Eribulin-based antibody-drug conjugates and methods of use

[0001] The present application is a continuation of U.S. patent application Ser. No. 15/448,497, filed Mar. 2, 2017, and claims the benefit of priority to U.S. Provisional Patent Application No. 62/302,562, filed Mar. 2, 2016, the entire contents of which are incorporated herein by reference.

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 28, 2017, is named 08061_0024-00304_SL.txt and is 230,910 bytes in size.

[0003] The present disclosure relates to antibody drug conjugates (ADCs) that bind human oncology antigen targets such as folate receptor alpha and/or provide anti-tubulin drug activity. The disclosure further relates to methods and compositions useful in the treatment and diagnosis of cancers that express folate receptor alpha and/or are amenable to treatment by disrupting tubulin.

[0004] Cancer is among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012. The most common causes of cancer death are cancers of: lung (1.59 million deaths); liver (745,000 deaths); stomach (723,000 deaths); colorectal (694,000 deaths); breast (521,000 deaths); and esophagus (400,000 deaths). The number of new cancer cases is expected to rise by about 70% over the next two decades, to approximately 22 million new cancer cases per year (World Cancer Report 2014).

[0005] Microtubules are dynamic filamentous cytoskeletal proteins that are involved in a variety of cellular functions, including intracellular migration and transport, cell signaling, and the maintenance of cell shape. Microtubules also play a critical role in mitotic cell division by forming the mitotic spindle required to segregate chromosomes into two daughter cells. The biological functions of microtubules in all cells are regulated in large part by their polymerization dynamics, which occurs by the reversible, non-covalent addition of a and 13 tubulin dimers at both ends of microtubules. This dynamic behavior and resulting control over microtubule length is vital to the proper functioning of the mitotic spindle. Even minor alteration of microtubule dynamics can engage the spindle checkpoint, arrest cell cycle progression at mitosis, and subsequently lead to cell death (Mukhtar et al. (2014) Mol. Cancer Ther. 13:275-84). Due to their rapid cell division, cancer cells are generally more sensitive to compounds that bind to tubulin and disrupt its normal function, as compared to normal cells. For this reason, tubulin inhibitors and other microtubule-targeted agents have become a promising class of drugs for the treatment of cancer (Dumontet and Jordan (2010) Nat. Rev. Drug Discov. 9:790-803).

[0006] Folate receptor alpha (FRA) is a glycophosphatidylinositol (GPI)-linked membrane protein that binds folate. While the role of FRA in the biology of normal and cancerous tissue is not fully understood, it is highly over-expressed on a high percentage of ovarian cancers of epithelial origin (O'Shannessy et al. (2013) Int. J. Gynecol. Pathol. 32(3):258-68), as well as in a percentage of non-small cell lung carcinomas (Christoph et al. (2014) Clin. Lung Cancer 15(5):320-30). FRA also has limited expression in normal tissues. These properties make FRA an attractive target for cancer immunotherapy.

[0007] The proto-oncogene human epidermal growth factor receptor 2 (HER2) encodes a transmembrane tyrosine kinase receptor that belongs to the human epidermal growth factor receptor (EGFR) family (King et al. (1985) Science 229:974-6). Overexpression of HER2 enables constitutive activation of growth factor signaling pathways, such as the PI3K-AKT-mTOR pathway, and thereby serves as an oncogenic driver in several types of cancers, including approximately 20% of invasive breast carcinomas (Slamon et al. (1989) Science 244:707-12; Gajria and Chandarlapaty (2011) Expert Rev. Anticancer Ther. 11:263-75). Given that HER2 amplification mediates the transformed phenotype, HER2 is another promising target for cancer treatment.

[0008] The present disclosure provides, in part, novel compounds with biological activity against tumor cells. The compounds may inhibit tumor growth in mammals, and may be useful for treating human cancer patients.

[0009] The present disclosure more specifically relates to antibody-drug conjugate compounds that are capable of binding, internalizing, and killing tumor cells (e.g., FRA-expressing tumor cells). Antibody-drug conjugate compounds comprising a linker that attaches a drug moiety to an antibody moiety are disclosed. Antibody-drug conjugate (ADC) compounds may be represented by Formula I:
Ab-(L-D)_p  (I)
wherein Ab is an internalizing antibody or an internalizing antigen-binding fragment thereof which targets a tumor cell;
D is eribulin;
L is a cleavable linker that covalently attaches Ab to D; and
p is an integer from 1 to 20.

[0010] In some embodiments, the linker is stable outside a cell, such that the ADC remains intact when present in extracellular conditions but is capable of being cleaved on internalization in a cell, e.g., a cancer cell. In some embodiments, the eribulin drug moiety is cleaved from the antibody moiety when the ADC enters a cell that expresses an antigen specific for the antibody moiety of the ADC, and cleavage releases an unmodified form of eribulin. In some embodiments, the linker comprises a cleavable moiety that is positioned such that no part of the linker or the antibody moiety remains bound to the eribulin drug moiety upon cleavage.

[0011] In some embodiments, the cleavable moiety in the linker is a cleavable peptide moiety. In some embodiments, an ADC that comprises a cleavable peptide moiety demonstrates lower aggregation levels, improved antibody: drug ratio, increased on-target killing of cancer cells, decreased off-target killing of non-cancer cells, and/or higher drug loading (p) relative to an ADC that comprises an alternate cleavable moiety. In some embodiments, adding a cleavable moiety increases cytotoxicity and/or potency relative to a non-cleavable linker. In some embodiments, the increased potency and/or cytotoxicity is in a cancer expressing moderate levels of the antigen targeted by the antibody moiety of the ADC (e.g., moderate FRA expression). In some embodiments, the cleavable peptide moiety is cleavable by an enzyme, and the linker is an enzyme-cleavable linker. In some embodiments, the enzyme is cathepsin, and the linker is a cathepsin-cleavable linker. In certain embodiments, the enzyme-cleavable linker (e.g., the cathepsin-cleavable linker) exhibits one or more of the improved properties mentioned above, as compared to an alternate cleavage mechanism.

[0012] In some embodiments, the cleavable peptide moiety in the linker comprises an amino acid unit. In some embodiments, the amino acid unit comprises valine-citrulline (Val-Cit). In some embodiments, an ADC that comprises Val-Cit demonstrates increased stability, decreased off-target cell killing, increased on-target cell killing, lower aggregation levels, and/or higher drug loading relative to an ADC that comprises an alternate amino acid unit or alternate cleavable moiety.

[0013] In some embodiments, the linker comprises at least one spacer unit joining the antibody moiety to the cleavable moiety. In some embodiments, the spacer unit in the linker may comprise at least one polyethylene glycol (PEG) moiety. The PEG moiety may, for example, comprise -(PEG)_m-, wherein m is an integer from 1 to 10. In some embodiments, the spacer unit in the linker comprises (PEG)₂. In some embodiments, an ADC that comprises a shorter spacer unit (e.g., (PEG)₂) demonstrates lower aggregation levels and/or higher drug loading relative to an ADC that comprises a longer spacer unit (e.g., (PEG)₈) despite the shorter linker length.

[0014] In some embodiments, the spacer unit in the linker attaches to the antibody moiety of the ADC via a maleimide moiety (Mal). In some embodiments, an ADC that comprises a linker attached to the antibody moiety via a Mal demonstrates higher drug loading relative to an ADC that comprises a linker attached to the antibody moiety via an alternate moiety. In some embodiments, the Mal in the linker is reactive with a cysteine residue on the antibody moiety. In some embodiments, the Mal in the linker is joined to the antibody moiety via a cysteine residue. In some embodiments, the Mal-spacer unit comprises a PEG moiety. In some embodiments, the linker comprises Mal-(PEG)_m, e.g., Mal-(PEG)₂. In some embodiments, the linker comprises Mal-(PEG)₂. In some embodiments, the Mal-spacer unit attaches the antibody moiety to the cleavable moiety in the linker. In some embodiments, the cleavable moiety in the linker is a cleavable peptide moiety, e.g., an amino acid unit. In some embodiments, the linker comprises Mal-(PEG)₂-Val-Cit.

[0015] In some embodiments, the cleavable moiety in the linker is directly joined to the eribulin drug moiety of the ADC, and the cleavable moiety is either directly connected to the antibody moiety or connected through a spacer unit. In some embodiments, a spacer unit also attaches the cleavable moiety in the linker to the eribulin drug moiety. In some embodiments, the spacer unit that attaches the cleavable moiety in the linker to the eribulin drug moiety is self-immolative. In some embodiments, the self-immolative spacer is capable of releasing unmodified eribulin in a target cell. In some embodiments, the self-immolative spacer unit comprises a p-aminobenzyl alcohol. In some embodiments, the self-immolative spacer unit comprises p-aminobenzyloxycarbonyl (pAB). The pAB in the linker, in some embodiments, attaches the cleavable moiety to the eribulin drug moiety. In some embodiments, the cleavable moiety is a cleavable peptide moiety, e.g., an amino acid unit. In some embodiments, the linker comprises Val-Cit-pAB. In some embodiments, the linker comprises Val-Cit-pAB and a PEG spacer unit joining the linker to the antibody moiety through a Mal.

[0016] In some embodiments, p is an integer from 1 to 6, from 2 to 5, or preferably, from 3 to 4. In the some embodiments, p is 4. In some embodiments, a pool of ADCs are provided, and the average p in the pool is about 4 (e.g., 3.5-4.5, such as about 3.8). In some embodiments, the linker comprises Mal-(PEG)₂-Val-Cit-pAB. In some embodiments, the linker comprises Mal-(PEG)₂-Val-Cit-pAB and p is 4. In some embodiments, a pool of ADCs are provided, wherein each ADC comprises a Mal-(PEG)₂-Val-Cit-pAB linker, and the average p in the pool is about 4 (e.g., 3.5-4.5, such as about 3.8).

[0017] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment (Ab or Ab moiety) of the ADC is an anti-folate receptor alpha (FRA) antibody or internalizing antibody fragment, and can bind FRA-expressing tumor cells (i.e., the ADC targets FRA-expressing cells). In some embodiments, the ADC comprising an anti-FRA Ab moiety and a cleavable peptide moiety demonstrates lower aggregation levels, improved antibody: drug ratio, increased on-target killing of cancer cells, decreased off-target killing of non-cancer cells, higher drug loading (p), increased cytotoxicity, and/or potency relative to a non-cleavable linker or an alternate cleavage mechanism. In some embodiments, the increased potency and/or cytotoxicity is in a cancer expressing moderate levels of the antigen targeted by the antibody moiety of the ADC (e.g., moderate FRA expression). In some embodiments, the cleavable peptide moiety is cleavable by an enzyme, and the linker is an enzyme-cleavable linker. In some embodiments, the enzyme is cathepsin, and the linker is a cathepsin-cleavable linker. In certain embodiments, the enzyme-cleavable linker (e.g., the cathepsin-cleavable linker) exhibits one or more of the improved properties mentioned above, as compared to an alternate cleavage mechanism. In some embodiments, the linker is a Mal-(PEG)_m-Val-Cit-pAB.

[0018] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to folate receptor alpha (FRA) and targets FRA-expressing tumor cells. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:2, heavy chain CDR2 consisting of SEQ ID NO:3, and heavy chain CDR3 consisting of SEQ ID NO:4; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:7, light chain CDR2 consisting of SEQ ID NO:8, and light chain CDR3 consisting of SEQ ID NO:9, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:13, heavy chain CDR2 consisting of SEQ ID NO:14, and heavy chain CDR3 consisting of SEQ ID NO:15; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:16, light chain CDR2 consisting of SEQ ID NO:17, and light chain CDR3 consisting of SEQ ID NO:18, as defined by the IMGT numbering system. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises human framework sequences. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:23 and a light chain variable domain of SEQ ID NO:24. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:23 and a light chain variable domain of SEQ ID NO:24. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to an epitope comprising alanine-histadine-lysine-aspartic acid (AHKD) (SEQ ID NO:365) (O'Shannessy et al., (2011) Oncotarget 2:1227-43). In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to an epitope comprising NTSQEAHKDVSYL (SEQ ID NO:366).

[0019] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is an internalizing anti-FRA antibody or internalizing antigen-binding fragment. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:2, heavy chain CDR2 consisting of SEQ ID NO:3, and heavy chain CDR3 consisting of SEQ ID NO:4; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:7, light chain CDR2 consisting of SEQ ID NO:8, and light chain CDR3 consisting of SEQ ID NO:9, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:13, heavy chain CDR2 consisting of SEQ ID NO:14, and heavy chain CDR3 consisting of SEQ ID NO:15; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:16, light chain CDR2 consisting of SEQ ID NO:17, and light chain CDR3 consisting of SEQ ID NO:18, as defined by the IMGT numbering system; the linker comprises Mal-(PEG)₂-Val-Cit-pAB; and p is 4. In some embodiments, a pool of such ADCs are provided andp is about 4 (e.g., about 3.8). In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:23 and a light chain variable domain of SEQ ID NO:24. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:23 and a light chain variable domain of SEQ ID NO:24. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to an epitope comprising SEQ ID NO:365. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to an epitope comprising SEQ ID NO:366.

[0020] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to human epidermal growth factor receptor 2 (her2) and targets her2-expressing tumor cells. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:71 heavy chain CDR2 consisting of SEQ ID NO:72, and heavy chain CDR3 consisting of SEQ ID NO:73; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:74, light chain CDR2 consisting of SEQ ID NO:75, and light chain CDR3 consisting of SEQ ID NO:76, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:191, heavy chain CDR2 consisting of SEQ ID NO:192, and heavy chain CDR3 consisting of SEQ ID NO:193; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:194, light chain CDR2 consisting of SEQ ID NO:195, and light chain CDR3 consisting of SEQ ID NO:196, as defined by the IMGT numbering system. In some embodiments, the antibody or internalizing antigen-binding fragment comprises human framework sequences. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:27 and a light chain variable domain of SEQ ID NO:28. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:27 and a light chain variable domain of SEQ ID NO:28.

[0021] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is an internalizing anti-her2 antibody or internalizing antigen-binding fragment. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:71 heavy chain CDR2 consisting of SEQ ID NO:72, and heavy chain CDR3 consisting of SEQ ID NO:73; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:74, light chain CDR2 consisting of SEQ ID NO:75, and light chain CDR3 consisting of SEQ ID NO:76, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:191, heavy chain CDR2 consisting of SEQ ID NO:192, and heavy chain CDR3 consisting of SEQ ID NO:193; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:194, light chain CDR2 consisting of SEQ ID NO:195, and light chain CDR3 consisting of SEQ ID NO:196, as defined by the IMGT numbering system; the linker comprises Mal-(PEG)₂-Val-Cit-pAB; and p is 4. In some embodiments, a pool of such ADCs are provided and p is about 4 (e.g., about 3.8). In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:27 and a light chain variable domain of SEQ ID NO:28. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:27 and a light chain variable domain of SEQ ID NO:28.

[0022] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment binds to mesothelin (MSLN) and targets MSLN-expressing tumor cells. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:65 heavy chain CDR2 consisting of SEQ ID NO:66, and heavy chain CDR3 consisting of SEQ ID NO:67; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:68, light chain CDR2 consisting of SEQ ID NO:69, and light chain CDR3 consisting of SEQ ID NO:70, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:185, heavy chain CDR2 consisting of SEQ ID NO:186, and heavy chain CDR3 consisting of SEQ ID NO:187; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:188, light chain CDR2 consisting of SEQ ID NO:189, and light chain CDR3 consisting of SEQ ID NO:190, as defined by the IMGT numbering system. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:25 and a light chain variable domain of SEQ ID NO:26. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:25 and a light chain variable domain of SEQ ID NO:26.

[0023] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment is an internalizing anti-MSLN antibody or internalizing antigen-binding fragment. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises three heavy chain CDRs and three light chain CDRs, wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:65 heavy chain CDR2 consisting of SEQ ID NO:66, and heavy chain CDR3 consisting of SEQ ID NO:67; and the three light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:68, light chain CDR2 consisting of SEQ ID NO:69, and light chain CDR3 consisting of SEQ ID NO:70, as defined by the Kabat numbering system; or wherein the heavy chain CDRs comprise heavy chain CDR1 consisting of SEQ ID NO:185, heavy chain CDR2 consisting of SEQ ID NO:186, and heavy chain CDR3 consisting of SEQ ID NO:187; and the light chain CDRs comprise light chain CDR1 consisting of SEQ ID NO:188, light chain CDR2 consisting of SEQ ID NO:189, and light chain CDR3 consisting of SEQ ID NO:190, as defined by the IMGT numbering system; the linker comprises Mal-(PEG)₂-Val-Cit-pAB; and p is 4. In some embodiments, a pool of such ADCs are provided and p is about 4 (e.g., about 3.8). In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a heavy chain variable domain of SEQ ID NO:25 and a light chain variable domain of SEQ ID NO:26. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment comprises a human IgG1 heavy chain constant domain and an Ig kappa light chain constant domain. In some embodiments, the internalizing antibody or internalizing antigen-binding competes for binding and/or binds the same epitope as an antibody comprising a heavy chain variable domain of SEQ ID NO:25 and a light chain variable domain of SEQ ID NO:26.

[0024] Also provided herein are compositions comprising multiple copies of any of the described ADCs, wherein the average drug loading (average p) of the ADCs in the composition is between about 3 and 4, or about 3.5 to about 4.5, or about 4. In some embodiments, the average p is between about 3.2 and 3.8. In some embodiments, the average p is between about 3.6 and 4.4.

[0025] Also provided herein are compositions comprising -L-D, wherein D is eribulin; and L is a cleavable linker that covalently attaches to D. In some embodiments, the cleavable linker covalently attaches to the C-35 amine on eribulin. In some embodiments, the cleavable linker comprises Val-Cit. In some embodiments, the cleavable linker comprises a PEG spacer unit. In some embodiments, the cleavable linker comprises Mal-(PEG)₂-Val-Cit-pAB.

[0026] Further provided herein are pharmaceutical compositions comprising an ADC and a pharmaceutically acceptable diluent, carrier, and/or excipient.

[0027] Another aspect of the present disclosure includes therapeutic and diagnostic uses for the described ADC compounds and compositions, e.g., in treating cancer. Another aspect includes methods of treating a cancer that expresses an antigen targeted by the antibody moiety of the ADC, such as FRA. In various embodiments, methods are provided of killing or inhibiting the proliferation of tumor cells or cancer cells by administering a therapeutically effective amount and/or regimen of any one of the described ADCs. Another aspect includes methods for detecting tumor cells or cancer cells that express FRA using the disclosed ADCs, and methods of screening for cancer patients that will be responsive to treatment with the described ADCs. In some embodiments, the cancer is a gastric cancer, a serous ovarian cancer, a clear cell ovarian cancer, a non-small cell lung cancer, a colorectal cancer, a triple negative breast cancer, an endometrial cancer, a serous endometrial carcinoma, a lung carcinoid, or an osteosarcoma. Methods of producing the described ADCs are also disclosed.

[0051] The disclosed compositions and methods may be understood more readily by reference to the following detailed description taken in connection with the accompanying figures, which form a part of this disclosure. It is to be understood that the disclosed compositions and methods are not limited to the specific compositions and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions and methods.

[0052] Throughout this text, the descriptions refer to compositions and methods of using said compositions. Where the disclosure describes or claims a feature or embodiment associated with a composition, such a feature or embodiment is equally applicable to the methods of using said composition. Likewise, where the disclosure describes or claims a feature or embodiment associated with a method of using a composition, such a feature or embodiment is equally applicable to the composition.

[0053] When a range of values is expressed, it includes embodiments using any particular value within the range. Further, reference to values stated in ranges includes each and every value within that range. All ranges are inclusive of their endpoints and combinable. When values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless the context clearly dictates otherwise. The use of “or” will mean “and/or” unless the specific context of its use dictates otherwise. All references cited herein are incorporated by reference for any purpose. Where a reference and the specification conflict, the specification will control.

[0054] It is to be appreciated that certain features of the disclosed compositions and methods, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

Definitions

[0055] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0056] As used herein, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise.

[0057] The terms “about” or “approximately” in the context of numerical values and ranges refers to values or ranges that approximate or are close to the recited values or ranges such that the embodiment may perform as intended, such as having a desired amount of nucleic acids or polypeptides in a reaction mixture, as is apparent to the skilled person from the teachings contained herein. This is due, at least in part, to the varying properties of nucleic acid compositions, age, race, gender, anatomical and physiological variations and the inexactitude of biological systems. Thus, these terms encompass values beyond those resulting from systematic error.

[0058] The terms “antibody-drug conjugate,” “antibody conjugate,” “conjugate,” “immunoconjugate,” and “ADC” are used interchangeably, and refer to a compound or derivative thereof that is linked to an antibody (e.g., an anti-FRA antibody) and is defined by the generic formula: Ab-(L-D)_p (Formula I), wherein Ab=an antibody moiety (i.e., antibody or antigen-binding fragment), L=a linker moiety, D=a drug moiety, and p=the number of drug moieties per antibody moiety.

[0059] The term “antibody” is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing through at least one antigen recognition site within the variable region of the immunoglobulin molecule. The heavy chain of an antibody is composed of a heavy chain variable domain (V_H) and a heavy chain constant region (C_H). The light chain is composed of a light chain variable domain (V_L) and a light chain constant domain (C_L). For the purposes of this application, the mature heavy chain and light chain variable domains each comprise three complementarity determining regions (CDR1, CDR2 and CDR3) within four framework regions (FR1, FR2, FR3 and FR4) arranged from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. An “antibody” can be naturally occurring or man-made, such as monoclonal antibodies produced by conventional hybridoma technology. The term “antibody” includes full-length monoclonal antibodies and full-length polyclonal antibodies, as well as antibody fragments such as Fab, Fab′, F(ab′)2, Fv, and single chain antibodies. An antibody can be any one of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses thereof (e.g., isotypes IgG1, IgG2, IgG3, IgG4). The term further encompasses human antibodies, chimeric antibodies, humanized antibodies and any modified immunoglobulin molecule containing an antigen recognition site, so long as it demonstrates the desired biological activity.

[0060] The term “monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of antibodies directed against (or specific for) different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352:624-8, and Marks et al. (1991) J. Mol. Biol. 222:581-97, for example.

[0061] The monoclonal antibodies described herein specifically include “chimeric” antibodies, in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind the target antigen and/or exhibit the desired biological activity.

[0062] The term “human antibody,” as used herein, refers an antibody produced by a human or an antibody having an amino acid sequence of an antibody produced by a human.

[0063] The term “chimeric antibody,” as used herein, refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some instances, the variable regions of both heavy and light chains corresponds to the variable regions of antibodies derived from one species with the desired specificity, affinity, and activity while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize an immune response in the latter species.

[0064] As used herein, the term “humanized antibody” refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies which contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The humanized antibody can be further modified by the substitution of residues, either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or activity.

[0065] The term “antigen-binding fragment” or “antigen-binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., FRA). Antigen-binding fragments preferably also retain the ability to internalize into an antigen-expressing cell. In some embodiments, antigen-binding fragments also retain immune effector activity. It has been shown that fragments of a full-length antibody can perform the antigen-binding function of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” or “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V_L, V_H, C_L, and C_H1 domains; (ii) a F(ab′)₂ fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the V_H and C_H1 domains; (iv) a Fv fragment consisting of the V_L and V_H domains of a single arm of an antibody; (v) a dAb fragment, which comprises a single variable domain, e.g., a V_H domain (see, e.g., Ward et al. (1989) Nature 341:544-6; and Winter et al., WO 90/05144); and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, V_L and V_H, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the V_L and V_H regions pair to form monovalent molecules (known as single chain Fv (scFv)). See, e.g., Bird et al. (1988) Science 242:423-6; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-83. Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” or “antigen-binding portion” of an antibody, and are known in the art as an exemplary type of binding fragment that can internalize into cells upon binding. See, e.g., Zhu et al. (2010) 9:2131-41; He et al. (2010) J. Nucl. Med. 51:427-32; and Fitting et al. (2015) MAbs 7:390-402. In certain embodiments, scFv molecules may be incorporated into a fusion protein. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which V_H and V_L domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites (see e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-8; and Poljak et al. (1994) Structure 2:1121-3). Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as are intact antibodies. Antigen-binding fragments may be prepared by cleavage of the intact protein, e.g., by protease or chemical cleavage.

[0066] “Internalizing” as used herein in reference to an antibody or antigen-binding fragment refers to an antibody or antigen-binding fragment that is capable of being taken through the cell's lipid bilayer membrane to an internal compartment (i.e., “internalized”) upon binding to the cell, preferably into a degradative compartment in the cell. For example, an internalizing anti-FRA antibody is one that is capable of being taken into the cell after binding to FRA on the cell membrane.

[0067] The term “folate receptor alpha” or “FRA,” as used herein, refers to any native form of human FRA. The term encompasses full-length FRA (e.g., NCBI Reference Sequence: NP_000793; SEQ ID NO: 19), as well as any form of human FRA that results from cellular processing. The term also encompasses naturally occurring variants of FRA, including but not limited to splice variants, allelic variants, and isoforms. FRA can be isolated from a human, or may be produced recombinantly or by synthetic methods.

[0068] The term “anti-FRA antibody” or “antibody that specifically binds FRA” refers to any form of antibody or fragment thereof that specifically binds FRA, and encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments so long as they specifically bind FRA. Preferably the anti-FRA antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. MORAb-003 is an exemplary internalizing anti-human FRA antibody. As used herein, the terms “specific,” “specifically binds,” and “binds specifically” refer to the selective binding of the antibody to the target antigen epitope. Antibodies can be tested for specificity of binding by comparing binding to appropriate antigen to binding to irrelevant antigen or antigen mixture under a given set of conditions. If the antibody binds to the appropriate antigen with at least 2, 5, 7, and preferably 10 times more affinity than to irrelevant antigen or antigen mixture, then it is considered to be specific. In one embodiment, a specific antibody is one that only binds the FRA antigen, but does not bind (or exhibits minimal binding) to other antigens.

[0069] The term “human epidermal growth factor receptor 2,” “her2,” or “her2/neu,” as used herein, refers to any native form of human her2. The term encompasses full-length her2 (e.g., NCBI Reference Sequence: NP 004439.2; SEQ ID NO: 21), as well as any form of human her2 that results from cellular processing. The term also encompasses naturally occurring variants of her2, including but not limited to splice variants, allelic variants, and isoforms. Her2 can be isolated from human, or may be produced recombinantly or by synthetic methods.

[0070] The term “anti-her2 antibody” or “antibody that specifically binds her2” refers to any form of antibody or fragment thereof that specifically binds her2, and encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments so long as they specifically bind her2. U.S. Pat. No. 5,821,337 (incorporated herein by reference) provides exemplary her2-binding sequences, including exemplary anti-her2 antibody sequences. Preferably the anti-her2 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. Trastuzumab is an exemplary internalizing anti-human her2 antibody.

[0071] The term “epitope” refers to the portion of an antigen capable of being recognized and specifically bound by an antibody. When the antigen is a polypeptide, epitopes can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of the polypeptide. The epitope bound by an antibody may be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, as well as monitoring the binding of the antibody to fragments or mutated variations of the antigen, or monitoring solvent accessibility of different parts of the antibody and the antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, limited proteolysis, site-directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry (see, e.g., Gershoni et al. (2007) 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev. Proteomics 2:745-56).

[0072] Competitive binding and epitope binning can also be used to determine antibodies sharing identical or overlapping epitopes. Competitive binding can be evaluated using a cross-blocking assay, such as the assay described in “Antibodies, A Laboratory Manual,” Cold Spring Harbor Laboratory, Harlow and Lane (1st edition 1988, 2nd edition 2014). In some embodiments, competitive binding is identified when a test antibody or binding protein reduces binding of a reference antibody or binding protein to a target antigen such as FRA or her2 (e.g., a binding protein comprising CDRs and/or variable domains selected from those identified in Tables 2, 4, and 6), by at least about 50% in the cross-blocking assay (e.g., 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5%, or more, or any percentage in between), and/or vice versa. In some embodiments, competitive binding can be due to shared or similar (e.g., partially overlapping) epitopes, or due to steric hindrance where antibodies or binding proteins bind at nearby epitopes. See, e.g., Tzartos, Methods in Molecular Biology (Morris, ed. (1998) vol. 66, pp. 55-66). In some embodiments, competitive binding can be used to sort groups of binding proteins that share similar epitopes, e.g., those that compete for binding can be “binned” as a group of binding proteins that have overlapping or nearby epitopes, while those that do not compete are placed in a separate group of binding proteins that do not have overlapping or nearby epitopes.

[0073] The term “k_on” or “k_a” refers to the on rate constant for association of an antibody to the antigen to form the antibody/antigen complex. The rate can be determined using standard assays, such as a Biacore or ELISA assay.

[0074] The term “k_off” or “k_a” refers to the off rate constant for dissociation of an antibody from the antibody/antigen complex. The rate can be determined using standard assays, such as a Biacore or ELISA assay.

[0075] The term “K_D” refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. K_D is calculated by k_a/k_d. The rate can be determined using standard assays, such as a Biacore or ELISA assay.

[0076] The term “p” or “antibody:drug ratio” or “drug-to-antibody ratio” or “DAR” refers to the number of drug moieties per antibody moiety, i.e., drug loading, or the number of -L-D moieties per antibody or antigen-binding fragment (Ab) in ADCs of Formula I. In compositions comprising multiple copies of ADCs of Formula I, “p” refers to the average number of -L-D moieties per antibody or antigen-binding fragment, also referred to as average drug loading.

[0077] A “linker” or “linker moiety” is any chemical moiety that is capable of covalently joining a compound, usually a drug moiety such as a chemotherapeutic agent, to another moiety such as an antibody moiety. Linkers can be susceptible to or substantially resistant to acid-induced cleavage, peptidase-induced cleavage, light-based cleavage, esterase-induced cleavage, and/or disulfide bond cleavage, at conditions under which the compound or the antibody remains active.

[0078] The term “agent” is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological materials. The term “therapeutic agent,” “drug,” or “drug moiety” refers to an agent that is capable of modulating a biological process and/or has biological activity.

[0079] The term “chemotherapeutic agent” or “anti-cancer agent” is used herein to refer to all chemical compounds that are effective in treating cancer regardless of mechanism of action. Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, and alkyl sulphonates; antimetabolites, for example, folic acid, purine or pyrimidine antagonists; anti-mitotic agents, for example, anti-tubulin agents such as eribulin or eribulin mesylate (Halaven™) or derivatives thereof, vinca alkaloids, and auristatins; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, for example, DNA minor groove binders; and growth factor receptor antagonists. In addition, chemotherapeutic agents include antibodies, biological molecules, and small molecules. A chemotherapeutic agent may be a cytotoxic or cytostatic agent. The term “cytostatic agent” refers to an agent that inhibits or suppresses cell growth and/or multiplication of cells.

[0080] The term “cytotoxic agent” refers to a substance that causes cell death primarily by interfering with a cell's expression activity and/or functioning. Examples of cytotoxic agents include, but are not limited to, anti-mitotic agents, such as eribulin, auristatins (e.g., monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF)), maytansinoids (e.g., maytansine), dolastatins, duostatins, cryptophycins, vinca alkaloids (e.g., vincristine, vinblastine), taxanes, taxols, and colchicines; anthracyclines (e.g., daunorubicin, doxorubicin, dihydroxyanthracindione); cytotoxic antibiotics (e.g., mitomycins, actinomycins, duocarmycins (e.g., CC-1065), auromycins, duomycins, calicheamicins, endomycins, phenomycins); alkylating agents (e.g., cisplatin); intercalating agents (e.g., ethidium bromide); topoisomerase inhibitors (e.g., etoposide, tenoposide); radioisotopes, such as At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹² or ²¹³, P³², and radioactive isotopes of lutetium (e.g., Lu¹⁷⁷); and toxins of bacterial, fungal, plant or animal origin (e.g., ricin (e.g., ricin A-chain), diphtheria toxin, Pseudomonas exotoxin A (e.g., PE40), endotoxin, mitogellin, combrestatin, restrictocin, gelonin, alpha-sarcin, abrin (e.g., abrin A-chain), modeccin (e.g., modeccin A-chain), curicin, crotin, Sapaonaria officinalis inhibitor, glucocorticoid).

[0081] The term “eribulin,” as used herein, refers to a synthetic analog of halichondrin B, a macrocyclic compound that was originally isolated from the marine sponge Halichondria okadais. The term “eribulin drug moiety” refers to the component of an ADC that has the structure of eribulin, and is attached to the linker of the ADC via its C-35 amine. Eribulin is a microtubule dynamics inhibitor, which is thought to bind tubulin and induce cell cycle arrest at the G2/M phase by inhibiting mitotic spindle assembly. The term “eribulin mesylate” refers to the mesylate salt of eribulin, which is marketed under the trade name Halaven™.

[0082] The term “homolog” refers to a molecule which exhibits homology to another molecule, by for example, having sequences of chemical residues that are the same or similar at corresponding positions.

[0083] The term “inhibit” or “inhibition of,” as used herein, means to reduce by a measurable amount, and can include but does not require complete prevention or inhibition.

[0084] The term “target-negative” or “target antigen-negative” refers to the absence of target antigen expression by a cell or tissue. The term “target-positive” or “target antigen-positive” refers to the presence of target antigen expression. For example, a cell or a cell line that does not express a target antigen may be described as target-negative, whereas a cell or cell line that expresses a target antigen may be described as target-positive.

[0085] The term “bystander killing” or “bystander effect” refers to the killing of target-negative cells in the presence of target-positive cells, wherein killing of target-negative cells is not observed in the absence of target-positive cells. Cell-to-cell contact, or at least proximity between target-positive and target-negative cells, enables bystander killing. This type of killing is distinguishable from “off-target killing,” which refers to the indiscriminate killing of target-negative cells. “Off-target killing” may be observed in the absence of target-positive cells.

[0086] The term “cancer” refers to the physiological condition in mammals in which a population of cells is characterized by unregulated cell growth. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, small cell lung cancer, nonsmall cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (e.g., triple negative breast cancer), osteosarcoma, melanoma, colon cancer, colorectal cancer, endometrial (e.g., serous) or uterine cancer, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, and various types of head and neck cancers. Triple negative breast cancer refers to breast cancer that is negative for expression of the genes for estrogen receptor (ER), progesterone receptor (PR), or Her2/neu.

[0087] The terms “tumor” and “neoplasm” refer to any mass of tissue that results from excessive cell growth or proliferation, either benign or malignant, including precancerous lesions.

[0088] The terms “cancer cell” and “tumor cell” refer to individual cells or the total population of cells derived from a tumor, including both non-tumorigenic cells and cancer stem cells. As used herein, the term “tumor cell” will be modified by the term “non-tumorigenic” when referring solely to those tumor cells lacking the capacity to renew and differentiate to distinguish those tumor cells from cancer stem cells.

[0089] The terms “subject” and “patient” are used interchangeably herein to refer to any animal, such as any mammal, including but not limited to, humans, non-human primates, rodents, and the like. In some embodiments, the mammal is a mouse. In some embodiments, the mammal is a human.

[0090] The term “co-administration” or administration “in combination with” one or more therapeutic agents includes concurrent and consecutive administration in any order.

[0091] A “pharmaceutical composition” refers to a preparation which is in such form as to permit administration and subsequently provide the intended biological activity of the active ingredient(s) and/or to achieve a therapeutic effect, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered. The pharmaceutical composition may be sterile.

[0092] A “pharmaceutical excipient” comprises a material such as an adjuvant, a carrier, pH-adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservative, and the like.

[0093] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans.

[0094] An “effective amount” of an ADC as disclosed herein is an amount sufficient to perform a specifically stated purpose, for example to produce a therapeutic effect after administration, such as a reduction in tumor growth rate or tumor volume, a reduction in a symptom of cancer, or some other indicia of treatment efficacy. An effective amount can be determined in a routine manner in relation to the stated purpose. The term “therapeutically effective amount” refers to an amount of an ADC effective to treat a disease or disorder in a subject. In the case of cancer, a therapeutically effective amount of ADC can reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and/or relieve one or more symptoms. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0095] As used herein, “to treat” or “therapeutic” and grammatically related terms, refer to any improvement of any consequence of disease, such as prolonged survival, less morbidity, and/or a lessening of side effects which are the byproducts of an alternative therapeutic modality. As is readily appreciated in the art, full eradication of disease is a preferred but albeit not a requirement for a treatment act. “Treatment” or “treat,” as used herein, refers to the administration of a described ADC to a subject, e.g., a patient. The treatment can be to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve or affect the disorder, the symptoms of the disorder or the predisposition toward the disorder, e.g., a cancer.

[0096] In some embodiments, a labeled ADC is used. Suitable “labels” include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like.

[0097] By “protein,” as used herein, is meant at least two covalently attached amino acids. The term encompasses polypeptides, oligopeptides, and peptides. In some embodiments, the two or more covalently attached amino acids are attached by a peptide bond. The protein may be made up of naturally occurring amino acids and peptide bonds, for example when the protein is made recombinantly using expression systems and host cells. Alternatively, the protein may include synthetic amino acids (e.g., homophenylalanine, citrulline, ornithine, and norleucine), or peptidomimetic structures, i.e., “peptide or protein analogs,” such as peptoids. Peptoids are an exemplary class of peptidomimetics whose side chains are appended to the nitrogen atom of the peptide backbone, rather than to the α-carbons (as they are in amino acids), and have different hydrogen bonding and conformational characteristics in comparison to peptides (see, e.g., Simon et al. (1992) Proc. Natl. Acad. Sci. USA 89:9367). As such, peptoids can be resistant to proteolysis or other physiological or storage conditions, and effective at permeating cell membranes. Such synthetic amino acids may be incorporated in particular when the antibody is synthesized in vitro by conventional methods well known in the art. In addition, any combination of peptidomimetic, synthetic and naturally occurring residues/structures can be used. “Amino acid” also includes imino acid residues, such as proline and hydroxyproline. The amino acid “R group” or “side chain” may be in either the (L)- or the (S)-configuration. In a specific embodiment, the amino acids are in the (L)- or (S)-configuration.

[0098] A “recombinant protein” is a protein made using recombinant techniques using any techniques and methods known in the art, i.e., through the expression of a recombinant nucleic acid. Methods and techniques for the production of recombinant proteins are well known in the art.

[0099] An “isolated” protein is unaccompanied by at least some of the material with which it is normally associated in its natural state, for example constituting at least about 5%, or at least about 50% by weight of the total protein in a given sample. It is understood that the isolated protein may constitute from 5 to 99.9% by weight of the total protein content depending on the circumstances. For example, the protein may be made at a significantly higher concentration through the use of an inducible promoter or high expression promoter, such that the protein is made at increased concentration levels. The definition includes the production of an antibody in a wide variety of organisms and/or host cells that are known in the art.

[0100] For amino acid sequences, sequence identity and/or similarity may be determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482, the sequence identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (1988) Proc. Nat. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described by Devereux et al. (1984) Nucl. Acid Res. 12:387-95, preferably using the default settings, or by inspection. Preferably, percent identity is calculated by FastDB based upon the following parameters: mismatch penalty of 1; gap penalty of 1; gap size penalty of 0.33; and joining penalty of 30 (“Current Methods in Sequence Comparison and Analysis,” Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149 (1988), Alan R. Liss, Inc).

[0101] An example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create the alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle (1987) J. Mol. Evol. 35:351-60; the method is similar to that described by Higgins and Sharp (1989) CABIOS 5:151-3. Useful PILEUP parameters including a default gap weight of 3.00, a default gap length weight of 0.10, and weighted end gaps.

[0102] Another example of a useful algorithm is the BLAST algorithm, described in: Altschul et al. (1990) J. Mol. Biol. 215:403-10; Altschul et al. (1997) Nucleic Acids Res. 25:3389-402; and Karin et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873-87. A particularly useful BLAST program is the WU-BLAST-2 program which was obtained from Altschul et al. (1996) Methods in Enzymology 266:460-80. WU-BLAST-2 uses several search parameters, most of which are set to the default values. The adjustable parameters are set with the following values: overlap span=1, overlap fraction=0.125, word threshold (T)=II. The HSP S and HSP S2 parameters are dynamic values and are established by the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched; however, the values may be adjusted to increase sensitivity.

[0103] An additional useful algorithm is gapped BLAST as reported by Altschul et al. (1993) Nucl. Acids Res. 25:3389-402. Gapped BLAST uses BLOSUM-62 substitution scores; threshold T parameter set to 9; the two-hit method to trigger ungapped extensions, charges gap lengths of k a cost of 10+k; Xu set to 16, and Xg set to 40 for database search stage and to 67 for the output stage of the algorithms. Gapped alignments are triggered by a score corresponding to about 22 bits.

[0104] Generally, the amino acid homology, similarity, or identity between proteins disclosed herein and variants thereof, including variants of FRA, variants of her2, variants of tubulin sequences, and variants of antibody variable domains (including individual variant CDRs), are at least 80% to the sequences depicted herein, and more typically with preferably increasing homologies or identities of at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and almost 100% or 100%.

[0105] In a similar manner, “percent (%) nucleic acid sequence identity” with respect to the nucleic acid sequence of the antibodies and other proteins identified herein is defined as the percentage of nucleotide residues in a candidate sequence that are identical with the nucleotide residues in the coding sequence of the antigen binding protein. A specific method utilizes the BLASTN module of WU-BLAST-2 set to the default parameters, with overlap span and overlap fraction set to 1 and 0.125, respectively.

[0106] While the site or region for introducing an amino acid sequence variation is predetermined, the mutation per se need not be predetermined. For example, in order to optimize the performance of a mutation at a given site, random mutagenesis may be conducted at the target codon or region and the expressed antigen binding protein CDR variants screened for the optimal combination of desired activity. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example, MI3 primer mutagenesis and PCR mutagenesis.

Antibody-Drug Conjugates

[0107] The compounds of the present disclosure include those with anti-cancer activity. In particular, the compounds include an antibody moiety (including an antigen-binding fragment thereof) conjugated (i.e., covalently attached by a linker) to a drug moiety, wherein the drug moiety when not conjugated to an antibody moiety has a cytotoxic or cytostatic effect. In various embodiments, the drug moiety exhibits reduced or no cytotoxicity when bound in a conjugate but resumes cytotoxicity after cleavage from the linker and antibody moiety. In various embodiments, the drug moiety exhibits reduced or no bystander killing when bound in a conjugate (e.g., using a non-cleavable linker) but exhibits increased bystander killing after cleavage from a conjugate (e.g., a conjugate having a cleavable Val-Cit cleavable moiety).

[0108] The development and production of an ADC for use as a human therapeutic agent, e.g., as an oncologic agent, may require more than the identification of an antibody capable of binding to a desired target or targets and attaching to a drug used on its own to treat cancer. Linking the antibody to the drug may have significant and unpredictable effects on the activity of one or both of the antibody and the drug, effects which will vary depending on the type of linker and/or drug chosen. In some embodiments, therefore, the components of the ADC are selected to (i) retain one or more therapeutic properties exhibited by the antibody and drug moieties in isolation, (ii) maintain the specific binding properties of the antibody moiety; (iii) optimize drug loading and drug-to-antibody ratios; (iv) allow delivery, e.g., intracellular delivery, of the drug moiety via stable attachment to the antibody moiety; (v) retain ADC stability as an intact conjugate until transport or delivery to a target site; (vi) minimize aggregation of the ADC prior to or after administration; (vii) allow for the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage in the cellular environment; (viii) exhibit in vivo anti-cancer treatment efficacy comparable to or superior to that of the antibody and drug moieties in isolation; (ix) minimize off-target killing by the drug moiety; and/or (x) exhibit desirable pharmacokinetic and pharmacodynamics properties, formulatability, and toxicologic/immunologic profiles. Screening each of these properties may be needed to identify an improved ADC for therapeutic use (Ab et al. (2015) Mol. Cancer Ther. 14:1605-13).

[0109] In various embodiments, the ADCs disclosed herein exhibit unexpectedly favorable properties in some or each of the categories listed above. For instance, in some embodiments, ADC constructs comprising a Mal attachment to an antibody, a PEG spacer unit (preferably a short PEG spacer unit), and/or peptide cleavable linker (e.g., a Val-Cit linker) exhibit surprisingly favorable drug loading, aggregation, and/or stability profiles, and/or preserve antibody binding function, drug activity, and/or improved bystander killing, while reducing off-target killing, as compared to ADCs using other cleavable or non-cleavable linker structures.

[0110] In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to an antibody (e.g., an anti-FRA antibody such as MORAb-003) exhibits particularly favorable properties across the listed categories, as compared to other cleavable or non-cleavable linkers joining eribulin to an antibody moiety. In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to an antibody (e.g., an anti-FRA antibody such as MORAb-003) exhibits particularly favorable bystander killing properties as compared to an uncleavable ADC. In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to an antibody (e.g., an anti-FRA antibody such as MORAb-003) exhibits particularly favorable bystander killing properties as compared to an ADC using alternate cleavable linker structures.

[0111] In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to MORAb-003 exhibits a higher and more desirable drug:antibody ratio (i.e., a ratio of about 3-4) relative to an ADC, e.g., comprising a linker attached to the antibody via an alternate moiety (e.g., a succinimide moiety). In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to MORAb-003 exhibits a higher and more desirable drug:antibody ratio, and/or lower aggregation levels, relative to an ADC, e.g., comprising a longer spacer unit (e.g., (PEG)₈). In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to MORAb-003 demonstrates a higher and more desirable drug:antibody ratio, lower aggregation levels, increased on-target killing, and/or decreased off-target killing relative to an ADC, e.g., comprising an alternate cleavable moiety (i.e., a non-peptide cleavable moiety, such as a cleavable disulfide or sulfonamide). In some embodiments, an ADC comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to MORAb-003 demonstrates increased stability, increased on-target killing, decreased off-target killing, lower aggregation levels, and/or a higher and more desirable drug:antibody ratio relative to an ADC, e.g., comprising an alternate amino acid unit (e.g., Ala-Ala-Asn) or alternate cleavable moiety (e.g., a cleavable disulfide or sulfonamide).

[0112] In some embodiments, some or all of the desirable features described above for ADCs comprising a Mal-(PEG)₂-Val-Cit-pAB linker joining eribulin to MORAb-003 may be observed with ADCs comprising the Mal-(PEG)₂-Val-Cit-pAB-eribulin linker-toxin conjugated to an anti-her2 antibody such as trastuzumab, or an anti-mesothelin antibody.

[0113] The ADC compounds of the present disclosure may selectively deliver an effective dose of a cytotoxic or cytostatic agent to cancer cells or to tumor tissue. It has been discovered that the disclosed ADCs have potent cytotoxic and/or cytostatic activity against cells expressing the respective target antigen (e.g., FRA or her2). In some embodiments, the cytotoxic and/or cytostatic activity of the ADC is dependent on the target antigen expression level in a cell. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells expressing a high level of target antigen, as compared to cancer cells expressing the same antigen at a low level. In some embodiments, the disclosed ADCs are particularly effective at killing cancer cells expressing the target antigen at a moderate level, as compared to cancer cells expressing the same antigen at a low level. Exemplary high FRA-expressing cancers include but are not limited to ovarian cancer (e.g., serous ovarian cancer, clear cell ovarian cancer), lung carcinoid, triple negative breast cancer, endometrial cancer, and nonsmall cell lung cancer (e.g., adenocarcinoma). Exemplary moderate FRA-expressing cancers include but are not limited to gastric cancer and colorectal cancer. Exemplary low FRA-expressing cancers include but are not limited to melanoma and lymphoma. Exemplary high her2-expressing cancers include but are not limited to breast cancer, gastric cancer, esophageal cancer, ovarian cancer, and endometrial cancer. Exemplary moderate her2-expressing cancers include but are not limited to lung cancer and bladder cancer.

[0114] In some embodiments, cleavage of an ADC releases eribulin from the antibody moiety and linker. In some embodiments, cleavage and release of the eribulin improves cytotoxicity of the ADC. In some embodiments, an ADC comprising a cleavable linker is particularly effective at killing cancer cells, including bystander killing, as compared to comparable treatment with an ADC comprising a non-cleavable linker. In some embodiments, an ADC comprising a cleavable linker (e.g., a Val-Cit linker) demonstrates increased on-target cell killing and/or decreased off-target cell killing relative to an ADC comprising a non-cleavable linker (e.g., a non-cleavable (PEG)₂ or (PEG)₄ linker), particularly wherein the cells and/or cancer treated with the ADC do not express high levels of the target antigen.

[0115] In some embodiments, the disclosed ADCs also demonstrate bystander killing activity, but low off-target cytotoxicity. Without being bound by theory, the bystander killing activity of an ADC may be particularly beneficial where its penetration into a solid tumor is limited and/or target antigen expression among tumor cells is heterogeneous. In some embodiments, an ADC comprising a cleavable linker is particularly effective at bystander killing and/or demonstrates improved bystander killing activity, as compared to comparable treatment with an ADC comprising a non-cleavable linker.

[0116] Provided herein are ADC compounds comprising an antibody or antigen-binding fragment thereof (Ab) which targets a tumor cell, a drug moiety (D), and a linker moiety (L) that covalently attaches Ab to D. In certain aspects, the antibody or antigen-binding fragment is able to bind to a tumor-associated antigen (e.g., FRA or her2) with high specificity and high affinity. In certain embodiments, the antibody or antigen-binding fragment is internalized into a target cell upon binding, e.g., into a degradative compartment in the cell. Preferred ADCs are thus those that internalize upon binding to a target cell, undergo degradation, and release the drug moiety to kill cancer cells. The drug moiety may be released from the antibody and/or the linker moiety of the ADC by enzymatic action, hydrolysis, oxidation, or any other mechanism.

[0117] An exemplary ADC has Formula I:
Ab-(L-D)_p  (I)
wherein Ab=antibody moiety (i.e., antibody or antigen-binding fragment), L=linker moiety, D=drug moiety, and p=the number of drug moieties per antibody moiety.
Antibodies

[0118] The antibody moiety (Ab) of Formula I includes within its scope any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell. The antibody or antigen-binding fragment may bind to a target antigen with a dissociation constant (K_D) of ≤1 mM, ≤100 nM or ≤10 nM, or any amount in between, as measured by, e.g., BIAcore® analysis. In certain embodiments, the K_D is 1 pM to 500 pM. In some embodiments, the K_D is between 500 pM to 1 μM, 1 μM to 100 nM, or 100 mM to 10 nM.

[0119] In some embodiments, the antibody moiety is a four-chain antibody (also referred to as an immunoglobulin), comprising two heavy chains and two light chains. In some embodiments the antibody moiety is a two-chain half body (one light chain and one heavy chain), or an antigen-binding fragment of an immunoglobulin.

[0120] In some embodiments, the antibody moiety is an internalizing antibody or internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody binds to a target cancer antigen expressed on the surface of a cell and enters the cell upon binding. In some embodiments, the drug moiety of the ADC is released from the antibody moiety of the ADC after the ADC enters and is present in a cell expressing the target cancer antigen (i.e., after the ADC has been internalized).

[0121] Amino acid and nucleic acid sequences of exemplary antibodies of the present disclosure are set forth in Tables 1-9.

[0122]

TABLE 1
Antibodies
mAb	Class/Isotype	Target
MORAb-003	humanized	human folate receptor alpha
MORAb-009	mouse-human chimeric	human mesothelin
trastuzumab	humanized	human her2/neu
33011-xi	rabbit-human chimeric	human mesothelin
33011-zu	humanized	human mesothelin
111B10-xi	rabbit-human chimeric	human mesothelin
111B10-zu	humanized	human mesothelin
201C15-xi	rabbit-human chimeric	human mesothelin
201C15-zu	humanized	human mesothelin
346C6-xi	rabbit-human chimeric	human mesothelin
346C6-zu	humanized	human mesothelin
Abbreviations:
xi—chimeric;
zu—humanized.

[0123]

TABLE 2
Amino acid sequences of mAb variable regions
	mAb	IgG chain	SEQ ID NO	Amino acid sequence
1	MORAb-003	Heavy chain	23	EVQLVESGGGVVQPGRSLRLSCSASGFT
				FSGYGLSWVRQAPGKGLEWVAMISSGGS
				YTYYADSVKGRFAISRDNAKNTLFLQMD
				SLRPEDTGVYFCARHGDDPAWFAYWGQG
				TPVTVSS
2	MORAb-003	Light chain	24	DIQLTQSPSSLSASVGDRVTITCSVSSS
				ISSNNLHWYQQKPGKAPKPWIYGTSNLA
				SGVPSRFSGSGSGTDYTFTISSLQPEDI
				ATYYCQQWSSYPYMYTFGQGTKVEIK
3	MORAb-009	Heavy chain	25	QVQLQQSGPELEKPGASVKISCKASGYS
				FTGYTMNWVKQSHGKSLEWIGLITPYNG
				ASSYNQKFRGKATLTVDKSSSTAYMDLL
				SLTSEDSAVYFCARGGYDGRGFDYWGSG
				TPVTVSS
4	MORAb-009	Light chain	26	DIELTQSPAIMSASPGEKVTMTCSASSS
				VSYMHWYQQKSGTSPKRWIYDTSKLASG
				VPGRFSGSGSGNSYSLTISSVEAEDDAT
				YYCQQWSKHPLTFGSGTKVEIK
5	trastuzumab	Heavy chain	27	EVQLVESGGGLVQPGGSLRLSCAASGFN
				IKDTYIHWVRQAPGKGLEWVARIYPTNG
				YTRYADSVKGRFTISADTSKNTAYLQMN
				SLRAEDTAVYYCSRWGGDGFYAMDYWGQ
				GTLVTVSS
6	trastuzumab	Light chain	28	DIQMTQSPSSLSASVGDRVTITCRASQD
				VNTAVAWYQQKPGKAPKLLIYSASFLYS
				GVPSRFSGSRSGTDFTLTISSLQPEDFA
				TYYCQQHYTTPPTFGQGTKVEIK
7	33011-xi	Heavy chain	29	QSVEESGGRLVTPGTPLTLTCTVSGISL
				SSDAISWVRQAPGKGLEYIGIINGGGNT
				YYASWAKGRFTISKTSTTVDLKITSPTT
				EDTATYFCARGIQHGGGNSDYYYYGMDL
				WGPGTLVTVSS
8	33011-xi	Light chain	30	EVLMTQTPSSVSAAVGDTVTIKCQASQS
				ISSVLSWYQQKPGQPPKLLIYLASTLAS
				GVPSRFSGSRSGTEFTLTISDLECDDAA
				TYYCQTNYGTSSSNYGFAFGGGTEVVVK
9	33011-zu	Heavy chain	31	EVQLVESGGGLVQPGGSLRLSCAASGIS
				LSSDAISWVRQAPGKGLEYIGIINGGGN
				TYYASWAKGRFTISRHNSKNTLYLQMNS
				LRAEDTAVYYCARGIQHGGGNSDYYYYG
				MDLWGQGTLVTVSS
10	33011-zu	Light chain	32	DIQMTQSPSSLSASVGDRVTITCQASQS
				ISSVLSWYQQKPGKAPKLLIYLASTLAS
				GVPSRFSGSGSGTDFTLTISSLQCEDIA
				TYYCQTNYGTSSSNYGFAFGGGTKVEIK
11	111B10-xi	Heavy chain	33	QSVEESGGRLVTPGTPLTLTCTVSGFSL
				NNYAMSWVRQAPGKGLEWIGSISTGGLA
				FYANWAKGRFTISRTSTTVDLKMTSLTT
				EDTATYFCGRNGGGSYIFYYFDLWGQGT
				LVTVSS
12	111B10-xi	Light chain	34	AFELTQTPSSVEAAVGGTITIKCQASQS
				ISSYLSWYQQKPGQPPKLLIYSASTLAS
				GVSSRFKGSGSGTEYTLTISDLECADAA
				TYFCQSYYDIGTSTFGGGTEVVVK
13	111B10-zu	Heavy chain	35	EVQLVESGGGLVQPGGSLRLSCAASGFS
				LNNYAMSWVRQAPGKGLEWIGSISTGGL
				AFYANWAKGRFTISRDNSKNTLYLQMNS
				LRAEDTAVYYCARNGGGSYIFYYFDLWG
				QGTLVTVSS
14	111B10-zu	Light chain	36	DIQMTQSPSSLSASVGDRVTITCQASQS
				ISSYLSWYQQKPGKAPKLLIYSASTLAS
				GVPSRFSGSGSGTDFTLTISSLQCEDAA
				TYYCQSYYDIGTSTFGGGTKVEIK
15	201C15-xi	Heavy chain	37	QSVKESGGRLVTPGTPLTLTCTVSGIDL
				SSYAMGWFRQAPGKGLEYIGTINIGGRV
				YYASWAKGRFTISRTSTTVDLKAPSLTA
				EDTATYFCARYYNGGSYDIWGPGTLVTV
				SL
16	201C15-xi	Light chain	38	DVVMTQTPASASEPVGGTVTIKCQASES
				IYRVLAWYQQKPGQPPKLLIYDTSTLAS
				GAPSRFKGSGYGTEFTLTISGVQCEDAA
				TYYCQGGYYADSYGIAFGGGTEVVVK
17	201C15-zu	Heavy chain	39	QVQLVESGGGLVQPGGSLRLSCSASGID
				LSSYAMGWVRQAPGKGLEYIGTINIGGR
				VYYASWAKGRFTISRDNSKNTLYLQMNS
				LRAEDTAVYYCARYYNGGSYDIWGQGTL
				VTVSS
18	201C15-zu	Light chain	40	DIQMTQSPSTLSASVGDRVTITCQASES
				IYRVLAWYQQKPGKAPKLLIYDTSTLAS
				GVPSRFSGSGSGTEFTLTISSLQCDDAA
				TYYCQGGYYADSYGIAFGGGTKVEIK
19	346C6-xi	Heavy chain	41	QSVEESGGRLVKPDESLTLTCTASGFSL
				SSYAMIWVRQAPGEGLEWIGTISTGGIT
				YYASWAKGRFTISKTSTTVDLKITSPTT
				EDTATYFCARGGYAASSAYYLPYYFDLW
				GQGTLVTVSS
20	346C6-xi	Light chain	42	AAVLTQTPSPVSAAVGGTVTISCQSSQS
				VYNNNNLAWFQQKPGQPPKLLIYLASTL
				ASGVPSRFSGSGSGTQFTLTISGVQCDD
				AATYYCLGGCDDDADTFAFGGGTEVVVK
21	346C6-zu	Heavy chain	43	EVQLVESGGGLVQPGGSLRLSCAASGFS
				LSSYAMIWVRQAPGKGLEWIGTISTGGI
				TYYASWAKGRFTISRDNSKNTLYLQMNS
				LRAEDTAVYYCARGGYAASSAYYLPYYF
				DLWGQGTLVTVSS
22	346C6-zu	Light chain	44	DIQMTQSPSSLSASVGDRVTITCQSSQS
				VYNNNNLAWYQQKPGKVPKLLIYLASTL
				ASGVPSRFSGSGSGTDFTLTISSLQCED
				AATYYCLGGCDDDADTFAFGGGTKVEIK

[0124]

TABLE 3
Nucleic acid sequences encoding mAb variable regions
	mAb	IgG chain	SEQ ID NO	Nucleic acid sequence
1	MORAb-003	Heavy chain	45	GAGGTCCAACTGGTGGAGAGCGGTGGAG
				GTGTTGTGCAACCTGGCCGGTCCCTGCG
				CCTGTCCTGCTCCGCATCTGGCTTCACC
				TTCAGCGGCTATGGGTTGTCTTGGGTGA
				GACAGGCACCTGGAAAAGGTCTTGAGTG
				GGTTGCAATGATTAGTAGTGGTGGTAGT
				TATACCTACTATGCAGACAGTGTGAAGG
				GTAGATTTGCAATATCGCGAGACAACGC
				CAAGAACACATTGTTCCTGCAAATGGAC
				AGCCTGAGACCCGAAGACACCGGGGTCT
				ATTTTTGTGCAAGACATGGGGACGATCC
				CGCCTGGTTCGCTTATTGGGGCCAAGGG
				ACCCCGGTCACCGTCTCCTCA
2	MORAb-003	Light chain	46	GACATCCAGCTGACCCAGAGCCCAAGCA
				GCCTGAGCGCCAGCGTGGGTGACAGAGT
				GACCATCACCTGTAGTGTCAGCTCAAGT
				ATAAGTTCCAACAACTTGCACTGGTACC
				AGCAGAAGCCAGGTAAGGCTCCAAAGCC
				ATGGATCTACGGCACATCCAACCTGGCT
				TCTGGTGTGCCAAGCAGATTCAGCGGTA
				GCGGTAGCGGTACCGACTACACCTTCAC
				CATCAGCAGCCTCCAGCCAGAGGACATC
				GCCACCTACTACTGCCAACAGTGGAGTA
				GTTACCCGTACATGTACACGTTCGGCCA
				AGGGACCAAGGTGGAAATCAAA
3	MORAb-009	Heavy chain	47	CAGGTACAACTGCAGCAGTCTGGGCCTG
				AGCTGGAGAAGCCTGGCGCTTCAGTGAA
				GATATCCTGCAAGGCTTCTGGTTACTCA
				TTCACTGGCTACACCATGAACTGGGTGA
				AGCAGAGCCATGGAAAGAGCCTTGAGTG
				GATTGGACTTATTACTCCTTACAATGGT
				GCTTCTAGCTACAACCAGAAGTTCAGGG
				GCAAGGCCACATTAACTGTAGACAAGTC
				ATCCAGCACAGCCTACATGGACCTCCTC
				AGTCTGACATCTGAAGACTCTGCAGTCT
				ATTTCTGTGCAAGGGGGGGTTACGACGG
				GAGGGGTTTTGACTACTGGGGATCCGGG
				ACCCCGGTCACCGTCTCCTCA
4	MORAb-009	Light chain	48	GACATCGAGCTCACTCAGTCTCCAGCAA
				TCATGTCTGCATCTCCAGGGGAGAAGGT
				CACCATGACCTGCAGTGCCAGCTCAAGT
				GTAAGTTACATGCACTGGTACCAGCAGA
				AGTCAGGCACCTCCCCCAAAAGATGGAT
				TTATGACACATCCAAACTGGCTTCTGGA
				GTCCCAGGTCGCTTCAGTGGCAGTGGGT
				CTGGAAACTCTTACTCTCTCACAATCAG
				CAGCGTGGAGGCTGAAGATGATGCAACT
				TATTACTGCCAGCAGTGGAGTAAGCACC
				CTCTCACGTTCGGATCCGGGACCAAGGT
				GGAAATCAAA
5	33011-xi	Heavy chain	49	CAGTCGGTGGAGGAGTCCGGGGGTCGCC
				TGGTCACGCCTGGGACACCCCTGACACT
				CACCTGCACCGTCTCTGGAATCTCCCTC
				AGTAGCGATGCAATAAGCTGGGTCCGCC
				AGGCTCCAGGGAAGGGGCTCGAATACAT
				CGGAATCATTAATGGTGGTGGTAACACA
				TACTACGCGAGCTGGGCGAAAGGCCGAT
				TCACCATCTCCAAAACCTCGACCACGGT
				GGATCTGAAAATCACCAGTCCGACAACC
				GAGGACACGGCCACCTATTTCTGTGCCA
				GAGGCATTCAACATGGTGGTGGTAATAG
				TGATTATTATTATTACGGCATGGACCTC
				TGGGGCCCAGGCACCCTGGTCACTGTCT
				CTTCA
6	33011-xi	Light chain	50	GAAGTGTTGATGACCCAGACTCCATCCT
				CCGTGTCTGCAGCTGTGGGAGACACAGT
				CACCATCAAGTGCCAGGCCAGTCAGAGC
				ATTAGTAGTGTCTTGTCCTGGTATCAGC
				AGAAACCAGGGCAGCCTCCCAAGCTCCT
				GATCTATCTGGCATCCACTCTGGCATCT
				GGGGTCCCATCGCGGTTCAGCGGCAGTA
				GATCTGGGACAGAGTTCACTCTCACCAT
				CAGCGACCTGGAGTGTGACGATGCTGCC
				ACTTACTACTGTCAAACCAATTATGGTA
				CTAGTAGTAGTAATTATGGTTTTGCTTT
				CGGCGGAGGGACCGAGGTGGTCGTCAAA
7	33011-zu	Heavy chain	51	GAAGTCCAACTGGTGGAAAGCGGGGGAG
				GACTGGTGCAGCCGGGCGGATCCCTCCG
				GCTGTCATGTGCTGCATCGGGAATTTCC
				CTCTCCTCCGACGCGATTAGCTGGGTCA
				GACAGGCCCCCGGAAAGGGGCTGGAGTA
				CATCGGTATCATCAACGGCGGCGGAAAC
				ACCTACTACGCCTCCTGGGCCAAGGGCC
				GCTTCACCATCTCGCGGCATAATTCCAA
				GAACACTCTGTACTTGCAAATGAACTCC
				CTGAGGGCCGAGGACACCGCCGTGTACT
				ACTGCGCGCGCGGCATCCAGCACGGTGG
				TGGAAACAGCGACTACTACTACTATGGG
				ATGGATCTGTGGGGCCAGGGAACTCTTG
				TGACCGTGTCGTCA
8	33011-zu	Light chain	52	GACATTCAGATGACCCAGTCCCCAAGCT
				CGCTGTCCGCCTCCGTGGGCGACCGCGT
				GACCATCACGTGCCAGGCGTCCCAGTCA
				ATTAGCAGCGTGCTCTCCTGGTACCAAC
				AGAAGCCGGGGAAAGCACCCAAGCTGCT
				GATCTACTTGGCCTCCACTCTGGCCTCG
				GGAGTGCCTTCACGGTTCTCCGGATCGG
				GATCTGGTACTGATTTCACCCTCACCAT
				CTCGAGCCTTCAGTGCGAGGACATCGCT
				ACTTACTATTGTCAAACCAACTACGGAA
				CCTCCAGCTCCAACTACGGCTTTGCCTT
				CGGTGGCGGGACCAAGGTCGAAATCAAA
9	111B10-xi	Heavy chain	53	CAGTCGGTGGAGGAGTCCGGGGGTCGCC
				TGGTCACGCCTGGGACACCCCTGACACT
				CACCTGCACAGTCTCTGGATTCTCCCTC
				AATAACTATGCAATGAGCTGGGTCCGCC
				AGGCTCCAGGGAAGGGGCTGGAATGGAT
				CGGATCCATTAGTACTGGTGGTCTCGCA
				TTCTACGCGAACTGGGCAAAAGGCCGAT
				TCACCATCTCCAGAACCTCGACCACGGT
				GGATCTGAAAATGACCAGTCTGACAACC
				GAGGACACGGCCACCTATTTCTGTGGCA
				GAAATGGTGGTGGTAGTTATATTTTCTA
				TTATTTTGACTTGTGGGGCCAAGGCACC
				CTCGTCACTGTCTCTTCA
10	111B10-xi	Light chain	54	GCATTCGAATTGACCCAGACTCCATCCT
				CCGTGGAGGCAGCTGTGGGAGGCACAAT
				CACCATCAAGTGCCAGGCCAGTCAGAGC
				ATTAGTAGTTACTTATCCTGGTATCAGC
				AGAAACCAGGGCAGCCTCCCAAGCTCCT
				GATCTATTCTGCATCCACTCTGGCATCT
				GGGGTCTCATCGCGGTTCAAAGGCAGTG
				GATCTGGGACAGAGTACACTCTCACCAT
				CAGCGACCTGGAGTGTGCCGATGCTGCC
				ACTTACTTCTGTCAAAGCTATTATGATA
				TTGGTACTAGTACTTTCGGCGGAGGGAC
				CGAGGTGGTCGTCAAA
11	111B10-zu	Heavy chain	55	GAAGTGCAGCTGGTGGAATCTGGCGGCG
				GACTGGTGCAGCCTGGCGGATCTCTGAG
				ACTGTCTTGTGCCGCCTCCGGCTTCTCC
				CTGAACAACTACGCCATGTCCTGGGTGC
				GACAGGCCCCTGGCAAAGGCCTGGAATG
				GATCGGCTCCATCAGCACAGGCGGCCTG
				GCCTTCTACGCCAATTGGGCCAAGGGCC
				GGTTCACCATCAGCCGGGACAACTCCAA
				GAACACCCTGTACCTCCAGATGAACTCC
				CTGCGGGCCGAGGACACCGCCGTGTACT
				ACTGTGCCAGAAACGGCGGAGGCTCCTA
				CATCTTCTACTACTTCGACCTGTGGGGC
				CAGGGCACCCTCGTGACAGTGTCATCT
12	111B10-zu	Light chain	56	GATATTCAGATGACCCAGTCCCCCTCCA
				GCCTGTCCGCTTCTGTGGGCGACAGAGT
				GACCATCACCTGTCAGGCCTCCCAGTCC
				ATCTCCTCCTACCTGTCCTGGTATCAGC
				AGAAGCCCGGCAAGGCCCCCAAGCTGCT
				GATCTACTCTGCCTCCACACTGGCCTCC
				GGCGTGCCCTCTAGATTCTCCGGCTCTG
				GCTCTGGCACCGACTTTACCCTGACCAT
				CAGCTCCCTCCAGTGCGAGGATGCCGCC
				ACCTACTACTGCCAGTCCTACTACGACA
				TCGGCACCTCCACCTTCGGCGGAGGCAC
				CAAGGTGGAAATCAAA
13	201C15-xi	Heavy chain	57	CAGTCAGTGAAGGAGTCCGGGGGTCGCC
				TGGTCACGCCTGGGACACCCCTGACACT
				CACCTGCACAGTCTCTGGAATCGACCTC
				AGTAGCTATGCAATGGGCTGGTTCCGCC
				AGGCTCCAGGGAAGGGGCTGGAATACAT
				CGGAACCATTAATATTGGTGGTCGCGTA
				TATTACGCGAGCTGGGCAAAAGGCCGAT
				TCACCATCTCCAGAACCTCGACCACGGT
				GGATCTGAAAGCGCCCAGTCTGACAGCC
				GAGGACACGGCCACCTATTTCTGTGCCA
				GATATTATAATGGTGGTAGTTATGACAT
				CTGGGGCCCAGGCACCCTGGTCACCGTC
				TCTTTA
14	201C15-xi	Light chain	58	GATGTTGTGATGACCCAGACTCCAGCCT
				CCGCGTCTGAACCTGTGGGAGGCACAGT
				CACCATCAAGTGCCAGGCCAGTGAGAGC
				ATTTATCGCGTATTGGCCTGGTATCAGC
				AGAAACCAGGGCAGCCTCCCAAGCTCCT
				GATCTATGATACATCCACTCTGGCATCT
				GGGGCCCCATCGCGGTTCAAAGGCAGTG
				GATATGGGACAGAGTTCACTCTCACCAT
				CAGCGGCGTGCAGTGTGAAGATGCTGCC
				ACTTACTACTGTCAAGGCGGTTATTATG
				CTGATAGTTATGGTATTGCTTTCGGCGG
				AGGGACCGAGGTGGTGGTCAAA
15	201C15-zu	Heavy chain	59	CAGGTGCAGCTGGTGGAATCTGGCGGAG
				GACTGGTGCAGCCTGGCGGCTCTCTGAG
				ACTGTCCTGTTCCGCCTCCGGAATCGAC
				CTGTCCTCCTACGCTATGGGCTGGGTGC
				GACAGGCTCCTGGCAAGGGCCTGGAGTA
				CATCGGCACCATCAACATCGGCGGCAGA
				GTGTACTACGCCTCCTGGGCCAAGGGCC
				GGTTCACCATCTCCAGAGACAACTCCAA
				GAACACCCTGTACCTCCAGATGAACTCC
				CTGCGGGCCGAGGACACCGCCGTGTACT
				ACTGCGCCCGGTACTACAACGGCGGCTC
				CTACGATATCTGGGGCCAGGGCACACTC
				GTGACCGTGTCCTCT
16	201C15-zu	Light chain	60	GATATCCAGATGACCCAGTCCCCCTCCA
				CCCTGTCTGCCTCTGTGGGCGACAGAGT
				GACCATCACCTGTCAGGCCTCCGAGTCC
				ATCTACCGGGTGCTGGCCTGGTATCAGC
				AGAAGCCTGGCAAGGCCCCCAAGCTGCT
				GATCTACGACACCAGCACACTGGCCTCC
				GGCGTGCCCTCTAGATTCTCCGGCTCTG
				GCTCTGGCACCGAGTTTACCCTGACCAT
				CTCCAGCCTCCAGTGCGACGACGCCGCC
				ACCTACTATTGTCAGGGCGGCTACTACG
				CCGACTCCTACGGAATCGCTTTCGGCGG
				AGGCACCAAGGTGGAAATCAAA
17	346C6-xi	Heavy chain	61	CAGTCGGTGGAGGAGTCCGGCGGTCGCC
				TGGTAAAGCCTGACGAATCCCTGACACT
				CACCTGCACAGCCTCTGGATTCTCCCTC
				AGTAGTTATGCAATGATCTGGGTCCGCC
				AGGCTCCAGGGGAGGGGCTGGAATGGAT
				CGGAACCATTAGTACTGGTGGTATCACA
				TACTACGCGAGCTGGGCGAAAGGCCGAT
				TCACCATCTCCAAAACCTCGACCACGGT
				GGATCTGAAAATCACCAGTCCGACAACC
				GAGGACACGGCCACCTATTTCTGTGCCA
				GAGGGGGATATGCTGCTAGTAGTGCTTA
				TTATCTCCCGTACTACTTTGACTTGTGG
				GGCCAAGGGACCCTGGTCACCGTCTCCT
				CA
18	346C6-xi	Light chain	62	GCAGCCGTGCTGACCCAGACACCATCAC
				CCGTGTCTGCAGCTGTGGGAGGCACAGT
				CACCATCAGTTGCCAGTCCAGTCAGAGT
				GTTTATAATAATAACAACTTAGCCTGGT
				TTCAGCAGAAACCCGGGCAGCCTCCCAA
				GCTTCTGATCTATCTGGCATCCACTCTG
				GCATCTGGGGTCCCATCACGGTTCAGCG
				GCAGTGGATCTGGGACACAGTTCACTCT
				CACCATCAGCGGCGTGCAGTGTGACGAT
				GCTGCCACTTATTACTGTCTAGGTGGTT
				GTGATGATGATGCTGATACTTTTGCTTT
				CGGCGGAGGGACTGAGGTGGTGGTCAAA
19	346C6-zu	Heavy chain	63	GAAGTGCAGCTGGTGGAATCTGGCGGCG
				GACTGGTGCAGCCTGGCGGATCTCTGAG
				ACTGTCTTGTGCCGCCTCCGGCTTCTCC
				CTGTCCTCCTACGCTATGATCTGGGTGC
				GACAGGCCCCTGGCAAGGGCCTGGAATG
				GATCGGCACCATCTCTACCGGCGGAATT
				ACCTACTACGCCTCCTGGGCCAAGGGCC
				GGTTCACCATCTCCAGAGACAACTCCAA
				GAACACCCTGTACCTCCAGATGAACTCC
				CTGCGGGCCGAGGACACCGCCGTGTACT
				ATTGTGCTAGAGGCGGCTACGCCGCCAG
				CTCCGCTTACTACCTGCCCTACTACTTC
				GACCTGTGGGGCCAGGGCACCCTCGTGA
				CAGTGTCATCT
20	346C6-zu	Light chain	64	GATATTCAGATGACCCAGTCCCCCTCCA
				GCCTGTCCGCTTCTGTGGGCGACAGAGT
				GACCATCACCTGTCAGTCCTCCCAGTCC
				GTGTATAACAACAACAACCTGGCCTGGT
				ATCAGCAGAAACCCGGCAAGGTGCCCAA
				GCTGCTGATCTACCTGGCCTCCACACTG
				GCCTCTGGCGTGCCCTCTAGATTCTCCG
				GCTCTGGCTCTGGCACCGACTTTACCCT
				GACCATCAGCTCCCTCCAGTGCGAGGAT
				GCCGCCACCTACTATTGCCTGGGCGGCT
				GCGACGACGACGCCGATACCTTTGCTTT
				TGGCGGAGGCACCAAGGTGGAAATCAAA

[0125]

TABLE 4
Amino acid sequences of mAb Kabat CDRs
		IgG		Amino acid
	mAb	chain	SEQ ID NO	sequence
1	MORAb-003	HC CDR1	2	GYGLS
2	MORAb-003	HC CDR2	3	MISSGGSYTYYADSVKG
3	MORAb-003	HC CDR3	4	HGDDPAWFAY
4	MORAb-003	LC CDR1	7	SVSSSISSNNLH
5	MORAb-003	LC CDR2	8	GTSNLAS
6	MORAb-003	LC CDR3	9	QQWSSYPYMYT
7	MORAb-009	HC CDR1	65	GYTMN
8	MORAb-009	HC CDR2	66	LITPYNGASSYNQKFRG
9	MORAb-009	HC CDR3	67	GGYDGRGFDY
10	MORAb-009	LC CDR1	68	SASSSVSYMH
11	MORAb-009	LC CDR2	69	DTSKLAS
12	MORAb-009	LC CDR3	70	QQWSKHPLT
13	trastuzumab	HC CDR1	71	DTYIH
14	trastuzumab	HC CDR2	72	RIYPTNGYTRYADSVKG
15	trastuzumab	HC CDR3	73	WGGDGFYAMDY
16	trastuzumab	LC CDR1	74	RASQDVNTAVA
17	trastuzumab	LC CDR2	75	SASFLYS
18	trastuzumab	LC CDR3	76	QQHYTTPPT
19	33011-xi	HC CDR1	77	SDAIS
20	33011-xi	HC CDR2	78	IINGGGNTYYASWAKG
21	33011-xi	HC CDR3	79	GIQHGGGNSDYYYYGMDL
22	33011-xi	LC CDR1	80	QASQSISSVLS
23	33011-xi	LC CDR2	81	LASTLAS
24	33011-xi	LC CDR3	82	QTNYGTSSSNYGFA
25	33011-zu	HC CDR1	83	SDAIS
26	33011-zu	HC CDR2	84	IINGGGNTYYASWAKG
27	33011-zu	HC CDR3	85	GIQHGGGNSDYYYYGMDL
28	33011-zu	LC CDR1	86	QASQSISSVLS
29	33011-zu	LC CDR2	87	LASTLAS
30	33011-zu	LC CDR3	88	QTNYGTSSSNYGFA
31	111B10-xi	HC CDR1	89	NYAMS
32	111B10-xi	HC CDR2	90	SISTGGLAFYANWAKG
33	111B10-xi	HC CDR3	91	NGGGSYIFYYFDL
34	111B10-xi	LC CDR1	92	QASQSISSYLS
35	111B10-xi	LC CDR2	93	SASTLAS
36	111B10-xi	LC CDR3	94	QSYYDIGTST
37	111B10-zu	HC CDR1	95	NYAMS
38	111B10-zu	HC CDR2	96	SISTGGLAFYANWAKG
39	111B10-zu	HC CDR3	97	NGGGSYIFYYFDL
40	111B10-zu	LC CDR1	98	QASQSISSYLS
41	111B10-zu	LC CDR2	99	SASTLAS
42	111B10-zu	LC CDR3	100	QSYYDIGTST
43	201C15-xi	HC CDR1	101	SYAMG
44	201C15-xi	HC CDR2	102	TINIGGRVYYASWAKG
45	201C15-xi	HC CDR3	103	YYNGGSYDI
46	201C15-xi	LC CDR1	104	QASESIYRVLA
47	201C15-xi	LC CDR2	105	DTSTLAS
48	201C15-xi	LC CDR3	106	QGGYYADSYGIA
49	201C15-zu	HC CDR1	107	SYAMG
50	201C15-zu	HC CDR2	108	TINIGGRVYYASWAKG
51	201C15-zu	HC CDR3	109	YYNGGSYDI
52	201C15-zu	LC CDR1	110	QASESIYRVLA
53	201C15-zu	LC CDR2	111	DTSTLAS
54	201C15-zu	LC CDR3	112	QGGYYADSYGIA
55	346C6-xi	HC CDR1	113	SYAMI
56	346C6-xi	HC CDR2	114	TISTGGITYYASWAKG
57	346C6-xi	HC CDR3	115	GGYAASSAYYLPYYFDL
58	346C6-xi	LC CDR1	116	QSSQSVYNNNNLA
59	346C6-xi	LC CDR2	117	LASTLAS
60	346C6-xi	LC CDR3	118	LGGCDDDADTFA
61	346C6-zu	HC CDR1	119	SYAMI
62	346C6-zu	HC CDR2	120	TISTGGITYYASWAKG
63	346C6-zu	HC CDR3	121	GGYAASSAYYLPYYFDL
64	346C6-zu	LC CDR1	122	QSSQSVYNNNNLA
65	346C6-zu	LC CDR2	123	LASTLAS
66	346C6-zu	LC CDR3	124	LGGCDDDADTFA

[0126]

TABLE 5
Nucleic acid sequences encoding mAb Kabat CDRs
	mAb	IgG chain	SEQ ID NO	Nucleic acid sequence
1	MORAb-003	HC CDR1	125	GGCTATGGGTTGTCT
2	MORAb-003	HC CDR2	126	ATGATTAGTAGTGGTGGTAGTTATACCTACTATG
				CAGACAGTGTGAAGGGT
3	MORAb-003	HC CDR3	127	CATGGGGACGATCCCGCCTGGTTCGCTTAT
4	MORAb-003	LC CDR1	128	AGTGTCAGCTCAAGTATAAGTTCCAACAACTTGC
				AC
5	MORAb-003	LC CDR2	129	GGCACATCCAACCTGGCTTCT
6	MORAb-003	LC CDR3	130	CAACAGTGGAGTAGTTACCCGTACATGTACACG
7	MORAb-009	HC CDR1	131	GGCTACACCATGAAC
8	MORAb-009	HC CDR2	132	CTTATTACTCCTTACAATGGTGCTTCTAGCTACA
				ACCAGAAGTTCAGGGGC
9	MORAb-009	HC CDR3	133	GGGGGTTACGACGGGAGGGGTTTTGACTAC
10	MORAb-009	LC CDR1	134	AGTGCCAGCTCAAGTGTAAGTTACATGCAC
11	MORAb-009	LC CDR2	135	GACACATCCAAACTGGCTTCT
12	MORAb-009	LC CDR3	136	CAGCAGTGGAGTAAGCACCCTCTCACG
13	33011-xi	HC CDR1	137	AGCGATGCAATAAGC
14	33011-xi	HC CDR2	138	ATCATTAATGGTGGTGGTAACACATACTACGCGA
				GCTGGGCGAAAGGC
15	33011-xi	HC CDR3	139	GGCATTCAACATGGTGGTGGTAATAGTGATTATT
				ATTATTACGGCATGGACCTC
16	33011-xi	LC CDR1	140	CAGGCCAGTCAGAGCATTAGTAGTGTCTTGTCC
17	33011-xi	LC CDR2	141	CTGGCATCCACTCTGGCATCT
18	33011-xi	LC CDR3	142	CAAACCAATTATGGTACTAGTAGTAGTAATTATG
				GTTTTGCT
19	33011-zu	HC CDR1	143	TCCGACGCGATTAGC
20	33011-zu	HC CDR2	144	ATCATCAACGGCGGCGGAAACACCTACTACGCCT
				CCTGGGCCAAGGGC
21	33011-zu	HC CDR3	145	GGCATCCAGCACGGTGGTGGAAACAGCGACTACT
				ACTACTATGGGATGGATCTG
22	33011-zu	LC CDR1	146	CAGGCGTCCCAGTCAATTAGCAGCGTGCTCTCC
23	33011-zu	LC CDR2	147	TTGGCCTCCACTCTGGCCTCG
24	33011-zu	LC CDR3	148	CAAACCAACTACGGAACCTCCAGCTCCAACTACG
				GCTTTGCC
25	111B10-xi	HC CDR1	149	AACTATGCAATGAGC
26	111B10-xi	HC CDR2	150	TCCATTAGTACTGGTGGTCTCGCATTCTACGCGA
				ACTGGGCAAAAGGC
27	111B10-xi	HC CDR3	151	AATGGTGGTGGTAGTTATATTTTCTATTATTTTG
				ACTTG
28	111B10-xi	LC CDR1	152	CAGGCCAGTCAGAGCATTAGTAGTTACTTATCC
29	111B10-xi	LC CDR2	153	TCTGCATCCACTCTGGCATCT
30	111B10-xi	LC CDR3	154	CAAAGCTATTATGATATTGGTACTAGTACT
31	111B10-zu	HC CDR1	155	AACTACGCCATGTCC
32	111B10-zu	HC CDR2	156	TCCATCAGCACAGGCGGCCTGGCCTTCTACGCCA
				ATTGGGCCAAGGGC
33	111B10-zu	HC CDR3	157	AACGGCGGAGGCTCCTACATCTTCTACTACTTCG
				ACCTG
34	111B10-zu	LC CDR1	158	CAGGCCTCCCAGTCCATCTCCTCCTACCTGTCC
35	111B10-zu	LC CDR2	159	TCTGCCTCCACACTGGCCTCC
36	111B10-zu	LC CDR3	160	CAGTCCTACTACGACATCGGCACCTCCACC
37	201C15-xi	HC CDR1	161	AGCTATGCAATGGGC
38	201C15-xi	HC CDR2	162	ACCATTAATATTGGTGGTCGCGTATATTACGCGA
				GCTGGGCAAAAGGC
39	201C15-xi	HC CDR3	163	TATTATAATGGTGGTAGTTATGACATC
40	201C15-xi	LC CDR1	164	CAGGCCAGTGAGAGCATTTATCGCGTATTGGCC
41	201C15-xi	LC CDR2	165	GATACATCCACTCTGGCATCT
42	201C15-xi	LC CDR3	166	CAAGGCGGTTATTATGCTGATAGTTATGGTATTG
				CT
43	201C15-zu	HC CDR1	167	TCCTACGCTATGGGC
44	201C15-zu	HC CDR2	168	ACCATCAACATCGGCGGCAGAGTGTACTACGCCT
				CCTGGGCCAAGGGC
45	201C15-zu	HC CDR3	169	TACTACAACGGCGGCTCCTACGATATC
46	201C15-zu	LC CDR1	170	CAGGCCTCCGAGTCCATCTACCGGGTGCTGGCC
47	201C15-zu	LC CDR2	171	GACACCAGCACACTGGCCTCC
48	201C15-zu	LC CDR3	172	CAGGGCGGCTACTACGCCGACTCCTACGGAATCG
				CT
49	346C6-xi	HC CDR1	173	AGTTATGCAATGATC
50	346C6-xi	HC CDR2	174	ACCATTAGTACTGGTGGTATCACATACTACGCGA
				GCTGGGCGAAAGGC
51	346C6-xi	HC CDR3	175	GGGGGATATGCTGCTAGTAGTGCTTATTATCTCC
				CGTACTACTTTGACTTG
52	346C6-xi	LC CDR1	176	CAGTCCTCCCAGTCCGTGTATAACAACAACAACC
				TGGCC
53	346C6-xi	LC CDR2	177	CTGGCATCCACTCTGGCATCT
54	346C6-xi	LC CDR3	178	CTAGGTGGTTGTGATGATGATGCTGATACTTTTG
				CT
55	346C6-zu	HC CDR1	179	TCCTACGCTATGATC
56	346C6-zu	HC CDR2	180	ACCATCTCTACCGGCGGAATTACCTACTACGCCT
				CCTGGGCCAAGGGC
57	346C6-zu	HC CDR3	181	GGCGGCTACGCCGCCAGCTCCGCTTACTACCTGC
				CCTACTACTTCGACCTG
58	346C6-zu	LC CDR1	182	CAGTCCTCCCAGTCCGTGTATAACAACAACAACC
				TGGCC
59	346C6-zu	LC CDR2	183	CTGGCCTCCACACTGGCCTCT
60	346C6-zu	LC CDR3	184	CTGGGCGGCTGCGACGACGACGCCGATACCTTTG
				CT

[0127]

TABLE 6
Amino acid sequences of mAb IMGT CDRs
		IgG	SEQ
	mAb	chain	ID NO	Amino acid sequence
1	MORAb-003	HC CDR1	13	GFTFSGYG
2	MORAb-003	HC CDR2	14	ISSGGSYT
3	MORAb-003	HC CDR3	15	ARHGDDPAWFAY
4	MORAb-003	LC CDR1	16	SSISSNN
5	MORAb-003	LC CDR2	17	GTS
6	MORAb-003	LC CDR3	18	QQWSSYPYMYT
7	MORAb-009	HC CDR1	185	GYSFTGYT
8	MORAb-009	HC CDR2	186	ITPYNGAS
9	MORAb-009	HC CDR3	187	ARGGYDGRGFDY
10	MORAb-009	LC CDR1	188	SSVSY
11	MORAb-009	LC CDR2	189	DTS
12	MORAb-009	LC CDR3	190	QQWSKHPLT
13	trastuzumab	HC CDR1	191	GFNIKDTY
14	trastuzumab	HC CDR2	192	IYPTNGYT
15	trastuzumab	HC CDR3	193	SRWGGDGFYAMDY
16	trastuzumab	LC CDR1	194	QDVNTA
17	trastuzumab	LC CDR2	195	SAS
18	trastuzumab	LC CDR3	196	QQHYTTPPT
19	33011-xi	HC CDR1	197	GISLSSDA
20	33011-xi	HC CDR2	198	INGGGNT
21	33011-xi	HC CDR3	199	ARGIQHGGGNSDYYYYGMDL
22	33011-xi	LC CDR1	200	QSISSV
23	33011-xi	LC CDR2	201	LAS
24	33011-xi	LC CDR3	202	QTNYGTSSSNYGFA
25	33011-zu	HC CDR1	203	GISLSSDA
26	33011-zu	HC CDR2	204	INGGGNT
27	33011-zu	HC CDR3	205	ARGIQHGGGNSDYYYYGMDL
28	33011-zu	LC CDR1	206	QSISSV
29	33011-zu	LC CDR2	207	LAS
30	33011-zu	LC CDR3	208	QTNYGTSSSNYGFA
31	111B10-xi	HC CDR1	209	GFSLNNYA
32	111B10-xi	HC CDR2	210	ISTGGLA
33	111B10-xi	HC CDR3	211	GRNGGGSYIFYYFDL
34	111B10-xi	LC CDR1	212	QSISSY
35	111B10-xi	LC CDR2	213	SAS
36	111B10-xi	LC CDR3	214	QSYYDIGTST
37	111B10-zu	HC CDR1	215	GFSLNNYA
38	111B10-zu	HC CDR2	216	ISTGGLA
39	111B10-zu	HC CDR3	217	ARNGGGSYIFYYFDL
40	111B10-zu	LC CDR1	218	QSISSY
41	111B10-zu	LC CDR2	219	SAS
42	111B10-zu	LC CDR3	220	QSYYDIGTST
43	201C15-xi	HC CDR1	221	GIDLSSYA
44	201C15-xi	HC CDR2	222	INIGGRV
45	201C15-xi	HC CDR3	223	ARYYNGGSYDI
46	201C15-xi	LC CDR1	224	ESIYRV
47	201C15-xi	LC CDR2	225	DTS
48	201C15-xi	LC CDR3	226	QGGYYADSYGIA
49	201C15-zu	HC CDR1	227	GIDLSSYA
50	201C15-zu	HC CDR2	228	INIGGRV
51	201C15-zu	HC CDR3	229	ARYYNGGSYDI
52	201C15-zu	LC CDR1	230	ESIYRV
53	201C15-zu	LC CDR2	231	DTS
54	201C15-zu	LC CDR3	232	QGGYYADSYGIA
55	346C6-xi	HC CDR1	233	GFSLSSYA
56	346C6-xi	HC CDR2	234	ISTGGIT
57	346C6-xi	HC CDR3	235	ARGGYAASSAYYLPYYFDL
58	346C6-xi	LC CDR1	236	QSVYNNNN
59	346C6-xi	LC CDR2	237	LAS
60	346C6-xi	LC CDR3	238	LGGCDDDADTFA
61	346C6-zu	HC CDR1	239	GFSLSSYA
62	346C6-zu	HC CDR2	240	ISTGGIT
63	346C6-zu	HC CDR3	241	ARGGYAASSAYYLPYYFDL
64	346C6-zu	LC CDR1	242	QSVYNNNN
65	346C6-zu	LC CDR2	243	LAS
66	346C6-zu	LC CDR3	244	LGGCDDDADTFA

[0128]

TABLE 7
Nucleic acid sequences encoding mAb IMGT CDRs
			SEQ ID
	mAb	IgG chain	NO	Nucleic acid sequence
1	MORAb-003	HC CDR1	245	GGCTTCACCTTCAGCGGCTATGGG
2	MORAb-003	HC CDR2	246	ATTAGTAGTGGTGGTAGTTATACC
3	MORAb-003	HC CDR3	247	GCAAGACATGGGGACGATCCCGCCTGGTTCGCT
				TAT
4	MORAb-003	LC CDR1	248	TCAAGTATAAGTTCCAACAAC
5	MORAb-003	LC CDR2	249	GGCACATCC
6	MORAb-003	LC CDR3	250	CAACAGTGGAGTAGTTACCCGTACATGTACACG
7	MORAb-009	HC CDR1	251	GGTTACTCATTCACTGGCTACACC
8	MORAb-009	HC CDR2	252	ATTACTCCTTACAATGGTGCTTCT
9	MORAb-009	HC CDR3	253	GCAAGGGGGGGTTACGACGGGAGGGGTTTTGAC
				TAC
10	MORAb-009	LC CDR1	254	TCAAGTGTAAGTTAC
11	MORAb-009	LC CDR2	255	GACACATCC
12	MORAb-009	LC CDR3	256	CAGCAGTGGAGTAAGCACCCTCTCACG
13	33011-xi	HC CDR1	257	GGAATCTCCCTCAGTAGCGATGCA
14	33011-xi	HC CDR2	258	ATTAATGGTGGTGGTAACACA
15	33011-xi	HC CDR3	259	GCCAGAGGCATTCAACATGGTGGTGGTAATAGT
				GATTATTATTATTACGGCATGGACCTC
16	33011-xi	LC CDR1	260	CAGAGCATTAGTAGTGTC
17	33011-xi	LC CDR2	261	CTGGCATCT
18	33011-xi	LC CDR3	262	CAAACCAATTATGGTACTAGTAGTAGTAATTAT
				GGTTTTGCT
19	33011-zu	HC CDR1	263	GGAATTTCCCTCTCCTCCGACGCG
20	33011-zu	HC CDR2	264	ATCAACGGCGGCGGAAACACC
21	33011-zu	HC CDR3	265	GCGCGCGGCATCCAGCACGGTGGTGGAAACAGC
				GACTACTACTACTATGGGATGGATCTG
22	33011-zu	LC CDR1	266	CAGTCAATTAGCAGCGTG
23	33011-zu	LC CDR2	267	TTGGCCTCC
24	33011-zu	LC CDR3	268	CAAACCAACTACGGAACCTCCAGCTCCAACTAC
				GGCTTTGCC
25	111B10-xi	HC CDR1	269	GGATTCTCCCTCAATAACTATGCA
26	111B10-xi	HC CDR2	270	ATTAGTACTGGTGGTCTCGCA
27	111B10-xi	HC CDR3	271	GGCAGAAATGGTGGTGGTAGTTATATTTTCTAT
				TATTTTGACTTG
28	111B10-xi	LC CDR1	272	CAGAGCATTAGTAGTTAC
29	111B10-xi	LC CDR2	273	TCTGCATCC
30	111B10-xi	LC CDR3	274	CAAAGCTATTATGATATTGGTACTAGTACT
31	111B10-zu	HC CDR1	275	GGCTTCTCCCTGAACAACTACGCC
32	111B10-zu	HC CDR2	276	ATCAGCACAGGCGGCCTGGCC
33	111B10-zu	HC CDR3	277	GCCAGAAACGGCGGAGGCTCCTACATCTTCTAC
				TACTTCGACCTG
34	111B10-zu	LC CDR1	278	CAGTCCATCTCCTCCTAC
35	111B10-zu	LC CDR2	279	TCTGCCTCC
36	111B10-zu	LC CDR3	300	CAGTCCTACTACGACATCGGCACCTCCACC
37	201C15-xi	HC CDR1	301	GGAATCGACCTCAGTAGCTATGCA
38	201C15-xi	HC CDR2	302	ATTAATATTGGTGGTCGCGTA
39	201C15-xi	HC CDR3	303	GCCAGATATTATAATGGTGGTAGTTATGACATC
40	201C15-xi	LC CDR1	304	GAGAGCATTTATCGCGTA
41	201C15-xi	LC CDR2	305	GATACATCC
42	201C15-xi	LC CDR3	306	CAAGGCGGTTATTATGCTGATAGTTATGGTATT
				GCT
43	201C15-zu	HC CDR1	307	GGAATCGACCTGTCCTCCTACGCT
44	201C15-zu	HC CDR2	308	ATCAACATCGGCGGCAGAGTG
45	201C15-zu	HC CDR3	309	GCCCGGTACTACAACGGCGGCTCCTACGATATC
46	201C15-zu	LC CDR1	310	GAGTCCATCTACCGGGTG
47	201C15-zu	LC CDR2	311	GACACCAGC
48	201C15-zu	LC CDR3	312	CAGGGCGGCTACTACGCCGACTCCTACGGAATC
				GCT
49	346C6-xi	HC CDR1	313	GGATTCTCCCTCAGTAGTTATGCA
50	346C6-xi	HC CDR2	314	ATTAGTACTGGTGGTATCACA
51	346C6-xi	HC CDR3	315	GCCAGAGGGGGATATGCTGCTAGTAGTGCTTAT
				TATCTCCCGTACTACTTTGACTTG
52	346C6-xi	LC CDR1	316	CAGAGTGTTTATAATAATAACAAC
53	346C6-xi	LC CDR2	317	CTGGCATCC
54	346C6-xi	LC CDR3	318	CTAGGTGGTTGTGATGATGATGCTGATACTTTT
				GCT
55	346C6-zu	HC CDR1	319	GGCTTCTCCCTGTCCTCCTACGCT
56	346C6-zu	HC CDR2	320	ATCTCTACCGGCGGAATTACC
57	346C6-zu	HC CDR3	321	GCTAGAGGCGGCTACGCCGCCAGCTCCGCTTAC
				TACCTGCCCTACTACTTCGACCTG
58	346C6-zu	LC CDR1	322	CAGTCCGTGTATAACAACAACAAC
59	346C6-zu	LC CDR2	323	CTGGCCTCC
60	346C6-zu	LC CDR3	324	CTGGGCGGCTGCGACGACGACGCCGATACCTTT
				GCT

[0129]

TABLE 8
Amino acid sequences of full-length mAb Ig chains
			SEQ
	mAb	IgG chain	ID NO	Amino acid sequence
1	MORAb-003	Heavy chain	1	EVQLVESGGGVVQPGRSLRLSCSASGFTFSGY
				GLSWVRQAPGKGLEWVAMISSGGSYTYYADSV
				KGRFAISRDNAKNTLFLQMDSLRPEDTGVYFC
				ARHGDDPAWFAYWGQGTPVTVSSASTKGPSVF
				PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW
				NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
				SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK
				THTCPPCPAPELLGGPSVFLFPPKPKDTLMIS
				RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
				AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE
				YKCKVSNKALPAPIEKTISKAKGQPREPQVYT
				LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
				SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK
				SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
				K
2	MORAb-003	Light chain	6	DIQLTQSPSSLSASVGDRVTITCSVSSSISSN
				NLHWYQQKPGKAPKPWIYGTSNLASGVPSRFS
				GSGSGTDYTFTISSLQPEDIATYYCQQWSSYP
				YMYTFGQGTKVEIKRTVAAPSVFIFPPSDEQL
				KSGTASVVCLLNNFYPREAKVQWKVDNALQSG
				NSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
				KVYACEVTHQGLSSPVTKSFNRGEC
3	MORAb-009	Heavy chain	325	QVQLQQSGPELEKPGASVKISCKASGYSFTGY
				TMNWVKQSHGKSLEWIGLITPYNGASSYNQKF
				RGKATLTVDKSSSTAYMDLLSLTSEDSAVYFC
				ARGGYDGRGFDYWGSGTPVTVSSASTKGPSVF
				PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSW
				NSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
				SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK
				THTCPPCPAPELLGGPSVFLFPPKPKDTLMIS
				RTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN
				AKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE
				YKCKVSNKALPAPIEKTISKAKGQPREPQVYT
				LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWE
				SNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK
				SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG
				K
4	MORAb-009	Light chain	326	DIELTQSPAIMSASPGEKVTMTCSASSSVSYM
				HWYQQKSGTSPKRWIYDTSKLASGVPGRFSGS
				GSGNSYSLTISSVEAEDDATYYCQQWSKHPLT
				FGSGTKVEIKRTVAAPSVFIFPPSDEQLKSGT
				ASVVCLLNNFYPREAKVQWKVDNALQSGNSQE
				SVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA
				CEVTHQGLSSPVTKSFNRGEC
5	trastuzumab	Heavy chain	327	EVQLVESGGGLVQPGGSLRLSCAASGFNIKDT
				YIHWVRQAPGKGLEWVARIYPTNGYTRYADSV
				KGRFTISADTSKNTAYLQMNSLRAEDTAVYYC
				SRWGGDGFYAMDYWGQGTLVTVSSASTKGPSV
				FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS
				WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVP
				SSSLGTQTYICNVNHKPSNTKVDKKVEPPKSC
				DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
				ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV
				HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
				KEYKCKVSNKALPAPIEKTISKAKGQPREPQV
				YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE
				WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
				DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS
				PGK
6	trastuzumab	Light chain	328	DIQMTQSPSSLSASVGDRVTITCRASQDVNTA
				VAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG
				SRSGTDFTLTISSLQPEDFATYYCQQHYTTPP
				TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSG
				TASVVCLLNNFYPREAKVQWKVDNALQSGNSQ
				ESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY
				ACEVTHQGLSSPVTKSFNRGEC
7	33011-xi	Heavy chain	329	QSVEESGGRLVTPGTPLTLTCTVSGISLSSDA
				ISWVRQAPGKGLEYIGIINGGGNTYYASWAKG
				RFTISKTSTTVDLKITSPTTEDTATYFCARGI
				QHGGGNSDYYYYGMDL
				WGPGTLVTVSSASTKGPSVFPLAPSSKSTSGG
				TAALGCLVKDYFPEPVTVSWNSGALTSGVHTF
				PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNV
				NHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL
				LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDV
				SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNS
				TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPA
				PIEKTISKAKGQPREPQVYTLPPSRDELTKNQ
				VSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
				PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCS
				VMHEALHNHYTQKSLSLSPGK
8	33011-xi	Light chain	330	EVLMTQTPSSVSAAVGDTVTIKCQASQSISSV
				LSWYQQKPGQPPKLLIYLASTLASGVPSRFSG
				SRSGTEFTLTISDLECDDAATYYCQTNYGTSS
				SNYGFAFGGGTEVVVKRTVAAPSVFIFPPSDE
				QLKSGTASVVCLLNNFYPREAKVQWKVDNALQ
				SGNSQESVTEQDSKDSTYSLSSTLTLSKADYE
				KHKVYACEVTHQGLSSPVTKSFNRGEC
9	33011-zu	Heavy chain	331	EVQLVESGGGLVQPGGSLRLSCAASGISLSSD
				AISWVRQAPGKGLEYIGIINGGGNTYYASWAK
				GRFTISRHNSKNTLYLQMNSLRAEDTAVYYCA
				RGIQHGGGNSDYYYYGMDLWGQGTLVTVSSAS
				TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP
				EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLS
				SVVTVPSSSLGTQTYICNVNHKPSNTKVDKKV
				EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKP
				KDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV
				DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQ
				DWLNGKEYKCKVSNKALPAPIEKTISKAKGQP
				REPQVYTLPPSRDELTKNQVSLTCLVKGFYPS
				DIAVEWESNGQPENNYKTTPPVLDSDGSFFLY
				SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK
				SLSLSPGK
10	33011-zu	Light chain	332	DIQMTQSPSSLSASVGDRVTITCQASQSISSV
				LSWYQQKPGKAPKLLIYLASTLASGVPSRFSG
				SGSGTDFTLTISSLQCEDIATYYCQTNYGTSS
				SNYGFAFGGGTKVEIKRTVAAPSVFIFPPSDE
				QLKSGTASVVCLLNNFYPREAKVQWKVDNALQ
				SGNSQESVTEQDSKDSTYSLSSTLTLSKADYE
				KHKVYACEVTHQGLSSPVTKSFNRGEC
11	111B10-xi	Heavy chain	333	QSVEESGGRLVTPGTPLTLTCTVSGFSLNNYA
				MSWVRQAPGKGLEWIGSISTGGLAFYANWAKG
				RFTISRTSTTVDLKMTSLTTEDTATYFCGRNG
				GGSYIFYYFDLWGQGTLVTVSSASTKGPSVFP
				LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWN
				SGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
				SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
				HTCPPCPAPELLGGPSVFLFPPKPKDTLMISR
				TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNA
				KTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY
				KCKVSNKALPAPIEKTISKAKGQPREPQVYTL
				PPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
				NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS
				RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
12	111B10-xi	Light chain	334	AFELTQTPSSVEAAVGGTITIKCQASQSISSY
				LSWYQQKPGQPPKLLIYSASTLASGVSSRFKG
				SGSGTEYTLTISDLECADAATYFCQSYYDIGT
				STFGGGTEVVVKRTVAAPSVFIFPPSDEQLKS
				GTASVVCLLNNFYPREAKVQWKVDNALQSGNS
				QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV
				YACEVTHQGLSSPVTKSFNRGEC
13	111B10-zu	Heavy chain	335	EVQLVESGGGLVQPGGSLRLSCAASGFSLNNY
				AMSWVRQAPGKGLEWIGSISTGGLAFYANWAK
				GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA
				RNGGGSYIFYYFDLWGQGTLVTVSSASTKGPS
				VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTV
				SWNSGALTSGVHTFPAVLQSSGLYSLSSVVTV
				PSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC
				DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM
				ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV
				HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNG
				KEYKCKVSNKALPAPIEKTISKAKGQPREPQV
				YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE
				WESNGQPENNYKTTPPVLDSDGSFFLYSKLTV
				DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS
				PGK
14	111B10-zu	Light chain	336	DIQMTQSPSSLSASVGDRVTITCQASQSISSY
				LSWYQQKPGKAPKLLIYSASTLASGVPSRFSG
				SGSGTDFTLTISSLQCEDAATYYCQSYYDIGT
				STFGGGTKVEIKRTVAAPSVFIFPPSDEQLKS
				GTASVVCLLNNFYPREAKVQWKVDNALQSGNS
				QESVTEQDSKDSTYSLSSTLTLSKADYEKHKV
				YACEVTHQGLSSPVTKSFNRGEC
15	201C15-xi	Heavy chain	337	QSVKESGGRLVTPGTPLTLTCTVSGIDLSSYA
				MGWFRQAPGKGLEYIGTINIGGRVYYASWAKG
				RFTISRTSTTVDLKAPSLTAEDTATYFCARYY
				NGGSYDIWGPGTLVTVSLASTKGPSVFPLAPS
				SKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL
				TSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
				QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP
				PCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
				TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP
				REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKV
				SNKALPAPIEKTISKAKGQPREPQVYTLPPSR
				DELTKNQVSLTCLVKGFYPSDIAVEWESNGQP
				ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ
				GNVFSCSVMHEALHNHYTQKSLSLSPGK
16	201C15-xi	Light chain	338	DVVMTQTPASASEPVGGTVTIKCQASESIYRV
				LAWYQQKPGQPPKLLIYDTSTLASGAPSRFKG
				SGYGTEFTLTISGVQCEDAATYYCQGGYYADS
				YGIAFGGGTEVVVKRTVAAPSVFIFPPSDEQL
				KSGTASVVCLLNNFYPREAKVQWKVDNALQSG
				NSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
				KVYACEVTHQGLSSPVTKSFNRGEC
17	201C15-zu	Heavy chain	339	QVQLVESGGGLVQPGGSLRLSCSASGIDLSSY
				AMGWVRQAPGKGLEYIGTINIGGRVYYASWAK
				GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA
				RYYNGGSYDIWGQGTLVTVSSASTKGPSVFPL
				APSSKSTSGGTAALGCLVKDYFPEPVTVSWNS
				GALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS
				LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH
				TCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
				PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK
				TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK
				CKVSNKALPAPIEKTISKAKGQPREPQVYTLP
				PSRDELTKNQVSLTCLVKGFYPSDIAVEWESN
				GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSR
				WQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
18	201C15-zu	Light chain	340	DIQMTQSPSTLSASVGDRVTITCQASESIYRV
				LAWYQQKPGKAPKLLIYDTSTLASGVPSRFSG
				SGSGTEFTLTISSLQCDDAATYYCQGGYYADS
				YGIAFGGGTKVEIKRTVAAPSVFIFPPSDEQL
				KSGTASVVCLLNNFYPREAKVQWKVDNALQSG
				NSQESVTEQDSKDSTYSLSSTLTLSKADYEKH
				KVYACEVTHQGLSSPVTKSFNRGEC
19	346C6-xi	Heavy chain	341	QSVEESGGRLVKPDESLTLTCTASGFSLSSYA
				MIWVRQAPGEGLEWIGTISTGGITYYASWAKG
				RFTISKTSTTVDLKITSPTTEDTATYFCARGG
				YAASSAYYLPYYFDLWGQGTLVTVSSASTKGP
				SVFPLAPSSKSTSGGTAALGCLVKDYFPEPVT
				VSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT
				VPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS
				CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL
				MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVE
				VHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN
				GKEYKCKVSNKALPAPIEKTISKAKGQPREPQ
				VYTLPPSRDELTKNQVSLTCLVKGFYPSDIAV
				EWESNGQPENNYKTTPPVLDSDGSFFLYSKLT
				VDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL
				SPGK
20	346C6-xi	Light chain	342	AAVLTQTPSPVSAAVGGTVTISCQSSQSVYNN
				NNLAWFQQKPGQPPKLLIYLASTLASGVPSRF
				SGSGSGTQFTLTISGVQCDDAATYYCLGGCDD
				DADTFAFGGGTEVVVKRTVAAPSVFIFPPSDE
				QLKSGTASVVCLLNNFYPREAKVQWKVDNALQ
				SGNSQESVTEQDSKDSTYSLSSTLTLSKADYE
				KHKVYACEVTHQGLSSPVTKSFNRGEC
21	346C6-zu	Heavy chain	343	EVQLVESGGGLVQPGGSLRLSCAASGFSLSSY
				AMIWVRQAPGKGLEWIGTISTGGITYYASWAK
				GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA
				RGGYAASSAYYLPYYFDLWGQGTLVTVSSAST
				KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPE
				PVTVSWNSGALTSGVHTFPAVLQSSGLYSLSS
				VVTVPSSSLGTQTYICNVNHKPSNTKVDKKVE
				PKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK
				DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD
				GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQD
				WLNGKEYKCKVSNKALPAPIEKTISKAKGQPR
				EPQVYTLPPSRDELTKNQVSLTCLVKGFYPSD
				IAVEWESNGQPENNYKTTPPVLDSDGSFFLYS
				KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS
				LSLSPGK
22	346C6-zu	Light chain	344	DIQMTQSPSSLSASVGDRVTITCQSSQSVYNN
				NNLAWYQQKPGKVPKLLIYLASTLASGVPSRF
				SGSGSGTDFTLTISSLQCEDAATYYCLGGCDD
				DADTFAFGGGTKVEIKRTVAAPSVFIFPPSDE
				QLKSGTASVVCLLNNFYPREAKVQWKVDNALQ
				SGNSQESVTEQDSKDSTYSLSSTLTLSKADYE
				KHKVYACEVTHQGLSSPVTKSFNRGEC

[0130]

TABLE 9
Nucleic acid sequences
encoding full-length mAb Ig chains+
			SEQ
	mAb	IgG chain	ID NO	Nucleic acid sequence
1	MORAb-003	Heavy chain	345	GAGGTCCAACTGGTGGAGAGCGGTGGAGGTGTT
				GTGCAACCTGGCCGGTCCCTGCGCCTGTCCTGC
				TCCGCATCTGGCTTCACCTTCAGCGGCTATGGG
				TTGTCTTGGGTGAGACAGGCACCTGGAAAAGGT
				CTTGAGTGGGTTGCAATGATTAGTAGTGGTGGT
				AGTTATACCTACTATGCAGACAGTGTGAAGGGT
				AGATTTGCAATATCGCGAGACAACGCCAAGAAC
				ACATTGTTCCTGCAAATGGACAGCCTGAGACCC
				GAAGACACCGGGGTCTATTTTTGTGCAAGACAT
				GGGGACGATCCCGCCTGGTTCGCTTATTGGGGC
				CAAGGGACCCCGGTCACCGTCTCCTCAGCCTCC
				ACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC
				TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCC
				CTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA
				CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG
				ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA
				CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
				GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
				ACCTACATCTGCAACGTGAATCACAAGCCCAGC
				AACACCAAGGTGGACAAGAAAGTTGAGCCCAAA
				TCTTGTGACAAAACTCACACATGCCCACCGTGC
				CCAGCACCTGAACTCCTGGGGGGACCGTCAGTC
				TTCCTCTTCCCCCCAAAACCCAAGGACACCCTC
				ATGATCTCCCGGACCCCTGAGGTCACATGCGTG
				GTGGTGGACGTGAGCCACGAAGACCCTGAGGTC
				AAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
				CATAATGCCAAGACAAAGCCGCGGGAGGAGCAG
				TACAACAGCACGTACCGTGTGGTCAGCGTCCTC
				ACCGTCCTGCACCAGGACTGGCTGAATGGCAAG
				GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC
				CCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
				AAAGGGCAGCCCCGAGAACCACAGGTGTACACC
				CTGCCCCCATCCCGGGATGAGCTGACCAAGAAC
				CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
				TATCCCAGCGACATCGCCGTGGAGTGGGAGAGC
				AATGGGCAGCCGGAGAACAACTACAAGACCACG
				CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
				TTATATTCAAAGCTCACCGTGGACAAGAGCAGG
				TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
				ATGCATGAGGCTCTGCACAACCACTACACGCAG
				AAGAGCCTCTCCCTGTCTCCCGGGAAATGA
2	MORAb-003	Light chain	346	GACATCCAGCTGACCCAGAGCCCAAGCAGCCTG
				AGCGCCAGCGTGGGTGACAGAGTGACCATCACC
				TGTAGTGTCAGCTCAAGTATAAGTTCCAACAAC
				TTGCACTGGTACCAGCAGAAGCCAGGTAAGGCT
				CCAAAGCCATGGATCTACGGCACATCCAACCTG
				GCTTCTGGTGTGCCAAGCAGATTCAGCGGTAGC
				GGTAGCGGTACCGACTACACCTTCACCATCAGC
				AGCCTCCAGCCAGAGGACATCGCCACCTACTAC
				TGCCAACAGTGGAGTAGTTACCCGTACATGTAC
				ACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA
				CGAACTGTGGCTGCACCATCTGTCTTCATCTTC
				CCGCCATCTGATGAGCAGTTGAAATCTGGAACT
				GCCTCTGTTGTGTGCCTGCTGAATAACTTCTAT
				CCCAGAGAGGCCAAAGTACAGTGGAAGGTGGAT
				AACGCCCTCCAATCGGGTAACTCCCAGGAGAGT
				GTCACAGAGCAGGACAGCAAGGACAGCACCTAC
				AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA
				GACTACGAGAAACACAAAGTCTACGCCTGCGAA
				GTCACCCATCAGGGCCTGAGCTCGCCCGTCACA
				AAGAGCTTCAACAGGGGAGAGTGTTAA
3	MORAb-009	Heavy chain	347	CAGGTACAACTGCAGCAGTCTGGGCCTGAGCTG
				GAGAAGCCTGGCGCTTCAGTGAAGATATCCTGC
				AAGGCTTCTGGTTACTCATTCACTGGCTACACC
				ATGAACTGGGTGAAGCAGAGCCATGGAAAGAGC
				CTTGAGTGGATTGGACTTATTACTCCTTACAAT
				GGTGCTTCTAGCTACAACCAGAAGTTCAGGGGC
				AAGGCCACATTAACTGTAGACAAGTCATCCAGC
				ACAGCCTACATGGACCTCCTCAGTCTGACATCT
				GAAGACTCTGCAGTCTATTTCTGTGCAAGGGGG
				GGTTACGACGGGAGGGGTTTTGACTACTGGGGA
				TCCGGGACCCCGGTCACCGTCTCCTCAGCCTCC
				ACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC
				TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCC
				CTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA
				CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG
				ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA
				CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTG
				GTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
				ACCTACATCTGCAACGTGAATCACAAGCCCAGC
				AACACCAAGGTGGACAAGAAAGTTGAGCCCAAA
				TCTTGTGACAAAACTCACACATGCCCACCGTGC
				CCAGCACCTGAACTCCTGGGGGGACCGTCAGTC
				TTCCTCTTCCCCCCAAAACCCAAGGACACCCTC
				ATGATCTCCCGGACCCCTGAGGTCACATGCGTG
				GTGGTGGACGTGAGCCACGAAGACCCTGAGGTC
				AAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
				CATAATGCCAAGACAAAGCCGCGGGAGGAGCAG
				TACAACAGCACGTACCGTGTGGTCAGCGTCCTC
				ACCGTCCTGCACCAGGACTGGCTGAATGGCAAG
				GAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC
				CCAGCCCCCATCGAGAAAACCATCTCCAAAGCC
				AAAGGGCAGCCCCGAGAACCACAGGTGTACACC
				CTGCCCCCATCCCGGGATGAGCTGACCAAGAAC
				CAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
				TATCCCAGCGACATCGCCGTGGAGTGGGAGAGC
				AATGGGCAGCCGGAGAACAACTACAAGACCACG
				CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTC
				CTCTACAGCAAGCTCACCGTGGACAAGAGCAGG
				TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTG
				ATGCATGAGGCTCTGCACAACCACTACACGCAG
				AAGAGCCTCTCCCTGTCTCCCGGGAAATGA
4	MORAb-009	Light chain	348	GACATCGAGCTCACTCAGTCTCCAGCAATCATG
				TCTGCATCTCCAGGGGAGAAGGTCACCATGACC
				TGCAGTGCCAGCTCAAGTGTAAGTTACATGCAC
				TGGTACCAGCAGAAGTCAGGCACCTCCCCCAAA
				AGATGGATTTATGACACATCCAAACTGGCTTCT
				GGAGTCCCAGGTCGCTTCAGTGGCAGTGGGTCT
				GGAAACTCTTACTCTCTCACAATCAGCAGCGTG
				GAGGCTGAAGATGATGCAACTTATTACTGCCAG
				CAGTGGAGTAAGCACCCTCTCACGTTCGGATCC
				GGGACCAAGGTGGAAATCAAACGAACTGTGGCT
				GCACCATCTGTCTTCATCTTCCCGCCATCTGAT
				GAGCAGTTGAAATCTGGAACTGCCTCTGTTGTG
				TGCCTGCTGAATAACTTCTATCCCAGAGAGGCC
				AAAGTACAGTGGAAGGTGGATAACGCCCTCCAA
				TCGGGTAACTCCCAGGAGAGTGTCACAGAGCAG
				GACAGCAAGGACAGCACCTACAGCCTCAGCAGC
				ACCCTGACGCTGAGCAAAGCAGACTACGAGAAA
				CACAAAGTCTACGCCTGCGAAGTCACCCATCAG
				GGCCTGAGCTCGCCCGTCACAAAGAGCTTCAAC
				AGGGGAGAGTGTTAA
5	33011-xi	Heavy chain	349	CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTC
				ACGCCTGGGACACCCCTGACACTCACCTGCACC
				GTCTCTGGAATCTCCCTCAGTAGCGATGCAATA
				AGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTC
				GAATACATCGGAATCATTAATGGTGGTGGTAAC
				ACATACTACGCGAGCTGGGCGAAAGGCCGATTC
				ACCATCTCCAAAACCTCGACCACGGTGGATCTG
				AAAATCACCAGTCCGACAACCGAGGACACGGCC
				ACCTATTTCTGTGCCAGAGGCATTCAACATGGT
				GGTGGTAATAGTGATTATTATTATTACGGCATG
				GACCTCTGGGGCCCAGGCACCCTGGTCACTGTC
				TCTTCAGCATCCACCAAGGGCCCATCGGTCTTC
				CCCCTGGCACCCTCCTCCAAGAGCACCTCTGGG
				GGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC
				TACTTCCCCGAACCGGTGACGGTGTCGTGGAAC
				TCAGGCGCCCTGACCAGCGGCGTGCACACCTTC
				CCGGCTGTCCTACAGTCCTCAGGACTCTACTCC
				CTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGC
				TTGGGCACCCAGACCTACATCTGCAACGTGAAT
				CACAAGCCCAGCAACACCAAGGTGGACAAGAAA
				GTTGAGCCCAAATCTTGTGACAAAACTCACACA
				TGCCCACCGTGCCCAGCACCTGAACTCCTGGGG
				GGACCGTCAGTCTTCCTCTTCCCCCCAAAACCC
				AAGGACACCCTCATGATCTCCCGGACCCCTGAG
				GTCACATGCGTGGTGGTGGACGTGAGCCACGAA
				GACCCTGAGGTCAAGTTCAACTGGTACGTGGAC
				GGCGTGGAGGTGCATAATGCCAAGACAAAGCCG
				CGGGAGGAGCAGTACAACAGCACGTACCGTGTG
				GTCAGCGTCCTCACCGTCCTGCACCAGGACTGG
				CTGAATGGCAAGGAGTACAAGTGCAAGGTCTCC
				AACAAAGCCCTCCCAGCCCCCATCGAGAAAACC
				ATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCA
				CAGGTGTACACCCTGCCCCCATCCCGGGATGAG
				CTGACCAAGAACCAGGTCAGCCTGACCTGCCTG
				GTCAAAGGCTTCTATCCCAGCGACATCGCCGTG
				GAGTGGGAGAGCAATGGGCAGCCGGAGAACAAC
				TACAAGACCACGCCTCCCGTGCTGGACTCCGAC
				GGCTCCTTCTTCTTATATTCAAAGCTCACCGTG
				GACAAGAGCAGGTGGCAGCAGGGGAACGTCTTC
				TCATGCTCCGTGATGCATGAGGCTCTGCACAAC
				CACTACACGCAGAAGAGCCTCTCCCTGTCTCCC
				GGGAAATGA
6	33011-xi	Light chain	350	GAAGTGTTGATGACCCAGACTCCATCCTCCGTG
				TCTGCAGCTGTGGGAGACACAGTCACCATCAAG
				TGCCAGGCCAGTCAGAGCATTAGTAGTGTCTTG
				TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCC
				AAGCTCCTGATCTATCTGGCATCCACTCTGGCA
				TCTGGGGTCCCATCGCGGTTCAGCGGCAGTAGA
				TCTGGGACAGAGTTCACTCTCACCATCAGCGAC
				CTGGAGTGTGACGATGCTGCCACTTACTACTGT
				CAAACCAATTATGGTACTAGTAGTAGTAATTAT
				GGTTTTGCTTTCGGCGGAGGGACCGAGGTGGTC
				GTCAAACGAACTGTGGCTGCACCATCTGTCTTC
				ATCTTCCCGCCATCTGATGAGCAGTTGAAATCT
				GGAACTGCCTCTGTTGTGTGCCTGCTGAATAAC
				TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG
				GTGGATAACGCCCTCCAATCGGGTAACTCCCAG
				GAGAGTGTCACAGAGCAGGACAGCAAGGACAGC
				ACCTACAGCCTCAGCAGCACCCTGACGCTGAGC
				AAAGCAGACTACGAGAAACACAAAGTCTACGCC
				TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC
				GTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA
7	33011-zu	Heavy chain	351	GAAGTCCAACTGGTGGAAAGCGGGGGAGGACTG
				GTGCAGCCGGGCGGATCCCTCCGGCTGTCATGT
				GCTGCATCGGGAATTTCCCTCTCCTCCGACGCG
				ATTAGCTGGGTCAGACAGGCCCCCGGAAAGGGG
				CTGGAGTACATCGGTATCATCAACGGCGGCGGA
				AACACCTACTACGCCTCCTGGGCCAAGGGCCGC
				TTCACCATCTCGCGGCATAATTCCAAGAACACT
				CTGTACTTGCAAATGAACTCCCTGAGGGCCGAG
				GACACCGCCGTGTACTACTGCGCGCGCGGCATC
				CAGCACGGTGGTGGAAACAGCGACTACTACTAC
				TATGGGATGGATCTGTGGGGCCAGGGAACTCTT
				GTGACCGTGTCGTCAGCATCCACCAAGGGCCCA
				TCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGC
				ACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG
				GTCAAGGACTACTTCCCCGAACCGGTGACGGTG
				TCGTGGAACTCAGGCGCCCTGACCAGCGGCGTG
				CACACCTTCCCGGCTGTCCTACAGTCCTCAGGA
				CTCTACTCCCTCAGCAGCGTGGTGACCGTGCCC
				TCCAGCAGCTTGGGCACCCAGACCTACATCTGC
				AACGTGAATCACAAGCCCAGCAACACCAAGGTG
				GACAAGAAAGTTGAGCCCAAATCTTGTGACAAA
				ACTCACACATGCCCACCGTGCCCAGCACCTGAA
				CTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCC
				CCAAAACCCAAGGACACCCTCATGATCTCCCGG
				ACCCCTGAGGTCACATGCGTGGTGGTGGACGTG
				AGCCACGAAGACCCTGAGGTCAAGTTCAACTGG
				TACGTGGACGGCGTGGAGGTGCATAATGCCAAG
				ACAAAGCCGCGGGAGGAGCAGTACAACAGCACG
				TACCGTGTGGTCAGCGTCCTCACCGTCCTGCAC
				CAGGACTGGCTGAATGGCAAGGAGTACAAGTGC
				AAGGTCTCCAACAAAGCCCTCCCAGCCCCCATC
				GAGAAAACCATCTCCAAAGCCAAAGGGCAGCCC
				CGAGAACCACAGGTGTACACCCTGCCCCCATCC
				CGGGATGAGCTGACCAAGAACCAGGTCAGCCTG
				ACCTGCCTGGTCAAAGGCTTCTATCCCAGCGAC
				ATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCG
				GAGAACAACTACAAGACCACGCCTCCCGTGCTG
				GACTCCGACGGCTCCTTCTTCTTATATTCAAAG
				CTCACCGTGGACAAGAGCAGGTGGCAGCAGGGG
				AACGTCTTCTCATGCTCCGTGATGCATGAGGCT
				CTGCACAACCACTACACGCAGAAGAGCCTCTCC
				CTGTCTCCCGGGAAATGA
8	33011-zu	Light chain	352	GACATTCAGATGACCCAGTCCCCAAGCTCGCTG
				TCCGCCTCCGTGGGCGACCGCGTGACCATCACG
				TGCCAGGCGTCCCAGTCAATTAGCAGCGTGCTC
				TCCTGGTACCAACAGAAGCCGGGGAAAGCACCC
				AAGCTGCTGATCTACTTGGCCTCCACTCTGGCC
				TCGGGAGTGCCTTCACGGTTCTCCGGATCGGGA
				TCTGGTACTGATTTCACCCTCACCATCTCGAGC
				CTTCAGTGCGAGGACATCGCTACTTACTATTGT
				CAAACCAACTACGGAACCTCCAGCTCCAACTAC
				GGCTTTGCCTTCGGTGGCGGGACCAAGGTCGAA
				ATCAAACGAACTGTGGCTGCACCATCTGTCTTC
				ATCTTCCCGCCATCTGATGAGCAGTTGAAATCT
				GGAACTGCCTCTGTTGTGTGCCTGCTGAATAAC
				TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG
				GTGGATAACGCCCTCCAATCGGGTAACTCCCAG
				GAGAGTGTCACAGAGCAGGACAGCAAGGACAGC
				ACCTACAGCCTCAGCAGCACCCTGACGCTGAGC
				AAAGCAGACTACGAGAAACACAAAGTCTACGCC
				TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC
				GTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA
9	111B10-xi	Heavy chain	353	CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTC
				ACGCCTGGGACACCCCTGACACTCACCTGCACA
				GTCTCTGGATTCTCCCTCAATAACTATGCAATG
				AGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTG
				GAATGGATCGGATCCATTAGTACTGGTGGTCTC
				GCATTCTACGCGAACTGGGCAAAAGGCCGATTC
				ACCATCTCCAGAACCTCGACCACGGTGGATCTG
				AAAATGACCAGTCTGACAACCGAGGACACGGCC
				ACCTATTTCTGTGGCAGAAATGGTGGTGGTAGT
				TATATTTTCTATTATTTTGACTTGTGGGGCCAA
				GGCACCCTCGTCACTGTCTCTTCAGCATCCACC
				AAGGGCCCATCGGTCTTCCCCCTGGCACCCTCC
				TCCAAGAGCACCTCTGGGGGCACAGCGGCCCTG
				GGCTGCCTGGTCAAGGACTACTTCCCCGAACCG
				GTGACGGTGTCGTGGAACTCAGGCGCCCTGACC
				AGCGGCGTGCACACCTTCCCGGCTGTCCTACAG
				TCCTCAGGACTCTACTCCCTCAGCAGCGTGGTG
				ACCGTGCCCTCCAGCAGCTTGGGCACCCAGACC
				TACATCTGCAACGTGAATCACAAGCCCAGCAAC
				ACCAAGGTGGACAAGAAAGTTGAGCCCAAATCT
				TGTGACAAAACTCACACATGCCCACCGTGCCCA
				GCACCTGAACTCCTGGGGGGACCGTCAGTCTTC
				CTCTTCCCCCCAAAACCCAAGGACACCCTCATG
				ATCTCCCGGACCCCTGAGGTCACATGCGTGGTG
				GTGGACGTGAGCCACGAAGACCCTGAGGTCAAG
				TTCAACTGGTACGTGGACGGCGTGGAGGTGCAT
				AATGCCAAGACAAAGCCGCGGGAGGAGCAGTAC
				AACAGCACGTACCGTGTGGTCAGCGTCCTCACC
				GTCCTGCACCAGGACTGGCTGAATGGCAAGGAG
				TACAAGTGCAAGGTCTCCAACAAAGCCCTCCCA
				GCCCCCATCGAGAAAACCATCTCCAAAGCCAAA
				GGGCAGCCCCGAGAACCACAGGTGTACACCCTG
				CCCCCATCCCGGGATGAGCTGACCAAGAACCAG
				GTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT
				CCCAGCGACATCGCCGTGGAGTGGGAGAGCAAT
				GGGCAGCCGGAGAACAACTACAAGACCACGCCT
				CCCGTGCTGGACTCCGACGGCTCCTTCTTCTTA
				TATTCAAAGCTCACCGTGGACAAGAGCAGGTGG
				CAGCAGGGGAACGTCTTCTCATGCTCCGTGATG
				CATGAGGCTCTGCACAACCACTACACGCAGAAG
				AGCCTCTCCCTGTCTCCCGGGAAATGA
10	111B10-xi	Light chain	354	GCATTCGAATTGACCCAGACTCCATCCTCCGTG
				GAGGCAGCTGTGGGAGGCACAATCACCATCAAG
				TGCCAGGCCAGTCAGAGCATTAGTAGTTACTTA
				TCCTGGTATCAGCAGAAACCAGGGCAGCCTCCC
				AAGCTCCTGATCTATTCTGCATCCACTCTGGCA
				TCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGA
				TCTGGGACAGAGTACACTCTCACCATCAGCGAC
				CTGGAGTGTGCCGATGCTGCCACTTACTTCTGT
				CAAAGCTATTATGATATTGGTACTAGTACTTTC
				GGCGGAGGGACCGAGGTGGTCGTCAAACGAACT
				GTGGCTGCACCATCTGTCTTCATCTTCCCGCCA
				TCTGATGAGCAGTTGAAATCTGGAACTGCCTCT
				GTTGTGTGCCTGCTGAATAACTTCTATCCCAGA
				GAGGCCAAAGTACAGTGGAAGGTGGATAACGCC
				CTCCAATCGGGTAACTCCCAGGAGAGTGTCACA
				GAGCAGGACAGCAAGGACAGCACCTACAGCCTC
				AGCAGCACCCTGACGCTGAGCAAAGCAGACTAC
				GAGAAACACAAAGTCTACGCCTGCGAAGTCACC
				CATCAGGGCCTGAGCTCGCCCGTCACAAAGAGC
				TTCAACAGGGGAGAGTGTTGA
11	111B10-zu	Heavy chain	355	GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTG
				GTGCAGCCTGGCGGATCTCTGAGACTGTCTTGT
				GCCGCCTCCGGCTTCTCCCTGAACAACTACGCC
				ATGTCCTGGGTGCGACAGGCCCCTGGCAAAGGC
				CTGGAATGGATCGGCTCCATCAGCACAGGCGGC
				CTGGCCTTCTACGCCAATTGGGCCAAGGGCCGG
				TTCACCATCAGCCGGGACAACTCCAAGAACACC
				CTGTACCTCCAGATGAACTCCCTGCGGGCCGAG
				GACACCGCCGTGTACTACTGTGCCAGAAACGGC
				GGAGGCTCCTACATCTTCTACTACTTCGACCTG
				TGGGGCCAGGGCACCCTCGTGACAGTGTCATCT
				GCATCCACCAAGGGCCCATCGGTCTTCCCCCTG
				GCACCCTCCTCCAAGAGCACCTCTGGGGGCACA
				GCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC
				CCCGAACCGGTGACGGTGTCGTGGAACTCAGGC
				GCCCTGACCAGCGGCGTGCACACCTTCCCGGCT
				GTCCTACAGTCCTCAGGACTCTACTCCCTCAGC
				AGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGC
				ACCCAGACCTACATCTGCAACGTGAATCACAAG
				CCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
				CCCAAATCTTGTGACAAAACTCACACATGCCCA
				CCGTGCCCAGCACCTGAACTCCTGGGGGGACCG
				TCAGTCTTCCTCTTCCCCCCAAAACCCAAGGAC
				ACCCTCATGATCTCCCGGACCCCTGAGGTCACA
				TGCGTGGTGGTGGACGTGAGCCACGAAGACCCT
				GAGGTCAAGTTCAACTGGTACGTGGACGGCGTG
				GAGGTGCATAATGCCAAGACAAAGCCGCGGGAG
				GAGCAGTACAACAGCACGTACCGTGTGGTCAGC
				GTCCTCACCGTCCTGCACCAGGACTGGCTGAAT
				GGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA
				GCCCTCCCAGCCCCCATCGAGAAAACCATCTCC
				AAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG
				TACACCCTGCCCCCATCCCGGGATGAGCTGACC
				AAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA
				GGCTTCTATCCCAGCGACATCGCCGTGGAGTGG
				GAGAGCAATGGGCAGCCGGAGAACAACTACAAG
				ACCACGCCTCCCGTGCTGGACTCCGACGGCTCC
				TTCTTCTTATATTCAAAGCTCACCGTGGACAAG
				AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGC
				TCCGTGATGCATGAGGCTCTGCACAACCACTAC
				ACGCAGAAGAGCCTCTCCCTGTCTCCCGGGAAA
				TGA
12	111B10-zu	Light chain	356	GATATTCAGATGACCCAGTCCCCCTCCAGCCTG
				TCCGCTTCTGTGGGCGACAGAGTGACCATCACC
				TGTCAGGCCTCCCAGTCCATCTCCTCCTACCTG
				TCCTGGTATCAGCAGAAGCCCGGCAAGGCCCCC
				AAGCTGCTGATCTACTCTGCCTCCACACTGGCC
				TCCGGCGTGCCCTCTAGATTCTCCGGCTCTGGC
				TCTGGCACCGACTTTACCCTGACCATCAGCTCC
				CTCCAGTGCGAGGATGCCGCCACCTACTACTGC
				CAGTCCTACTACGACATCGGCACCTCCACCTTC
				GGCGGAGGCACCAAGGTGGAAATCAAACGAACT
				GTGGCTGCACCATCTGTCTTCATCTTCCCGCCA
				TCTGATGAGCAGTTGAAATCTGGAACTGCCTCT
				GTTGTGTGCCTGCTGAATAACTTCTATCCCAGA
				GAGGCCAAAGTACAGTGGAAGGTGGATAACGCC
				CTCCAATCGGGTAACTCCCAGGAGAGTGTCACA
				GAGCAGGACAGCAAGGACAGCACCTACAGCCTC
				AGCAGCACCCTGACGCTGAGCAAAGCAGACTAC
				GAGAAACACAAAGTCTACGCCTGCGAAGTCACC
				CATCAGGGCCTGAGCTCGCCCGTCACAAAGAGC
				TTCAACAGGGGAGAGTGTTGA
13	201C15-xi	Heavy chain	357	CAGTCAGTGAAGGAGTCCGGGGGTCGCCTGGTC
				ACGCCTGGGACACCCCTGACACTCACCTGCACA
				GTCTCTGGAATCGACCTCAGTAGCTATGCAATG
				GGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTG
				GAATACATCGGAACCATTAATATTGGTGGTCGC
				GTATATTACGCGAGCTGGGCAAAAGGCCGATTC
				ACCATCTCCAGAACCTCGACCACGGTGGATCTG
				AAAGCGCCCAGTCTGACAGCCGAGGACACGGCC
				ACCTATTTCTGTGCCAGATATTATAATGGTGGT
				AGTTATGACATCTGGGGCCCAGGCACCCTGGTC
				ACCGTCTCTTTAGCATCCACCAAGGGCCCATCG
				GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC
				TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC
				AAGGACTACTTCCCCGAACCGGTGACGGTGTCG
				TGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC
				ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
				TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
				AGCAGCTTGGGCACCCAGACCTACATCTGCAAC
				GTGAATCACAAGCCCAGCAACACCAAGGTGGAC
				AAGAAAGTTGAGCCCAAATCTTGTGACAAAACT
				CACACATGCCCACCGTGCCCAGCACCTGAACTC
				CTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCA
				AAACCCAAGGACACCCTCATGATCTCCCGGACC
				CCTGAGGTCACATGCGTGGTGGTGGACGTGAGC
				CACGAAGACCCTGAGGTCAAGTTCAACTGGTAC
				GTGGACGGCGTGGAGGTGCATAATGCCAAGACA
				AAGCCGCGGGAGGAGCAGTACAACAGCACGTAC
				CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG
				GACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
				GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG
				AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
				GAACCACAGGTGTACACCCTGCCCCCATCCCGG
				GATGAGCTGACCAAGAACCAGGTCAGCCTGACC
				TGCCTGGTCAAAGGCTTCTATCCCAGCGACATC
				GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
				AACAACTACAAGACCACGCCTCCCGTGCTGGAC
				TCCGACGGCTCCTTCTTCTTATATTCAAAGCTC
				ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC
				GTCTTCTCATGCTCCGTGATGCATGAGGCTCTG
				CACAACCACTACACGCAGAAGAGCCTCTCCCTG
				TCTCCCGGGAAATGA
14	201C15-xi	Light chain	358	GATGTTGTGATGACCCAGACTCCAGCCTCCGCG
				TCTGAACCTGTGGGAGGCACAGTCACCATCAAG
				TGCCAGGCCAGTGAGAGCATTTATCGCGTATTG
				GCCTGGTATCAGCAGAAACCAGGGCAGCCTCCC
				AAGCTCCTGATCTATGATACATCCACTCTGGCA
				TCTGGGGCCCCATCGCGGTTCAAAGGCAGTGGA
				TATGGGACAGAGTTCACTCTCACCATCAGCGGC
				GTGCAGTGTGAAGATGCTGCCACTTACTACTGT
				CAAGGCGGTTATTATGCTGATAGTTATGGTATT
				GCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAA
				CGAACTGTGGCTGCACCATCTGTCTTCATCTTC
				CCGCCATCTGATGAGCAGTTGAAATCTGGAACT
				GCCTCTGTTGTGTGCCTGCTGAATAACTTCTAT
				CCCAGAGAGGCCAAAGTACAGTGGAAGGTGGAT
				AACGCCCTCCAATCGGGTAACTCCCAGGAGAGT
				GTCACAGAGCAGGACAGCAAGGACAGCACCTAC
				AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA
				GACTACGAGAAACACAAAGTCTACGCCTGCGAA
				GTCACCCATCAGGGCCTGAGCTCGCCCGTCACA
				AAGAGCTTCAACAGGGGAGAGTGTTGA
15	201C15-zu	Heavy chain	359	CAGGTGCAGCTGGTGGAATCTGGCGGAGGACTG
				GTGCAGCCTGGCGGCTCTCTGAGACTGTCCTGT
				TCCGCCTCCGGAATCGACCTGTCCTCCTACGCT
				ATGGGCTGGGTGCGACAGGCTCCTGGCAAGGGC
				CTGGAGTACATCGGCACCATCAACATCGGCGGC
				AGAGTGTACTACGCCTCCTGGGCCAAGGGCCGG
				TTCACCATCTCCAGAGACAACTCCAAGAACACC
				CTGTACCTCCAGATGAACTCCCTGCGGGCCGAG
				GACACCGCCGTGTACTACTGCGCCCGGTACTAC
				AACGGCGGCTCCTACGATATCTGGGGCCAGGGC
				ACACTCGTGACCGTGTCCTCTGCATCCACCAAG
				GGCCCATCGGTCTTCCCCCTGGCACCCTCCTCC
				AAGAGCACCTCTGGGGGCACAGCGGCCCTGGGC
				TGCCTGGTCAAGGACTACTTCCCCGAACCGGTG
				ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGC
				GGCGTGCACACCTTCCCGGCTGTCCTACAGTCC
				TCAGGACTCTACTCCCTCAGCAGCGTGGTGACC
				GTGCCCTCCAGCAGCTTGGGCACCCAGACCTAC
				ATCTGCAACGTGAATCACAAGCCCAGCAACACC
				AAGGTGGACAAGAAAGTTGAGCCCAAATCTTGT
				GACAAAACTCACACATGCCCACCGTGCCCAGCA
				CCTGAACTCCTGGGGGGACCGTCAGTCTTCCTC
				TTCCCCCCAAAACCCAAGGACACCCTCATGATC
				TCCCGGACCCCTGAGGTCACATGCGTGGTGGTG
				GACGTGAGCCACGAAGACCCTGAGGTCAAGTTC
				AACTGGTACGTGGACGGCGTGGAGGTGCATAAT
				GCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC
				AGCACGTACCGTGTGGTCAGCGTCCTCACCGTC
				CTGCACCAGGACTGGCTGAATGGCAAGGAGTAC
				AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCC
				CCCATCGAGAAAACCATCTCCAAAGCCAAAGGG
				CAGCCCCGAGAACCACAGGTGTACACCCTGCCC
				CCATCCCGGGATGAGCTGACCAAGAACCAGGTC
				AGCCTGACCTGCCTGGTCAAAGGCTTCTATCCC
				AGCGACATCGCCGTGGAGTGGGAGAGCAATGGG
				CAGCCGGAGAACAACTACAAGACCACGCCTCCC
				GTGCTGGACTCCGACGGCTCCTTCTTCTTATAT
				TCAAAGCTCACCGTGGACAAGAGCAGGTGGCAG
				CAGGGGAACGTCTTCTCATGCTCCGTGATGCAT
				GAGGCTCTGCACAACCACTACACGCAGAAGAGC
				CTCTCCCTGTCTCCCGGGAAATGA
16	201C15-zu	Light chain	360	GATATCCAGATGACCCAGTCCCCCTCCACCCTG
				TCTGCCTCTGTGGGCGACAGAGTGACCATCACC
				TGTCAGGCCTCCGAGTCCATCTACCGGGTGCTG
				GCCTGGTATCAGCAGAAGCCTGGCAAGGCCCCC
				AAGCTGCTGATCTACGACACCAGCACACTGGCC
				TCCGGCGTGCCCTCTAGATTCTCCGGCTCTGGC
				TCTGGCACCGAGTTTACCCTGACCATCTCCAGC
				CTCCAGTGCGACGACGCCGCCACCTACTATTGT
				CAGGGCGGCTACTACGCCGACTCCTACGGAATC
				GCTTTCGGCGGAGGCACCAAGGTGGAAATCAAA
				CGAACTGTGGCTGCACCATCTGTCTTCATCTTC
				CCGCCATCTGATGAGCAGTTGAAATCTGGAACT
				GCCTCTGTTGTGTGCCTGCTGAATAACTTCTAT
				CCCAGAGAGGCCAAAGTACAGTGGAAGGTGGAT
				AACGCCCTCCAATCGGGTAACTCCCAGGAGAGT
				GTCACAGAGCAGGACAGCAAGGACAGCACCTAC
				AGCCTCAGCAGCACCCTGACGCTGAGCAAAGCA
				GACTACGAGAAACACAAAGTCTACGCCTGCGAA
				GTCACCCATCAGGGCCTGAGCTCGCCCGTCACA
				AAGAGCTTCAACAGGGGAGAGTGTTGA
17	346C6-xi	Heavy chain	361	CAGTCGGTGGAGGAGTCCGGCGGTCGCCTGGTA
				AAGCCTGACGAATCCCTGACACTCACCTGCACA
				GCCTCTGGATTCTCCCTCAGTAGTTATGCAATG
				ATCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTG
				GAATGGATCGGAACCATTAGTACTGGTGGTATC
				ACATACTACGCGAGCTGGGCGAAAGGCCGATTC
				ACCATCTCCAAAACCTCGACCACGGTGGATCTG
				AAAATCACCAGTCCGACAACCGAGGACACGGCC
				ACCTATTTCTGTGCCAGAGGGGGATATGCTGCT
				AGTAGTGCTTATTATCTCCCGTACTACTTTGAC
				TTGTGGGGCCAAGGGACCCTGGTCACCGTCTCC
				TCAGCATCCACCAAGGGCCCATCGGTCTTCCCC
				CTGGCACCCTCCTCCAAGAGCACCTCTGGGGGC
				ACAGCGGCCCTGGGCTGCCTGGTCAAGGACTAC
				TTCCCCGAACCGGTGACGGTGTCGTGGAACTCA
				GGCGCCCTGACCAGCGGCGTGCACACCTTCCCG
				GCTGTCCTACAGTCCTCAGGACTCTACTCCCTC
				AGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG
				GGCACCCAGACCTACATCTGCAACGTGAATCAC
				AAGCCCAGCAACACCAAGGTGGACAAGAAAGTT
				GAGCCCAAATCTTGTGACAAAACTCACACATGC
				CCACCGTGCCCAGCACCTGAACTCCTGGGGGGA
				CCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAG
				GACACCCTCATGATCTCCCGGACCCCTGAGGTC
				ACATGCGTGGTGGTGGACGTGAGCCACGAAGAC
				CCTGAGGTCAAGTTCAACTGGTACGTGGACGGC
				GTGGAGGTGCATAATGCCAAGACAAAGCCGCGG
				GAGGAGCAGTACAACAGCACGTACCGTGTGGTC
				AGCGTCCTCACCGTCCTGCACCAGGACTGGCTG
				AATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC
				AAAGCCCTCCCAGCCCCCATCGAGAAAACCATC
				TCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG
				GTGTACACCCTGCCCCCATCCCGGGATGAGCTG
				ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC
				AAAGGCTTCTATCCCAGCGACATCGCCGTGGAG
				TGGGAGAGCAATGGGCAGCCGGAGAACAACTAC
				AAGACCACGCCTCCCGTGCTGGACTCCGACGGC
				TCCTTCTTCTTATATTCAAAGCTCACCGTGGAC
				AAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA
				TGCTCCGTGATGCATGAGGCTCTGCACAACCAC
				TACACGCAGAAGAGCCTCTCCCTGTCTCCCGGG
				AAATGA
18	346C6-xi	Light chain	362	GCAGCCGTGCTGACCCAGACACCATCACCCGTG
				TCTGCAGCTGTGGGAGGCACAGTCACCATCAGT
				TGCCAGTCCAGTCAGAGTGTTTATAATAATAAC
				AACTTAGCCTGGTTTCAGCAGAAACCCGGGCAG
				CCTCCCAAGCTTCTGATCTATCTGGCATCCACT
				CTGGCATCTGGGGTCCCATCACGGTTCAGCGGC
				AGTGGATCTGGGACACAGTTCACTCTCACCATC
				AGCGGCGTGCAGTGTGACGATGCTGCCACTTAT
				TACTGTCTAGGTGGTTGTGATGATGATGCTGAT
				ACTTTTGCTTTCGGCGGAGGGACTGAGGTGGTG
				GTCAAACGAACTGTGGCTGCACCATCTGTCTTC
				ATCTTCCCGCCATCTGATGAGCAGTTGAAATCT
				GGAACTGCCTCTGTTGTGTGCCTGCTGAATAAC
				TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG
				GTGGATAACGCCCTCCAATCGGGTAACTCCCAG
				GAGAGTGTCACAGAGCAGGACAGCAAGGACAGC
				ACCTACAGCCTCAGCAGCACCCTGACGCTGAGC
				AAAGCAGACTACGAGAAACACAAAGTCTACGCC
				TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC
				GTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA
19	346C6-zu	Heavy chain	363	GAAGTGCAGCTGGTGGAATCTGGCGGCGGACTG
				GTGCAGCCTGGCGGATCTCTGAGACTGTCTTGT
				GCCGCCTCCGGCTTCTCCCTGTCCTCCTACGCT
				ATGATCTGGGTGCGACAGGCCCCTGGCAAGGGC
				CTGGAATGGATCGGCACCATCTCTACCGGCGGA
				ATTACCTACTACGCCTCCTGGGCCAAGGGCCGG
				TTCACCATCTCCAGAGACAACTCCAAGAACACC
				CTGTACCTCCAGATGAACTCCCTGCGGGCCGAG
				GACACCGCCGTGTACTATTGTGCTAGAGGCGGC
				TACGCCGCCAGCTCCGCTTACTACCTGCCCTAC
				TACTTCGACCTGTGGGGCCAGGGCACCCTCGTG
				ACAGTGTCATCTGCATCCACCAAGGGCCCATCG
				GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACC
				TCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC
				AAGGACTACTTCCCCGAACCGGTGACGGTGTCG
				TGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC
				ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTC
				TACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
				AGCAGCTTGGGCACCCAGACCTACATCTGCAAC
				GTGAATCACAAGCCCAGCAACACCAAGGTGGAC
				AAGAAAGTTGAGCCCAAATCTTGTGACAAAACT
				CACACATGCCCACCGTGCCCAGCACCTGAACTC
				CTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCA
				AAACCCAAGGACACCCTCATGATCTCCCGGACC
				CCTGAGGTCACATGCGTGGTGGTGGACGTGAGC
				CACGAAGACCCTGAGGTCAAGTTCAACTGGTAC
				GTGGACGGCGTGGAGGTGCATAATGCCAAGACA
				AAGCCGCGGGAGGAGCAGTACAACAGCACGTAC
				CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG
				GACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
				GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAG
				AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
				GAACCACAGGTGTACACCCTGCCCCCATCCCGG
				GATGAGCTGACCAAGAACCAGGTCAGCCTGACC
				TGCCTGGTCAAAGGCTTCTATCCCAGCGACATC
				GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
				AACAACTACAAGACCACGCCTCCCGTGCTGGAC
				TCCGACGGCTCCTTCTTCTTATATTCAAAGCTC
				ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAAC
				GTCTTCTCATGCTCCGTGATGCATGAGGCTCTG
				CACAACCACTACACGCAGAAGAGCCTCTCCCTG
				TCTCCCGGGAAATGA
20	346C6-zu	Light chain	364	GATATTCAGATGACCCAGTCCCCCTCCAGCCTG
				TCCGCTTCTGTGGGCGACAGAGTGACCATCACC
				TGTCAGTCCTCCCAGTCCGTGTATAACAACAAC
				AACCTGGCCTGGTATCAGCAGAAACCCGGCAAG
				GTGCCCAAGCTGCTGATCTACCTGGCCTCCACA
				CTGGCCTCTGGCGTGCCCTCTAGATTCTCCGGC
				TCTGGCTCTGGCACCGACTTTACCCTGACCATC
				AGCTCCCTCCAGTGCGAGGATGCCGCCACCTAC
				TATTGCCTGGGCGGCTGCGACGACGACGCCGAT
				ACCTTTGCTTTTGGCGGAGGCACCAAGGTGGAA
				ATCAAACGAACTGTGGCTGCACCATCTGTCTTC
				ATCTTCCCGCCATCTGATGAGCAGTTGAAATCT
				GGAACTGCCTCTGTTGTGTGCCTGCTGAATAAC
				TTCTATCCCAGAGAGGCCAAAGTACAGTGGAAG
				GTGGATAACGCCCTCCAATCGGGTAACTCCCAG
				GAGAGTGTCACAGAGCAGGACAGCAAGGACAGC
				ACCTACAGCCTCAGCAGCACCCTGACGCTGAGC
				AAAGCAGACTACGAGAAACACAAAGTCTACGCC
				TGCGAAGTCACCCATCAGGGCCTGAGCTCGCCC
				GTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA
+Nucleic acid sequences listed do not include leader sequences.