US 12,060,432 B2Grant

Combination therapies with anti-CD38 antibodies

Issue Date:2024-08-13

•20 Claims

•6 Drawing Sheets

Abstract

The present invention relates to combination therapies with anti-CD38 antibodies.

Metadata

Assignee

JANSSEN BIOTECH, INC.

Inventor

Parul Doshi

Application Information

Application Number:US 17/015,017

Filing Date:2020-09-08

Priority Date:2014-02-28

Art Unit:RD00

Classifications

IPC:

A61K39/00A61K31/00A61K31/4745A61K31/475A61K31/573A61K31/65A61K31/675A61K31/704A61K39/395C07K16/28

Field of Search:

A61K 39/39558A61K 39/001126C07K 2317/732C07K 2317/734A61P 35/00A61P 35/02

Patent Drawings (6 sheets)

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 15/445,225, filed on Feb. 28, 2017, which is a continuation of U.S. application Ser. No. 14/629,941, filed on Feb. 24, 2015, issued as U.S. Pat. No. 9,603,927, which claims the benefit of U.S. Provisional Application No. 61/946,002, filed on Feb. 28, 2014 and U.S. Provisional Application No. 62/006,386, filed on Jun. 2, 2014. The entire teachings of the above applications are incorporated herein by reference.

INCORPORATION BY REFERENCE OF MATERIAL IN ASCII TEXT FILE

[0002] This application incorporates by reference the Sequence Listing contained in the following ASCII text file being submitted concurrently herewith:

- [0003] a) File name: 01482026005_SEQUENCELISTING.txt; created on Sep. 4, 2020, 19 KB in size.

FIELD OF THE INVENTION

[0004] The present invention relates to combination therapies with anti-CD38 antibodies.

BACKGROUND OF THE INVENTION

[0005] CD38 is a multifunctional protein having function in receptor-mediated adhesion and signaling as well as mediating calcium mobilization via its ecto-enzymatic activity, catalyzing formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al., J Immunolog 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38, via its NAD glycohydrolase activity, also regulates extracellular NAD⁺ levels, which have been implicated in modulating the regulatory T-cell compartment (Adriouch et al., 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to signaling via Ca²⁺, CD38 signaling occurs via cross-talk with antigen-receptor complexes on T- and B-cells or other types of receptor complexes, e.g., MHC molecules, involving CD38 in several cellular responses, but also in switching and secretion of IgG1.

[0006] CD38 is a type II transmembrane glycoprotein expressed on hemopoietic cells such as medullary thymocytes, activated T- and B-cells, resting NK cells and monocytes, lymph node germinal center lymphoblasts, plasma B cells, intrafollicular cells and dendritic cells. A portion of normal bone marrow cells, particular precursor cells as well as unbilical cord cells are CD38-positive. In addition to lymphoid precursor cells, CD38 is expressed on erythrocytes and on platelets, and expression is also found in some solid tissues such as gut, brain, prostate, bone, and pancreas. Mature resting T- and B-cells express limited to no surface CD38.

[0007] CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma, leukemias and lymphomas, such as B-cell chronic lymphocytic leukemia, T- and B-cell acute lymphocytic leukemia, Waldenstrom macroglobulinemia, primary systemic amyloidosis, mantle-cell lymphoma, pro-lymphocytic/myelocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, follicular lymphoma, Burkitt's lymphoma, large granular lymphocytic (LGL) leukemia, NK-cell leukemia and plasma-cell leukemia. Expression of CD38 has been described on epithelial/endothelial cells of different origin, including glandular epithelium in prostate, islet cells in pancreas, ductal epithelium in glands, including parotid gland, bronchial epithelial cells, cells in testis and ovary and tumor epithelium in colorectal adenocarcinoma. Other diseases, where CD38 expression may be involved, include, e.g., broncho-epithelial carcinomas of the lung, breast cancer (evolving from malignant proliferation of epithelial lining in ducts and lobules of the breast), pancreatic tumors evolving from the β-cells (insulinomas), tumors evolving from epithelium in the gut (e.g., adenocarcinoma and squamous cell carcinoma), carcinoma in the prostate gland, and seminomas in testis and ovarian cancers. In the central nervous system, neuroblastomas express CD38.

[0008] B-cell malignancies may arise in all lymphoid tissues where B-cells are normally being produced. Most patients with B-cell malignancies are initially diagnosed with disease involving bone marrow or lymph nodes. In the case of bone marrow involvement, the transformed B cells frequently circulate through the blood and become widely disseminated throughout peripheral lymphoid tissues. However, B-cell malignancies may also arise in some nonlymphoid tissues such as the thyroid, gastrointestinal tract, salivary glands and conjunctiva.

[0009] Well known B-cell malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, hairy cell leukemia, primary effusion lymphoma and AIDS-related Non-Hodgkin's Lymphoma (NHL). B-cell malignancies comprise more than 85% of diagnosed lymphomas.

[0010] NHL is a broad classification of lymphomas originating from the lymphatic system when lymphocytes (B-cells or T-cells) become malignant and proliferate uncontrollably to form a tumor mass. In total, NHL encompasses around 30 different subtypes of lymphoma with a range of phenotypes and prognoses. It is projected that the incidence of NHL will reach over 140,000 in the major market countries by 2019.

[0011] Diffuse Large B-cell Lymphoma (DLBCL) is an aggressive most common subtype of NHL, accounting for 30-40% of lymphoid malignancy, and encompasses a biologically and clinically diverse set of diseases. Gene expression profiling studies suggest that DLBCL can be separated into two groups on the basis of gene expression profiles; these groups are known as germinal center B-cell like (GCB) and activated B-cell-like (ABC) lymphomas.

[0012] The standard of care for treatment of DLBCL is commonly called CHOP, a combination of cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone, or R-CHOP, a combination of anti-CD20 antibody rituximab and CHOP. In addition, following remission, hematopoietic stem cell transplantation may be considered.

[0013] Despite the current treatment options, the survival rates within high risk groups of aggressive NHL can be as low as 30% over 5 years. Therefore, there is a need for effective treatments and combination treatments for NHL and B-cell malignancies.

SUMMARY OF THE INVENTION

[0014] One embodiment of the invention is a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces killing of CD38-expressing cells in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or modulation of CD38 enzymatic activity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. 1A shows efficacy of daratumumab in a patient-derived model of diffuse large B-cell lymphoma (DLBCL) alone or in combination of CHOP or R-CHOP. Resected DLBCL tumors were implanted in SCID/Beige mice. Treatments were initiated when the tumors reached approximately 125-250 mm³. Daratumumab was administered at 20 mg/kg once a week for three weeks. CHOP and R-CHOP were administered once on day 0 except prednisone was administered on days 0-4 using the following regimens: CHOP: (cyclophosphoamide (CTX): 30 mg/kg i.v.; doxorubicin: 2.5 mg/kg i.v; vincristine: 0.4 mg/kg i.v); prednisone: 0.15 mg/kg p.o; R-CHOP: rituximab 20 mg/kg i.p. DAY 0. Tumor volume was measured every three days. The Y-axis represents tumor volume±SEM.

[0016] FIG. 1B shows the median survival time plotted against days after tumor inoculation of the study of FIG. 1A.

[0017] FIG. 2 shows efficacy of daratumumab in a preclinical model of non-Hodgkin's lymphoma alone or in combination with CHOP. 2×10⁵NAMALWA cells in matrigel were implanted into NOD SCID mice and treatment initiated when the main tumor size reached approximately 189 mm³. Daratumumab was administered at 10 mg/kg once a week for three weeks. CHOP was administered daily on days 0-5 using following doses: cyclophosphoamide (CTX): 5 mg/kg i.v.; doxorubicin: 0.5 mg/kg i.v; vincristine: 0.08 mg/kg i.v., prednisone: 0.03 mg/kg p.o. Tumor volume was measured every three days. The Y-axis represents tumor volume±SEM

[0018] FIG. 3 shows efficacy of of daratumumab in a preclinical model of DLBCL alone or in combination with CHOP. 5×10⁶SU-DHL-6 cells were implanted into NOD SCID mice and treatment initiated when the main tumor size reached approximately 154 mm³. Daratumumab was administered at 10 mg/kg once a week for four weeks. CHOP was administered daily on days 0-5 using following doses: cyclophosphoamide (CTX): 5 mg/kg i.v.; doxorubicin: 0.5 mg/kg i.v; vincristine: 0.08 mg/kg i.v., prednisone: 0.03 mg/kg p.o. Tumor size was plotted as Mean±SEM.

[0019] FIG. 4 shows efficacy of daratumumab in a patient-derived model of diffuse large B-cell lymphoma (DLBCL) in combination with CHOP or R-CHOP administered simultaneously or sequentially up to day 45 of the study. Daratumumab was administered at 20 mg/kg once a week for three weeks at day 0 or at day 7. CHOP was administered once on day 0 except prednisone was administered on days 0-4 using following regimens: CHOP: (cyclophosphoamide (CTX): 30 mg/kg i.v.; doxorubicin: 2.5 mg/kg i.v; vincristine: 0.4 mg/kg i.v); prednisone: 0.15 mg/kg p.o. Rituximab was administered at 20 mg/kg i.p. at either day 0 or day 7. Tumor size was plotted as Mean±SEM. CNTO3930: isotype control. Values in parenthesis indicate the day of dosing. The data represents results from an ongoing study at day 44.

[0020] FIG. 5 shows efficacy of daratumumab in a patient-derived model of DLBCL in combination with CHOP or R-CHOP administered simultaneously or sequentially up to day 101 of the study. Dosing was as in FIG. 4. Tumor size was plotted as Mean±SEM. CNTO3930: isotype control. Values in parenthesis indicate the day of dosing. Statistical differences in tumor volume were determined using a two-tailed, one-way ANOVA followed by Dunnett's multiple comparisons test comparing treated single-agent groups with control and combinations with standard agent. *P<0.05 versus control, †P<0.05 versus CHOP, cyclophospharnide, doxorubicin, vincristine, and prednisone; DLBCL, diffuse large B-cell lymphoma. IHC, immunohistochemistry; i.v., intravenous; i.p., intraperitoneal.

DETAILED DESCRIPTION OF THE INVENTION

[0021] “CD38” refers to the human CD38 protein (synonyms: ADP-ribosyl cyclase 1, cADPr hydrolase 1, Cyclic ADP-ribose hydrolase 1). Human CD38 has an amino acid sequence shown in SEQ ID NO: 1.

[0022] The term “antibodies” as used herein is meant in a broad sense and includes immunoglobulin molecules including polyclonal antibodies, monoclonal antibodies including murine, human, human-adapted, humanized and chimeric monoclonal antibodies, antibody fragments, bispecific or multispecific antibodies, dimeric, tetrameric or multimeric antibodies, and single chain antibodies.

[0023] Immunoglobulins can be assigned to five major classes, namely IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA₁, IgA₂, IgG₁, IgG₂, IgG₃and IgG₄. Antibody light chains of any vertebrate species can be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains.

[0024] The term “antibody fragments” refers to a portion of an immunoglobulin molecule that retains the heavy chain and/or the light chain antigen binding site, such as heavy chain complementarity determining regions (HCDR) 1, 2 and 3, light chain complementarity determining regions (LCDR) 1, 2 and 3, a heavy chain variable region (VH), or a light chain variable region (VL). Antibody fragments include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; a F(ab)₂fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CHI domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a domain antibody (dAb) fragment (Ward et al., Nature 341:544-546, 1989), which consists of a VH domain. VH and VL domains can be engineered and linked together via a synthetic linker to form various types of single chain antibody designs where the VH/VL domains pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chain antibody constructs, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody; described for example in Intl. Pat. Publ. Nos. WO1998/44001, WO1988/01649, WO1994/13804, and WO1992/01047. These antibody fragments are obtained using well known techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are full length antibodies.

[0025] The phrase “isolated antibody” refers to an antibody or antibody fragment that is substantially free of other antibodies having different antigenic specificities (e.g., an antibody that specifically binds CD38. An isolated antibody that specifically binds CD38, however, can have cross-reactivity to other antigens, such as orthologs of human CD38 such as Macaca fascicularis (cynomolgus) CD38. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0026] An antibody variable region consists of a “framework” region interrupted by three “antigen binding sites”. The antigen binding sites are defined using various terms such as Complementarity Determining Regions (CDRs), three in the VH (HCDR1, HCDR2, HCDR3), and three in the VL (LCDR1, LCDR2, LCDR3), are based on sequence variability (Wu and Kabat J Exp Med 132:211-50, 1970; Kabat et al Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991) or “Hypervariable regions”, “HVR”, or “HV”, three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3), refer to the regions of an antibody variable domains which are hypervariable in structure as defined by Chothia and Lesk (Chothia and Lesk Mol Biol 196:901-17, 1987). Other terms include “IMGT®-CDRs” (Lefranc et al., Dev Comparat Immunol 27:55-77, 2003) and “Specificity Determining Residue Usage” (SDRU) (Almagro, Mol Recognit 17:132-43, 2004). The International ImMunoGeneTics (IMGT®) database (www_imgt_org) provides a standardized numbering and definition of antigen-binding sites. The correspondence between CDRs, HVs and IMGT delineations is described in Lefranc et al., Dev Comparat Immunol 27:55-77, 2003.

[0027] “Chothia residues” as used herein are the antibody VL and VH residues numbered according to Al-Lazikani (Al-Lazikani et al., J Mol Biol 273:927-48, 1997).

[0028] “Framework” or “framework sequences” are the remaining sequences of a variable region other than those defined to be antigen binding sites. Because the antigen binding sites can be defined by various terms as described above, the exact amino acid sequence of a framework depends on how the antigen-binding site was defined.

[0029] “Humanized antibody” refers to an antibody in which the antigen binding sites are derived from non-human species and the variable region frameworks are derived from human immunoglobulin sequences. Humanized antibodies may include substitutions in the framework regions so that the framework may not be an exact copy of expressed human immunoglobulin or germline gene sequences.

[0030] “Human-adapted” antibodies or “human framework adapted (HFA)” antibodies refers to humanized antibodies adapted according to methods described in U.S. Pat. Publ. No. US2009/0118127. Human-adapted antibodies are humanized by selecting the acceptor human frameworks based on the maximum CDR and FR similarities, length compatibilities and sequence similarities of CDR1 and CDR2 loops and a portion of light chain CDR3 loops.

[0031] “Human antibody” refers to an antibody having heavy and light chain variable regions in which both the framework and the antigen binding sites are derived from sequences of human origin. If the antibody contains a constant region, the constant region also is derived from sequences of human origin.

[0032] A human antibody comprises heavy or light chain variable regions that are “derived from” sequences of human origin where the variable regions of the antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such systems include human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice carrying human immunoglobulin loci as described herein. A human antibody may contain amino acid differences when compared to the human germline or rearranged immunoglobulin sequences due to for example naturally occurring somatic mutations or intentional introduction of substitutions in the framework or antigen binding sites. Typically, a human antibody is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical in amino acid sequence to an amino acid sequence encoded by a human germline or rearranged immunoglobulin gene. In some cases, a human antibody may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., J Mol Biol 296:57-86, 2000), or synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., J Mol Biol 397:385-96, 2010 and Intl. Pat. Publ. No. WO2009/085462). Antibodies in which antigen binding sites are derived from a non-human species are not included in the definition of human antibody.

[0033] Isolated humanized antibodies may be synthetic. Human antibodies, while derived from human immunoglobulin sequences, may be generated using systems such as phage display incorporating synthetic CDRs and/or synthetic frameworks, or can be subjected to in vitro mutagenesis to improve antibody properties, resulting in antibodies that do not naturally exist within the human antibody germline repertoire in vivo.

[0034] The term “recombinant antibody” as used herein, includes all antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom (described further below), antibodies isolated from a host cell transformed to express the antibody, antibodies isolated from a recombinant combinatorial antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences, or antibodies that are generated in vitro using Fab arm exchange such as bispecific antibodies.

[0035] The term “monoclonal antibody” as used herein refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope, or in a case of a bispecific monoclonal antibody, a dual binding specificity to two distinct epitopes.

[0036] The term “epitope” as used herein means a portion of an antigen to which an antibody specifically binds. Epitopes usually consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope can be composed of contiguous and/or discontiguous amino acids that form a conformational spatial unit. For a discontiguous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3-dimensional space through the folding of the protein molecule.

[0037] “Variant” as used herein refers to a polypeptide or a polynucleotide that differs from a reference polypeptide or a reference polynucleotide by one or more modifications for example, substitutions, insertions or deletions.

[0038] “Synergy”, “synergism” or “synergistic” mean more than the expected additive effect of a combination.

[0039] The term “in combination with” as used herein means that two or more therapeutics can be administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0040] The terms “treat” or “treatment” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of tumor or tumor cells. Beneficial or desired clinical results include alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if a subject was not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0041] “Inhibits growth” (e.g., referring to cells, such as tumor cells) refers to a measurable decrease in the cell growth in vitro or in vivo when contacted with a therapeutic or a combination of therapeutics or drugs when compared to the growth of the same cells grown in appropriate control conditions well known to the skilled in the art. Inhibition of growth of a cell in vitro or in vivo may be at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. Inhibition of cell growth can occur by a variety of mechanisms, for example by antibody-dependent cell-mediated toxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, necrosis, or inhibition of cell proliferation.

[0042] A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response in the individual. Exemplary indicators of an effective therapeutic or combination of therapeutics that include, for example, improved well-being of the patient, reduction of a tumor burden, arrested or slowed growth of a tumor, and/or absence of metastasis of cancer cells to other locations in the body.

[0043] The invention provides methods for treating patients having CD38-positive hematological malignancy. The invention is based on the discovery that an anti-CD38 antibody administered in combination with CHOP or R-CHOP provides a synergistically potent therapeutic efficacy in vivo in relevant tumor models of hematological malignancy.

[0044] One embodiment of the invention disclosed herein, including in the numbered embodiments listed below, is a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces killing of CD38-expressing cells in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or modulation of CD38 enzymatic activity.

[0045] In some embodiments of the invention disclosed herein, including in the numbered embodiments listed below, the anti-CD38 antibody induces in vitro killing of the CD38-expressing cells by ADCC or CDC.

[0046] “CD38-positive hematological malignancy” refers to a hematological malignancy characterized by the presence of tumor cells expressing CD38 including leukemias, lymphomas and myeloma. Examples of such CD38-positive hematological malingancies include precursor B-cell lymphoblastic leukemia/lymphoma and B-cell non-Hodgkin's lymphoma; acute promyelocytic leukemia, acute lymphoblastic leukemia and mature B-cell neoplasms, such as B-cell chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), B-cell acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma (FL), including low-grade, intermediate-grade and high-grade FL, cutaneous follicle center lymphoma, marginal zone B-cell lymphoma (MALT type, nodal and splenic type), hairy cell leukemia, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), plasmacytoma, multiple myeloma, plasma cell leukemia, post-transplant lymphoproliferative disorder, Waldenstrom's macroglobulinemia, plasma cell leukemias and anaplastic large-cell lymphoma (ALCL).

[0047] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is multiple myeloma.

[0048] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is diffuse large B-cell lymphoma (DLBCL).

[0049] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is non-Hodgkin's lymphoma.

[0050] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is acute lymphoblastic leukemia (ALL).

[0051] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is follicular lymphoma (FL).

[0052] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is Burkitt's lymphoma (BL).

[0053] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD-38 positive hematological malignancy is mantle cell lymphoma (MCL).

[0054] In one embodiment of the invention disclosed herein, including in the numbered embodiments listed below, the CD38-positive hematological malignancy is multiple myeloma, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL) or mantle-cell lymphoma (MCL).

[0055] Examples of B-cell non-Hodgkin's lymphomas are lymphomatoid granulomatosis, primary effusion lymphoma, intravascular large B-cell lymphoma, mediastinal large B-cell lymphoma, heavy chain diseases (including γ, μ, and a disease), lymphomas induced by therapy with immunosuppressive agents, such as cyclosporine-induced lymphoma, and methotrexate-induced lymphoma.

[0056] In one embodiment of the present invention, including in the numbered embodiments listed below the disorder involving cells expressing CD38 is Hodgkin's lymphoma.

[0057] Other examples of disorders involving cells expressing CD38 include malignancies derived from T and NK cells including: mature T cell and NK cell neoplasms including T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T cell lymphoma, nasal type, 78 enteropathy-type T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, blastic NK cell lymphoma, Mycosis Fungoides/Sezary Syndrome, primary cutaneous CD30 positive T-cell lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma C-ALCL, lymphomatoid papulosis, borderline lesions), angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma unspecified, and anaplastic large cell lymphoma.

[0058] Examples of malignancies derived from myeloid cells include acute myeloid leukemia, including acute promyelocytic leukemia, and chronic myeloproliferative diseases, including chronic myeloid leukemia.

[0059] Any anti-CD38 antibody may be used in the methods of the invention as disclosed herein, including in the numbered embodiments listed below, provided that the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or modulation of CD38 enzymatic activity. The variable regions of the anti-CD38 antibodies may be obtained from existing anti-CD38 antibodies, and cloned as full length antibodies using standard methods. Exemplary variable regions binding CD38 that may be used are described, e.g., in Intl. Pat. Publ. Nos. WO05/103083, WO06/125640, WO07/042309, WO08/047242, WO12/092612, WO06/099875 and WO11/154453A1.

[0060] An exemplary anti-CD38 antibody that may be used is daratumumab. Daratumumab comprises heavy chain variable region (VH) and a light chain variable region (VL) amino acid sequences shown in SEQ ID NO: 4 and 5, respectively, heavy chain CDRs HCDR1, HCDR2 and HCDR3 of SEQ ID NOs: 6, 7 and 8, respectively, and light chain CDRs LCDR1, LCDR2 and LCDR3 of SEQ ID NOs: 9, 10 and 11, respectively, and is of IgG1/κ subtype. Daratumumab heavy chain amino acid sequence is shown in SEQ ID NO: 12 and light chain amino acid sequence shown in SEQ ID NO: 13.

[0061]

SEQ ID NO: 1

MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQW

SGPGTTKRFPETVLARCVKYTEIHPEIVIRHVDCQSVWDAFKGAFISKHP

CNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDT

LLGYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAE

AACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGRE

DSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTS

SEQ ID NO: 2

SKRNIQFSCKNIYR

SEQ ID NO: 3

EKVQTLEAWVIHGG

SEQ ID NO: 4

EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSA

ISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDK

ILWFGEPVFDYWGQGTLVTVSS

SEQ ID NO: 5

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQ

GTKVEIK

SEQ ID NO: 6

SFAMS

SEQ ID NO: 7

AISGSGGGTYYADSVKG

SEQ ID NO: 8

DKILWFGEPVFDY

SEQ ID NO: 9

RASQSVSSYLA

SEQ ID NO: 10

DASNRAT

SEQ ID NO: 11

QQRSNWPPTF

SEQ ID NO: 12

EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVS

AISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAK

DKILWFGEPVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAAL

GCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS

SLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSV

FLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKT

KPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK

AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY

TQKSLSLSPGK

SEQ ID NO: 13

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIY

DASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTF

GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQ

WKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV

THQGLSSPVTKSFNRGEC

[0062] Another exemplary anti-CD38 antibody that may be used is mAb003 comprising the VH and VL sequences of SEQ ID NOs: 14 and 15, respectively and described in U.S. Pat. No. 7,829,693.

[0063]

SEQ ID NO: 14

QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGR

VIPFLGIANSAQKFQGRVTITADKSTSTAY

MDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS

SEQ ID NO: 15

DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYA

ASSLQSGVPSRFSGSGSGTDFTLTISSLQP

EDFATYYCQQYNSYPRTFGQGTKVEIK

[0064] Another exemplary anti-CD38 antibody that may be used is mAb024 comprising the VH and VL sequences of SEQ ID NOs: 16 and 17, respectively, described in U.S. Pat. No. 7,829,693.

[0065]

SEQ ID NO: 16

EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGI

IYPHDSDARYSPSFQGQVTFSADKSISTAY

LQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS

SEQ ID NO: 17

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYD

ASNRATGIPARFSGSGSGTDFTLTISSLEP

EDFAVYYCQQRSNWPPTFGQGTKVEIK

[0066] Another exemplary anti-CD38 antibody that may be used is MOR-202 (MOR-03087) comprising the VH and VL sequences of SEQ ID NOs: 18 and 19, respectively, described in U.S. Pat. No. 8,088,896.

[0067]

SEQ ID NO: 18

QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSG

ISGDPSNTYYADSVKGRFTISRDNSKNTLY

LQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS

SEQ ID NO: 19

DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGD

SKRPSGIPERFSGSNSGNTATLTISGTQAE

DEADYYCQTYTGGASLVFGGGTKLTVLGQ

[0068] Anti-CD38 antibodies used in the methods of the invention disclosed herein, including in the numbered embodiments listed below, may also be selected de novo from, e.g., a phage display library, where the phage is engineered to express human immunoglobulins or portions thereof such as Fabs, single chain antibodies (scFv), or unpaired or paired antibody variable regions (Knappik et al., J Mol Biol 296:57-86, 2000; Krebs et al., J Immunol Meth 254:67-84, 2001; Vaughan et al., Nature Biotechnology 14:309-314, 1996; Sheets et al., PITAS (USA) 95:6157-6162, 1998; Hoogenboom and Winter, J Mol Biol 227:381, 1991; Marks et al., J Mol Biol 222:581, 1991). CD38 binding variable domains may be isolated from e.g., phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage pIX coat protein as described in Shi et al., J. Mol. Biol. 397:385-96, 2010 and PCT Intl. Publ. No. WO09/085462). The antibody libraries can be screened for binding to human CD38 extracellular domain, obtained positive clones further characterized, Fabs isolated from the clone lysates, and subsequentely cloned as full length antibodies. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698, 5,427,908, 5,580,717, 5,969,108, 6,172,197, 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915; and 6,593,081.

[0069] The Fc portion of the antibody may mediate antibody effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complement dependent cytotoxicity (CDC). Such functions may be mediated by binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system. Typically, the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of target cells, e.g., CD38-expressing cells. Human IgG isotypes IgG1, IgG2, IgG3 and IgG4 exhibit differential capacity for effector functions. ADCC may be mediated by IgG1 and IgG3, ADCP may be mediated by IgG1, IgG2, IgG3 and IgG4, and CDC may be mediated by IgG1 and IgG3.

[0070] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.

[0071] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by ADCC.

[0072] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by CDC.

[0073] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody induces killing of CD38-expressing cells by ADCP in vitro.

[0074] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody induces killing of CD38-expressing cells by apoptosis in vitro.

[0075] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody induces killing of CD38-expressing cells by ADCC and CDC in vitro.

[0076] While not wishing to be bound to any particular theory on mechanism of action, it is expected that the anti-CD38 antibody of the invention will induce in vivo killing of CD38-expressing cells by ADCC, CDC, ADCP, apoptosis or in vivo modulation of CD38 enzymatic activity.

[0077] “Antibody-dependent cellular cytotoxicity,” or “antibody-dependent cell-mediated cytotoxicity” or “ADCC” is a mechanism for inducing cell death that depends upon the interaction of antibody-coated target cells with effector cells possessing lytic activity, such as natural killer cells, monocytes, macrophages and neutrophils via Fc gamma receptors (FcγR) expressed on effector cells. For example, NK cells express FcγRIIIa, whereas monocytes express FcγRI, FcγRII and FcvRIIIa. Death of the antibody-coated target cell, such as CD38-expressing cells, occurs as a result of effector cell activity through the secretion of membrane pore-forming proteins and proteases. To assess ADCC activity of an anti-CD38 antibody in vitro, the antibody may be added to CD38-expressing cells in combination with immune effector cells, which may be activated by the antigen antibody complexes resulting in cytolysis of the target cell. Cytolysis is generally detected by the release of label (e.g., radioactive substrates, fluorescent dyes or natural intracellular proteins) from the lysed cells. Exemplary effector cells for such assays include peripheral blood mononuclear cells (PBMC) and NK cells. Exemplary target cells include Daudi cells (ATCC® CCL-213™) or B cell leukemia or lymphoma tumor cells expressing CD38. In an exemplary assay, target cells are labeled with 20 μCi of ⁵¹Cr for 2 hours and washed extensively. Cell concentration of the target cells can be adjusted to 1×10⁶cells/ml, and anti-CD38 antibodies at various concentrations are added. Assays are started by adding Daudi cells at an effector:target cell ratio of 40:1. After incubation for 3 hr at 37° C. assays are stopped by centrifugation, and ⁵¹Cr release from lysed cells are measured in a scintillation counter. Percentage of cellular cytotoxicity may be calculated as % maximal lysis which may be induced by adding 3% perchloric acid to target cells. Anti-CD38 antibodies used in the methods of the invention may induce ADCC by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of control (cell lysis induced by 3% perchloric acid).

[0078] “Antibody-dependent cellular phagocytosis” (“ADCP”) refers to a mechanism of elimination of antibody-coated target cells by internalization by phagocytic cells, such as macrophages or dentricit cells. In vitro ADCP may be evaluated by using monocyte-derived macrophages as effector cells and Daudi cells (ATCC® CCL-213™) or B cell leukemia or lymphoma tumor cells expressing CD38 as target cells engineered to express GFP or other labeled molecule. Effctor:target cell ratio may be for example 4:1. Effector cells may be incubated with target cells for 4 hours with or without anti-CD38 antibody. After incubation, cells may be detached using accutase. Macrophages can be identified with anti-CD11b and anti-CD14 antibodies coupled to a fluorescent label, and percent phagocytosis can be determined based on % GFP fluorescent in the CD11⁺CD14⁺ macrophages using standard methods. Anti-CD38 antibodies used in the methods of the invention may induce ADCP by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0079] “Complement-dependent cytotoxicity”, or “CDC”, refers to a mechanism for inducing cell death in which an Fc effector domain of a target-bound antibody binds and activates complement component C1q which in turn activates the complement cascade leading to target cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes. CDC of CD38-expressing cells can be measured in vitro for example by plating Daudi cells at 1×10⁵cells/well (50 μl/well) in RPMI-B (RPMI supplemented with 1% BSA), adding 50 μl anti-CD38 antibodies to the wells at final concentration between 0-100 μg/ml, incubating the reaction for 15 min at room temperature, adding 11 μl of pooled human serum to the wells, and incubation the reacton for 45 min at 37° C. Percentage (%) lysed cells may be detected as % propidium iodide stained cells in FACS assay using standard methods. Anti-CD38 antibodies used in the methods of the invention may induce CDC by about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%

[0080] The ability of monoclonal antibodies to induce ADCC can be enhanced by engineering their oligosaccharide component. Human IgG1 or IgG3 are N-glycosylated at Asn297 with the majority of the glycans in the well known biantennary G0, G0F, G1, G1F, G2 or G2F forms. Antibodies produced by non-engineered CHO cells typically have a glycan fucose content of about at least 85%. The removal of the core fucose from the biantennary complex-type oligosaccharides attached to the Fc regions enhances the ADCC of antibodies via improved FcγRIIIa binding without altering antigen binding or CDC activity. Such antibodies can be achieved using different methods reported to lead to the expression of relatively high defucosylated antibodies bearing the biantennary complex-type of Fc oligosaccharides such as control of culture osmolality (Konno et al., Cytotechnology 64:249-65, 2012), application of a variant CHO line Lec13 as the host cell line (Shields et al., J Biol Chem 277:26733-40, 2002), application of a variant CHO line EB66 as the host cell line (Olivier et al., MAbs; 2(4), 2010; Epub ahead of print; PMID:20562582), application of a rat hybridoma cell line YB2/0 as the host cell line (Shinkawa et al., J Biol Chem 278:3466-3473, 2003), introduction of small interfering RNA specifically against the α 1,6-fucosyltrasferase (FUT8) gene (Mori et al., Biotechnol Bioeng88:901-908, 2004), or co-expression of β-1,4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II or a potent alpha-mannosidase I inhibitor, kifunensine (Ferrara et al., J Biol Chem281:5032-5036, 2006, Ferrara et al., Biotechnol Bioeng 93:851-861, 2006; Xhou et al., Biotechnol Bioeng 99:652-65, 2008). ADCC elicited by anti-CD38 antibodies used in the methods of the invention, and in some embodiments of each and every one of the numbered embodiments listed below, may also be enhanced by certain substitutions in the antibody Fc. Exemplary substitutions are, for example, substitutions at amino acid positions 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430 (residue numbering according to the EU index) as described in U.S. Pat. No. 6,737,056.

[0081] In some methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibodies comprise a substitution in the antibody Fc.

[0082] In some methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibodies comprise a substitution in the antibody Fc at amino acid positions 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430 (residue numbering according to the EU index).

[0083] Another embodiment of the invention, including in the numbered embodiments listed below, is a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, wherein the anti-CD38 antibody competes for binding to CD38 with an antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5 (daratumumab).

[0084] Antibodies can be evaluated for their competition with daratumumab having VH of SEQ ID NO: 4 and VL of SEQ ID NO: 5 for binding to CD38 using well known in vitro methods. In an exemplary method, CHO cells recombinantly expressing CD38 may be incubated with unlabeled daratumumab for 15 min at 4° C., followed by incubation with an excess of fluorescently labeled test antibody for 45 min at 4° C. After washing in PBS/BSA, fluorescence may be measured by flow cytometry using standard methods. In another exemplary method, extracellular portion of human CD38 may be coated on the surface of an ELISA plate. Excess of unlabelled daratumumab may be added for about 15 minutes and subsequently biotinylated test antibodies may be added. After washes in PBS/Tween, binding of the test biotinylated antibodies may be detected using horseradish peroxidase (HRP)-conjugated streptavidine and the signal detected using standard methods. It is readily apparent that in the competition assays, daratumumab may be labelled and the test antibody unlabeled. The test antibody competes with daratumumab when daratumumab inhibits binding of the test antibody, or the test antibody inhibits binding of daratumumab by 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95% or 100%. The epitope of the test antibody can further be defined, for example, by peptide mapping or hydrogen/deuterium protection assays using known methods.

[0085] Another embodiment of the invention disclosed herein, including in the numbered embodiments listed below, is a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody that binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1) in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity. The epitope of the antibody includes some or all of the residues in these regions having the sequences shown in SEQ ID NO: 2 or SEQ ID NO: 3. In some embodiments disclosed herein, including in the numbered embodiments listed below, the antibody epitope comprises at least one amino acid in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and at least one amino acid in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). In some embodiments disclosed herein, including in the numbered embodiments listed below, the antibody epitope comprises at least two amino acids in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and at least two amino acids in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). In some embodiments disclosed herein, including in the numbered embodiments listed below, the antibody epitope comprises at least three amino acids in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and at least three amino acids in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). In some embodiments disclosed herein, including in the numbered embodiments listed below, the anti-CD38 antibody binds to an epitope comprising at least KRN in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and comprising at least VQLT (SEQ ID NO: 20) in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[0086] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody binds to an epitope comprising at least KRN in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and comprising at least VQLT (SEQ ID NO: 20) in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[0087] An exemplary antibody that binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1) or minimally to residues KRN and VQLT (SEQ ID NO: 20) as shown above is daratumumab having certain VH, VL and CDR sequences as described above. Antibodies that bind to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1) can be generated, for example, by immunizing mice with peptides having the amino acid sequences shown in SEQ ID NOs: 2 and 3 using standard methods and as described herein. Antibodies can be further evaluated, for example, by assaying competition between daratumumab and a test antibody for binding to CD38 as described above.

[0088] In the methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody can bind human CD38 with a range of affinities (K_D). In one embodiment according to the invention, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody binds to CD38 with high affinity, for example, with a K_Dequal to or less than about 10⁻M, such as but not limited to, 1-9.9 (or any range or value therein, such as 1, 2, 3, 4, 5, 6, 7, 8, or 9)×10⁻⁸, 10⁻⁹, 10⁻¹⁰, 10⁻¹¹, 10⁻¹², 10⁻¹³, 10¹⁴, 10⁻¹⁵or any range or value therein, as determined by surface plasmon resonance or the KINEXA® method, as practiced by those of skill in the art. One exemplary affinity is equal to or less than 1×10⁻⁸M. Another exemplary affinity is equal to or less than 1×10⁻⁹M.

[0089] In some methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody has a a biantennary glycan structure with fucose content of about between 0% to about 15%, for example 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%.

[0090] In some methods described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody has a a biantennary glycan structure with fucose content of about 50%, 40%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%

[0091] Substitutions in the Fc and reduced fucose content may enhance the ADCC activity of the anti-CD38 antibody.

[0092] “Fucose content” means the amount of the fucose monosaccharide within the sugar chain at Asn297. The relative amount of fucose is the percentage of fucose-containing structures related to all glycostructures. These may be characterized and quantified by multiple methods, for example: 1) using MALDI-TOF of N-glycosidase F treated sample (e.g. complex, hybrid and oligo- and high-mannose structures) as described in Int Pat. Publ. No. WO2008/077546; 2) by enzymatic release of the Asn297 glycans with subsequent derivatization and detection/quantitation by HPLC (UPLC) with fluorescence detection and/or HPLC-MS (UPLC-MS); 3) intact protein analysis of the native or reduced mAb, with or without treatment of the Asn297 glycans with Endo S or other enzyme that cleaves between the first and the second GlcNAc monosaccharides, leaving the fucose attached to the first GlcNAc; 4) digestion of the mAb to constituent peptides by enzymatic digestion (e.g., trypsin or endopeptidase Lys-C), and subsequent separation, detection and quantitation by HPLC-MS (UPLC-MS); or 5) separation of the mAb oligosaccharides from the mAb protein by specific enzymatic deglycosylation with PNGase F at Asn 297. The oligosaccharides released may be labeled with a fluorophore, separated and identified by various complementary techniques which allow fine characterization of the glycan structures by matrix-assisted laser desorption ionization (MALDI) mass spectrometry by comparison of the experimental masses with the theoretical masses, determination of the degree of sialylation by ion exchange HPLC (GlycoSep C), separation and quantification of the oligosacharride forms according to hydrophilicity criteria by normal-phase HPLC (GlycoSep N), and separation and quantification of the oligosaccharides by high performance capillary electrophoresis-laser induced fluorescence (HPCE-LIF).

[0093] “Low fucose” or “low fucose content” as used in the application refers to antibodies with fucose content of about 0%-15%.

[0094] “Normal fucose” or ‘normal fucose content” as used herein refers to antibodies with fucose content of about over 50%, typically about over 60%, 70%, 80% or over 85%.

[0095] The anti-CD38 antibodies used in the methods, and in some embodiments of each and every one of the numbered embodiments listed below, may induce CD38-positive cell killing in vitro by apoptosis. Methods for evaluating apoptosis are well known, and include for example annexin IV staining using standard methods. The anti-CD38 antibodies used in the methods of the invention may induce apoptosis in about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% of cells.

[0096] The anti-CD38 antibodies used in the methods, and in some embodiments of each and every one of the numbered embodiments listed below, may induce CD38-positive cell killing by modulation of CD38 enzymatic activity. CD38 is a multifunctional ectoenzme with ADP-ribosyl cyclase 1 activity catalyzing the formation of cyclic ADP-ribose (cADPR) and ADPR from NAD⁺, and also functions to hydrolyze NAD⁺ and cADPR to ADPR. CD38 also catalyzes the exchange of the nicotinamide group of NADP⁺ with nicotinic acid under acidic conditions, to yield NAADP⁺ (nicotinic acid-adenine dinucleotide phosphate). Modulation of the enzymatic activity of human CD38 with anti-CD38 antibodies used in the methods of the invention may be measured in an assay described in Graeff et al., J. Biol. Chem. 269, 30260-30267 (1994). For example, substrate NGD⁺ may be incubated with CD38, and the modulation of the production of cyclic GDP-ribose (cGDPR) may be monitored spectrophotometrically at excitation at 340 nM and emission at 410 nM at different time points after addition of the antibody at various concentrations. Inhibition of the synthesis of cADPR may be determined according to the HPLC method described in Munshi et al., J. Biol. Chem. 275, 21566-21571 (2000). The anti-CD38 antibodies used in the methods of the invention may inhibit CD38 enzymatic activity by at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%.

[0097] In some methods of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the the anti-CD38 antibody comprises the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively.

[0098] In some methods of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody comprises the light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively.

[0099] In some methods of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5.

[0100] In some methods of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody comprises a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.

[0101] In some methods of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody comprises a heavy chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 12 and a light chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 13.

[0102] Antibodies that are substantially identical to the antibody comprising the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13 may be used in the methods of the invention, and in some embodiments of each and every one of the numbered embodiments listed below. The term “substantially identical” as used herein means that the two antibody heavy chain or light chain amino acid sequences being compared are identical or have “insubstantial differences.” Insubstantial differences are substitutions of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids in an antibody heavy chain or light chain that do not adversely affect antibody properties. Percent identity can be determined for example by pairwise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen, Carlsbad, Calif.). The protein sequences of the present invention can be used as a query sequence to perform a search against public or patent databases to, for example, identify related sequences. Exemplary programs used to perform such searches are the XBLAST or BLASTP programs (www_ncbi_nlm/nih_gov), or the GENOMEQUEST® (GenomeQuest, Westborough, Mass.) suite using the default settings. Exemplary substitutions that can be made to the anti-CD38 antibodies used in the methods of the invention are for example conservative substitutions with an amino acid having similar charge, hydrophobic, or stereochemical characteristics. Conservative substitutions may also be made to improve antibody properties, for example stability or affinity, or to improve antibody effector functions. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid substitutions may be made for example to the heavy or the light chain of the anti-CD38 antibody. Furthermore, any native residue in the heavy or light chain may also be substituted with alanine, as has been previously described for alanine scanning mutagenesis (MacLennan et al., Acta Physiol Scand Suppl 643:55-67, 1998; Sasaki et al., Adv Biophys 35:1-24, 1998). Desired amino acid substitutions may be determined by those skilled in the art at the time such substitutions are desired. Amino acid substitutions may be done for example by PCR mutagenesis (U.S. Pat. No. 4,683,195). Libraries of variants may be generated using well known methods, for example using random (NNK) or non-random codons, for example DVK codons, which encode 11 amino acids (Ala, Cys, Asp, Glu, Gly, Lys, Asn, Arg, Ser, Tyr, Trp) and screening the libraries for variants with desired properties. The generated variants may be tested for their binding to CD38, their ability to induce ADCC, ADCP or apoptosis in vitro using methods described herein.

[0103] In some embodiments, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibody is a bispecific antibody. The VL and/or the VH regions of the existing anti-CD38 antibodies or the VL and VH regions identified de novo as described above may be engineered into bispecific full length antibodies. Such bispecific antibodies may be made by modulating the CH3 interactions between the two monospecific antibody heavy chains to form bispecific antibodies using technologies such as those described in U.S. Pat. No. 7,695,936; Int. Pat. Publ. No. WO04/111233; U.S. Pat. Publ. No. U52010/0015133; U.S. Pat. Publ. No. US2007/0287170; Int. Pat. Publ. No. WO2008/119353; U.S. Pat. Publ. No. US2009/0182127; U.S. Pat. Publ. No. U52010/0286374; U.S. Pat. Publ. No. US2011/0123532; Int. Pat. Publ. No. WO2011/131746; Int. Pat. Publ. No. WO2011/143545; or U.S. Pat. Publ. No. US2012/0149876. Additional bispecific structures into which the VL and/or the VH regions of the antibodies of the invention can be incorporated are for example Dual Variable Domain Immunoglobulins (Int. Pat. Publ. No. WO2009/134776), or structures that include various dimerization domains to connect the two antibody arms with different specificity, such as leucine zipper or collagen dimerization domains (Int. Pat. Publ. No. WO2012/022811, U.S. Pat. Nos. 5,932,448; 6,833,441).

[0104] Another embodiment of the invention is a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, wherein the CD38-positive hematological malignancy is multiple myeloma, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL) or mantle-cell lymphoma (MCL).

[0105] A therapeutic regimen of the anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) can provide a synergistic efficacy in in vivo tumor killing when compared to the standard of care CHOP or R-CHOP, and therefore can provide a benefit in a patient population when compared to CHOP or R-CHOP used alone.

[0106] The invention also provides for a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, wherein the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody.

[0107] The invention also provides for a method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, wherein the subject has discontinued treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody due to side-effects.

[0108] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is cyclophosphamide, doxorubicin, vincristine, prednisone, ifosfamide, carboplatin or etoposide.

[0109] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

[0110] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, wherein the at least one chemotherapeutic agent is a combination of ifosfamide, carboplatin and etoposide (ICE).

[0111] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the anti-CD 20 antibody is rituximab (RITUXAN®), ofatumumab (ARZERRA®), veltuzumab, ocrelizumab, obinutuzumab (GA-101), PRO13192 or ocratuzumab (AME-133v).

[0112] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the anti-CD 20 antibody is rituximab.

[0113] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the at least one chemotherapeutic agent is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), and the anti-CD 20 antibody is rituximab (RITUXAN®), ofatumumab (ARZERRA®), veltuzumab, ocrelizumab, obinutuzumab (GA-101), PRO13192 or ocratuzumab (AME-133v).

[0114] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the at least one chemotherapeutic agent is a combination of ifosfamide, carboplatin and etoposide (ICE), and the anti-CD 20 antibody is rituximab (RITUXAN®), ofatumumab (ARZERRA®), veltuzumab, ocrelizumab, obinutuzumab (GA-101), PRO13192 or ocratuzumab (AME-133v).

[0115] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the at least one chemotherapeutic agent is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) and the anti-CD20 antibody is rituximab.

[0116] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject is resistant to or has acquired resistance to treatment with a combination of at least one chemotherapeutic agent and an anti-CD20 antibody, wherein the at least one chemotherapeutic agent is a combination of ifosfamide, carboplatin and etoposide (ICE), and the anti-CD20 antibody is rituximab.

[0117] Various qualitative and/or quantitative methods may be used to determine if a subject is resistant, has developed or is susceptible to developing a resistance to treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody. Symptoms that may be associated with resistance include, for example, a decline or plateau of the well-being of the patient, an increase in the size of a tumor, increase in the numbe of cancer cells, arrested or slowed decline in growth of a tumor or tumor cells, and/or the spread of cancerous cells in the body from one location to other organs, tissues or cells. Re-establishment or worsening of various symptoms associated with tumor may also be an indication that a subject has developed or is susceptible to developing resistance to at least one chemotherapeutic agent and an anti-CD20 antibody. The symptoms associated with cancer may vary according to the type of cancer. For example, symptoms associated with B-cell malignanices may include swollen lymp nodes in neck, groin or armpits, fever, night sweats, coughing, chest pain, unexplained weight loss, abdominal swelling or pain, or a feeling of fullness. Remission in malignant lymphomas is standardized using the Cheson criteria (Cheson et al., J Clin Oncology 25:579-586, 2007), which guidelines can be used to determine if a subject has developed a resistance to at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody.

[0118] The heavy and light chain amino acid sequences of the antibodies identified by their United States Adopted Names (USAN) are typically available via the American Medical Association at www_ama-assn_org or via the CAS registry, or at International Nonproprietary Names (INN) at _www_drugs_com/inn_html.

[0119] In some embodiments of the invention described herein, and in some embodiments of each and every one of the numbered embodiments listed below, the subject having a CD38-positive hematological malignancy is homozygous for phenylalanine at position 158 of CD16 (FcγRIIIa-158F/F genotype) or heterozygous for valine and pheynylalanine at position 158 of CD16 (FcγRIIIa-158F/V genotype). CD16 is also known as the Fc gamma receptor Ma (FcγRIIIa) or the low affinity immunoglobulin gamma Fc region receptor III-A isoform. Valine/phenylalanine (V/F) polymorphism at FcγRIIIa protein residue position 158 has been shown to affect FcγRIIIa affinity to human IgG. Receptor with FcγRIIIa-158F/F or FcγRIIIa-158F/V polymorphisms demonstrates reduced Fc engagement and therefore reduced ADCC when compared to the FcγRIIIa-158V/V. The lack of or low amount of fucose on human N-linked oligosaccharides improves the ability of the antibodies to induce ADCC due to improved binding of the antibodies to human FcγRIIIa (CD16) (Shields et al., J Biol Chem 277:26733-40, 2002). Patients can be analyzed for their FcγRIIIa polymorphism using routine methods.

[0120] The invention also provides for the method of treating a subject having a CD38-positive hematological malignancy, comprising administering to a patient in need thereof an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, wherein the subject is homozygous for phenylalanine at position 158 of CD16 or heterozygous for valine and pheynylalanine at position 158 of CD16.

Administration/Pharmaceutical Compositions

[0121] In the methods of the invention, and in some embodiments of each and every one of the numbered embodiments listed below, the anti-CD38 antibodies may be provided in suitable pharmaceutical compositions comprising the anti-CD38 antibody and a pharmaceutically acceptable carrier. The carrier may be diluent, adjuvant, excipient, or vehicle with which the anti-CD38 antibody is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating and coloring agents, etc. The concentration of the molecules or antibodies of the invention in such pharmaceutical formulation may vary widely, i.e., from less than about 0.5%, usually to at least about 1% to as much as 15 or 20% by weight and will be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the particular mode of administration selected. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in e.g. Remington: The Science and Practice of Pharmacy, 21^stEdition, Troy, D. B. ed., Lipincott Williams and Wilkins, Philadelphia, Pa. 2006, Part 5, Pharmaceutical Manufacturing pp 691-1092, see especially pp. 958-989.

[0122] The mode of administration of the anti-CD38 antibody in the methods of the invention may be any suitable route such as parenteral administration, e.g., intradermal, intramuscular, intraperitoneal, intravenous or subcutaneous, pulmonary, transmucosal (oral, intranasal, intravaginal, rectal) or other means appreciated by the skilled artisan, as well known in the art.

[0123] The anti-CD38 antibody in the methods of the invention, and in some embodiments of each and every one of the numbered embodiments listed below, may be administered to a patient by any suitable route, for example parentally by intravenous (i.v.) infusion or bolus injection, intramuscularly or subcutaneously or intraperitoneally. i.v. infusion may be given over for, example, 15, 30, 60, 90, 120, 180, or 240 minutes, or from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours.

[0124] The dose given to a patient having a CD38-positive hematological malignancy is sufficient to alleviate or at least partially arrest the disease being treated (“therapeutically effective amount”) and may be sometimes 0.005 mg/kg to about 100 mg/kg, e.g. about 0.05 mg/kg to about 30 mg/kg or about 5 mg to about 25 mg/kg, or about 4 mg/kg, about 8 mg/kg, about 16 mg/kg or about 24 mg/kg, or, e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/kg, but may even higher, for example about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50, 60, 70, 80, 90 or 100 mg/kg.

[0125] A fixed unit dose may also be given, for example, 50, 100, 200, 500 or 1000 mg, or the dose may be based on the patient's surface area, e.g., 500, 400, 300, 250, 200, or 100 mg/m². Usually between 1 and 8 doses, (e.g., 1, 2, 3, 4, 5, 6, 7 or 8) may be administered to treat a CD38-positive B-cell malignancy, but 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more doses may be given.

[0126] The administration of the anti-CD38 antibody in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be repeated after one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, two months, three months, four months, five months, six months or longer. Repeated courses of treatment are also possible, as is chronic administration. The repeated administration may be at the same dose or at a different dose. For example, the anti-CD38 antibody in the methods of the invention may be administered at 8 mg/kg or at 16 mg/kg at weekly interval for 8 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every two weeks for an additional 16 weeks, followed by administration at 8 mg/kg or at 16 mg/kg every four weeks by intravenous infusion.

[0127] The anti-CD38 antibodies may be administered in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, by maintenance therapy, such as, e.g., once a week for a period of 6 months or more.

[0128] For example, anti-CD38 antibodies in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be provided as a daily dosage in an amount of about 0.1-100 mg/kg, such as 0.5, 0.9, 1.0, 1.1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 mg/kg, per day, on at least one of day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, or alternatively, at least one of week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 after initiation of treatment, or any combination thereof, using single or divided doses of every 24, 12, 8, 6, 4, or 2 hours, or any combination thereof.

[0129] Anti-CD38 antibodies in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may also be administered prophylactically in order to reduce the risk of developing cancer, delay the onset of the occurrence of an event in cancer progression, and/or reduce the risk of recurrence when a cancer is in remission. This may be especially useful in patients wherein it is difficult to locate a tumor that is known to be present due to other biological factors.

[0130] The anti-CD38 antibody in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be lyophilized for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective with conventional protein preparations and well known lyophilization and reconstitution techniques can be employed.

[0131] The anti-CD38 antibody in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be administered in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

[0132] For example, CHOP and the individual constituents thereof, can be administered as described, in Moharhmad et al., Gun. Cancer Res 25:4950, 2000; McKelvey et al., Cancer 1484-1493; 1976; Armitage et al., J. Clin. Oncol. 2:898-902, 1984; Skeel, R. T., Handbook of Cancer Gliemotherapy, 3rd Edition, Little, Brown& Co., 1991:343. Typical routes of administration are intraperitoneal (i.p)., intravenous (i.v.) or oral (p.o.). Regimens may be either daily, every other day or every fourth day. Typical doses of the CHOP components are as follows: cyclophosphamide, up to 30 mg/kg single dose i.v. or i.p., or 20 mg/kg daily for eight days i.v. or i.p.; doxorubicin, up to 6 mg/kg single does i.v. or i.p.; vincristine, 0.2 to 0.5 mg/kg single dose i.p. or i.v.; prednisone, up to 10 mg/kg/day as a single agent, p.o.

[0133] For example CHOP may be administered at doses: cyclophosphamide 30 mg/kg, doxorubicin 2.5 mg/kg, vincristine 0.4 mg/kg prednisone 0.15 mg/kg. CHOP may be given every 21 days for different number of cycles. Cyclopshophamide, doxorubicin and vincristine may be given as i.v. infusion. Prednisone may be given as a tablet, taken daily by mouth for five days at the beginning of each cycle.

[0134] In the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, the combination of the anti-CD38 antibody and CHOP may be administered over any convenient timeframe. For example, the anti-CD38 antibody and CHOP may be administered to a patient on the same day, and even in the same intravenous infusion, except for prednisone. However, the anti-CD38 antibody and CHOP may also be administered on alternating days or alternating weeks or months, and so on. In some methods, the anti-CD38 antibody and CHOP may be administered with sufficient proximity in time that they are simultaneously present (e.g., in the serum) at detectable levels in the patient being treated. In some methods, an entire course of treatment with the anti-CD38 antibody consisting of a number of doses over a time period is followed or preceded by a course of treatment with CHOP, consisting of a number of doses. A recovery period of 1, 2 or several days or weeks may be used between administration of the anti-CD38 antibody and CHOP.

[0135] The anti-CD38 antibody in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be administered in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

[0136] The anti-CD38 antibody in the methods of the invention and in some embodiments of each and every one of the numbered embodiments listed below, may be administered in combination with cyclophosphamide, doxorubicin, vincristine, prednisone and an anti-CD20 antibody rituximab (R-CHOP).

[0137] Rituximab may be given as an intravenous infusion at a dose of 375 mg/m²and may be administered once weekly for 4 or 8 doses.

[0138] The combination of anti-CD38 antibody and CHOP may be administered together with any form of radiotherapy including external beam radiation, intensity modulated radiation therapy (IMIRT) and any form of radiosurgery including Gamma Knife, Cyberknife, Linac, and interstitial radiation (e.g. implanted radioactive seeds, GliaSite balloon), and/or with surgery. Radiotherapy may be used in patients having bulky disease (tumor size over about 10 cm) or in a palliative setting for patients who are not candidates for chemotherapy.

[0139] While having described the invention in general terms, the embodiments of the invention will be further disclosed in the following examples that should not be construed as limiting the scope of the claims.

FURTHER EMBODIMENTS OF THE INVENTION

[0140] Set out below are certain further embodiments of the invention according to the disclosures elsewhere herein. Features from embodiments of the invention set out above described as relating to the invention disclosed herein also relate to each and every one of these further numbered embodiments.

[0141] 1. An anti-CD38 antibody for use in treating a subject having a CD38-positive hematological malignancy, in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

[0142] 2. Cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) for use in treating a subject having a CD38-positive hematological malignancy, in combination with an anti-CD38 antibody.

[0143] 3. The combination of an anti-CD38 antibody, cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) for use in treating a subject having a CD38-positive hematological malignancy.

[0144] 4. The anti-CD38 antibody for use according to embodiment 1, the CHOP for use according to embodiment 2, or the combination according to embodiment 3, wherein the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, preferably wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by ADCC or CDC in vitro.

[0145] 5. The anti-CD38 antibody for use according to embodiment 1 or 4, the CHOP for use according to embodiment 2 or 4, or the combination for use according to embodiment 3 or 4, wherein the anti-CD38 antibody competes for binding to CD38 with an antibody comprising the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5.

[0146] 6. The anti-CD38 antibody for use according to embodiment 1, 4 or 5, the CHOP for use according to embodiment 2, 4 or 5, or the combination for use according to embodiment 3, 4 or 5, wherein the anti-CD38 antibody competes for binding to CD38 with an antibody comprising the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5.

[0147] 7. The anti-CD38 antibody for use according to any one of embodiments 1 or 4-6, the CHOP for use according to any one of embodiments 2 or 4-6, or the combination for use according to any one of embodiments 3-6, wherein the anti-CD38 antibody binds to an epitope comprising at least one amino acid in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and comprising at least one amino acid in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[0148] 8. The anti-CD38 antibody, CHOP or combination for use according to embodiment 7, wherein the anti-CD38 antibody binds to an epitope comprising at least KRN in the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and comprising at least VQLT (SEQ ID NO: 20) in the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1).

[0149] 9. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-8, the CHOP for use according to any one of embodiments 2, or 4-8, or the combination for use according to any one of embodiments 3-8, wherein the anti-CD38 antibody:

[0150] (i) is of IgG1, IgG2, IgG3 or IgG4 isotype;

[0151] (ii) has a biantennary glycan structure with fucose content of about 50%, 40%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%;

[0152] (iii) comprises a substitution in the antibody Fc at amino acid position 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430, when residue numbering according to the EU index; and/or

[0153] (iv) binds to CD38 with an affinity of 1×10⁻⁹or less, 1×10⁻¹⁰or less, 1×10⁻¹¹or less, or 1×10⁻¹²or less.

[0154] 10. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-9, the CHOP for use according to any one of embodiments 2, or 4-9, or the combination for use according to any one of embodiments 3-9, wherein the anti-CD38 antibody comprises:

[0155] (i) the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively;

[0156] (ii) the light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively;

[0157] (iii) comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5;

[0158] (iv) comprises a heavy chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 12 and a light chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 13; or

[0159] (v) comprises the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13.

[0160] 11. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-10, the CHOP for use according to any one of embodiments 2, or 4-10, or the combination for use according to any one of embodiments 3-10, wherein the CD38-positive hematological malignancy is multiple myeloma, acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL) or mantle-cell lymphoma (MCL), specifically wherein the CD38-positive hematological malignancy is DLBCL.

[0161] 12. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-11, the CHOP for use according to any one of embodiments 2, or 4-11, or the combination for use according to any one of embodiments 3-11, wherein:

[0162] (i) the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody; and/or

[0163] (ii) the subject has discontinued treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody due to side-effects.

[0164] 13. The anti-CD38 antibody, CHOP or combination for use according to embodiment 12, wherein the anti-CD20 antibody is rituximab (RITUXAN®), ofatumumab (ARZERRA®), veltuzumab, ocrelizumab, obinutuzumab (GA-101), PRO13192 or ocratuzumab (AME-133v), specifically wherein the anti-CD20 antibody is rituximab.

[0165] 14. The anti-CD38 antibody, CHOP or combination for use according to embodiment 12 or 13, wherein the at least one chemotherapeutic agent is cyclophosphamide, doxorubicin, vincristine, prednisone, ifosfamide, carboplatin or etoposide, optionally wherein:

[0166] (i) the at least one chemotherapeutic agent is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP); or

[0167] (ii) the at least one chemotherapeutic agent is a combination of ifosfamide, carboplatin and etoposide (ICE).

[0168] 15. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-14, the CHOP for use according to any one of embodiments 2, or 4-14, or the combination for use according to any one of embodiments 3-14, wherein the anti-CD38 antibody, cyclophosphamide, doxorubicin, vincristine and prednisone are administered simultaneously, sequentially or separately.

[0169] 16. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-15, the CHOP for use according to any one of embodiments 2, or 4-15, or the combination for use according to any one of embodiments 3-15, wherein the subject is further treated with radiotherapy.

[0170] 17. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-16, the CHOP for use according to any one of embodiments 2, or 4-16, or the combination for use according to any one of embodiments 3-16, wherein:

[0171] (i) the anti-CD38 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5;

[0172] (ii) the anti-CD38 antibody is IgG1; and

[0173] (iii) wherein the CD38-positive hematological malignancy is DLBCL.

[0174] 18. The anti-CD38 antibody for use according to any one of embodiments 1, or 4-16, the CHOP for use according to any one of embodiments 2, or 4-16, or the combination for use according to any one of embodiments 3-16, wherein:

[0175] (i) the anti-CD38 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5;

[0176] (ii) the anti-CD38 antibody is IgG1; and

[0177] (iii) wherein the CD38-positive hematological malignancy is Burkitt's lymphoma.

Example 1 Combination Therapy with Daratumumab and CHOP in Patient Derived Non-Hodkgin's Lymphoma (NHL) Models

Methods

[0178] ST1361 is a NHL-DLBCL (diffuse large B-cell lymphoma) PDX (patient derived xenograft) model originating from a fifty-eight year old Hispanic male chemo-naïve prior to metastatic sample collection. The patient had been treated with 8 cycles of R-CHOP prior to the resection, with subsequent treatments with R-ICE and R-GEMOX.

[0179] Tumors were implanted in immunocompromised mice between 5-8 weeks of age. When tumors reached approximately 125-250 mm³(day 0) animals were randomized into treatment and control groups and dosing was initiated on Day 0. Daratumumab was dosed at 20 mg/kg once a week for 3 weeks. CHOP and R-CHOP at the concentrations described below were dosed once on day 0. CHOP (cyclophosphoamide: 30 mg/kg; doxorubicin: 2.5 mg/kg; vincristine: 0.4 mg/kg)-IV DAY 0; prednisone: 0.15 mg/kg DAYS 0-4; R-CHOP: rituximab 20 mg/kg-IP DAY 0. Beginning Day 0, tumor volume was measured twice weekly by digital caliper and data including individual and mean estimated tumor volumes (Mean TV±SEM) recorded for each group. The study was used to measure tumor growth inhibition until the control group was terminated and then continued as a survival study to evaluate the duration of daratumumab efficacy.

[0180] For the study, beginning Day 0, tumor dimensions were measured twice weekly by digital caliper and data including individual and mean estimated tumor volumes (mean TV±SEM) recorded for each group. Tumor volume (TV) was calculated using the formula: TV=width²×length×0.52. % tumor growth inhibition (% TGI) values were calculated for each treatment group (T) versus control (C) using initial (i) and final (f) tumor measurements by the formula: % TGI=1−T_f−T_i/C_f−C.

Results

[0181] Daratumumab in combination with CHOP or R-CHOP was highly effective in this patient-derived tumor model of DLBCL. On day 31, CHOP regimen by itself slowed the tumor growth by about 27% whereas daratumumab inhibited tumor growth by ˜71%. R-CHOP was a more effective therapy with 82% tumor growth inhibition. Combination of daratumumab with CHOP or R-CHOP showed tumor regression and by the end of the study none of the animals had measurable tumors. Beyond day 31, 100% of the animals in Table 1.

[0182]

TABLE 1

	Mean tumor volume
Treatment	(mm³) ± SEM	% TGI

Isotype control	2192 ± 160
Daratumumab	744 ± 236	71%
CHOP	1634 ± 159	27%
R-CHOP	513 ± 104	82%
Daratumumab/CHOP	0	107%
Daratumumab/R-CHOP	0	107%

% TGI: percent tumor growth inhibition

daratumumab+CHOP and daratumumab+R-CHOP survived, the other groups showed loss of animals due to tumor progression. FIG. 1A shows the tumor volume over time for each treatment group, and FIG. 1B shows the median % survival over time. Table 1 shows the % TGI up to day 31 of the study. At day zero, tumor volume for each group was 145-146 mm³. Combination of daratumumab and CHOP resulted in 100% TGI even after 60 days of initiation of the study.

[0183] In this study, the efficacy of daratumumab was evaluated in a patient-derived DLBCL model. This patient was treated with R-CHOP and responded to R-CHOP initially but later died due to disease progression. The goal of this study was to determine if addition of daratumumab would offer greater benefit for DLBCL patients. Compared to monotherapy (daratumumab, CHOP or R-CHOP), addition of daratumumab to CHOP or R-CHOP resulted in tumor regression in all animals while the animals in all other groups succumbed to death as a result of disease burden. The combination of daratumumab with CHOP or R-CHOP showed greater than additive effect on tumor growth inhibition.

Example 2. Efficacy of Daratumumab in Combination with CHOP in Burkitt's Lymphoma

[0184] As a model for Burkitt's lymphoma, NAMALWA cells were utilized to study the efficacy of daratumumab alone or in combination with CHOP.

Methods

[0185] Namalwa cells were maintained in vitro in RPMI 1640 medium supplemented with fetal bovine serum (10% v/v), and L-glutamine (2 mM) at 37° C. in an atmosphere of 5% CO2 in air. The cells were routinely subcultured twice weekly by trypsin-EDTA treatment. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The mice were injected with 2×10⁵Namalwa cells in 0.1 ml of PBS with matrigel (1:1) subcutaneously and the treatments were started when the mean tumor size reached 189 mm³. The date of tumor cell inoculation is denoted as day 0. The major endpoint was to see if the tumor growth can be delayed or tumor-bearing mice can be cured. Tumor sizes were measured twice weekly and % TGI values calculated as described in Example 1.

Results

[0186] Animals were divided in four treatment groups and were administered vehicle (isotype control), daratumumab, CHOP or daratumumab in combination with CHOP at dosages as described in Table 2.

[0187]

TABLE 2

			Dose	Dosing
Groups	n	Treatment	(mg/kg)	Route	Schedule


1	10	Vehicle (IgG)	10	i.p.	QW × 3
2	10	Daratumumab	10	i.p.	QW × 3
3	10	CHOP	CTX	5	i.v.	QD × 5
			Doxorubicin	0.5	i.v.
			Vincristine	0.08	i.v.
			Prednisone	0.03	p.o.
4	10	Daratumumab	10	i.p.	QW × 3
	CHOP	CTX	5	i.v.	QD × 5
		Doxorubicin	0.5	i.v.
		Vincristine	0.08	i.v.
		Prednisone	0.03	p.o.

	n, animal number
	i.p intraperitoneal injection
	i.v. intravenous injection
	p.o. oral administration
	QD: daily dosing
	QW: once a week
	CTX: cyclophosphoamide

[0188] FIG. 2 shows results of the efficacy of daratumumab alone or in combination with CHOP in NAMALWA model of Burkitt's lymphoma. The reduction in tumor sizes (measured as tumor volume) in different treatment groups at different time points after tumor inoculation are shown in FIG. 2. The mean tumor size of the vehicle group (Group1) reached 4,281 mm³at day 26 post tumor inoculation. Treatment with daratumumab at 10 mg/kg, CHOP and daratumumab at 10 mg/kg in combination with CHOP produced significant antitumor activity in tumor size at day 26 post tumor inoculation separately. The mean tumor sizes were 3,017 mm³(T/C value=70.46%, p value <0.001), 3,304 mm³(T/C value=77.17%, p value=0.003) and 2,303 mm³(T/C value=53.79%, p value <0.001) at the same time with tumor growth delay of 2, 1 and 4 day(s) respectively at tumor size of 2,303 mm³.

Example 3. Efficacy of Daratumumab in Combination with CHOP in Non-Hodgkin's Lymphoma

[0189] SU-DHL-6 cell line based NHL-DLBCL model was utilized to study the efficacy of daratumumab alone or in combination with CHOP.

Methods

[0190] The SU-DHL-6 cells were maintained separately in vitro in RPMI1640 medium supplemented with 20% fetal bovine serum (v/v) at 37° C. in an atmosphere of 5% CO2 in air. The cells were routinely subcultured twice weekly. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. NOD SCID mice were γ-irradiated (200 rads) at 24 h before injection. Each mouse was inoculated subcutaneously at the right flank with SU-DHL-6 tumor cells (5×10⁶) in 0.1 ml of PBS with matrigel (1:1) for tumor development. The treatments were started when the tumor size reaches approximately 154 mm³. The date of tumor cell inoculation is denoted as day 0. Tumor sizes were measured twice weekly and % TGI values calculated as described in Example 1.

[0191] Animals were divided in four treatment groups and were administered vehicle, daratumumab, CHOP or daratumumab in combination with CHOP at dosages as described in Table 3.

[0192] The results of tumor sizes in different groups at different time points after tumor inoculation are shown in FIG. 3. The mean tumor size of the vehicle group (Group1) reached 4,281 mm³at day 32 post tumor inoculation. Treatment with daratumumab at 10 mg/kg and daratumumab at 10 mg/kg in combination with CHOP produced significant antitumor activity in tumor size at day 32 post tumor inoculation separately. The mean tumor sizes were 1,946 mm³(T/C value=45.45%, p value=0.006) and 1,611 mm³(T/C value=37.62%, p value=0.002) at the same time with tumor growth delay of 3 and 3.5 days respectively at tumor size of 1,500 mm³. Treatment with CHOP could decrease tumor size when compared to vehicle group but the decrease didn't reach significant difference.

[0193]

TABLE 3

			Dose	Dosing
Groups	n^a	Treatment	(mg/kg)	Route^b	Schedule^c


1	10	Vehicle (IgG)	10	i.p.	QW × 4
2	10	Daratumumab	10	i.p.	QW × 4
3	10	CHOP	CTX	5	i.v.	QD × 5
			Doxorubicin	0.5	i.v.
			Vincristine	0.08	i.v.
			Prednisone	0.03	p.o.
4	10	Daratumumab	10	i.p.	QW × 4
	CHOP	CTX	5	i.v.	QD × 5
		Doxorubicin	0.5	i.v.
		Vincristine	0.08	i.v.
		Prednisone	0.03	p.o.

	n, animal number
	i.p. intraperitoneal injection
	i.v. intravenous injection
	p.o. oral administration
	QD: daily dosing
	QW: once a week
	CTX: cyclophosphoamide

Example 4. Sequential or Simultaneous Therapy with Daratumumab in Combination with CHOP or R-CHOP Provides Efficacy in Patient Derived Non-Hodgkin's Lymphoma (NHL) Models

[0194] Efficacy of daratumumab alone or in combination with CHOP or R-CHOP was assssed using simultaneous or sequential dosing in the patient derived DLBCL tumor model ST1361 and according to methods described in Example 1.

[0195] Animals were divided into treatment groups and dosed as shown in Table 4. Daratumumab and R-CHOP were dosed simultaneously at day 0 or at 7 day interval.

[0196]

TABLE 4

			Dose	Dosing
Group	n	Treatment	(mg/kg)	Route	Schedule


1	10	Vehicle (IgG)	10	i.p.	QW × 3
2	10	Daratumumab	20	i.p.	QW × 3
	CHOP	CTX	5	i.v.	D 0
		Doxorubicin	0.5	i.v.	D 0
		Vincristine	0.08	i.v.	D 0
		Prednisone	0.03	p.o.	D 0-4
3	10	Daratumumab	20	i.p.	QW × 3
	R-CHOP	Rituximab	20	i.p.	QW × 3
		CTX	5	i.v.	D 0
		Doxorubicin	0.5	i.v.	D 0
		Vincristine	0.08	i.v.	D 0
		Prednisone	0.03	p.o.	D 0-4
4	10	Daratumumab	20	i.p.	D 7
		R-CHOP	Rituximab	20	i.p.	D 0
			CTX	5	i.v.	D 0
			Doxorubicin	0.5	i.v.	D 0
			Vincristine	0.08	i.v.	D 0
			Prednisone	0.03	p.o.	D 0-4
5	10	Daratumumab	Daratumumab	20	i.p.	D 0
		R-CHOP	Rituximab	20	i.p.	D 7
			CTX	5	i.v.	D 0
			Doxorubicin	0.5	i.v.	D 0
			Vincristine	0.08	i.v.	D 0
			Prednisone	0.03	p.o.	D 0-4

n, animal number
i.p intraperitoneal injection
i.v. intravenous injection
p.o. oral administration
QD: daily dosing
QW: once a week dosing
D 0 = day 0 dosing
D 0-4 = dosing once a day at days d 0-d 4

Results

[0197] FIG. 4 shows the results of tumor growth curves in response treatment up to 45 days of the study. Tumors in the vehicle control group reached a mean tumor volume of 2134 mm³by day 17. Tumors in the daratumumab+CHOP group regressed to a mean tumor volume of 96 mm³by day 45. Tumors in animals treated with daratumumab and R-CHOP simultaneously on day 0 (group 4), completely regressed by day 45. Tumors in animals treated with R-CHOP on day 0, followed by daratumumab on day 7 (group 5) showed mean tumor volume of 998 mm³. Tumors that were treated with daratumumab on day 0, followed by R-CHOP on day 7 (group 6) showed mean tumor volume of 633 mm³. The study was continued to up to 101 days. Animals treated with daratumumab and R-CHOP simultaneously on day 0 (group 4), completely regressed by day 101 also.

Claims

What is claimed is:

1. A method of treating non-Hodgkin's lymphoma (NHL) in a subject in need thereof, comprising administering to the subject an anti-CD38 antibody in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), wherein:

a) the NHL is diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL) or mantle-cell lymphoma (MCL),

b) the anti-CD38 antibody induces in vitro killing of CD38-expressing cells by antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modulation of CD38 enzymatic activity, and

c) the anti-CD38 antibody comprises a heavy chain complementarity determining region 1 (HCDR1), a HCDR2 and a HCDR3 amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively, and a light chain complementarity determining region 1 (LCDR1), a LCDR2 and a LCDR3 amino acid sequences of SEQ ID NOs: 9, 10 and 11, respectively.

2. The method of claim 1, wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by ADCC or CDC in vitro.

3. The method of claim 2, wherein the anti-CD38 antibody is of IgG1, IgG2, IgG3 or IgG4 isotype.

4. The method of claim 3, wherein the anti-CD38 antibody has a biantennary glycan structure with fucose content of about 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 14%, 13%, 12%, 11% 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or 0%.

5. The method of claim 3, wherein the anti-CD38 antibody comprises a substitution in the antibody Fc at amino acid position 256, 290, 298, 312, 356, 330, 333, 334, 360, 378 or 430, wherein residue numbering is according to the EU index.

6. The method of claim 1, wherein the anti-CD38 antibody comprises a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5.

7. The method of claim 1, wherein the anti-CD38 antibody comprises a heavy chain of SEQ ID NO: 12 and a light chain of SEQ ID NO: 13.

8. The method of claim 1, wherein the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody.

9. The method of claim 1, wherein the subject has discontinued treatment with at least one chemotherapeutic agent or a combination of at least one chemotherapeutic agent and an anti-CD20 antibody due to side effects.

10. The method of claim 8 or 9, wherein the anti-CD20 antibody is rituximab, ofatumumab, veltuzumab, ocrelizumab, obinutuzumab (GA-101), PRO13192 or ocratuzumab (AME-133v).

11. The method of claim 10, wherein the anti-CD20 antibody is rituximab.

12. The method of claim 8 or 9, wherein the at least one chemotherapeutic agent is cyclophosphamide, doxorubicin, vincristine, prednisone, ifosfamide, carboplatin or etoposide.

13. The method of claim 12, wherein the at least one chemotherapeutic agent is a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP).

14. The method of claim 12, wherein the at least one chemotherapeutic agent is a combination of ifosfamide, carboplatin and etoposide (ICE).

15. The method of claim 1, wherein the anti-CD38 antibody, cyclophosphamide, doxorubicin, vincristine and prednisone are administered simultaneously.

16. The method of claim 1, wherein the subject is further treated with radiotherapy.

17. The method of claim 1, wherein the anti-CD38 antibody, cyclophosphamide, doxorubicin, vincristine and prednisone are administered sequentially or separately.

18. The method of claim 1, wherein the NHL is BL.

19. The method of claim 1, wherein the NHL is FL.

20. The method of claim 1, wherein the NHL is MCL.

Patent Citations (218)

Patent	Date	Inventor	Cited By
US6737056(B1)	2004-05-01	Presta	Applicant
US7183387(B1)	2007-02-01	Presta	Applicant
US7223397(B1)	2007-05-01	Rosenblum et al.	Applicant
US7829673(B2)	2010-11-01	DeWeers	Applicant
US7829693(B2)	2010-11-01	Kreutzer et al.	Applicant
US8008449(B2)	2011-08-01	Korman et al.	Applicant
US8088896(B2)	2012-01-01	Tesar et al.	Applicant
US8153765(B2)	2012-04-01	Park et al.	Applicant
US8318154(B2)	2012-11-01	Frost et al.	Applicant
US8354509(B2)	2013-01-01	Carven et al.	Applicant
US8431380(B2)	2013-04-01	Bookbinder et al.	Applicant
US9040050(B2)	2015-05-01	Van De Winkel	Applicant
US9603927(B2)	2017-03-01	Doshi	Applicant
US9732154(B2)	2017-08-01	Doshi	Applicant
US10385135(B2)	2019-08-01	Janssen et al.	Applicant
US10556961(B2)	2020-02-01	Doshi	Applicant
US10604580(B2)	2020-03-01	Lokhorst	Applicant
US10668149(B2)	2020-06-01	Doshi et al.	Applicant
US10766965(B2)	2020-09-01	Chaulagain	Applicant
US10781261(B2)	2020-09-01	Janssen et al.	Applicant
US10793630(B2)	2020-10-01	Doshi et al.	Applicant
US10800851(B2)	2020-10-01	Doshi	Applicant
US11021543(B2)	2021-06-01	Ahmadi et al.	Applicant
US11566079(B2)	2023-01-01	Jansson et al.	Applicant
US11618787(B2)	2023-04-01	Ahmadi et al.	Applicant
US11634499(B2)	2023-04-01	Larmore	Applicant
US11708419(B2)	2023-07-01	Jansson et al.	Applicant
US11708420(B2)	2023-07-01	Jansson	Applicant
US11713355(B2)	2023-08-01	Doshi et al.	Applicant
US11732051(B2)	2023-08-01	Jansson et al.	Applicant
US20040141982(A1)	2004-07-01	Lust et al.	Applicant
US20040268425(A1)	2004-12-01	Bookbinder et al.	Applicant
US20060257397(A1)	2006-11-01	Throsby	Applicant
US20070148178(A1)	2007-06-01	Fyfe et al.	Applicant
US20080063642(A1)	2008-03-01	Adelman et al.	Applicant
US20080166344(A1)	2008-07-01	Nakahara et al.	Applicant
US20090076249(A1)	2009-03-01	Deweers et al.	Applicant
US20090148449(A1)	2009-06-01	DeWeers	Applicant
US20090304687(A1)	2009-12-01	Drachman	Applicant
US20090304710(A1)	2009-12-01	Park et al.	Applicant
US20100068136(A1)	2010-03-01	Hansen	Applicant
US20100074885(A1)	2010-03-01	Schiff et al.	Applicant
US20100092489(A1)	2010-04-01	van de Winkel et al.	Applicant
US20100285004(A1)	2010-11-01	Tesar et al.	Applicant
US20110044997(A1)	2011-02-01	Adler et al.	Applicant
US20110053247(A1)	2011-03-01	Baker	Applicant
US20110066111(A1)	2011-03-01	Teschner et al.	Applicant
US20110076273(A1)	2011-03-01	Adler et al.	Applicant
US20110099647(A1)	2011-04-01	De Weers et al.	Applicant
US20110293606(A1)	2011-12-01	Lejeune	Applicant
US20110300157(A1)	2011-12-01	Devy et al.	Applicant
US20120171153(A1)	2012-07-01	Frost et al.	Applicant
US20120201827(A1)	2012-08-01	Elias	Applicant
US20120219551(A1)	2012-08-01	Johnson et al.	Applicant
US20120231008(A1)	2012-09-01	Guo et al.	Applicant
US20120244110(A1)	2012-09-01	Chen et al.	Applicant
US20120258081(A1)	2012-10-01	Corringham et al.	Applicant
US20120259095(A1)	2012-10-01	Beliard et al.	Applicant
US20120295864(A1)	2012-11-01	Taube et al.	Applicant
US20130022588(A1)	2013-01-01	Yang et al.	Applicant
US20130109593(A1)	2013-05-01	Hartmann et al.	Applicant
US20130137134(A1)	2013-05-01	Mordechai et al.	Applicant
US20130209355(A1)	2013-08-01	De Weers et al.	Applicant
US20130302400(A1)	2013-11-01	Maneval et al.	Applicant
US20130309250(A1)	2013-11-01	Cogswell et al.	Applicant
US20130323247(A1)	2013-12-01	Zugmaier et al.	Applicant
US20140051662(A1)	2014-02-01	Moussy et al.	Applicant
US20140099254(A1)	2014-04-01	Chang et al.	Applicant
US20140155584(A1)	2014-06-01	Elias et al.	Applicant
US20140248238(A1)	2014-09-01	Wilson et al.	Applicant
US20140271644(A1)	2014-09-01	Elias et al.	Applicant
US20140309183(A1)	2014-10-01	Kerr	Applicant
US20140314800(A1)	2014-10-01	Mathieu et al.	Applicant
US20140356318(A1)	2014-12-01	Barken	Applicant
US20150118251(A1)	2015-04-01	Deslandes	Applicant
US20150125447(A1)	2015-05-01	Heider	Applicant
US20150231235(A1)	2015-08-01	Van De Winkel	Applicant
US20150246123(A1)	2015-09-01	Doshi	Applicant
US20150246975(A1)	2015-09-01	Doshi	Applicant
US20150376276(A1)	2015-12-01	Lewis et al.	Applicant
US20160009683(A1)	2016-01-01	Hansen et al.	Applicant
US20160067205(A1)	2016-03-01	Lokhorst	Applicant
US20160222106(A1)	2016-08-01	Doshi et al.	Applicant
US20160367663(A1)	2016-12-01	Doshi et al.	Applicant
US20160376373(A1)	2016-12-01	Ahmadi	Applicant
US20170008966(A1)	2017-01-01	Chaulagain	Applicant
US20170044265(A1)	2017-02-01	Ahmadi	Applicant
US20170107295(A1)	2017-04-01	Lokhorst	Applicant
US20170121414(A1)	2017-05-01	Jansson et al.	Applicant
US20170121417(A1)	2017-05-01	Jansson et al.	Applicant
US20170174780(A1)	2017-06-01	Doshi	Applicant
US20170320961(A1)	2017-11-01	Doshi	Applicant
US20180117150(A1)	2018-05-01	O'Dwyer	Applicant
US20190127479(A1)	2019-05-01	Ahmadi et al.	Applicant
US20190144557(A1)	2019-05-01	Ahmadi et al.	Applicant
US20190233533(A1)	2019-08-01	Otten	Applicant
US20190330363(A1)	2019-10-01	Janssen et al.	Applicant
US20190352421(A1)	2019-11-01	Adams et al.	Applicant
US20200002433(A1)	2020-01-01	Janssen et al.	Applicant
US20200121588(A1)	2020-04-01	Campbell et al.	Applicant
US20200148782(A1)	2020-05-01	Jansson et al.	Applicant
US20200223936(A1)	2020-07-01	Doshi et al.	Applicant
US20200231697(A1)	2020-07-01	Jansson et al.	Applicant
US20200268847(A1)	2020-08-01	Qi	Applicant
US20200308284(A1)	2020-10-01	Bandekar et al.	Applicant
US20200308296(A1)	2020-10-01	Bandekar et al.	Applicant
US20200316197(A1)	2020-10-01	Bandekar et al.	Applicant
US20200330593(A1)	2020-10-01	Bandekar et al.	Applicant
US20200339701(A1)	2020-10-01	Jansson et al.	Applicant
US20200392242(A1)	2020-12-01	Liu	Applicant
US20200397896(A1)	2020-12-01	Liu	Applicant
US20200405854(A1)	2020-12-01	Liu	Applicant
US20200407459(A1)	2020-12-01	Chaulagain et al.	Applicant
US20210047401(A1)	2021-02-01	Doshi et al.	Applicant
US20210095042(A1)	2021-04-01	Jansson	Applicant
US20210107991(A1)	2021-04-01	Jansson et al.	Applicant
US20210403592(A1)	2021-12-01	Ahmadi et al.	Applicant
US20220041745(A1)	2022-02-01	Bandekar et al.	Applicant
US20220062415(A1)	2022-03-01	Xie et al.	Applicant
US20220204638(A1)	2022-06-01	Liu et al.	Applicant
US20220275090(A1)	2022-09-01	Alvarez Arias	Applicant
US20220275101(A1)	2022-09-01	Schecter	Applicant
US20220401465(A1)	2022-12-01	Fan et al.	Applicant
US20230340145(A1)	2023-10-01	Ahmadi et al.	Applicant
US20230391884(A1)	2023-12-01	Otten	Applicant
AU2013203186(A1)	2013-05-01		Applicant
CL2013001944(A1)	2014-09-01		Applicant
CL2016002158(A1)	2017-07-01		Applicant
EA9383(B1)	2007-12-01		Applicant
EA15584(B1)	2011-10-01		Applicant
EA201390993	2013-12-01		Applicant
EP2561868(A1)	2013-02-01		Applicant
EP2567976(A2)	2013-03-01		Applicant
EP2459167(B1)	2013-05-01		Applicant
EP2477603(B1)	2016-03-01		Applicant
JP2008-533977(A)	2008-08-01		Applicant
JP2009-511033(A)	2009-03-01		Applicant
JP2010-504363(A)	2010-02-01		Applicant
JP2010-506582(A)	2010-03-01		Applicant
JP2014-509837(A)	2014-04-01		Applicant
NZ576122	2012-09-01		Applicant
WO89/08114(A1)	1989-09-01		Applicant
WO92/01049(A2)	1992-01-01		Applicant
WO94/17184(A1)	1994-08-01		Applicant
WO96/16990(A1)	1996-06-01		Applicant
WO98/16245(A1)	1998-04-01		Applicant
WO98/16254(A1)	1998-04-01		Applicant
WO98/50435(A1)	1998-11-01		Applicant
WO99/62526(A2)	1999-12-01		Applicant
WO/06194(A2)	2000-02-01		Applicant
WO/40265(A1)	2000-07-01		Applicant
WO2001/060803(A1)	2001-08-01		Applicant
WO1/97844(A1)	2001-12-01		Applicant
WO2/06347(A1)	2002-01-01		Applicant
WO2/32288(A2)	2002-04-01		Applicant
WO2002-534396(A)	2002-10-01		Applicant
WO2003/106498(A2)	2003-12-01		Applicant
WO2004/058288(A1)	2004-07-01		Applicant
WO2004/078140(A2)	2004-09-01		Applicant
WO2004/092160(A1)	2004-10-01		Applicant
WO2005/042019(A1)	2005-05-01		Applicant
WO2005/044855(A2)	2005-05-01		Applicant
WO2005/063819(A2)	2005-07-01		Applicant
WO2005/103083(A2)	2005-11-01		Applicant
WO2006/088951(A2)	2006-08-01		Applicant
WO2006/099875(A1)	2006-09-01		Applicant
WO2006/125640(A2)	2006-11-01		Applicant
WO2007/042309(A2)	2007-04-01		Applicant
WO2008/037257(A2)	2008-04-01		Applicant
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Non-Patent Literature (557)

Pui et al Nature Reviews vol. 6 p. 149 (2007), (Year: 2007).Examiner
Thomas et al Cancer vol. 106 p. 1569 (2006) (Year: 2006).Examiner
Laurini et al Blood, vol. 120 p. 4795 (2012) (Year: 2012).Examiner
“A Prospective Phase II of Daratumumab in Previously Treated Systemic Light Chain (AL) Amyloidosis”, published online at //cms.cws.net/content/beta.myelomasociety.org/files/2017ash/Roussel,%20Murielle-ASH2017.pdf (2017).Applicant
Aarhust, et al., “ADP-ribosyl Cyclase and CD38 Catalyze the Synthesis of a Calcium mobilizing Metabolite from NADP+,” The Journal of Biological Chemistry, 270(51): 30327-30333 (1995).Applicant
Abdi, J. et al., “Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms,” Oncotarget, vol. 4; No. 12; 2186-2207 (2013).Applicant
Adriouch et al., “Extracellular NAD+: a danger signal hindering regulatory T cells,” Microbes and Infection, 14:1284-1292 (2012).Applicant
Agheli, A. et al., “A Rare Case of Primary Amyloidosis, Presenting with Severe Pulmonary Hypertension and Bilateral Pleural Effusion,” Blood, vol. 106: p. 5100 (2005).Applicant
Almagro, J.C. and Fransson, J., “Humanization of antibodies,” Frontiers in Bioscience, vol. 13; 1619-1633 (2008).Applicant
Arican, et al., “Philadelphia Chromosome (+) T-Cell Acute Lymphoblastic Leukemia After Renal Transplantation,” Transplantation Proceedings, vol. 31; 3242-3243 (1999).Applicant
Armitage et al., “Long-Term Remission Durability and Functional Status of Patients Treated for Diffuse Histiocytic Lymphoma with the CHOP Regimen,” J. Clin. Oncol. 2:898-902, (1984).Applicant
Arthur, “Innovations in subcutaneous infusions,” J. Infus. Nurs. 38(3); 179-87; May/Jun. 2015.Applicant
Bachireddy, et al., “Haematologic Malignancies: at the Forefront of Immunotherapeutic Innovation,” Nature Reviews Cancer, vol. 15, No. 4, pp. 201-215, Apr. 1, 2015 (Apr. 1, 2015).Applicant
Bahlis, N.J. et al., “Daratumumab, lenalidomide, and dexamethasone (DRd) vs lenalidomide and dexamethasone (Rd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety updated (POLLUX),” Journal of Clinical Oncology, vol. 35; No. 15; 8025; Abstract (2017).Applicant
Berglund, L. et al., “The epitope space of the human proteome,” Protein Science, vol. 17; 606-613 (2008).Applicant
Blankestijn, et al., “Could daratumumab be used to treat severe allergy?,” Journal of Allergy and Clinical Immunology, Elsevier, Amsterdam, NL, vol. 139, No. 5, p. 1677-1678, Jan. 19, 2017.Applicant
Bose, P. et al., “Treatment of Relapsed/Refractory Acute Myeloid Leukemia,” Curr. Treat. Options in Oncol., vol. 18; No. 17; 30 pages (2017).Applicant
Brand, F-X. et al., “Prospect for Anti-HER2 Receptor Therapy in Breast Cancer,” AntiCancer Research, vol. 26; 463-470 (2006).Applicant
Brown, et al., “Tolerance of single, but not multiple, amino acid replacements in antibody VH CDR 2: a means of minimizing B cell wastage from somatic hypermutation?” The Journal of Immunology, 156: 3285-3291 (1996).Applicant
Carter et al., “Identification and validation of cell surface antigens for antibody targeting in oncology,” Endocrine-Related Cancer, vol. 11, pp. 659-687, (2004).Applicant
Chari et al., “Subcutaneous Delivery of Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): PAVO, an Open-label, Multicenter, Dose Escalation Phase 1b Study,” American Society of Hematology, Clinical Trials.gov Identifier NCTO2519452, Dec. 2017.Applicant
Chari A. et al., “Subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (RRMM): PAVO, an openlabel, multicenter, dose escalation phase 1b study,” 2017 ASH Annual Meeting ANZMAP Multiple Myeloma Highlights, 2017.Applicant
Chaulagain, C.P., et al., “How we Treat Systemic Light-Chain Amyloidosis,” Clinical Advances in Hematology & Oncology, vol. 13; No. 5; 315-324 (2015).Applicant
Chaulagain, C.P. and Comenzo, R.L., “New Insights and Modern Treatment of AL Amyloidosis,” Curr Hematol Malig Rep, vol. 8; 291-298 (2013).Applicant
Chen, et al., “Selection and Analysis of an Optimized Anti-VEGF Antibody: Crystal Structure of an Affinity-matured Fab in Complex with Antigen,” Journal of Molecular Biology, 293: 865-881 (1999).Applicant
Cheson et al., “Revised Response Criteria for Malignant Lymphoma,” Journal of Clinical Oncology, vol. 25, No. 5, 579-586 (Feb. 10, 2007).Applicant
Chiarugi, A. et al., “The NAD metabolome—a key determinant of cancel cell biology,” Nature Reviews, vol. 12; 741-752 (2012).Applicant
Chillemi, A. et al., “Anti-CD38 Antibody Therapy: Windows of Opportunity Yielded by the Functional Characteristics of the Target Molecule,” Molecular Medicine, vol. 19; 99-108 (2013).Applicant
Chou, et al., “Drug Combination Studies and their Synergy Quantification Using the Chou-Talalay Method,” Cancer Research, 70(2): 440-446 (2010).Applicant
Clinicaltrials.gov, “Daratumumab in Combination with ATRA (DARA/ATRA),” Identifier: NCT02751255; First posted: Apr. 26, 2016 (11 pages).Applicant
ClinicalTrials.gov “Study of YM155 in Refractory Diffuse Large B-cell Lymphoma (DLBCL) Subjects,” Interventional Studies, U.S. National Library of Medicine, //clinicaltrials.gov/ct2/show/record/NCT00498914, First posted Jul. 11, 2007 [retrieved on Sep. 10, 2018] (14 pages).Applicant
Clinicaltrials.gov, “A Study of Daratumumab with the Addition of Recombinant Human Hyaluronidase (rHuPH20) for the Treatment of Participants with Relapsed or Refractory Multiple Myeloma,” Identifier: NCT02519452; First Posted: Aug. 11, 2015 (13 pages).Applicant
Clinicaltrials.gov, “A Study to Evaluate Subcutaneous Daratumumab in Combination with Standard Multiple Myeloma Treatment Regimens,” Identifier: NCT03412565, First Posted: Jan. 26, 2018 (16 pages).Applicant
Clinicaltrials.gov, “A Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of TAK-079 in Healthy Participants,” Identifier: NCT02219256, 13 pages; Latest version posted: Mar. 22, 2017. (13 pages).Applicant
Colman, “Effects of amino acid sequence changes on antibody-antigen interactions,” A Structural View of Immune Recognition by Antibodies, Biomolecular Research Institute, 33-36, (1994).Applicant
Comenzo, R.L. et al., “Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis,” Leukemia, vol. 26; 2317-2325 (2012).Applicant
Cotner, et al., “Human T Cell Proteins Recognized by Rabbit Heteroantisera and Monoclonal Antibodies,” International Journal of Immunopharmaceuticals, 3(3): 255-268 (1981).Applicant
Data show daratumumab achieved a pronounced overall response rate as a single-agent with tolerable safety profile in heavily pre-treated multiple myeloma patients, Johnson & Johnson Press release[online](retrived on Jul. 27, 2020), May 30, 2015, retrieved from the Internet<URL:https://www.jnj.com/media-center/press-releases/Data-show-daratumumab-achieved-a-pronounced-overall-response-rate-as-a-single-agent-with-tolerable-safety-profile-in-heavily-pre-treated-multiple-myeloma-patients>; 4 pages.Applicant
Davies, et al., “Affinity improvement of single antibody VH domains: residues in all three hypervariable regions affect antigen binding,” Immunotechnology, 2: 169-179 (1996).Applicant
Davis, et al., “Transgenic mice as a source of fully human antibodies for the treatment of cancer,” Cancer and Metastasis Reviews, 18: 421-425 (1999).Applicant
Deckert, et al., “SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor Activity in Models of Multiple Myeloma and Other CD38β Hematologic Malignancies,” Clinical Cancer Research. vol. 20, No. 17, pp. 4574-4583 (2014).Applicant
Dennis, “Off by a Whisker,” Nature, 442 (17): 749-741 (2006).Applicant
DePascalis, et al., “Grafting of ‘Abbreviated’ Complementarity-Determining Regions Containing Specificity-Determining Residues Essential for Ligand Contact to Engineer a Less Immunogenic Humanized Monoclonal Antibody,” The Journal of Immunology, 169: 3076-3084 (2002).Applicant
Dewolf, S. and Tallman, M., “How I Treat Relapsed or Refractory AML,” Blood, downloaded from: https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2019001982/460740/How-I-Treat-Relapsed-or-Refractory-AML?redirectedFrom=PDF; 32 pages (2020).Applicant
De Haart, S.J. et al., “Accessory Cells of the Microenvironment Protect Multiple Myeloma from T-Cell Cytotoxicity through Cell Adhesion-Mediated Immune Resistance,” Clinical Cancer Research, vol. 19; No. 20; 5591-5601 (2013).Applicant
De Weers, et al., “Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma and Other Hematological Tumors,” The Journal of Immunology, 186: 1840-1848 (Pre-published online Dec. 27, 2010).Applicant
De Weers, M. et al., “Humax-CD38, a New Human CD38 Monoclonal Antibody, Effectively Mediates Killing of Multiple Myeloma and Plasma Cell Leukemia Cells,” abstract, Submitted for the 16th European Congress of Immunology—ECI2006, Paris, France, [Sep. 6-9, 2006].Applicant
De Weers et al., “HuMax-CD38, a new human CD38 monoclonal antibody, effectively mediates killing of multiple myeloma and plasma cell leukemia cells,” The 23rd International Conference on 'Advances in the Application of Monoclonal Antibodies in Clinical Oncology, (Jun. 26-28, 2006), Royal Myconian Resort & Thalasso Spa Center, Mykonos, Greece (Abstract).Applicant
Dimopoulos, M.A. et al., “Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma,” The New England Journal of Medicine, vol. 375; No. 14; 1319-1331 (2016).Applicant
Dimopoulos, M.A. et al., “Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX,” Haematologica, vol. 103; No. 12; 2088-2096 (2018).Applicant
Dispenzieri, A. et al., “Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement,” Mayo Clin Proc., vol. 90; No. 8; 1054-1081 (2015).Applicant
DMC recommends termination of study into daratumumab with atezolizumab to treat NSCLC, European Pharmaceutic Manufacturer[online](retrieved on Jul. 26, 2020), May 30, 2018, retrieved from the Internet<URL:https://www.epmmagazine.com/news/dmc-recommends-termination-of-study-into-daratumumab/>; 3 pages.Applicant
Dos Santos, et al., Anti-Leukemic Activity of Daratumumab in Acute Myeloid Leukemia Cells and Patient-Derived Xenografts, Blood, vol. 124, Abstract 2312, (2014).Applicant
Doshi, et al., “Daratumumab Treatment in Combination with Chop or R-Chop Results in the Inhibition or Regression of Tumors in Preclinical Models of Non-Hodgkins Lymphoma,” Haematologica, The Hematology Journal, 99(1): 138 (2014).Applicant
Eldfors, et al., “Landscape of Mutations in Relapsed Acute Myeloid Leukemia,” vol. 124: No. 21, p. 2367; (2014).Applicant
Ellis, et al., “Engineered Anti-CD38 Monoclonal Antibodies for Immunotherapy of Multiple Myeloma,” The Journal of Immunology, 155: 925-937 (1995).Applicant
Engert, et al., “A Phase-I Study of an Anti-CD25 Ricin A-Chain Immunotoxin (RFT5-SMPT-dgA) in Patients with Refractory Hodgkin's Lymphoma,” Blood, 89(2): 403-410 (1997).Applicant
Ettinger, R. et al., “Pathogenic mechanisms of IgE-mediated inflammation in self-destructive autoimmune responses,” Autoimmunity, vol. 50; No. 1; 25-36 (2017).Applicant
Ferrero, et al., Characterization and phylogenetic epitope mapping of CD38 ADPR cyclase in the cynomolgus macaque, BMC Immunology, 5(21): 1-13 (2004).Applicant
Field-Smith, “Bortezomid (Velcade™) in the treatment of multiple myeloma,” Therapeutic and Clinical Risk Management, 2(3): 271-279 (2006).Applicant
Flavell, et al., “Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin,” Br. J. Cancer, vol. 84, No. 4, pp. 571-578, (2001).Applicant
Franco, et al., “The transmembrane glycoprotein CD38 is a catalytically active transporter responsible for generation and influx of the second messenger cyclic ADP-ribose across membranes,” FASEB Journal, 12: 1507-1520 (1998).Applicant
Fujimori, et al., “A Modeling Analysis of Monoclonal Antibody Percolation Though Tumors: A Binding-Site Barrier,” Journal of Nucleic Medicine, 31: 1191-1198 (1990).Applicant
Fujioka, Y. and Kurokawa, M., “Follicular lymphoma presenting with massive splenomegaly,” International J Hematol, vol. 95; 3-4 (2012).Applicant
Funaro et al., “CD38 Functions Are Regulated Through an Internalization Step,” Journal of Immunology, 160: 2238-2247 (1998).Applicant
Funaro, et al., “Human CD38: a versatile leukocyte molecule with emerging clinical prospectives,” Fundamental and Clinical Immunology, 3(3): 101-113 (1995).Applicant
Funaro, et al., “Identification and characterization of an active soluble form of human CD38 in normal and pathological fluids,” International Immunology, 8(11): 1643-1650 (1996).Applicant
Funaro, et al., “Involvement of the Multilineage CD38 Molecule in a Unique Pathway of Cell Activation and Proliferation,” The Journal of Immunology, 145: 2390-2396 (1990).Applicant
Gallo, et al., “The human immunoglobulin loci introduced into mice: V(D) and J gene segment usage similar to that of adult humans,” European Journal of Immunology, 30: 534-540 (2000).Applicant
Genmab “Humanx-CD38 Effective in Preclinical Studies,” Genmab A/S, Stock Exchange Release 57/2005.Applicant
Genmab “Daratumumab Receives Breakthrough Therapy Designation from US Food and Drug Administration”, Copenhagen, Denmark; May 1, 2013—Genmab A/S (OMX: GEN) disponible en: http://files.shareholder.com/downloads/AMDA-KPIBN/0x0x659093/64b187b8-830c-4252-acd6-8019b4199069/18%20Daratumumab%20breakthrough%20status_010513_uk.pdf, (May 1, 2013).Applicant
Genmab Announces Daratumumab and Ofatumumab Data to Be Presented at American Society of Hematology Annual Meeting (ASH), American Society of Hematology Annual Meeting and Exposition, San Francisco, California, Media Release 06; pp. 1-3 (Nov. 2014).Applicant
George, et al., “Differential Effects of Anti-β2-Glycoprotein I Antibodies on Endothelial Cells and on the Manifestations of Experimental Antiphospholipid Syndrome,” Circulation, 97: 900-906 (1998).Applicant
Goldmacher, et al., “Anti-CD38-Blocked Ricin: An immunotoxin for the Treatment of Multiple Myeloma,” The American Society of Hematology, 84(9): 3017-3025 (1994).Applicant
Goodwin, “Subcutaneous Daratumumab Potential Game Changer for Multiple Myeloma,” Oncology Times, 2017 American Society of Hematology Annual Meeting, p. 49, (2017).Applicant
Gopalakrishnan, et al. “Daratumumab improves the anti-myeloma effect of newly emerging multidrug therapies,” Blood and Lymphatic Cancer: Targets and Therapy, 3: 19-24 (2013).Applicant
Graeff, et al., “Enzymatic Synthesis and Characterizations of Cyclic GDp-ribose,” The Journal of Biological Chemistry, 269(48): 30260-30267 (1994).Applicant
Green, “Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies,” Journal of Immunological Methods, 231: 11-23 (1999).Applicant
Green, et al., “Antigen-specific human monoclonal antibodies from mice engineered with hyman Ig heavy and light chain YACs,” Nature Genetics, 7: 13-21 (1994).Applicant
Gupta, R. et al., “The Economic Impact of Childhood Food Allergy in the United States,” JAMA Pediatrics, vol. 167; No. 11; 1026-1031 (2013).Applicant
Guse et al., “Regulation of calcium signaling in T lymphocytes by the second messenger cyclic ADP-ribose,” Nature 398:70-73, (1999).Applicant
Haart, et al., “Sepantronium bromide (YM155) improves daratumumab-mediated cellular lysis of multiple myeloma cells by abrogation of bone marrow stromal cell-induced resistance,” Haematologica, Letters to the Editor, vol. 101, No. 8, pp. e339-e343, (2016).Applicant
Hara-Yokoyama, “Alteration of enzymatic properties of cell-surface antigen CD38 by agonistic anti-CD38 antibodies that prolong B cell survival and induce activation,” International Immunopharmacology, 8: 59-70 (2008).Applicant
Hartmann, Radioimmunotherapy of Nude Mice Bearing a Human Interleukin 2 Receptor α-expressing Lymphoma Utilizing the α-emitting Radionuclide-conjugated Monoclonal Antibody 212Bi-anti-Tac, Cancer Research, 54: 4362-4370 (1994).Applicant
Henry, et al., “the use of basiliximab in solid organ transplantation,” Expert Opinion Pharmacotherapy, 3(10): 1657-1663 (2002).Applicant
Holgate, S.T., “New strategies with anti-IgE in allergic diseases,” World Allergy Organization Journal, vol. 7; No. 17; 6 pages (2014).Applicant
Holm, et al., “Functional mapping and single chain construction of the anti-cytokeratin 8 monoclonal antibody TS1,” Molecular Immunology, 44: 1075-1084 (2017).Applicant
Hoshino, et al., “Mapping of the Catalylic and Epitopic Sites of Human CD38/NAD+ Glycohydrolase to a Functional Domain in the Carboxyl Terminus1,” The Journal of Immunology, 158: 741-747 (1997).Applicant
Howard, et al., “Formation and Hydrolysis of Cyclic ADP-Ribose Catalyzed by lymphocyte Antigen CD38,” Science, 262(5136): 1056-1059 (1993).Applicant
Hu, Y., et al., “Immunophenotypic analysis of abnormal plasma cell clones in bone marrow of primary systemic light chain amyloidosis patients,” Chin Med J., vol. 127; No. 15; 2765-2770; Abstract only (2014).Applicant
Hu, Y. et al., “The Significance of Abnormal Plasma Cell Clone in Bone Marrow of Primary Systemic Light Chain Amyloidosis Patients,” Blood, vol. 122; p. 5342 (2013).Applicant
Ikehata, et al., “Autoantibodies against CD38 (ADP-ribosyl Cyclase/Cyclic ADP-ribose Hydrolase) that Impair Glucose-induced Insulin Secretion in Noninsulin-dependent Diabetes Patients,” Journal of Clinical Investigations, 102(2): 395-401 (1998).Applicant
Inaba, H. et al., “Acute lymphoblastic leukaemia,” Lancet, vol. 381; 27 pages (2013).Applicant
Jackisch, et al., “Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study,” Annals of Oncology, vol. 26, pp. 320-325, (2015).Applicant
Jackson, et al., “Isolation of a cDNA Encoding The Human CD38 (T10) molecule, A Cell Surface Glycoprotein With An Unusual Discontinuous Pattern of Expression During Lymphocyte Differentiation,” The Journal of Immunology, 144(7): 2811-2815 (1990).Applicant
Jagannath, et al. Treatment (tx) journeys in newly diagnosed multiple myeloma (NDMM) patients (pts): Results from the Connect MM Registry. Multiple Myeloma Update from the American Society of Clinical Oncology. (ASCO) 41st Annual meeting, (Jun. 4, 2018).Applicant
Jakob, et al., “Stage-dependent Expression of CD7, CD45RO, CD45RA and CD25 on CD4-positive Peripheral Blood T-lymphocytes in Cutaneous T-cell Lymphoma,” Acta Derm Venerology, 76: 34-36 (1996).Applicant
Jakobovits, “the long-awaited magic bullets: therapeutic human monoclonal antibodies from transgenic mice”, Expert Opinion on Investigational Drugs, 7(4): 607-614 (1998).Applicant
Jang, et al., “The structural basis for DNA binding by an anti-DNA autoantibody,” Molecular Immunology, 35: 1207-1217 (1998).Applicant
Johnson, et al., “Primary plasma cell leukemia: morphologic, immunophenotypic , and cytogenetic features of 4 cases treated with chemotherapy and stem cell transplantation,” Annals of Diagnostic Pathology, 10: 263-268 (2006).Applicant
Johnson & Johnson, Janssen to Demonstrate Breadth of Oncology Portfolio with 42 Clinical Data Presentation at the 2014 American Society of Hematology (ASH) Annual Meeting, San Francisco, California (Nov. 2014).Applicant
Jones, et al., “Depletion of CD25+ regulatory calls results in suppression of melanoma growth and induction of autoreactivity in mice,” Cancer Immunity, 2: 1 (2002). Abstract.Applicant
Jones, et al., “Replacing the complementarity-determining regions in a human antibody with those from a mouse,” Nature, 321: 522-525 (1986).Applicant
Kaufman, G.P. et al., “Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis,” Blood, vol. 130; No. 7; 900-902 (2017).Applicant
Kita et al., “Antitumor effects of YM155, a novel suppressant, against human aggressive non-Hodgkin Lymphoma,” Leukemia Research, vol. 35, pp. 787-792, (2011).Applicant
Kita, A., et al., “Sepantronium Bromide (YM155) Enhances Response of Human B-Cell Non-Hodgkin Lymphoma to Rituximab,” The Journal of Pharmacology and Experimental Therapeutics, vol. 343; No. 1; 178-183 (2012).Applicant
Konapleva, et al., “Ligation of Cell Surface CD38 Protein with Agonistic Monoclonal Antibody Induced a Cell Growth Signal in Myeloid Leukemia Cells,” The Journal of Immunology, 161: 4702-4708 (1998).Applicant
Kong, S.Y., et al., “Daratumumab Directly Induces Human Multiple Myeloma Cell Death and Acts Synergistically with Conventional and Novel Anti-Myeloma Drugs,” Blood, vol. 116; Abstract 3013 (2010).Applicant
Konopleva, et al., “CD38 in Hematopoietic Malignancies,” Chemical Immunol. Basel Karger, 75: 189-206 (2000).Applicant
Kreitman, et al., Phase I Trial of Recombinant Immunotoxin Anti-Tac (Fv)-PE38 (LMB-2) in Patients with Hematologic Malignancies, Journal of Clinical Oncology, 18: 1622-1636 (2000).Applicant
Krejcik, J. et al., “Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma,” Blood, vol. 128; No. 3; 384-394 (2016).Applicant
Krejcik, J. et al., Immunomodulatory Effects and Adaptive Immune Response to Daratumumab in Multiple Myeloma,: Blood, vol. 126; 3037; 7 pages (2015).Applicant
Kreuger, et al., “Successful in vivo blockade of CD25 (high-affinity interleukin 2 receptor) on T cells by administration of humanized anti-Tac antibody to patients with psoriasis,” Journal of American Academy of Dermatology, 41(3): 448-458 (2000).Applicant
Kropff, et al., “Bortezomib in combination with dexamethoasone for relapsed multiple myeloma,” Leukemia Research, 29: 587-590 (2005).Applicant
Kumar, S. et al., “Expression of CD52 on plasma cells in plasma cell proliferative disorders,” Blood, vol. 102; No. 3; 1075-1077 (2003).Applicant
Kupiec-Weglinski, “CD25-Targeted Therapy Revisited,” Transplantation, 69(3): 328-330 (2000).Applicant
Lakshman, A. et al., “Efficacy of daratumumab-based therapies in patients with relapsed, refractory multiple myeloma treated outside of clinical trials,” Am J. Hematol., vol. 92; 1146-1155 (2017).Applicant
Lande, et al., “CD38 ligation plays a direct role in the induction of IL-1β, I-6, and IL-10 secretion in resting human monocytes,” Cellular Immunology, 220: 30-38 (2002).Applicant
Laubach, J.P., “Daratumumab granted breakthrough drug status,” Expert Opinion Investig. Drugs, vol. 23; No. 4; 445-452 (2014).Applicant
Laurie, et al., “The role of CD4+CD25+ immunoregulatory T cells in the induction of autoimmune gastritis,” Immunology and Cell Biology, 80: 567-573 (2002).Applicant
Lazar, et al., “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 (1988).Applicant
Leonard, et al., “Molecular cloning and expression of cDNAs for the human interleukin-2 receptor,” Nature 311(18): 626-631 (1984).Applicant
Lepenies, B. and Jacobs, T., “The Role of Negative Costimulators During Parasitic Infections,” Endocrine, Metabolic & Immune Disorders—Drug Targets, vol. 8; 279-288 (2008).Applicant
Leveque “Subcutaneous Administration of Anticancer Agents” Anticancer Research, Departments of Pharmacy, University Hospital, Strasbourg, France, vol. 34, pp. 1579-1586 (2014).Applicant
Li, et al., “Creation of Patient Derived AML Xenografts Displaying Distinct Phenotypes and Geneotypes,” Blood, vol. 122: No. 21, p. 5018 (2013).Applicant
Lin, et al., “Structure-Function Relationships in Glucagon: Properties of Highly Purified Des-His1-, Monoiodi-, and [Des-Asn28, Thr29](homoserine lactone27)-glucagon,” Biochemistry, 14(9): 1559-1563 (1975).Applicant
Lippincott-Schwartz, “Antibodies as cell Biological Tools,” Current Protocols in Cell Biology, 16.0.1-16.0.2, (2002).Applicant
Liu et al., “Induction of Chemoresistance by All-Trans Retinoic Acid via a Noncanonical Signaling in Multiple Myeloma Cells,” PLOS One, vol. 9, No. 1, page Article No. e85571, Jan. 2014.Applicant
Lonberg, et al., “Antigen-specific human antibodies from mice comprising four distinct genetic modifications,” Nature: 308: 856-859 (1994).Applicant
Lu et al., “Issues Related to Targeted Delivery of Proteins & Peptides,” The AAPS Journal, vol. 8, No. 3, Article 55, pp. E466-E478, Jul. 21, 2006.Applicant
MacCallum, et al., “Antibody-antigen Interactions: Contact Analysis and Binding Site Topography,” Journal of Molecular Biology, 262, 732-745 (1998).Applicant
Machida, H. et al., “Aggressive plasma cell leukemia with cleaved, multilobated and monocytoid nuclei,” International Journal of Hematol., vol. 73; Suppl 1; 158; Abstract No. 411 (2001).Applicant
Mai, E. et al., “Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (Pad) in newly diagnosed myeloma,” Leukemia, vol. 29; 1721-1729 (2015).Applicant
Malavasi, et al., “Human CD38: a glycoprotein in search of a function,” Immunology Today, 15(3): 95-97 (1994).Applicant
Maloney, et al., “Antibody Therapy for Treatment of Multiple Myeloma,” Semin Hematol. 36 (Suppl. 3): 30-33 (1999).Applicant
Manier, S. et al., “Bone Marrow Microenvironment in Multiple Myeloma Progession,” Journal of Biomedicine and Biotechnology, vol. 2012; 5 pages (2012).Applicant
Matas-Cespedes, A. et al., “The human CD38 monoclonal antibody daratumumab shows anti-tumor activity and hampers leukemia-microenvironment interactions in chronic lympocytic leukemia,” Clinical Cancer Research, vol. 23; No. 6; 1493-1505 (2017).Applicant
Mauri, C. and Menon, M., “The expanding family of regulatory B cells,” International Immunology, vol. 27; No. 10; 479-486 (2015).Applicant
McCarthy, P.L., “Strategies for induction, autologous hematopoietic stem cell transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma patients”, Hematology, vol. 2013, NI. 1, pp. 496-503 (Dec. 2013).Applicant
McKelvey, et al., “Hydroxyldaunomycian (Adriamycin) Combination Chemotherapy in Malignant Lymphoma,” Cancer, vol. 38, No. 4, pp. 1485-1493 (Oct. 1976).Applicant
Merlini, G. and Bellotti, V., “Molecular Mechanisms of Amyloidosis,” The New England Journal of Medicine, vol. 349; No. 6; 583-596 (2003).Applicant
Mills, et al., Characterization of Monoclonal Antibodies that Inhibit CD38 Adp-ribosyl Cyclase Activity, LSSURP HLB Program, Department of Pharmacology, University of Minnesota, 2007.Applicant
Mills, E.N.C. et al., “The prevalence, cost and basis of food allergy across Europe,” Allergy, vol. 62; 717-722 (2007).Applicant
Mikhael et al., “Cyclophosphamide-Bortezomib-Dexamethasone (CYBORD) Produces Rapid and Complete Hematological Response in Patients with AL Amyloidosis,” Blood 119:4391-94 (Year: 2012).Applicant
Mohammad et al., “The Addition of Bryostatin 1 to Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) Chemotherapy Improves Response in a CHOP-resistant Human Diffuse Large Cell Lymphoma Xenograft Model,” Clinical Cancer Research, vol. 6, 4950-4956 (Dec. 2000).Applicant
Morrison, et al., “Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains,” Proceedings of the National Academy of Science USA, vol. 81; 6851-6855 (1984).Applicant
Mrowietz, “Treatment of Severe Psoriasis with Anti-CD25 Monoclonal Antibodies,” Arch. Dermatology, 136: 675-676 (2000).Applicant
Mukherjee, et al., “Production and Characterization of Protective Human Antibodies against Shiga Toxin 1,” Infection and Immunity, 70(10): 5896-5899 (2012).Applicant
Muyldermans, “Single domain camel antibodies: current status,” Reviews in molecular Biotechnology, 74: 277-302 (2001).Applicant
Muyldermans, et al., “Recognition of antigens by single-domain antibody fragments: the superfluous luxury of paired domains,” Trends in Biochemical Sciences, 26(4): 230-235 (2001).Applicant
Najjar et al., “Abstract P227: Accumulation of MDSC Subsets in Renal Cell Carcinoma Correlates with Grade and Progression Free Survival, and is Associated with Intratumoral Expression of IL-1β, IL-8 and CXCL5,” Journal for Immunotherapy of Cancer, Nov. 6, 2014, vol. 2, p. 110-112.Applicant
Nijhof, I.S. et al., Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib. Clin Cancer Res., vol. 21, No. 12, pp. 2802-2810 (2014).Applicant
Nijhof, et al.,“Modulation of CD 38 Expression Levels on Multiple Myeloma Tumor Cells By All-Trans Retinoic Acid Improves the Efficacy of the Anti-CD 38 Monoclonal Antibody Daratumumab,” Blood, American Society of Hematology, US, vol. 124, No. 21, p. 2096, Dec. 6, 2014. (Abstract Only).Applicant
Nijhof, I.S. et al., Combination of the anti-CD38 monoclonal antibody daratumumab and all-trans retinoic acid (Abstract in Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies). Clin Cancer Res, Sep. 20, 2014, vol. 21, No. 17 Suppl, pages Abstract A12; Abstract.Applicant
Nijhof I.S. et al.: “Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab”, Leukemia, vol. 29, No. 10, ISSN 1476-5551, pp. 2039-2049 (2015).Applicant
Nikaido, et al., “Molecular cloning of cDNA encoding human interleukin-2 receptor,” Nature, 311: 631-635 (1984).Applicant
Offidani et al., “An evidence-based review of ixazomib citrate and its potential in the treatment of newly diagnosed multiple myeloma,” OncoTargets and Therapy, vol. 7, pp. 1793-1800, 2014.Applicant
Onizuka, et al., “Tumor Rejection by in Vivo Administration of Anti-CD25 (Interleukin-2 Receptor a Monoclonal Antibody,” Cancer Research, 59: 3128-3133 (1999).Applicant
Orlowski, “The Ubiquitin Proteasome pathway from Bench to Bedside,” American Society of Hematology, 220-225 (2005).Applicant
Ostberg, et al., “Human and humanized monoclonal antibodies: preclinical studies and clinical experience,” Biochemical Society Transactions, 23: 1-6 (1995).Applicant
Padlan, et al., “Identification of specificity-determining resides in antibodies,” FASEB Journal, 9: 135-139 (1995).Applicant
Palumbo, A. et al., “Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma,” The New England Journal of Medicine, vol. 375; No. 8; 754-766 (2016).Applicant
Palumbo, A. et al., “Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma,” The New England Journal of Medicine, vol. 375; No. 8; 754-766; Suppl. Material: the protocol; total pp. 119 (2016).Applicant
Park, S. et al., “Successful Treatment by Rituximab of an Ebv-Related Lymphoma after Autologous Transplantation for Angioimmunoblastic T-Cell Lymphoma,” International Journal of Hematol., vol. 76; Suppl. 1; 118; Abstract No. P340 (2002).Applicant
Parren et al., “HuMax-CD38, a new human CD38 monoclonal antibody, effectively mediates killing of multiple myeloma and plasma cell leukemia cells,” American Society of Hematology 47th annual meeting, Atlanta, Georgia, USA, Dec. 10-13, 2005 (Abstract).Applicant
Parren, et al., HuMax-CD38, Myconos, Jun. 26, 2006.Applicant
Parren, et al., HuMax-CD38, Torino, Jun. 8-10, 2006.Applicant
Pascual, et al., “Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab,” Nephrology Dial. Transplant, 16: 1756-1760 (2001).Applicant
Patel, J.P., “Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia,” The New England Journal of Medicine, vol. 366; No. 12; 1079-1089 (2012).Applicant
Patton, D.T. et al., “The P13K p110δ Regulates Expression of CD38 on Regulatory T Cells,” PLOS one, vol. 6; No. 3; e17359; 8 pages (2011).Applicant
Paul, M.D., “Fundamental Immunology,” Chapter 9, Raven Press, New York, 3rd ed., 292-295 (1993).Applicant
Peipp, et al., “Fully Human CD38 Antibodies Efficiently Trigger ADCC and CDC of Multiple Myeloma Cell Lines and Primary Tumor Cells (Poster),” Blood, vol. 106(11): 944A, 47th Annual Meeting of the American Society of Hematology, 2005; published (Nov. 16, 2005).Applicant
Peipp, et al., Fully Human CD38 Antibodies Efficiently Trigger ADCC and CDC of Multiple Myeloma and Plasma Cell Leukemia Cells (Poster 2) Conference proceedings, poster presentation at the 2005 Annual Meeting of the American Society of Hematology, (Dec. 12, 2005).Applicant
Peipp, et al., 47th Annual Meeting of the American Society of Hematology, Atlanta, GA, Dec. 10-13, 2005. (Meeting Abstract).Applicant
Peng, et al., “Oncolytic measles viruses displaying a single-chain antibody against CD38, a myeloma cell marker,” Blood, 101, 2557-2562 (2003).Applicant
Phase ½ Dose Escalation and Efficacy Study of Anti-CD38 Monoclonal Antibody in Patients With Selected CD38+ Hematological Malignancies, First posted Mar. 10, 2010, ClinicalTrials.gov. identifier No. NCT01084252.Applicant
Prosniak, M. et al.: “Development of a Cocktail of Recombinant-Expressed Human Rabies Virus-Neutralizing Monoclonal Antibodies for Postexposure Prophylaxis of Rabies,” The Journal of Infectious Diseases, vol. 187; 53-56 (2003).Applicant
Rai, S. et al., “Successful Allogeneic Hematopoietic Stem Cell Transplantation in a Young Patient with Richter Syndrome Presenting with Chronic Lymphocytic Leukemia and Diffuse Large B-Cell Lymphoma with Different Cell Origins,” Intern Med, vol. 52; 273-276 (2013).Applicant
Richardson, et al., “Daratumumab,” Drugs of the Future, 38(8): 545-554 (2013).Applicant
Rituxan Hycela Label, “Highlights of prescribing information. Rituxan Hycela™ (rituximab and hyaluronidase human) injection, for subcutaneous use,” 32 pages (Jun. 2017).Applicant
Sachchithanantham, S. et al., “Use of Plasma Cell Immunophenotype as Prognostic Markers in Patients with Systemic AL Amyloidosis,” Blood, vol. 122; p. 3120 (2013).Applicant
Sagaster, V. et al., “Bortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a chromosome 13q-deletion,” Leukemia, vol. 21; 164-168 (2007).Applicant
Saito, M. et al., “A Case of Retroperitoneal Extramedullary Plasmacytoma,” Acta Urol. Jpn., vol. 49; 735-739 (2003).Applicant
Salar et al., “Comparison of Subcutaneous Versus Intravenous Administration of Rituximab As Maintenance Treatment for Follicular Lymphoma: Results From a Two-Stage, Phase IB Study,” Journal of Clinical Oncology, vol. 32, No. 17, pp. 1782-1791, (Jul. 10, 2014).Applicant
Sanchez-Gonzalez et al., “Rituximab subcutaneous in B-Cell non-Hodgkin lymphoma: clinical experience in a single center,” Leukemia & Lymphoma, vol. 59, No. 4, pp. 1019-1021 (2018).Applicant
San-Miguel, J. et al., “Efficacy by cytogenetic risk status for daratumumab in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone in relapsed or refractory multiple myeloma,” EHA22; EHA Learning Center; Abstract; 4 pages (2017).Applicant
San-Miguel, J., “New approaches to myeloma treatment in 2017,” EHA Learning Center; Abstract; 4 pages (2017).Applicant
Schonland, S., et al., “Detection and Charaterization of Plasma Cell and B Cell Clones in Patients with Systemic Light Chain Amyloidosis Using Flow Cytometry,” Blood, vol. 142, p. 2068 (2014).Applicant
Sher, T. et al., “First report of safety and efficacy of daratumumab in 2 cases of advanced immunoglobulin light chain amyloidosis,” Blood, vol. 128; No. 15; 1987-1989 (2016).Applicant
Shields, et al., “High Resolution mapping of the binding site on human IgG1 for FcγRi, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR,” J. Biol. Chem., vol. 276, No. 9, pp. 6591-6604, (2001).Applicant
Shpilberg, et al., “Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase,” British Journal of Cancer, vol. 109, pp. 1556-1561, 2013.Applicant
Shubinsky, et al., “The CD38 Lymphocyte Differentiation Marker: New Insight into Its Ectoenzymatic Activity and Its Role as a Signal Transducer,” Immunity, 7: 315-324 (1997).Applicant
Sicherer, S.H. and Sampson, H.A., “Food allergy: Epidemiology, pathogenesis, diagnosis, and treatment,” J. Allergy Clin Inmmunol, vol. 133; 291-307 (2014).Applicant
Skeel, Handbook of Cancer Gliemotherapy, 3rd edition, Little, Brown & Co., pp. 330-350 (1991).Applicant
Smithson, G. et al., “TAK-079 is a high affinity monoclonal antibody that effectively mediates CD38+ cell depletion,” Journal of Immunol., vol. 198; Suppl. 1; 224.20; Abstract (2017).Applicant
Sonneveld, P. and Annemiek Broijl, “Treatment of Relapsed and Refractory Multiple Myeloma,” Review Article, Leaders in Hematology, review series, Haematologica, 101(4):396-406 (2016).Applicant
Spencer, A et al., “Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR,” Haematologica, vol. 103; No. 12; 2079-2087 (2018).Applicant
Strome, S.E. et al., “A Mechanistic Perspective of Monoclonal Antibodies in Cancer Therapy Beyond Target-Related Effects,” The Oncologist, vol. 12; 1084-1095 (2007).Applicant
Swaika, A. et al., “Current state of anti-PD-L1 and anti-PD-1 agents in cancer therapy,” Molecular Immunology, vol. 67; 4-17 (2015).Applicant
Tabernero, et al., “Adult precursor B-ALL with BCR/ABL gene rearrangements displays a unique 20mmunophenotyped based on the pattern of CD10, CD34, CD13, and CD38 expression,” Leukemia, vol. 15, No. 3, pp. 406-414, (2001).Applicant
Talmadge, J.E. and Gabrilovich, D.I, “History of myeloid-derived suppressor cells,” Nature Reviews, vol. 13; 739-752 (2013).Applicant
Terhorst, et al., “Biochemical Studies of the Human Thymocyte Cell-Surface Antigens T6, T9 and T10,” Cell, 23: 771-780 (1981).Applicant
The Cancer Genome Atlas Research Network et al., “Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia,” N. Engl. J. Med, vol. 368; No. 22; 2059-2074 (2013).Applicant
Topalian, S.L., et al., “Immune Checkpoint Blockade: A Common Denominator Approach to Cancer Therapy,” Cancer Cell, vol. 27; 450-461 (2015).Applicant
Tzartos, S.J., et al., “Epitope Mapping by Antibody Competition,” Methods in Molecular Biology, vol. 66; 55-66 (1996).Applicant
Usmani, et al., “Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma,” Blood, vol. 128, No. 1, pp. 37-44, (May 23, 2016).Applicant
Usmani, S.Z. et al., “Efficacy of Daratumumab, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma Patients with 1 to 3 Prior Lines of Therapy: Updated Analysis of Pollux,” Blood, vol. 128; No. 22; 1151; 10 pages (2016).Applicant
Usmani, S.Z. et al., “Open-Label, Multicenter, Dose Escalation Phase 1b Study to Assess the Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma,” Blood, vol. 128; No. 22; 1149 (2016).Applicant
Usmani, S.Z. et al., “Subcutaneous delivery of daratumumab in relapsed or refractory multiple myeloma,” Blood, vol. 134; No. 8; 668-677 (2019).Applicant
Vadjos, et al., “Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis,” Journal of Molecular Biology, 320: 415-428 (2002).Applicant
Van Bueren, et al., “Direct In Vitro Comparison of Daratumumab With Surrogate Analogs of Anti-CD38 Antibodies,” New Evidence Oncology Issue, Apr. 2015 [retrieved on Feb. 3, 2016] Retrieved from the Internet: URL: Http:///www.newevidence.com/oncology/direct-in-vitro-comparison-of-daratumumab-with-surrogate-analogs-of-anti-cd38-antibodies>.Applicant
Van de Donk et al., “Monoclonal antibodies targeting CD38 in hematological malignancies and beyond,” Immunological Reviews, vol. 270, pp. 95-112, (2016).Applicant
Venner et al., “Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival,” Blood, vol. 119, No. 9, pp. 4387-4390, (2012).Applicant
Vorre, et al., “Multiple Daratumumab Abstracts to be Presented at EHA,” Array Diagnostica, Abstract Only (2014).Applicant
Wagner, V., et al., “Preclinical Efficacy of Sepantronium Bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1,” Oncotarget, 5(21): 10237-10250 (2014).Applicant
Wagner et al., Survivin in Multiple Myeloma: Prognostic and Therapeutic Implications, vol. 118, Article 137, 2011 (Abstract Only).Applicant
Wang, L. et al., “VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses,” J. Exp. Med., vol. 208; No. 3; 577-592 (2011).Applicant
WCJ van de Donk, “A Phase 1 and Phase 2 Study of Daratumumab in Combination With All-Trans Retinoic Acid in Relapsed/Refractory Multiple Myeloma,” Clinical Trials.gov Identification No. NCT02751255; (First posted Apr. 26, 2016).Applicant
Wei, W. et al., “Roles and mechanisms of the CD38/cyclic adenosine diphosphate ribose/Ca2+ signaling pathway,” World Journal of Biological Chemistry, vol. 5; No. 1; 58-67 (2014).Applicant
Weisel, K.C. et al., “Efficacy of daratumumab in combination with lenalidomide plus dexamethasone (DRd) or bortezomib plus dexamethasone (RVd) in relapsed or refractory multiple myeloma (RRMM) based on cytogenetic risk status,” Journal of Clinical Oncology, vol. 35; No. 15; 8006; Abstract (2017).Applicant
Williams, B.A. et al., “Antibody Therapies for Acute Myeloid Leukemia: Unconjugated, Toxin-Conjugated, Radio-Conjugated and Multivalent Formats,” Journal of Clinical Medicine, vol. 8; No. 1261; 31 pages (2019).Applicant
Ye et al, “Abstract P240: Treg Increases HepG2 Cell Growth by RANK-RANKL pathway.” Journal for Immunotherapy of Cancer, vol. 2; Suppl 3; P240 (Nov. 6, 2014).Applicant
International Preliminary Report on Patentability dated May 8, 2018 for International Application No. PCT/US2016/59893, entitled “Subcutaneous Formulations of ANTI-CD38 Antibodies and Their Uses”.Applicant
International Search Report and Written Opinion dated Jan. 24, 2017 for International Application No. PCT/US2016/59893, entitled “Subcutaneous Formulations of ANTI-CD38 Antibodies and Their Uses”.Applicant
International Preliminary Report on Patentability dated Dec. 26, 2017 for International Application No. PCT/US2016/038702, entitled “Combination Therapies for Heme Malignancies With ANTI-CD38 Antibodies and Sur Vivin Inhibitors”.Applicant
International Search Report and Written Opinion dated Nov. 29, 2016 for International Application No. PCT/US2016/038702, entitled “Combination Therapies for Heme Malignancies With ANTI-CD38 Antibodies and Sur Vivin Inhibitors”.Applicant
International Preliminary Report on Patentability dated Mar. 14, 2017 for International Application No. PCT/US2015/048899, entitled “Combination Therapies With ANTI-CD38 Antibodies”.Applicant
International Search Report and Written Opinion dated Apr. 8, 2016 for International Application No. PCT/US2015/048899, entitled “Combination Therapies With ANTI-CD38 Antibodies”.Applicant
International Preliminary Report on Patentability dated Nov. 21, 2017 for International Application No. PCT/US2016/033544, entitled “ANTI-CD38 Antibodies for Treatment of Light Chain Amyloidosis and Other CD38- Positive Hematological Malignancies”.Applicant
International Search Report and Written Opinion dated Oct. 24, 2016 for International Application No. PCT/US2016/033544, entitled “ANTI-CD38 Antibodies for Treatment of Light Chain Amyloidosis and Other CD38- Positive Hematological Malignancies”.Applicant
International Preliminary Report on Patentability dated Jun. 6, 2016 for International Application No. PCT/US2015/063371, entitled “ANTI-CD38 Antibodies for Treatment of Acute Myeloid Leukemia”.Applicant
International Search Report and Written Opinion dated Feb. 19, 2016 for International Application No. PCT/US2015/063371, entitled “ANTI-CD38 Antibodies for Treatment of Acute Myeloid Leukemia”.Applicant
International Preliminary Report on Patentability dated Dec. 26, 2017 for International Application No. PCT/US2016/039165, entitled “Immune Modulation and Treatment of Solid Tumors With Antibodies That Specifically Bind CD38”.Applicant
International Search Report and Written Opinion dated Oct. 14, 2016 for International Application No. PCT/US2016/039165, entitled “Immune Modulation and Treatment of Solid Tumors With Antibodies That Specifically Bind CD38”.Applicant
International Preliminary Report on Patentability dated Sep. 6, 2016 for International Application No. PCT/US2015/017425, entitled “ANTI-CD38 Antibodies for Treatment of Acute Lymphoblastic Leukemia”.Applicant
International Search Report and Written Opinion dated Sep. 21, 2015 for International Application No. PCT/US2015/017425, entitled “ANTI-CD38 Antibodies for Treatment of Acute Lymphoblastic Leukemia”.Applicant
International Preliminary Report on Patentability dated Jan. 10, 2019 for International Application No. PCT/EP2017/066063, entitled “Treatment Of IgE-MEDIATED Diseases With Antibodies That Specifically Bind CD38”.Applicant
International Search Report and Written Opinion dated Sep. 25, 2017 for International Application No. PCT/EP2017/066063, entitled “Treatment Of IgE-Mediated Diseases With Antibodies That Specifically Bind CD38”.Applicant
International Preliminary Report on Patentability dated May 14, 2020 for International Application No. PCT/US2018/058561, entitled “Methods of Treating High Risk Multiple Myeloma”.Applicant
International Search Report and Written Opinion dated Feb. 12, 2019 for International Application No. PCT/US2018/058561, entitled “Methods of Treating High Risk Multiple Myeloma”.Applicant
International Search Report and Written Opinion dated Apr. 24, 2020 for International Application No. PCT/US2019/056838, entitled “Method of Providing Subcutaneous Administration of Anti-CD38 Antibodies”.Applicant
International Preliminary Report on Patentability dated Sep. 6, 2016 for International Application No. PCT/US2015/017420, entitled “Combination Therapies With ANTI-CD38 Antibodies”.Applicant
International Search Report and Written Opinion dated Jul. 8, 2015 for International Application No. PCT/US2015/017420, entitled “Combination Therapies With ANTI-CD38 Antibodies”.Applicant
Intellectual Property Office of Singapore Written Opinion dated Apr. 17, 2018 for Application No. 11201701867S, entitled “Combination Therapies with Anti-CD38 Antibodies”.Applicant
Supplementary European Search Report dated Feb. 21, 2018 for European Application No. EP 15839752 , entitled “Combination Therapies with Anti-CD38 Antibodies”.Applicant
Non Final Office Action for U.S. Appl. No. 15/340,290 dated Nov. 20, 2017.Applicant
Final Office Action for U.S. Appl. No. 15/340,290 dated May 16, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/340,290 dated Oct. 10, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/366,474 dated Nov. 20, 2017.Applicant
Final Office Action for U.S. Appl. No. 15/366,474 dated May 16, 2018.Applicant
Applicant Initiated Interview for U.S. Appl. No. 15/366,474 dated Sep. 17, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/366,474 dated Oct. 11, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/189,577 dated Oct. 31, 2017.Applicant
Final Office Action for U.S. Appl. No. 15/189,577 dated Apr. 13, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/189,577 dated Sep. 28, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 14/847,428 dated Sep. 23, 2016.Applicant
Non Final Office Action for U.S. Appl. No. 15/386,391 dated Jun. 18, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/160,476 dated Sep. 15, 2017.Applicant
Non Final Office Action for U.S. Appl. No. 15/160,476 dated Nov. 5, 2018.Applicant
Final Office Action for U.S. Appl. No. 15/160,476 dated Apr. 23, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 14/956,890 dated Nov. 25, 2016.Applicant
Final Office Action for U.S. Appl. No. 14/956,890 dated Jul. 24, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/340,214 dated May 16, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 14/629,965 dated Dec. 21, 2015.Applicant
Final Office Action for U.S. Appl. No. 14/629,965 dated Apr. 29, 2016.Applicant
Notice of Allowance for U.S. Appl. No. 14/629,965 dated Apr. 13, 2017.Applicant
Non Final Office Action for U.S. Appl. No. 15/445,225 dated Jun. 29, 2018.Applicant
Final Office Action for U.S. Appl. No. 15/445,225 dated Dec. 17, 2018.Applicant
Non Final Office Action for U.S. Appl. No. 15/651,333 dated Sep. 27, 2018.Applicant
Final Office Action for U.S. Appl. No. 15/386,391 dated Dec. 28, 2018.Applicant
Final Office Action for U.S. Appl. No. 14/956,890 dated Jan. 14, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/651,333 dated Feb. 21, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/189,577 dated Mar. 5, 2019.Applicant
Final Office Action for U.S. Appl. No. 15/340,290 dated Mar. 11, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/386,391 dated Mar. 29, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/340,290 dated May 22, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/651,333 dated May 31, 2019.Applicant
Final Office Action for U.S. Appl. No. 15/160,476 dated Jun. 14, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/386,391 dated Jul. 30, 2019.Applicant
Non-Final Office Action for U.S. Appl. No. 14/956,890 dated Jul. 30, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/189,577 dated Sep. 12, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/651,333 dated Oct. 9, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/386,391 dated Nov. 18, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/189,577 dated Dec. 19, 2019.Applicant
Non Final Office Action for U.S. Appl. No. 15/160,476 dated Dec. 20, 2019.Applicant
Final Office Action for U.S. Appl. No. 14/956,890 dated Jan. 7, 2020.Applicant
Non-Final Office Action for U.S. Appl. No. 15/798,670 dated Jan. 22, 2020.Applicant
English translation of Office Action for JP Application No. 2016-554350, dated Nov. 27, 2018.Applicant
Notice of Allowance for U.S. Appl. No. 15/189,577 dated Mar. 31, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 15/160,476 dated May 4, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 16/380,994 dated May 12, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 16/460,754 dated May 18, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 14/956,890 dated Jul. 29, 2020.Applicant
Non-Final Office Action for U.S. Appl. No. 15/798,670 dated Aug. 7, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 16/380,994 dated Aug. 12, 2020.Applicant
Non-Final Office Action for U.S. Appl. No. 16/162,355 dated Aug. 13, 2020.Applicant
Non-Final Office Action for U.S. Appl. No. 16/177,239 dated Aug. 24, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 16/460,754 dated Sep. 10, 2020.Applicant
ASH Clinical News, “Is Daratumumab Plus Lenalidomide-Dexamethasone a New Standard for Transplant-Ineligible Myeloma,” Dated Jan. 1, 2019, Retrieved from Internet URL: https://www.ashclinicalnews.org/on-location/ash-annual-meeting/daratumumab-plus-lenalidomid; Rctricved Oct. 28, 2022 (2 pages).Applicant
Avet-Loiseau, H. et al., “Evaluation of Minimal Residual Disease (MRD) in Relapsed/Refractory Multiple Myeloma (RRMM) Patients Treated with Daratumumab in Combination with Lenalidomide Plus Dexamethasone or Bortezomib Plus Dexamethasone,” Blood, vol. 128; No. 22; 246; 7 pages (2016).Applicant
Bauer, Fromming, Fuhrer, “Lehrbuch der Pharmazeutischen Technologie”8th Edition, Wissenschaftliche Verlagsgesellschaft Stuttgart, Chapter 9; 238-243 (2006). concise explanation met by submission of the enclosed Opponent's submission filed by Dr. Markus Breuer cited as Other Document 134).Applicant
Bittner, B. et al., “Development of a Subcutaneous Formulation for Trastuzumab—Nonclinical and Clinical Bridging Approach to the Approved Intravenous Dosing Regimen,” Arzneimittelforschung, vol. 62; 401-409 (2012).Applicant
Bittner, B. et al., “Non-Clinical Pharmacokinetic /Pharmacodynamic and Early Clinical Studies Supporting Development of a Novel Subcutaneous Formulation for the Monoclonal Antibody Rituximab,” Drug Res., vol. 64; 569-575 (2014).Applicant
Bittner, B. et al., “Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities,” BioDrugs, vol. 32; 425-440 (2018).Applicant
Bookbinder, L.H. ct al., “A recombinant human enzyme for enhanced interstitial transport of therapeutics,” Journal of Controlled Release, vol. 114; 230-241 (2006).Applicant
CAS Registry Results, dated Oct. 9, 2020, Registry No. 757971-58-7, “36-482-Hyaluronoglucosaminidase PH20 (human),” 6 pages.Applicant
Chari, A., et al., “Subcutaneous Daratumumab (DARA) in Patients (Pts) With Relapsed or Refractory Multiple Myeloma (RRMM): Part 2 Update of the Open-label, Multicenter, Dose-escalation Phase 1b Study (PAVO)”, Poster Presented at the Annual Meeting of the American Society of Clinical Oncology (ASCO); June Jan. 5, 2018; Chicago, Illinois.Applicant
Chaulagain, C.P. et al., “Pre-clinical translational studies of daratumumab in patients with myeloma or AL amyloidosis undergoing autologous hematopoietic stem cell transplantation (SCT),” Journal of Clinical Oncology, May 20, 2015, vol. 33, No. 15 suppl., pp. 8587-8587.Applicant
CHMP Assessment Report for Herceptin (trastuzumab), 70 pages (2013).Applicant
CHMP Assessment Report for Mabthera (rituximab), 103 pages (2014).Applicant
Chung, C.H., “Managing Premedications and the Risk for Reactions to Infusional Monoclonal Antibody Therapy,” The Oncologist, vol. 13; 725-732 (2008).Applicant
ClinicalTrials.gov, “Daratumumab (HuMax-CD38) Safety Study in Multiple Myeloma,” Identifier: NCT00574288; Latest version posted: Apr. 27, 2018 (10 pages).Applicant
Clinicaltrials.gov, “An Investigational Immuno-Therapy Study to Determine the Safety and Effectiveness of Nivolumab and Daratumumab in Patients with Multiple Myeloma,” Identifier: NCT01592370; Latest version posted: Jun. 18, 2021 (10 pages).Applicant
Clinicaltrials.gov, “History of Changes for Study: NCT02252172: Study Comparing Daratumumab, Lenalidomide, and Dexamethasone With Lenalidomide and Dexamethasone in Participants With Previously Untreated Multiple Myeloma,” U.S. National Library of Medicine, ClinicalTrials.gov Archive, Oct. 17, 2017 (24 pages).Applicant
Clinicaltrials.gov, “History of Changes for Study: NCT02519452: A Study of Daratumumab With the Addition of Recombinant Human Hyaluronidase (rHuPH20) for the Treatment of Participants with Relapsed or Refractory Multiple Myeloma,” U.S. National Library of Medicine, ClinicalTrials.gov Archive, Dec. 3, 2020 (12 pages).Applicant
Clinicaltrials.gov, “A Study of Daratumumab with the Addition of Recombinant Human Hyaluronidasc (rHuPH20) for the Treatment of Participants with Relapsed or Refractory Multiple Myeloma,” Identifier: NCT02519452; First Received: Aug. 6, 2015 (5 pages).Applicant
Colson, K., “Treatment-related symptom management in patients with multiple myeloma: a review,” Support Care Cancer, vol. 23; 1431-1445 (2015).Applicant
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, U.S. Department of Health and Human Services, 4 pages (2010).Applicant
Complete Specification for Indian Application No. 4718/CHENP/2007; published on Jan. 11, 2008 (225 Pages).Applicant
Consolidated list of references from Opposition in parent patent EP No. 3370770, 4 pages; Feb. 24, 2022.Applicant
Darzalex, Highlights and Prescribing Information, FDA Label, 24 pages (2015).Applicant
Darzalex, Highlights and Prescribing Information, FDA Label, 32 pages (2018).Applicant
Davies, A. et al., “Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study,” The Lancet, vol. 15; 343-352 (2014).Applicant
Dimopoulos, M.A. et al., “Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma,” The New England Journal of Medicine, vol. 375; No. 14; 1319-1331 (2016); Suppl. Material: the protocol; total pp. 111 (2016).Applicant
Dimopoulos, M.A. et al., “Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial,” Lancet Oncol, vol. 22; 801-812 (2021).Applicant
Doessegger, L. and Banholzer, M.L., “Clinical development methodology for infusion-related reactions with monoclonal antibodies,” Clinical & Translational Immunology, vol. 4; e39; 9 pages (2015).Applicant
Drach, J. et al., “Retinoic Acid-induced Expression of CD38 Antigen in Myeloid Cells is Mediated through Retinoic Acid Receptor-α1,” Cancer Research, vol. 54; 1746-1752 (1994).Applicant
Durie, B.G.M. et al., “International Uniform Response Criteria for Multiple Myeloma,” Leukemia, vol. 20; 1467-1473 (2006).Applicant
European Medicines Agency, Summary of Product Characteristics for Rituximab; 153 pages; Oct. 30, 2009, https://www.ema.europa.eu/en/documents/product-information/mabthera-epar-product-information_en.pdf.Applicant
European Union Clinical Trials Register Clinical Trials Register, EudraCT No. 2014-002272-88; Title: “A Phase 3, Randomized, Controlled, Open-label Study of VELCADE (Bortezomlb) Melphalan-Prednisone (VMP) Compared to Daratumumab In Combination with VMP (D-VMP), In Subjects with Previously Untreated Multiple Mycloma who are Incllgible for High-dosc Therapy,” 6 pages (2015).Applicant
European Union Clinical Trials Register Clinical Trials Register, EudraCT No. 2014-002273-11; Title: “A Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) In Subjects with Previously Untreated Multiple Myeloma who are Ineligible for High Dose Therapy,” 7 pages (2015).Applicant
European Union Clinical Trials Register Clinical Trials Register, EudraCT No. 2013-005525-23; Title: “Phase 3 Study Comparing Daratumumab, Lenalidomide, and Dexamethasone (DRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects with Relapsed or Refractory Multiple Myeloma,” 7 pages (2014).Applicant
European Union Clinical Trials Register Clinical Trials Register, EudraCT No. 2014-000255-85; Title: “Phase 3 Study Comparing Daratumumab, Bortezomlb and Dexamethasone (DVd) vs Bortezomib and Dexamethasone (Vd) In Subjects With Relapsed or Refractory Multiple Mycloma,” 6 pages (2014).Applicant
Facon, T. et al., “Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA),” Blood, vol. 132 (Suppl 1); 8 Pages (2018).Applicant
Faiman, B. et al., “Steroid-Associated Side Effects in Patents with Multiple Myeloma: Consensus Statement of the IMF Nurse Leadership Board,” Clinical Journal of Oncology Nursing, vol. 12; No. 3; 53-63 (2008).Applicant
Frost, G.I., “Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration,” Expert Opinion Drug Deliv., vol. 4; No. 4; 427-440 (2007).Applicant
Gay, F. and Palumbo, A., “Management of Older Patients with Multiple Myeloma,” Blood Reviews, vol. 25; 65-73 (2011).Applicant
Goel, M. et al., “Plasticity within the Antigen-Combining Site May Manifest as Molecular Mimicry in the Humoral Immune Response,” The Journal of Immunology, vol. 173; 7358-7367 (2004).Applicant
Haller, M.F., “Converting Intravenous Dosing to Subcutaneous Dosing,” Pharmaceutical Technology, 118-132 (2007).Applicant
Halozyme, “Halozyme Therapeutics Reports Selection of First Product Candidate Under Janssen Collaboration,” Press Release, 4 pages (2015).Applicant
Hamizi, S. et al., “Subcutaneous trastuzumab: development of a new formulation for treatment of HER2-positive early breast cancer,” OncoTargets and Therapy, vol. 6; 89-94 (2013).Applicant
Herceptin, Highlights and Prescribing Information, FDA Label, 33 pages (1998).Applicant
Highlights of Prescribing Information, Rituxan, 53 pages (1997).Applicant
Highlights of Prescribing Information, Rituxan (rituximab) injection, 44 pages (1997).Applicant
Hydase, Highlights and Prescribing Information, FDA Label, 6 pages (2005).Applicant
Hylenex, Highlights and Prescribing Information, FDA Label, 9 pages (2005).Applicant
Jaccard, A. et al., “Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III),” Haematologica, vol. 99; No. 9; 1479-1485 (2014).Applicant
Jackisch, C. et al., “Subcutaneous Administration of Monoclonal Antibodies in Oncology,” Geburtsh Frauenhelk, vol. 74; 343-349 (2014).Applicant
Janssen Initiates Rolling Submission of Biologic License Application (BLA) for daratumumab with U.S. FDA for the Treatment of Multiple Myeloma, News Release, 3 pages (2015).Applicant
Janssen to Demonstrate Breadth of Oncology Portfolio with 41 Clinical Data Presentations at the 2014 American Society of Hematology (ASH) Annual Meeting [online], Nov. 6, 2014, Internet:<URL: https://www.jnj.com/media-center/press-releases/janssen-to-demonstrate-breadth-of-oncology-portfolio-with-41-clinical-data-presentations-at-the-2014-american-society-of-hematology-ash-annual-mccting>; 8 pages.Applicant
Janssen Submits Marketing Authorisation Application for Daratumumab for European Patients with Heavily Pre-treated Multiple Myeloma, Janssen-Cilag International NV; 7 pages (2015).Applicant
Jolles, S., “Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency,” Immuno Targets and Therapy, vol. 2; 125-133 (2013).Applicant
Kang, W. ct al., “Inference of synergy/antagonism between anticancer drugs from the poolcd analysis of clinical trials,” BMC Medical Research Methodology, vol. 13; No. 77; 8 pages (2013).Applicant
Khagi, Y. and Mark, T., “Potential role of daratumumab in the treatment of multiple myeloma,” Onco Targets and Therapy, 1095-1100 (2014).Applicant
Khan, T. and Salunke, D.M., “Adjustable Locks and Flexible Keys: Plasticity of Epitope-Paratope Interactions in Germline Antibodies,” The Journal of Immunology, vol. 192; 5398-5405 (2014).Applicant
Kim, H. et al., “Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data,” Br. J. Clin. Pharmacol., vol. 77; No. 1; 116-121 (2013).Applicant
Knowles, S.P. et al., “Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery,” Expert Opinion on Drug Delivery, vol. 18; No. 11; 1673-1685 (2021).Applicant
Kyle, R.A. and Rajkumar, S.V., “Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma,” Leukemia, vol. 23; 3-9 (2009).Applicant
Kyle, R.A. et al., “Clinical Course and Prognosis of Smoldering (Asymptomatic) Multiple Myeloma,” The New England Journal of Medicine, vol. 356; 2582-2590 (2007).Applicant
Kyle, R.A. et al., “Review of 1027 Patients with Newly Diagnosed Multiple Myeloma,” May Clinic Proc., vol. 78; 21-33 (2003).Applicant
Laubach, J.P. et al., “The challenge of cross-trial comparisons using limited data,” haematologica, vol. 99; e145; 2 pages (2014).Applicant
Lefranc, M. et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains,” Developmental & Comparative Immunology, vol. 27; 55-77 (2003).Applicant
Lokhorst, H.M. et al., “Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma,” The New England Journal of Medicine, vol. 373; 1207-1219 (2015).Applicant
Lokhorst, H.M. ct al., “Targeting CD38 with Daratumumab Monotherapy in Multiple Mycloma,” The New England Journal of Medicine, vol. 373; 1207-1219 (2015); Supplemental Appendix.Applicant
Lonial, S. et al., “Phase II study of daratumumab (DARA) monotherapy in patients with greater than or equal to 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius),” Journal of Clinical Oncology, vol. 33; No. 18 Suppl (2015).Applicant
Lonial, S. et al., “Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives,” Leukemia, vol. 30; 526-535 (2016).Applicant
Mahajan, S. et al., “The evolution of stem-cell transplantation in multiple myeloma,” Therapeutic Advances in Hematology, vol. 9; No. 5; 123-133 (2018).Applicant
Mariuzza, R.A. eet al., “The Structural Basis of Antigen-Antibody Recognition,” Ann. Rev. Biophys. Biophys. Chem., vol. 16; 139-159 (1987).Applicant
Matcos, M. ct al., “Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma,” N England J Med, vol. 378; 518-528 (2018).Applicant
Maury, M. et al., “Spray-drying of proteins: effects of sorbitol and trehalose on aggregation and FT-IR amide I spectrum of an immunoglobulin G,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 59; 251-261 (2005).Applicant
McCudden, C. et al., “Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference,” Clin Chem Lab Med, vol. 54; No. 6; 1095-1104 (2016).Applicant
Moreau, P. et al., “Rituximab in CD20 positive multiple myeloma,” Leukemia, vol. 21; 835-836 (2007).Applicant
Moreau, P. et al., “Practical Considerations for the Use of Daratumumab, a Novel CD38 Monoclonal Antibody, in Myeloma,” Drugs, vol. 76; 853-867 (2016).Applicant
Nahi, H. et al., “An open-label, dosc escalation phasc 1b study of subcutancous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO),” Journal of Clinical Oncology, vol. 34; No. 15; 4 pages (2016).Applicant
Negrin, R., Patient education: Hematopoietic transplantation (bone marrow transplantation) (Beyond the Basics), Retrieved from Internet URL: https://www.uptodate.com/contents/hematopoietic-cell-transplantation-bone-marrow-transplantation-beyond-the-basics, 15 pages; Retrieved on Oct. 27, 2022.Applicant
Ocio, E.M. et al., “New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG),” Leukemia, vol. 28; 525-542 (2014).Applicant
Ohaegbulam K C et al.: “Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway”, Trends in Molecular Medicine, Jan. 2015; 21 (1): 24-33.Applicant
Ortolani, C., “CD38: Antigen: Flow Cytometry of Hematological Malignancies,” Blackwell Publishing, 1st Edition, 68-70 (2011).Applicant
Palumbo, A. et al., “International Myeloma Working Group guidelines for the management of multiple myeloma patients ineligible for standard high-dose chemotherapy with autologous stem cell transplantation,” Leukemia, vol. 23; 1716-1730 (2009).Applicant
Palumbo, A. and Anderson, K., “Multiple Myeloma,” The New England Journal of Medicine, vol. 364; 1046-1060 (2011).Applicant
Patent Assignment Cover Sheet for U.S. Appl. No. 16/380,994, 6 pages; filed Sep. 11, 2019.Applicant
Phase 3 COLUMBIA study Investigating a Subcutaneous Formulation of DARZALEX (daratumumab) Showed Non-Inferiority to Intravenous Administration in Patients with Relapsed/Refractory Multiple Myeloma, Chicago, 7 pages (2019).Applicant
Phipps, C., et al., “Daratumumab and its potential in the treatment of multiple myeloma: overview of the preclinical and clinical development,” Ther. Adv. Hematol., vol. 6; No. 3; 120-127 (2015).Applicant
Pivot, X. et al., “Patients' preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study,” Annals of Oncology, vol. 25; 1979-1987 (2014).Applicant
Poosarla, V.G. et al., “Computational De Novo Design of Antibodies Binding to a Peptide With High Affinity,” Biotechnology & Bioengineering, vol. 114; No. 6; 1331-1342 (2017).Applicant
Pre-Grant Notice of Opposition filed in Indian Application No. 201617029109, by Indian Pharmaceutical Alliance, dated Feb. 24, 2022 (30 pages).Applicant
Preliminary Opinion of the Opposition Division, as cited in EP Opposition against EP Patent No. 3370770; 13 pages; dated Aug. 8, 2022.Applicant
Rader, C. et al., “A phage display approach for rapid antibody humanization: Designed combinatorial V gene libraries,” Proc. Natl. Acad. Sci, vol. 95; 8910-8915 (1998).Applicant
Raj, T.A. et al., “Vincristine sulfate liposomal injection for acute lymphoblastic leukemia,” International Journal of Nanomedicine, vol. 8; 4361-4369 (2013).Applicant
Rajkumar, S.V. et al., “Consensus recommendations for the uniform reporting of clinical trials: Report of the International Myeloma Workshop Consensus Panel 1,” Blood, vol. 117; No. 18; 4691-4695 (2011).Applicant
Rituxan (tituximab), Highlights of prescribing information. Rituxan (IV administered Rituximab; 35 pages (1997).Applicant
Rosengren, S. et al., Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration, The AAPS Journal, vol. 17; No. 5; 1144-1156 (2015).Applicant
Ruberg, E-M. and FrieB, W., “Sensibel und stressanfallig,” Pharmazeutische Zeitung, 156 JG, AUSG. 50; 15 pages (2011). concise explanation met by submission of the enclosed Notice of Opposition filed by Dr. Markus Breuer, cited as Other Document 128).Applicant
Rudikoff, S. et al., “Single amino acid substitution altering antigen-binding specificity,” Proc. Natl. Acad., col. 79; 1979-1983 (1982).Applicant
Ryan, et al., “Potentiation of Anti-Myeloma Activity of Daratumumab with Combination of Cyclophosphamide, Lenalidomide or Bortezomib via a Tumor Secretory Response That Greatly Augments Macrophage-Induced ADCP,” Annual Meeting at the Haematology Association of Ireland, Oct. 15, 2016; 20 pages.Applicant
San-Miguel, J., et al., “Subcutaneous Daratumumab in Patients with Relapsed or Refractory Multiple Myeloma: Part 2 Update of the Open-label, Multicenter, Dose Escalation Phase 1b Study (PAVO)”, Poster Presented at the 23rd European Hematology Association (EHA) Annual Congress; Jun. 14-17, 2018; Stockholm, Sweden.Applicant
Solal-Deligny, P., “Rituximab by subcutaneous route,” Expert Rev. Hematol., vol. 8; No. 2; 147-153 (2015).Applicant
Sondergeld, P. ct al., “Monclonal Antibodies in Mycloma,” Clinical Advances in Hematology & Oncology, vol. 13; Issue 9; 599-609 (2015).Applicant
Statement on a Nonproprietary Name Adopted by the USAN Council, Hyaluronidase, CAS Registry No. 757971-58-7; 1 page; No date provided.Applicant
Strickley, R.G. and Lambert, W.J., “A review of formulations of commercially available antibodies,” Journal of Pharmaceutical Sciences, vol. 110; 2590-2608 (2021).Applicant
Taussig, D.C. et al., “Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells,” Blood, vol. 112; No. 3; 568-575 (2008).Applicant
Usmani, S.Z. et al., “Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma,” Haematologica, vol. 107; 2408-2417 (2022).Applicant
Wang, W. ct al., “Antibody Structure, Instability, and Formulation,” Journal of Pharmaceutical Sciences, vol. 96; 1-26 (2007).Applicant
Warne, N.W., “Development of high concentration protein biopharmaceuticals: The use of platform approaches in formulation development,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 78; 208-212 (2011).Applicant
Wasserman, R.L., “Progress in Gammaglobulin Therapy for Immunodeficiency: From Subcutaneous to Intravenous Infusions and Back Again,” J. Clin. Immunol., vol. 32 ;1153-1164 (2012).Applicant
Wasserman, R.L., “Overview of recombinant human hyaluronidase-facilitated subcutaneous infusion of IgG in primary immunodeficiencies,” Immunotherapy, vol. 6; No. 5; 553-567 (2014).Applicant
WHO Drug Information, International Nonproprietary Names for Pharmaceutical Substances (INN), Proposed INN: List 101, vol. 23; No. 2; 64 pages (2009).Applicant
WHO Drug Information, International Nonproprietary Names for Pharmaceutical Substances (INN), Recommended INN: List 63, 40 pages (2010).Applicant
Wu, et al., An Analysis of the Sequences of the Variable Regions of Bence Jones Proteins and Myeloma Light Chains and Their Implications for Antibody Complementarity, Journal of Experimental Medicine, 132: 211-250 (1970).Applicant
Wunderlich, M. et al., “AML cells are differentially sensitive to chemotherapy treatment in a human xenograft model,” eBlood, vol. 121; No. 12; e90-e97 (2013).Applicant
Yamamoto, H. et al., “A mammalian homolog of the zebrafish transmembrane protein 2 (TMEM2) is the long-sought-after cell-surface hyaluronidase,” J. Biol. Chem., vol. 292; No. 18; 7304-7313 (2017).Applicant
Zadnikova, P. et al., “The Degradation of Hyaluronan in the skin,” Biomolecules, vol. 12; 251, 17 pages (2022).Applicant
Zagouri, F. et al., “Emerging antibodies for the treatment of multiple myeloma,” Expert Opinion on Emerging Drugs, vol. 21; No. 2; 225-237 (2016).Applicant
Zojer, N. et al., “Rituximab treatment provides no clinical benefit in patients with pretreated advanced multiple myeloma,” Leukemia & Lymphoma, vol. 47; No. 6; 1103-1109 (2006).Applicant
International Preliminary Report on Patentability dated Apr. 29, 2021 for International Application No. PCT/US2019/056838, entitled “Method of Providing Subcutaneous Administration of Anti-CD38 Antibodies”.Applicant
International Preliminary Report on Patentability for International Application No. PCT/IB2020/051484, dated Sep. 2, 2021.Applicant
International Search Report and Written Opinion for International Application No. PCT/IB2020/051484, dated Jul. 2, 2020.Applicant
Declaration of Professor Paul Anthony Dalby, in Opposition Proceedings against European Patent No. 3370770, 20 pages (Dated May 2022).Applicant
Declaration of Professor Christian Jackisch, in Opposition Proceedings against European Patent No. 3370770, 8 pages (Dated May 10, 2022).Applicant
Declaration of Professor Adrian Llewellyn Harris, in Opposition Proceedings against European Patent No. 3370770, 109 pages (Dated Dec. 20, 2022).Applicant
Declaration of Dr. Richard Senderoff, in Opposition Proceedings against European Patent No. 3370770, 28 pages (Dated Dec. 20, 2022).Applicant
Declaration of Professor Dr. Andreas Zimmer, in Opposition Proceedings against European Patent No. 3370770, 5 pages (Dated Jan. 9, 2023).Applicant
Second Declaration of Professor Christian Jackisch, in Opposition Proceedings against European Patent No. 3370770, 8 pages (Dated Jan. 6, 2023).Applicant
Notice of Opposition Dated Oct. 20, 2021 by Opponent König Szynka Tilmann von Renesse, filed in European Patent No. 3 370 770 B1.Applicant
Notice of Opposition Dated Oct. 19, 2021 by Opponent Patent Boutique LLP, filed in European Patent No. 3 370 770 B1.Applicant
Notice of Opposition Dated Oct. 20, 2021 by Opponent Dr. Markus Breuer, filed in European Patent No. 3 370 770 B1.Applicant
Notice of Opposition Dated Dec. 22, 2022 by Opponent Dr. Hans Ulrich Dorries, filed in European Patent No. 3 827 845 B1; 44 Pages.Applicant
Notice of Opposition Dated Dec. 27, 2022 by Opponent Konig Szynka Tilmann von Renesse, filed in European Patent No. 3 827 845 B1; 49 Pages.Applicant
Notice of Opposition Dated Dec. 28, 2022 by Opponent Michalski Huttermann & Partner, filed in European Patent No. 3 827 845 B1; 44 Pages.Applicant
Notice of Opposition Dated Dec. 29, 2022 by Opponent Patent Boutique LLP, filed in European Patent No. 3 827 845 B1; 49 Pages.Applicant
Notice of Opposition Dated Dec. 21, 2022 by Opponent Xbrane Biopharma AB, filed in European Patent No. 3 827 845 B1; 68 Pages.Applicant
Opponent's submission by Dr. Markus Breuer dated Oct. 4, 2022 filed in European Patent No. 3 370 770 B1.Applicant
Opponent's submission by Konig Szynka Tilmann von Renesse dated Jan. 11, 2023, filed in European Patent No. 3 370 770 B1; 27 Pages.Applicant
Opponent's submission by Dr. Markus Breuer dated Jan. 13, 2023, filed in European Patent No. 3 370 770 B1; 11 Pages.Applicant
Opponent's submission by Patent Boutique LLP dated Jan. 12, 2023, filed in European Patent No. 3 370 770 B1; 56 Pages.Applicant
Reply to Notice of Opposition, filed in European Patent No. 3 370 770 B1, entitled: “Subcutaneous Formulations Of Anti-CD38 Antibodies And Their Uses,” 416 pages, dated May 12, 2022.Applicant
Reply to Notice of Opposition, filed in European Patent No. 3 370 770 B1, entitled: “Subcutaneous Formulations Of Anti-CD38 Antibodies And Their Uses,” 19 pages, dated Jan. 13, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 16/840,153 dated Aug. 16, 2022.Applicant
Applicant Initiated Interview Summary for U.S. Appl. No. 16/840,153 dated Jun. 8, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/840,153 dated Mar. 22, 2022.Applicant
Applicant Initiated Interview Summary for U.S. Appl. No. 16/840,153 dated Apr. 6, 2022.Applicant
Notice of Allowance for U.S. Appl. No. 16/840,153 dated Dec. 21, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/927,947 dated Mar. 7, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 17/116,822 dated Mar. 8, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 17/116,835 dated Mar. 8, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 16/986,214 dated Feb. 28, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 17/005,039 dated Dec. 9, 2022.Applicant
Notice of Allowance for U.S. Appl. No. 16/162,355 dated Apr. 9, 2021.Applicant
Non Final Office Action for U.S. Appl. No. 16/741,542 dated Jul. 12, 2022.Applicant
Notice of Allowance for U.S. Appl. No. 16/741,542 dated Nov. 2, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/741,542 dated Mar. 17, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 16/312,133 dated Oct. 28, 2021.Applicant
Notice of Allowance for U.S. Appl. No. 16/312,133 dated Sep. 2, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/312,133 dated May 12, 2022.Applicant
Final Office Action for U.S. Appl. No. 15/798,670 dated Aug. 10, 2021.Applicant
Non-Final Office Action for U.S. Appl. No. 15/798,670 dated Apr. 2, 2021.Applicant
Final Office Action for U.S. Appl. No. 15/798,670 dated Dec. 16, 2020.Applicant
Non-Final Office Action for U.S. Appl. No. 15/798,670 dated Feb. 4, 2022.Applicant
Non-Final Office Action for U.S. Appl. No. 16/177,239 dated Sep. 21, 2021.Applicant
Final Office Action for U.S. Appl. No. 16/177,239 dated Feb. 10, 2021.Applicant
Notice of Allowance for U.S. Appl. No. 16/177,239, dated Oct. 13, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/177,239 dated Mar. 4, 2022.Applicant
Notice of Allowance for U.S. Appl. No. 16/177,239 dated Feb. 3, 2023.Applicant
Notice of Allowability for U.S. Appl. No. 16/177,239, dated Feb. 27, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 16/656,569 dated Aug. 26, 2021.Applicant
Notice of Allowance for U.S. Appl. No. 15/445,225 dated Mar. 25, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 15/445,225 dated Jul. 15, 2020.Applicant
Notice of Allowance for U.S. Appl. No. 15/445,225 dated Dec. 4, 2019.Applicant
Notice of Allowance for U.S. Appl. No. 15/445,225 dated Jul. 29, 2019.Applicant
Non Final Office Action for U.S. Appl. No. 16/797,301 dated Jul. 28, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/797,301 dated Feb. 17, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 17/475,975 dated Mar. 10, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 16/830,585 dated Mar. 17, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/830,585 dated Oct. 26, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/830,763 dated Mar. 17, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/830,763 dated Oct. 24, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/830,810 dated Mar. 15, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/830,810 dated Oct. 25, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 16/830,909 dated Mar. 17, 2022.Applicant
Final Office Action for U.S. Appl. No. 16/830,909 dated Oct. 26, 2022.Applicant
AstraZeneca 206162 Clinical Pharmacology Review 2014, (https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206162Orig1s000ClinPharmR.pdf; Application No. 206162Orig1s000; 117 pages.Applicant
Child, J.A. et al., “High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma,” N Engl J Med, vol. 348; 1875-1883 (2003).Applicant
City of Hope, “What's the Difference? Biosimilar and generic drug,” City of Hope, retrieved from: https://www .cancercenter.com/community/blog/2018/12/whats-the-difference-biosimi lar-and-generic-drugs; 3 Pages (Year: 2018).Applicant
Clinicaltrials.gov, “A Study to Evaluate Daratumumab in Transplant Eligible Participants with Previously Untreated Multiple Myeloma (Cassiopeia),” Identifier: NCT02541383; First Posted: Sep. 4, 2015 (29 pages).Applicant
Darzalex, Highlights and Prescribing Information, FDA Label, 11 pages (2017).Applicant
Demarest, T.G. et al., “NAD+ Metabolism in Aging and Cancer,” Annual Rev. Cancer Biol., vol. 3; 105-130 (2019).Applicant
Gariani, K. et al., “Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease,” Journal of Hepatology, vol. 66; 132-141 (2017).Applicant
Kaufman, J.L. et al., “Bortezomib, Thalidomide, and Dexamethasone as Induction Therapy for Patients with Symptomatic Multiple Myeloma,” Cancer, vol. 116; 3143-3151 (2010).Applicant
King, T. et al., “Best Practice for the Administration of Daratumumab in Multiple Myeloma: Australian Myeloma Nurse Expert Opinion,” Asia Pac J Oncol Nurs, vol. 5; 270-284 (2018).Applicant
Moreau, P. et al., “Multiple Myeloma: ESMO Clinical Practice Guidelines for dianosis, treatment and follow up,” Annals of Oncology, vol. 28; Suppl 4; iv52-iv61 (2017).Applicant
Multiple Myeloma Treatment Regiments (MMTR), Multiple Myeloma Treatment Regiments (Part 1 of 9), Haymarket Media, Inc., 9 Pages (2017).Applicant
Myeloma Australia, “Steroids,” Treatment Fact Sheet, Myeloma Australia, retrieved from: https://myeloma.org.au/wp-content/uploads/2018/09/Steroid-FS-Sep18.pdf 2 Pages (2018).Applicant
Decision Revoking the European Patent issued in EP Patent No. 3370770, mailed Apr. 20, 2023; 22 Pages.Applicant
Provision of the Minutes in Accordance with Rule 124(4) EPC regarding EP Patent No. 3370770, mailed Apr. 20, 2023, 14 pages.Applicant
Applicant Initiated Interview Summary for U.S. Appl. No. 16/927,947 dated Apr. 19, 2023.Applicant
Notice of Allowance for U.S. Appl. No. 16/927,947 dated Jun. 22, 2023.Applicant
Applicant Initiated Interview Summary for U.S. Appl. No. 17/116,822 dated Apr. 19, 2023.Applicant
Notice of Allowance for U.S. Appl. No. 17/116,822 dated May 12, 2023.Applicant
Applicant Initiated Interview Summary for U.S. Appl. No. 17/116,835 dated Apr. 19, 2023.Applicant
Notice of Allowance for U.S. Appl. No. 17/116,835 dated May 11, 2023.Applicant
Final Office Action for U.S. Appl. No. 17/005,039 dated Apr. 28, 2023.Applicant
Notice of Allowance for U.S. Appl. No. 16/741,542 dated Apr. 10, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 16/312,133 dated Dec. 8, 2022.Applicant
Non Final Office Action for U.S. Appl. No. 17/002,860 dated Jun. 27, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 17/674,397 dated Apr. 24, 2023.Applicant
Clinicaltrials.gov, “Safety and Efficacy Study of Eculizumab in Patients with Refractory Generalized Myasthenia Gravis,” Identifier: NCT00727194; Latest version: Sep. 13, 2019 (6 pages).Applicant
Davies, A. et al., “Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study,” The Lancet, vol. 15; 343-352 (2014); Supplemental Appendix (8 Pages).Applicant
Davis, T.A. et al., “Rituximab Anti-CD20 Monoclonal Antibody Therapy in Non-Hodgkin's Lymphoma: Safety and Efficacy of Re-Treatment,” Journal of Clinical Oncology, vol. 18; No. 17; 3135-3143 (2000).Applicant
Freeley et al., “The ‘Ins and Outs’ of complement-driven immune responses”, Immunol Rev., 274(1), pp. 16-32, Nov. 2016.Applicant
Karakasheva et al., “CD38-Expressing Myeloid-Derived Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer”, Microenvironment and Immunol., 75(19), pp. 4074-4085, Oct. 1, 2015.Applicant
Kwan et al., “Complement regulation of T cell immunity”, Immunol Res, 54(0), pp. 247-253, Dec. 2012.Applicant
Matsuda, M. et al., “Phenotypic analysis of plasma cells in bone marrow using flow cytometry in AL amyloidosis,” Amyloid, 10(2), 110-116 (2003).Applicant
McLaughlin, P. et al., “Pituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program,” Journal of Clinical Oncology, vol. 16; No. 8; 2825-2833 (1998).Applicant
Piro, L.D. et al., “Extended Rituximab )anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkins lymphoma,” Annals of Oncology, vol. 10; 655-661 (1999).Applicant
Rituxan (tituximab), Highlights of prescribing information. Rituxan (IV administered Rituximab; 44 pages (1997); Revised 2014.Applicant
van Beurden-Tan et al., “Systemic Literature Review and Network Meta-Analysis of Treatment Outcomes in Relapsed and/or Refractory Multiple Myeloma,” Journal of Clinical Oncology, vol. 35; No. 12; 1312-1319 (2017).Applicant
Whatcott ct al., “Targeting the tumor microenvironment in cancer: why hyaluronidase deserves a second look”, Cancer Discov., 1(4), pp. 291-296, Sep. 2011.Applicant
Declaration of Professor Paul Anthony Dalby, in Opposition Proceedings against European Patent No. 3827845, 20 pages (Dated Jul. 19, 2023).Applicant
Declaration of Peter Hellemans, in Opposition Proceedings against European Patent No. 3827845, 5 pages (Dated Jul. 21, 2023).Applicant
Declaration of Tara Masterson, in Opposition Proceedings against European Patent No. 3827845, 4 pages (Dated Jul. 2023).Applicant
Declaration of Professor Christian Jackisch, in Opposition Proceedings against European Patent No. 3827845, 11 pages (Dated Jul. 19, 2023).Applicant
Reply of the Patentee to the Notices of Opposition in European Patent No. 3 827 845 B1, Jul. 23, 2023 (203 pages).Applicant
Final Office Action for U.S. Appl. No. 16/986,214 dated Aug. 23, 2023.Applicant
Applicant Initiated Interview for U.S. Appl. No. 16/986,214 dated Oct. 17, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 17/005,039 dated Sep. 1, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 17/691,050 dated Oct. 3, 2023.Applicant
Final Office Action for U.S. Appl. No. 17/674,397 dated Oct. 18, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 16/797,301 dated Sep. 22, 2023.Applicant
BC Cancer Agency Cancer drug Manual, Oct. 1, 2013, “Hydroxyurea”. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Hydroxyurea_monograph_1Oct2013.pdf; Retrieved on Nov. 20, 2023; 7 pages (No Author given).Applicant
CHMP Assessment Report for HyQvia, 68 pages (2013).Applicant
Consolidated list of references from Opposition in patent EP No. 3827845, 6 pages; Jul. 24, 2023.Applicant
Consolidated list of references from Opposition in patent EP No. 3370770, 4 pages; 2023.Applicant
Dakhil, S. et al., “Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma,” Leukemia & Lymphoma, vol. 55; No. 10; 2335-2340 (2014).Applicant
Genmab, “Genmab Announces Positive Topline Results in Phase III Cassiopeia Study of Daratumumab in Front Line Multiple Myeloma,” Genmab News, 4 Pages (2018).Applicant
Leukemia—Acute Myeloid—AML—Treatment Options. Cancer.Net, Nov. 19, 2013. archived by the Wayback Machine at https://web.archive.org/web/20131120003806/http://www.cancer.net/print/19072; Retrieved on Nov. 20, 2023; 6 pages (No Author Listed).Applicant
Lokhorst, H.M., “Dose-Dependent efficacy of daratumumab (DARA) as monotherapy in patients with relapsed or refractory multiple myeloma (RR MM),” Journal of Clinical Oncology, vol. 32; No. 15; 4 pages (2014).Applicant
Morcos, P.N. et al., “Pharmacokinetics and pharmacodynamics of single subcutaneous doses of tocilizumab administered with or without rHuPH20,” International Journal of Clinical Pharmacology and Therapeutics, vol. 15, No. 7/2013; 537-548 (2013).Applicant
Quartino, A.L. et al., “Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous ”manual syringe“ injection or intravenously in women with HER2-positive early breast cancer,” Cancer Chemother Pharmacol, vol. 77; 77-88 (2016).Applicant
Rituxan (tituximab), Highlights of prescribing information. Rituxan (IV administered Rituximab; 53 pages (1997); Revised 2021.Applicant
Wasserman, R.L. et al., “Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency,” J Allergy Clin Immunol, vol. 130; 951-957 (2012).Applicant
Wynne, C. et al., “Comparison of Subcutaneous and Intravenous Administration of Trastuzumab: A Phase I/Ib Trial in Healthy Male Volunteers and Patients with HER2-Positive Breast Cancer,” The Journal of Clinical Pharmcology, vol. 53; No. 2; 192-201 (2012).Applicant
Annex to Form 2300—Notice of Opposition, filed on behalf of Konig Szynka Tilmann von Renesse, filed in Opposition for EP Patent 3370770, 39 pages (2024).Applicant
Second Declaration of Professor Adrian Llewellyn Harris, in Opposition Proceedings against European Patent No. 3370770, 5 pages (Dated Jan. 3, 2024).Applicant
Declaration of Peter Hellemans, in Opposition Proceedings against European Patent No. 3370770, 5 pages (Dated Aug. 24, 2023).Applicant
Declaration of Tara Masterson, in Opposition Proceedings against European Patent No. 3370770, 4 pages (Dated Aug. 2023).Applicant
Opponent's submission by Dr. Markus Bruer dated Jan. 15, 2024, filed in European Patent No. 3 370 770 B1; 53 Pages.Applicant
Opponents Submission by Dr. Markus Bruer to Comments on Proprietor's Submission , filed in EP Opposition for EP Patent 3370770, 17 pages; dated Oct. 4, 2022.Applicant
Representation for Indian Pharmaceutical Alliance in Opposition of Patent for IN Application No. 201617029321, dated May 5, 2022 (29 pages).Applicant
Reply of the Patentee, Janssen Biotech, Inc., to the Notices of Opposition in European Patent No. 3370770, Aug. 2023 (63 pages).Applicant
Response to Patentee's Statement of Grounds of Appeal, filed by Patent Boutique LLP in European Patent No. 3370770 , dated Jan. 12, 2024 (74 pages).Applicant
Response to Patentee's Statement of Grounds of Appeal, filed on behalf of Konig Szynka Tilmann von Renesse in European Patent No. 3370770 , dated Jan. 15, 2024 (106 pages).Applicant
Response to Summons to Attend Oral Proceedings in Opposition against EP 3770770, filed on behalf of Dr. Markus Bruer, 11 pages; filed on Jan. 13, 2023.Applicant
Non Final Office Action for U.S. Appl. No. 16/986,214 date mailed Dec. 26, 2023.Applicant
Final Office Action for U.S. Appl. No. 17/005,039 date mailed Dec. 22, 2023.Applicant
Non-Final Office Action for U.S. Appl. No. 17/329,057 mailed Dec. 12, 2023.Applicant
Final Office Action for U.S. Appl. No. 17/002,860 date mailed Nov. 30, 2023.Applicant
Final Office Action for U.S. Appl. No. 16/797,301 date mailed Jan. 29, 2024.Applicant

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

INCORPORATION BY REFERENCE OF MATERIAL IN ASCII TEXT FILE

[0002] This application incorporates by reference the Sequence Listing contained in the following ASCII text file being submitted concurrently herewith:

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