albumin Genes; Three New Variants,” Ann. Hum. Genet., 37:219-26.Applicant

Wetzel et al., (2001), “BAY50-4798, an Interleukin-2 (IL-2) Variant, Demonstrates Selective Activation of Human and Chipanzee T Cells Relative to NK Cells but Shows Less Selectivity for T Cells from Monkeys and Rodents,” 2001 ASCO Annual Meeting.Applicant

Woof et al., (1986), “Localisation of the Monocyte-Binding Region on Human Immunoglobulin G,” Mol. Immunol., 23:319-30.Applicant

Wyatt et al., (1998), “The Antigenic Structure of the HIV gp120 Envelope Glycoprotein,” Nature, 393:705-11.Applicant

Wysocka et al., (1995), “Interleukin-12 is Required for Interferon-γ Production and Lethality in Lipopolysaccharide-Induced Shock in Mice,” Eur. J. Immunol., 25:672-6.Applicant

Yan et al., (1996), “Characterization of an Ig VH Idiotope that Results in Specific Homophilic Binding and Increased Avidity for Antigen,” J. Immunol., 157:1582-8.Applicant

Yeh et al., (1992), “Design of Yeast-Secreted Albumin Derivatives for Human Therapy: Biological and Antiviral Properties of a Serum Albumin-CD4 Genetic Conjugate,” Proc. Natl. Acad. Sci. USA, 89:1904-8.Applicant

Zhang et al., (1994), “Structure/Activity Analysis of Human Monocyte Chemoattractant Protein-1 (MCP-1) by Mutagenesis,” J. Biol. Chem., 269:15918-24.Applicant

Zhu et al., (2001), “MHC Class I-Related Neonatal Fc Receptor for IgG Is Functionally Expressed in Monocytes, Intestinal Macrophages, and Dendritic Cells,” J. Immunol., 166:3266-3276.Applicant

Zuckier et al., (1998), “Chimeric Human-Mouse IgG Antibodies with Shuffled Constant Region Exons Demonstrate that Multiple Domains Contribute to In Vivo Half-Life,” Cancer Res., 58(17):3905-8.Applicant