CD138 Humanized Antibody Molecule and Its Uses

Abstract

A humanized antibody molecule that specifically binds to CD138 is disclosed. This humanized antibody molecule can be used to treat, prevent, and / or diagnose diseases such as multiple myeloma.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 62 / 862,457, filed June 17, 2019, and U.S. Provisional Application No. 63 / 035,323, filed June 5, 2020. The contents of the above applications are incorporated herein by reference in their entirety.

[0003] sequence list

[0004] This application contains a sequence list electronically submitted in ASCII format, and its entire contents are incorporated herein by reference. The ASCII copy created on 12.06.20 is named P2029-7029WO_SL.txt and is 128,635 bytes in size. Background Technology

[0005] Multiple myeloma (MM) is a cancer formed from malignant plasma cells. These tumors typically develop in the bone, but occasionally they are found in other tissues. A disease with a single plasmacytoma is called an isolated (or solitary) plasmacytoma. When more than one plasmacytoma is present, it is called multiple myeloma. In the United States, an estimated 30,000 new cases were diagnosed in 2017, with an estimated 10,000 deaths. Despite advances in treatment for multiple myeloma, it remains an incurable disease for most patients.

[0006] There is a need to develop new methods for the treatment, prevention, and diagnosis of multiple myeloma and other diseases with similar disease mechanisms. Summary of the Invention

[0007] The present disclosure provides, at least in part, humanized antibody molecules that bind to CD138 (e.g., human CD138) comprising one or more properties disclosed herein, e.g., one or more functional, biophysical, and structural properties. For example, the humanized antibody molecules described herein can have reduced immunogenicity, greater therapeutic efficacy (e.g., lower tumor burden and / or increased overall survival), improved target binding (e.g., affinity), improved in vitro or in vivo stability, and higher levels of mammalian recombinant expression. In one embodiment, the antibody molecule is capable of eliciting effector function (e.g., antibody-dependent cellular cytotoxicity (ADCC) activity) on a cell expressing CD138. In one embodiment, the antibody molecule preferentially binds to membrane-bound CD138 as compared to soluble CD138. In one embodiment, the antibody molecule binds to an epitope in the extracellular region of CD138 that is proximal to the transmembrane domain. In one embodiment, the antibody molecule does not bind to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule does not bind to the IBD of CD138. Without intending to be limited by theory, it is believed that in one embodiment, by targeting certain extracellular regions on membrane-bound CD138 proximal to the cell membrane, improved or optimal cytotoxicity can be achieved.

[0008] In one embodiment, the antibody molecule is selected from Table 1, or competes for binding to CD138 with an anti-CD138 monoclonal antibody selected from Table 1. In one embodiment, the antibody molecule binds to the same or overlapping epitope as an epitope recognized by an anti-CD138 monoclonal antibody selected from Table 1. In one embodiment, the antibody molecule comprises one or more heavy chain variable regions (VH) and / or one or more light chain variable regions (VL) described in Table 1. In one embodiment, the antibody molecule comprises a heavy chain (HC) and a light chain (LC) described in Tables 6-8. In one embodiment, the antibody molecule comprises one or more heavy chain CDRs and / or one or more light chain CDRs described in Table 1, 7, or 8.

[0009] In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from Table 2, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a VH comprising an amino acid sequence selected from Table 2. In one embodiment, the antibody molecule comprises a light chain variable region (VL) comprising an amino acid sequence selected from Table 2, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a VL comprising an amino acid sequence selected from Table 2. In one embodiment, the antibody molecule comprises a VH and a VL, each comprising an amino acid sequence selected from Table 2, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a VH and a VL comprising an amino acid sequence selected from Table 2. In one embodiment, the antibody molecule binds to the same or an overlapping epitope as an epitope recognized by an anti-CD138 monoclonal antibody comprising a VH and / or VL comprising an amino acid sequence selected from Table 2. In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2, or 3) heavy chain CDRs and / or one or more (e.g., 1, 2, or 3) light chain CDRs described in Table 2.

[0010] In one embodiment, the antibody molecule comprises a heavy chain (HC) comprising an amino acid sequence selected from Table 6 or 7, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a HC comprising an amino acid sequence selected from Table 6 or 7. In one embodiment, the antibody molecule comprises a light chain (LC) comprising an amino acid sequence selected from Table 6 or 8, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a LC comprising an amino acid sequence selected from Table 6 or 8. In one embodiment, the antibody molecule comprises a HC and a LC, each comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8, or competes for binding to CD138 with an anti-CD138 monoclonal antibody comprising a HC and a LC comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8. In one embodiment, the antibody molecule binds to the same or an overlapping epitope as an epitope recognized by an anti-CD138 monoclonal antibody comprising a HC and / or LC comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8. In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2, or 3) heavy chain CDRs and / or one or more (e.g., 1, 2, or 3) light chain CDRs described in Table 7 or 8.

[0011] In one embodiment, there are also provided antibody molecule-drug conjugates (ADCs), nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, containers, and methods for making antibody molecules. The antibody molecules disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent, and / or diagnose diseases associated with CD138, such as cancer or precancerous conditions (e.g., multiple myeloma or smoldering myeloma).

[0012] Thus, in certain aspects, the present disclosure provides humanized antibody molecules, e.g., humanized antibody molecules described herein, having one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or all of) the following properties a) - dd):

[0013] a) binds to CD138 (e.g., human CD138) with high affinity (e.g., dissociation constant (K D ) of less than about 100 nM, typically about 10 nM, more typically about 10-0.001 nM, about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1 nM, or stronger, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or 0.001 nM),

[0014] b) binds to membrane-bound CD138 with high affinity (e.g., dissociation constant (K D ) of less than about 100 nM, typically about 10 nM, more typically about 10-0.001 nM, about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1 nM, or stronger, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or 0.001 nM),

[0015] c) i) binds to CD138 (e.g., human CD138) with high affinity (e.g., dissociation constant (K D) less than about 100 nM, typically about 10 nM, more typically about 10-0.001 nM, about 10-0.01 nM, about 5-0.01 nM, about 3-0.05 nM, about 1-0.1 nM, or stronger, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005, or 0.001 nM); or ii) binds to soluble CD138 with low affinity (e.g., dissociation constant (K D ) greater than about 100 nM, e.g., greater than about 200, 300, 400, or 500 nM), to soluble CD138,

[0016] d) binds to membrane-bound CD138 or the intact extracellular domain of CD138, i) preferably with a binding affinity that is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10-fold higher for membrane-bound CD138 or the intact extracellular domain of CD138 than for soluble CD138; or ii) with a binding affinity that is similar to the binding affinity for soluble CD138, e.g., the binding affinity for membrane-bound CD138 or the intact extracellular domain of CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the binding affinity for soluble CD138,

[0017] e) binds to one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or more) CD138 amino acid residues in the extracellular region proximal to the transmembrane domain of CD138, e.g., within 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 amino acids N-terminal from the transmembrane domain,

[0018] f) i) binds to a CD138 extracellular region distal from the transmembrane domain, e.g., at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids C-terminal from the transmembrane domain; or ii) does not bind or binds with low affinity to a CD138 extracellular region distal from the transmembrane domain, e.g., at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids C-terminal from the transmembrane domain,

[0019] g) an integrin binding domain (IBD) that binds to CD138 or the N-terminal region of an IDB, or ii) an IBD or the N-terminal region of an IDB that does not bind or binds with low affinity to CD138,

[0020] h) binds to a CD138 epitope comprising four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more) contiguous amino acid residues in an extracellular region proximal to a transmembrane domain (e.g., a region comprising amino acids 176-250 (e.g., 176-214 or 210-250) of any one of SEQ ID NOs: 1-3 or 450), optionally wherein the epitope further comprises four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) contiguous amino acid residues in an extracellular region distal to the transmembrane domain (e.g., a region comprising amino acids 23-50, 51-95, 88-121, 88-102 or 111-150 of any one of SEQ ID NOs: 1-3 or 450),

[0021] i) binds to two or more different regions in CD138, e.g., a multivalent (e.g., bivalent, trivalent or tetravalent) antibody molecule comprising two identical or substantially identical sets of VH-VL pairs (each of which binds to the same two or more regions) or comprising different sets of VH-VL pairs (each of which independently binds to a different region),

[0022] i) does not bind to a CD138 epitope comprising four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 15, 20, 25, 30, 35 or more) contiguous amino acid residues in an extracellular region distal to the transmembrane domain (e.g., a region comprising amino acids 23-50, 51-95, 88-121, 88-101 or 111-150 of any one of SEQ ID NOs: 1-3 or 450),

[0023] k) binds with high affinity to a CD138-expressing cancer cell or precancerous cell (e.g., a myeloma cell),

[0024] 1) binds to an Fc receptor (FcR) (e.g., one or more of FcyRI, FcyRIIa, FcyRIIb, FcyRIIc, FcyRIIIa or FcyRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte or an eosinophil),

[0025] m) induces effector function (e.g., ADCC activity) on target cells expressing CD138.

[0026] n) binds to C1q and induces complement-dependent cytotoxicity (CDC) on target cells expressing CD138.

[0027] o) Mediates isotype adhesion of one or more CD138-expressing cells.

[0028] p) Inhibit the effect of proteases on membrane-bound CD138, for example, by reducing the shedding of CD138;

[0029] q) Reduce (e.g., inhibit) one or more biological activities of CD138-expressing cells in vitro, in vitro, or in vivo.

[0030] r) Reduce (e.g., inhibit) one or more functions of CD138 (e.g., CD138 binding to ligands) in vitro, in vitro, or in vivo.

[0031] s) Reduce (e.g., inhibit) the proliferation of CD138-expressing cancer cells or precancerous cells,

[0032] t) binds to epitopes on CD138 that are the same as, similar to, or overlap with the epitopes recognized by the anti-CD138 monoclonal antibodies described herein.

[0033] u) Shows the same or similar binding affinity or specificity as the anti-CD138 monoclonal antibody described herein, or both.

[0034] v) exhibits the same or similar binding affinity or specificity, or both, with humanized antibody molecules containing the heavy chain variable region and / or light chain variable region described herein (e.g., the heavy chain variable region and / or light chain variable region of any anti-CD138 monoclonal antibody described herein).

[0035] w) exhibits the same or similar binding affinity or specificity, or both, to a humanized antibody molecule containing one or more (e.g., two or three) heavy chain CDRs and / or one or more (e.g., two or three) light chain CDRs (e.g., one or more (e.g., two or three) heavy chain CDRs and / or one or more (e.g., two or three) light chain CDRs of any anti-CD138 monoclonal antibody described herein.

[0036] x) exhibits the same or similar binding affinity or specificity as, or both, that of humanized antibody molecules containing the amino acid sequence described herein.

[0037] y) exhibits the same or similar binding affinity or specificity as, or both, that of humanized antibody molecules containing an amino acid sequence encoded by the nucleotide sequence described herein.

[0038] z) inhibits (e.g., competitively inhibits) the binding of a second antibody molecule to CD138, wherein the second antibody molecule is a humanized antibody molecule described herein,

[0039] aa) competes for binding to CD138 with a second antibody molecule, wherein the second antibody molecule is a humanized anti-CD138 monoclonal antibody described herein,

[0040] bb) has one or more biological properties of a humanized anti-CD138 monoclonal antibody described herein,

[0041] cc) has one or more structural properties of a humanized anti-CD138 monoclonal antibody described herein, or

[0042] dd) has one or more pharmacokinetic properties of a humanized anti-CD138 monoclonal antibody described herein.

[0043] In one aspect, the disclosure features a humanized anti-CD138 antibody molecule comprising one or both of:

[0044] (a) a heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of: (i) a HCDR1 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or that has at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of a HCDR1 of an anti-CD138 monoclonal antibody disclosed herein (e.g., any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422, e.g., listed in Table 1 or 2); (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or that has at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of a HCDR2 of the anti-CD138 antibody; or (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or that has at least 85, 90, 95, 99, or 100% homology to the amino acid sequence of a HCDR3 of the anti-CD138 antibody; or

[0045] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0046] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0047] In one embodiment, VH comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the anti-CD138 antibody.

[0048] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0049] In one embodiment, VL comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0050] In one embodiment, the antibody molecule comprises:

[0051] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and

[0052] (a) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the anti-CD138 antibody by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0053] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the anti-CD138 antibody; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0054] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VH of the anti-CD138 antibody. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH of the anti-CD138 antibody.

[0055] In one embodiment, the amino acid sequence contained in the VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of the VL containing the anti-CD138 antibody. In one embodiment, the VL comprises the amino acid sequence of the VL containing the anti-CD138 antibody.

[0056] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH of the anti-CD138 antibody by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL of the anti-CD138 antibody by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0057] In one embodiment, VH comprises the amino acid sequence of VH containing the anti-CD138 antibody, while VL comprises the amino acid sequence of VL containing the anti-CD138 antibody.

[0058] In one embodiment, the antibody molecule includes an Fc region (e.g., the Fc region described herein). In one embodiment, the antibody molecule includes the heavy chain constant region of IgG, such as IgG1. In one embodiment, the antibody molecule also includes the light chain constant region of κ.

[0059] In one embodiment, the antibody molecule comprises a heavy chain (HC) containing an amino acid sequence that differs from the HC of the anti-CD138 antibody by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with it. In one embodiment, the HC comprises the amino acid sequence of the HC of the anti-CD138 antibody.

[0060] In one embodiment, the antibody molecule comprises a light chain (LC) containing an amino acid sequence that differs from the amino acid sequence of the anti-CD138 antibody LC by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology with it. In one embodiment, the LC comprises the amino acid sequence of the anti-CD138 antibody LC.

[0061] In one embodiment, the antibody molecule comprises: (a) a heavy chain (HC) having an amino acid sequence that differs from the amino acid sequence of the HC of the anti-CD138 antibody by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) a light chain (LC) having an amino acid sequence that differs from the amino acid sequence of the LC of the anti-CD138 antibody by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the HC comprises the amino acid sequence of the HC of the anti-CD138 antibody, while the LC comprises the amino acid sequence of the LC of the anti-CD138 antibody.

[0062] In one embodiment, the antibody molecule comprises: (a) a heavy chain (HC) having an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 527 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) a light chain (LC) having an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 528 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the HC comprises the amino acid sequence of SEQ ID NO: 527 or the LC comprises the amino acid sequence of SEQ ID NO: 528. In one embodiment, HC contains the amino acid sequence of SEQ ID NO: 527 and LC contains the amino acid sequence of SEQ ID NO: 528.

[0063] On the one hand, this disclosure is characterized by an antibody molecule that competitively binds to CD138 with the humanized anti-CD138 monoclonal antibody described herein (e.g., any one of antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0064] On the one hand, this disclosure is characterized by an antibody molecule that binds to, or substantially binds to, an epitope that completely or partially overlaps with an epitope of a humanized anti-CD138 monoclonal antibody described herein (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0065] On the one hand, this disclosure is characterized by an antibody-drug conjugate (ADC) comprising the humanized antibody molecule described herein, optionally comprising a cytotoxic agent, and also optionally comprising an adapter.

[0066] On the one hand, this disclosure is characterized by a composition comprising the humanized antibody molecule or the ADC described herein, optionally wherein the composition is a pharmaceutical composition.

[0067] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0068] On the one hand, this disclosure is characterized by nucleic acid molecules encoding the heavy chain variable region (VH), light chain variable region (VL), or both of the humanized antibody molecules described herein.

[0069] In one aspect, one feature of this disclosure is a carrier that contains the nucleic acid molecules described herein.

[0070] On the one hand, this disclosure is characterized by a cell containing the nucleic acid molecules or vectors described herein, optionally wherein the cell is an isolated cell.

[0071] On the one hand, this disclosure is characterized by a kit comprising the humanized antibody molecule described herein, the ADC described herein, or the composition described herein, and instructions for use of the antibody molecule or composition.

[0072] On the one hand, this disclosure is characterized by a container that contains the humanized antibody molecule described herein, the ADC described herein, or the composition described herein.

[0073] On the one hand, this disclosure is characterized by a method for generating humanized anti-CD138 antibody molecules, the method comprising culturing the cells described herein under conditions that allow for the generation of said humanized antibody molecules, thereby generating said antibody molecules.

[0074] In one embodiment, the method further includes isolating or purifying antibody molecules.

[0075] On the one hand, this disclosure is characterized by the method of using the humanized antibody molecules, ADCs, or compositions described herein for treating cancer in a subject.

[0076] In one embodiment, the cancer is a blood cancer. In one embodiment, the cancer is multiple myeloma. In one embodiment, the cancer is a solid tumor, such as the solid tumor described herein. In one embodiment, antibody molecules reduce the tumor burden in a subject, such as a subject suffering from multiple myeloma.

[0077] In one embodiment, the antibody molecule, ADC, or composition is administered intravenously to the subject. In another embodiment, the antibody molecule is administered intraperitoneally to the subject.

[0078] In one embodiment, the antibody molecule, ADC, or composition is administered to the subject at the following doses: 0.1 mg / kg-50 mg / kg, 0.2 mg / kg-25 mg / kg, 0.5 mg / kg-10 mg / kg, 0.5 mg / kg-5 mg / kg, 0.5 mg / kg-3 mg / kg, 0.5 mg / kg-2.5 mg / kg, 0.5 mg / kg-2 mg / kg, 0.5 mg / kg-1.5 mg / kg, 0.5 mg / kg-1 mg / kg, 1 mg / kg-1.5 mg / kg, 1 mg / kg-2 mg / kg, 1 mg / kg-2.5 mg / kg, 1 mg / kg-3 mg / kg, 1 mg / kg-2.5 mg / kg, or 1 mg / kg-5 mg / kg. In one embodiment, the antibody molecule, ADC, or composition is administered at doses of 1-50 mg / kg, such as 1-40 mg / kg, 1 mg / kg-30 mg / kg, 1 mg / kg-20 mg / kg, 1 mg / kg-10 mg / kg, or 1 mg / kg-5 mg / kg. In one embodiment, the antibody molecule is administered at a dose of about 4 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg.

[0079] In one embodiment, the antibody molecule, ADC, or composition is administered to the subject at the following fixed doses: 10 mg-1000 mg, 10 mg-500 mg, 10 mg-250 mg, 10 mg-150 mg, 10 mg-100 mg, 10 mg-50 mg, 250 mg-500 mg, 150 mg-500 mg, 100 mg-500 mg, 50 mg-500 mg, 25 mg-250 mg, 50 mg-150 mg, 50 mg-100 mg, 100 mg-150 mg, 100 mg-200 mg, or 150 mg-250 mg.

[0080] In one implementation, the antibody molecule, ADC, or composition is administered once a week, twice a week, once every two weeks, once every three weeks, or once every four weeks.

[0081] In one embodiment, the use also includes determining the level of CD138 in a sample from the subject. In one embodiment, the use also includes administering a second therapy against cancer to the subject.

[0082] On the one hand, this disclosure is characterized by the humanized antibody molecules, ADCs, or compositions described herein, and their methods of treating precancerous conditions or preventing cancer.

[0083] In one embodiment, the precancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS). In one embodiment, the cancer is multiple myeloma.

[0084] On the one hand, this disclosure is characterized by a method for inducing ADCC activity, the method comprising contacting a cell or object with the humanized antibody molecule described herein, the ADC described herein, or the composition described herein, thereby inducing ADCC activity.

[0085] On the one hand, this disclosure is characterized by a method for treating cancer, which includes administering an effective amount of the humanized antibody molecule described herein, the ADC described herein, or the composition described herein to a subject in need of such treatment, thereby treating cancer.

[0086] In one aspect, this disclosure is characterized by a method for treating precancerous conditions or preventing cancer, the method comprising administering to a subject in need an effective amount of the humanized antibody molecule described herein, the ADC described herein, or the composition described herein, thereby treating precancerous conditions or preventing cancer.

[0087] On the one hand, this disclosure is characterized by a method for detecting anti-CD138 molecules, which includes contacting cells or objects with the humanized antibody molecules described herein to detect CD138 molecules.

[0088] In one embodiment, the antibody molecule is conjugated to a detectable marker. In one embodiment, the CD138 molecule is detected in vitro, ex vivo, or in vivo.

[0089] This disclosure encompasses all combinations of any one or more of the foregoing aspects and / or implementations, as well as combinations with any one or more implementations provided in the detailed description and examples.

[0090] Other features, purposes, and advantages of the compositions and methods described herein are readily apparent from the specification, drawings, and claims.

[0091] Brief description of the attached figures

[0092] Figure 1 The binding of different doses of humanized anti-CD138 antibody to the CD138+ multiple myeloma cell line U266 was demonstrated.

[0093] Figure 2 This study demonstrates the ADCC activity of different doses of humanized anti-CD138 antibody targeting CD138+ lymphoblastic myeloma cells. In the ADCC mechanism of action (MOA) analysis, a bioluminescent reporter assay was used to quantify the antibody's bioactivity against pathway activation, thereby assessing ADCC activity. This bioassay included engineered Jurkat cells stably expressing the FcγRIIIa receptor, and NFAT response elements driving firefly luciferase expression as effector cells.

[0094] Figures 3A-3C It is a series of graphs showing the dose-dependent binding of humanized anti-CD138 antibody to three multiple myeloma cell lines: MM1.S, LP-1, and RPMI 8226.

[0095] Figures 4A-4D This is a series of graphs showing how humanized anti-CD138 antibodies induce ADCC in four multiple myeloma cell lines: U266, MM1.S, LP-1, and RPMI 8226.

[0096] Figures 5A-5D This is a series of graphs showing the in vivo efficacy of monoclonal anti-CD138 antibody 2810. It displays the mean BLI ± 95% CI for quantifying disseminated multiple myeloma by IVIS imaging at specific time points. Figure 5A ). Statistical data of the treatment groups were compared using multiple t-tests (Bonferroni Dunn). Comparison of systemic tumor burden in mice between the load-bearing group and the monoclonal antibody 2810 group (mean plus minimum-maximum value also shown). Figure 5B ). In skeletal tissue examined 42 days post-execution, in the spine ( Figure 5C) and hind limbs ( Figure 5D Bioluminescence (BLI) of tumor burden was measured. Statistical data were determined using an unpaired t-test. BLI data were plotted on a logarithmic scale.

[0097] Figures 6A-6C This is a series of graphs showing the in vivo efficacy of monoclonal anti-CD138 antibodies. The mean BLI ± standard error (BSI) of the quantitative disseminated multiple myeloma quantified by IVIS imaging at specific time points and dose levels is shown. Figure 6A Statistical analysis was performed using a two-way ANOVA (Tuge multiple comparisons). Comparison of systemic tumor burden in individual mice between the load-controlled humanized anti-CD138 antibody mAb 4320 and the mouse chimeric anti-CD138 mAb 2810 treatment groups. Figure 6B The median is also shown in a bar chart as mean + minimum - maximum. BLI data are plotted on a logarithmic scale. Percentage of animals in the load group versus those treated with anti-CD138 antibody mAbs 2810 and 4320 (…). Figure 6C Survival rate or survival percentage is defined as mice that survive to a predetermined euthanasia criterion associated with disease-related morbidity (e.g., weight loss exceeding 20%, severe impairment of central nervous system function, severe motor impairment, or loss of righting reflex). The log-rank test (Mantel-Cox) is used to compare survival curves (VC vs. animals treated with anti-CD138 antibody).

[0098] Figure 7 This is a series of graphs assessing the thermal stability of the anti-CD138 antibody using differential scanning fluorescence (DSF) analysis. Thermal melting curves are shown as the first derivative transformation of the thermal scan (d(fluorescence) / d(temperature)). Thermal transitions (Tm1 and Tm2) are represented by vertical lines and summarized in Table 4.

[0099] Figure 8 This is a graph showing the relative levels of anti-CD138 antibodies in the serum of mice in the Tg 276 transgenic human FcRn hemizygous mouse strain after a single dose. The anti-CD138 monoclonal antibody was administered via tail vein injection at a dose level of 2.5 mg / kg. Antibody titers in serum samples collected approximately 65 hours post-injection were determined by ELISA (for detecting human IgG1 Fc) and plotted as the percentage of remaining antibodies normalized to serum antibody titers measured at an early post-administration time point (1 hour). The levels of chimeric antibody mAb2810 (white bar) and humanized anti-CD138 mAb 4320 (black bar) are indicated by dashed lines. For ease of comparison, the anti-RSV antibody motavizumab (MVZ) was also included in this analysis.

[0100] Figures 9A-9BThis is a series of graphs showing the comparative dose-dependent cell binding and Fc effector-mediated ADCC activity of the humanized antibody mAb 4320 and the reference antibody BB4. (Analysis was performed using flow cytometry.) Figure 9A The binding of cells to the human lymphoblastic cell line U266 (expressing CD138) was measured. The antibody binding to CD138 on the cell surface was quantified as mean fluorescence intensity. ADCC activity was measured using the Jurkat reporter bioassay, with human FcrγIIia transgenic cells used as effector cells. Figure 9B Data were standardized to the fold induction relative to the negative antibody control.

[0101] Figure 10 This study summarizes the differential binding of humanized anti-CD138 antibody mAb 4320 and reference antibody BB4 to different concentrations of human CD138 and selected soluble extracellular domains of CD138-derived peptides. Protein and peptide binding was quantified by ligand capture ELISA. CD138 peptides corresponding to the integrin-binding domain (designated as peptide 2A) or the proximal membrane region (designated as peptide 6A) were labeled.

[0102] Figure 11 This is a schematic diagram of an in vivo multiple myeloma dissemination (xenograft) model used to evaluate the therapeutic effect of mAb 4320. The experimental overview lists the mouse background (CB.17SCID mice), human MM1.S (Luc) cell line, imaging analysis (in vivo imaging / whole-body chemiluminescence to measure tumor burden), and dosing schedule (intravenous injection, twice weekly for more than 8 weeks). Treatment groups (N = 8 mice / group) included a load control, mAb 2810 (4 mg / kg), and variable doses of mAb 4320 (4, 8, and 16 mg / kg). The experimental design diagram indicates three phases: staging phase, dosing phase (effective), and survival phase. BLI, bioluminescence.

[0103] Figure 12 This presents population efficacy data after treating a mouse model of multiple myeloma with the antibody molecules shown. Disseminated tumor burden is shown as mean BLI ± standard error of disseminated multiple myeloma quantified by IVIS imaging at specific time points and dose levels. Efficacy is divided into time-assessment size (BLI equal to 1 x 10⁻⁶). 9 p / s was determined and represented by a horizontal dashed line. Two-way ANOVA (Tuge multiple comparisons) was used for statistical analysis to compare the mAb 4320 treatment group with other treatment groups. P-values ​​were calculated based on interaction as a source of variance. BLI data were plotted on a logarithmic scale.

[0104] Figure 13This is a graph showing the efficacy data of individual mice in a multiple myeloma xenograft model after treatment with the antibody molecules shown. It compares the systemic tumor burden in the carrier control group to the antibody treatment group. Mean BLI values ​​are represented by horizontal bars.

[0105] Figure 14 This is a series of images showing the bioluminescence (BLI) results of xenograft studies from multiple myeloma. As shown in the figure, BLI images of individual mice in the mAb 4320, mAb 2810, and load cell groups are compared at day 35 after tumor implantation.

[0106] Figure 15 The population survival results of a multiple myeloma xenotransplantation study are shown. Kaplan-Meier survival curves are presented for animals in the load group compared to animals treated with anti-CD138 antibodies mAb 2810 and mAb 4320. Survival rate or percentage of survival is defined as mice surviving to predetermined euthanasia criteria related to disease-associated morbidity (e.g., weight loss exceeding 20%, severe impairment of central nervous system function, severe motor impairment, or loss of righting reflex). The p-value for comparing VC with mAb 4320 treatment was calculated using the Mantel-Cox test (log-rank test).

[0107] Figure 16 This is a graph showing changes in body weight in animals during a multiple myeloma xenotransplantation study. Percentage changes in body weight are plotted as the standard error of the mean. Animals corresponding to the mAb 4320 treatment group are indicated by hollow symbols; animals corresponding to the carrier control (VC) group are indicated by solid circles. The carrier control group showed the largest changes in body weight, indicating a correlation with disease progression.

[0108] Figure 17 Pharmacokinetic (PK) results of the multiple myeloma xenotransplantation study are presented in the form of antibody molecular serum titers. Serum samples were collected weekly (N=4 mice). Antibody serum titers were quantified by optimized detection of human IgG1 Fc using ELISA. Serum from the VC group served as a negative control. Inset: A graph of antibody molecular serum titer of mAb 4320 on day 13 versus dose level (antibody concentration).

[0109] Figures 18A-18BThis is a series of charts showing the efficacy of mAb 4320 and bortezomib treatment. MM1.S(Luc) cells were administered to CB17 SCID mice via intravenous injection on day 0, and staging was performed on day 14, which also corresponded to day 1 of administration of the load control, mAb 4320 (4 mg / kg), bortezomib (1 mg / kg), or a combination of mAb 4320 and bortezomib. N = 9 mice / treatment group. Tumor burden was assessed by whole-body bioluminescence (BLI) and quantified by IVIS imaging as described in Methods (Section 3.2). Treatment was stopped on day 53 (dose administration phase), followed by a three-week washout period, and the study ended on day 73. (A) Group efficacy data. Disseminated tumor burden is reported as the standard error of bioluminescence (BLI) ± mean at each time point. (B) Individual mice.

[0110] Figures 19A-19D This is a representative series of bioluminescence (BLI) images, selected on day 36 from individual mice that received the specified treatment based on their proximity to the BLI median. For standardization (minimum value 1.0 x 10⁻⁶), the images are... 6 The maximum value is 3.0 x 10. 8 Image intensity was adjusted, but this does not mean there was no tumor burden on day 14 (the day of staging and before the first dose). All animals in the load control group were sacrificed before day 53.

[0111] Figure 20 The survival rate of mice given the specified treatment over time is displayed in the form of Kaplan-Meier survival curves. Treatment was discontinued on day 53. Survival rate was defined as mice surviving to predetermined euthanasia criteria related to disease-associated morbidity, such as weight loss exceeding 20%, severe impairment of central nervous system function, severe motor impairment, or loss of righting reflex.

[0112] Figure 21 This is a graph showing the change in body weight of animals after administration of the specified treatment. The percentage change in body weight is plotted as the standard error of the mean. The animals in the load-controlled group showed the largest change in body weight, indicating a correlation with disease progression. Weight loss was also observed in the bortezomib monotherapy group, which may be due to drug toxicity. Detailed Implementation

[0113] This document discloses humanized antibody molecules that bind to CD138 (e.g., human CD138). Advantageously, at least several of the humanized antibody molecules described herein possess improved ability to inhibit cells expressing CD138, for example, by initiating effector function. Without intending to be theoretically limited, it is believed that in one embodiment, an anti-CD138 antibody binding to a desired epitope described herein has enhanced effector function and preferential binding to membrane-associated forms of CD138. Effective targeting of CD138 can lead to broad activity and a favorable therapeutic index against myeloma and other cancers.

[0114] Compared to parental non-humanized antibody molecules, the humanized antibody molecules described herein may possess one or more improved properties, such as those described herein. For example, improved properties may include, but are not limited to, therapeutic efficacy, immunogenicity reduction, improvements in biophysical, physicochemical, and pharmaceutical properties, improved target binding, improved biological activity, and higher recombinant expression in mammalian cell lines used for antibody production. Without wishing to be bound by theory, it is believed that in one embodiment, the humanized antibody molecules described herein are more suitable for human therapeutic or pharmaceutical use than non-humanized antibody molecules. In one embodiment, the humanized antibody molecule exhibits higher therapeutic efficacy (e.g., lower tumor burden and / or higher survival). In one embodiment, the humanized antibody molecule exhibits increased stability (in vitro and / or in vivo). In one embodiment, the humanized antibody molecule exhibits higher expression levels (e.g., in cell lines). In one embodiment, compared to parental non-humanized antibodies, the humanized antibody molecule has comparable or improved CD138 binding affinity, effector function (e.g., ADCC activity), or both.

[0115] The anti-CD138 antibody molecules described herein (e.g., humanized anti-CD138 antibody molecules) can be used to treat a variety of diseases, such as multiple myeloma and other oncology indications. Without wishing to be bound by theory, it is believed that in one implementation, the disease involves CD138-positive cancer cells and / or CD138-mediated biological activities related to disease pathophysiology. For example, CD138 plays an important role in the KRAS-driven pathway underlying tumorigenesis and drug resistance in various cancers, such as pancreatic ductal adenocarcinoma.

[0116] The anti-CD138 antibody molecules described herein (e.g., humanized anti-CD138 antibody molecules) may possess bioactivity particularly suitable for the treatment of human diseases. For example, the exemplary humanized anti-CD138 antibody molecule mAb 4320 exhibits robust in vitro activity associated with its immune-mediated therapeutic mechanism of action. These properties include, for example, sub-nanomolar binding to CD138+ myeloma cells and antibody-dependent cell-mediated cytotoxicity (ADCC) against several MM cell lines, as assessed in a biologically relevant natural killer (NK) cell-based ADCC analysis using human NK cells. This potent cytotoxic activity, both dose- and target-dependent, has proven highly effective against many variable-expressing CD138 multiple myeloma cell lines, including drug-resistant MM cell lines, such as proliferating stable cell lines resistant to bortezomib or lenalidomide, which are often used in combination as standard of care for patients for induction, consolidation, or maintenance therapy. mAb 4320 is effective in killing autologous myeloma cells from relapsed / refractory patients who are unresponsive to this type of treatment. Other related mechanisms of action, such as antibody-dependent cytophagy (ADCP), direct inhibition of myeloma cell survival, and blocking of integrin binding, may also be present. In a mouse xenograft disease model involving disseminated MM1.S tumors in CB.17 mice, the in vivo efficacy of mAb 4320 as a single agent or in combination with a proteasome inhibitor (e.g., bortezomib) for synergistic effects has also been demonstrated.

[0117] Antibody-drug conjugates (ADCs), nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, and methods for preparing antibody molecules are also provided. The antibody molecules and pharmaceutical compositions disclosed herein (alone or in combination with other agents or therapeutic modalities) can be used to treat, prevent, and / or diagnose diseases and conditions, such as those related to CD138, such as cancer or precancerous conditions.

[0118] definition

[0119] This article uses the articles “a” and “a kind” to indicate one or more kinds (i.e., at least one kind) as the grammatical object of the article.

[0120] Unless the context clearly indicates otherwise, the term “or” as used herein means “and / or” and may be used interchangeably with it.

[0121] "Approximately" and "about" should generally indicate an acceptable degree of error in the measured quantity, taking into account the nature or precision of the measurement. Exemplary error levels are within 20% of a given range or value, typically within 10%, and more often within 5%. When "approximately" or "about" precedes a series of numbers or a range, it should be understood that "approximately" or "about" modifies each number in that series or range. Similarly, when "at least," "greater than," "not greater than," "less than," "not less than," or "within" precedes a series of numbers or a range, it should be understood that "at least," "greater than," "not greater than," "less than," "not less than," or "within" modifies each number in that series or range. As used herein, ranges include upper and lower limits.

[0122] The compositions and methods described herein include polypeptides and nucleic acids having a specified sequence, or polypeptides and nucleic acids having a sequence substantially identical or similar to the specified sequence (e.g., at least 85%, 90%, 95% or higher identical to the specified sequence).

[0123] In describing amino acid sequences, the term "substantially identical" as used herein means that the first amino acid contains a sufficient or minimum number of amino acid residues that are: i) identical to the aligned amino acid residues in the second amino acid sequence, or ii) have conserved substitutions of the aligned amino acid residues in the second amino acid sequence, such that the first and second amino acid sequences may have a common domain and / or common functional activity. For example, an amino acid sequence containing a common domain that is at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a reference sequence (e.g., the sequence provided herein).

[0124] In describing nucleotide sequences, the term "substantially identical" as used herein means that the first nucleic acid sequence contains a sufficient or minimum number of nucleotides identical to the aligned nucleotides in the second nucleic acid sequence, such that the first and second nucleotide sequences encode polypeptides with the same functional activity, or encode a shared structural polypeptide domain or shared functional polypeptide activity. For example, a nucleotide sequence containing at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with a reference sequence (e.g., the sequence provided herein).

[0125] The term "functional variant" refers to a polypeptide that has a substantially identical amino acid sequence to the natural sequence or is encoded by a substantially identical nucleotide sequence and is capable of having one or more activities of the natural sequence.

[0126] The calculation of sequence homology or sequence identity (these terms are used interchangeably in this paper) is performed as follows.

[0127] To determine the percentage similarity between two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of the first and second amino acid or nucleic acid sequences to achieve optimal alignment, and non-homologous sequences can be disregarded for comparison purposes). In a typical embodiment, the reference sequence used for comparison is at least 30% of its length, such as at least 40%, 50%, 60%, or even at least 70%, 80%, 90%, or 100%. The amino acid residues or nucleotides at corresponding amino acid or nucleotide positions are then compared. When the amino acid residues or nucleotides occupying a position in the first sequence are the same as those at the corresponding position in the second sequence, the molecules are identical at that position.

[0128] Considering the number of gaps required for optimal alignment of two sequences and the length of each gap, the percentage similarity between two sequences is related to the number of common positions in the sequences.

[0129] Sequence comparison and determination of the percentage identity between two sequences can be accomplished using mathematical algorithms. In some embodiments, the percentage identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48): 444-453 (1970)) algorithm, which has been incorporated into the GAP program in the GCG software package (available from gcg.com), using a Blossum 62 matrix or a PAM250 matrix with nick weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6. In some embodiments, the percentage identity between two nucleotide sequences is calculated using the GAP program in the GCG software package (available from gcg.com), employing an NWSgapdna.CMP matrix and nick weights of 40, 50, 60, 70, or 80, and length weights of 1, 2, 3, 4, 5, or 6. A suitable set of parameters (and the set of parameters to be used unless otherwise specified) is the Blossum 62 scoring matrix, with a gap penalty of 12, a gap extension penalty of 4, and a decoding gap penalty of 5.

[0130] The percentage of similarity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4:11-17 (1989)), which has been incorporated into the ALIGN program (version 2.0) using the PAM120 weighted residue table with a gap length penalty of 12 and a gap penalty of 4.

[0131] The nucleic acid and protein sequences disclosed herein can also be used as "query sequences" to search public databases for, for example, to identify other family components or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) described in Altschul et al., 1990, J. Mol. Biol., 215:403-10. A BLAST nucleotide search can be performed using the NBLAST program with a score of 100 and a word length of 12 to obtain nucleotide sequences homologous to the nucleic acids described herein. A BLAST protein search can be performed using the XBLAST program with a score of 50 and a word length of 3 to obtain amino acid sequences homologous to the protein molecules described herein. For gap alignment results for comparative purposes, gap BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res., 25:3389-3402. When using the BLAST and gap BLAST programs, the default parameters for each program (e.g., XBLAST and NBLAST) can be used. See ncbi.nlm.nih.gov.

[0132] As used herein, the term "hybridization under low, medium, high, or very high stringency conditions" refers to the conditions for hybridization and washing. Instructions for conducting hybridization reactions can be found in *Current Protocols in Molecular Biology* (John Wiley & Sons, NY, 1989, 6.3.1–6.3.6), which is incorporated herein by reference. This reference describes both aqueous and non-aqueous methods, and either method may be used. The specific hybridization conditions described herein are as follows: 1) Low-strict hybridization conditions: in 6X sodium chloride / sodium citrate (SSC) at approximately 45°C, followed by two washes in 0.2X SSC and 0.1% SDS at at least 50°C (the wash temperature can be increased to 55°C for low-strict conditions); 2) Medium-strict hybridization conditions: in 6X-SSC at approximately 45°C, followed by one or more washes in 0.2X SSC and 0.1% SDS (60°C); 3) High-strict hybridization conditions: in 6X-SSC at approximately 45°C, followed by one or more washes in 0.2X SSC and 0.1% SDS (65°C); and preferably 4) Very high-strict hybridization conditions: 0.5M sodium phosphate, 7% SDS, 65°C, followed by one or more washes in 0.2X SSC and 1% SDS (65°C). Very high-strict condition 4) is suitable and should be used (unless otherwise stated).

[0133] It should be understood that the molecules described herein may have other conserved or non-essential amino acid substitutions, which do not substantially affect the molecular function.

[0134] The term "amino acid" encompasses all molecules containing both amino and acid functional groups that can be incorporated into polymers formed from naturally occurring amino acids, whether natural or synthetic. Exemplary amino acids include naturally occurring amino acids; their analogs, derivatives, and congeners; amino acid analogs having variant side chains; and any of the stereoisomers listed above. As used herein, the term "amino acid" includes D- and L-mirror isomers and peptide mimics.

[0135] "Conservative amino acid substitution" refers to the substitution of one amino acid residue by another amino acid residue with a similar side chain. Families of amino acid residues with similar side chains have been defined in the art. These families include: amino acids with basic side chains (such as lysine, arginine, and histidine); amino acids with acidic side chains (such as aspartic acid and glutamic acid); amino acids with nonpolar side chains (such as glycine, asparagine, glutamine, serine, threonine, tyrosine, and cysteine); amino acids with nonpolar side chains (such as alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan); amino acids with β-branched side chains (such as threonine, valine, and isoleucine); and amino acids with aromatic side chains (such as tyrosine, phenylalanine, tryptophan, and histidine).

[0136] The terms “polypeptide,” “peptide,” and “protein” (if single-chain) are used interchangeably herein to refer to a polymer of amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may intercalate non-amino acids. The term also includes polymers of modified amino acids; for example, those subjected to disulfide bond formation, glycosylation, esterification, acetylation, phosphorylation, or any other manipulation, such as coupling with a labeled component. Polypeptides may be isolated from natural sources, may be produced from a prokaryotic or eukaryotic host using recombinant techniques, or may be products of synthetic methods.

[0137] The terms “nucleic acid,” “nucleic acid sequence,” “nucleotide sequence,” or “polynucleotide sequence” and “polynucleotide” are used interchangeably herein. They refer to any length of nucleotide polymeric form, whether deoxyribonucleotides or ribonucleotides or their analogues. Polynucleotides can be single-stranded or double-stranded, and if single-stranded, can be coding or non-coding (antisense) strands. Polynucleotides may include modified nucleotides, such as methylated nucleotides and nucleotide analogues. Non-nucleotide components may be intercalated in the nucleotide sequence. Polynucleotides may be further modified after polymerization, such as by coupling with labeled components. Nucleic acids can be recombinant polynucleotides, or genomic, cDNA, semi-synthetic, or synthetically derived polynucleotides, i.e., not naturally occurring or linked to another polynucleotide in a non-natural arrangement.

[0138] As used herein, the term "isolated" means that a substance is separated from its native or natural environment (e.g., from the natural environment if it is naturally occurring). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but a polynucleotide or polypeptide isolated from some or all of the coexisting substances in the natural system is isolated. Such a polynucleotide may be a part of a carrier and / or such a polynucleotide or polypeptide may be a part of a composition, but it is still isolated because the carrier or composition is not part of the natural environment in which the polynucleotide or polypeptide exists.

[0139] As used herein, the term "treating" a condition (e.g., myeloma) means, in one embodiment, that a subject (e.g., a human) with a condition (e.g., myeloma) and / or experiencing symptoms of a condition (e.g., myeloma) will experience less severe symptoms and / or recover more quickly after receiving an antibody molecule than if they had not received the antibody molecule. In one embodiment, when treating myeloma, a bone marrow biopsy will show fewer clonal plasma cells after effective treatment of the myeloma. For example, after administering the antibody molecule described herein to effectively treat myeloma, diagnostic assays will detect fewer clonal plasma cells in the subject's biological sample. Other assays, urine tests, or blood tests may also be used to monitor a patient's treatment or to detect the presence of myeloma symptoms in a subject after treatment, such as a reduction (or absence). In one embodiment, when treating myeloma, the level of β2-microglobulin (β2M) in serum or urine will decrease after effective treatment of the myeloma. Treatment may, for example, partially or completely alleviate, improve, relieve, suppress, or reduce the severity and / or incidence of a condition, and may optionally delay the onset or development of one or more consequences, symptoms, features, and / or causes of a condition (e.g., myeloma). In one embodiment, treatment is given to subjects who do not exhibit certain signs of a condition (e.g., myeloma) and / or who exhibit only early signs of a condition (e.g., kidney disease). In one embodiment, treatment is given to subjects who have one or more identified signs of a condition (e.g., myeloma). In one embodiment, treatment is given to subjects diagnosed with a disease (e.g., myeloma).

[0140] As used in this article, the term “preventing” a disease (e.g., myeloma) means that if a subject (e.g., a person) receives an antibody molecule, that subject (e.g., a person) is less likely to develop the disease (e.g., myeloma).

[0141] The various aspects of the compositions and methods described herein are further described in detail below. Other definitions are provided throughout the specification.

[0142] CD138

[0143] CD138 is a protein encoded by the SDC1 gene in humans. CD138 is also known as Syndecan 1, Syndecan-1, CD138 antigen, SYND1, SDC, Syndecan-1, or Syndecan.

[0144] CD138 is a transmembrane (type I) heparan sulfate proteoglycan (HSPG) and a member of the multiligand proteoglycan family. Highly expressed on differentiated plasma cells (PCs), CD138 is a major diagnostic biomarker for multiple myeloma (MM) and an indicator of poor clinical prognosis. CD138 is also stably and significantly overexpressed in MM cells derived from patients at multiple stages of disease progression, with over 70% of patients showing increased CD138 expression on the cell surface in MM cells derived from autologous fresh BM aspirates. CD138 gene expression in patient-derived MM cells is also several times higher than in “normal” plasma cells from healthy control groups. Without wishing to be bound by theory, it is believed that in one implementation, CD138 is a target for MM immunotherapy, including but not limited to smoldering myeloma, a relatively early and largely asymptomatic stage of the disease for which early therapeutic intervention is acceptable. Without wishing to be bound by theory, it is believed that in one implementation, targeting CD138 could provide additional therapeutic benefits based on its key function as a promoter of myeloma cell growth, adhesion, and survival, as well as other key aspects of myeloma biology. Multiligand glycans mediate cell binding, cell signaling, and cytoskeleton organization, and multiligand glycan receptors are essential for the internalization of HIV-1tat protein. CD138 functions as an intact membrane protein and participates in cell proliferation, cell migration, and cell-matrix interactions through its extracellular matrix protein receptor. Altered CD138 expression has been detected in several different tumor types.

[0145] The core of CD138 comprises three main domains: 1) a short cytoplasmic domain; 2) a hydrophobic domain that crosses the plasma membrane; and 3) a long extracellular domain. The functions of the CD138 domains are described, for example, in Stepp et al. Adv Wound Care (New Rochelle). 2015; 4(4): 235-249. The cytoplasmic domain can transmit signals and can also bind to anchoring molecules, including members of the PDZ family. The heparan sulfate chain of CD138 also has important biological functions. In mammals, CD138 is a major heparan sulfate proteoglycan (HSPG) that is highly expressed on epithelial cells (Fuki et al. J Clin Invest. 1997; 100(6): 1611-1622). Unintentionally limited by theory, it is believed that CD138's HSPG allows proteoglycans to bind to heparin-binding sites present on many ECM proteins, growth factors, cytokines and other proteins (Stepp et al., Adv Wound Care (New Rochelle). 2015; 4(4): 235-249).

[0146] For example, for human CD138 protein (e.g., any one of SEQ ID NO: 1-3 or 450), the signal peptide contains residues 1-22; the extracellular domain contains residues 23-254; the transmembrane domain contains residues 255-275; the cytoplasmic domain contains residues 276-310; or the integrin-binding domain (IBD) contains residues 88-122.

[0147] In one embodiment, the anti-CD138 antibody molecule described herein can modulate (e.g., inhibit) the binding of CD138 to one or more proteins that interact with (e.g., directly or indirectly) the extracellular domain of CD138. In one embodiment, the anti-CD138 antibody molecule described herein can modulate (e.g., inhibit) the function associated with proteins that interact with (e.g., directly or indirectly) the extracellular domain of CD138. In one embodiment, the protein interacting with CD138 binds directly to the extracellular domain of CD138. In one embodiment, the protein interacting with CD138 binds to the extracellular domain of CD138 via a glycosaminoglycan (GAG) chain.

[0148] Examples of proteins that interact with CD138 and their functions are described, for example, in Stepp et al. Adv WoundCare (New Rochelle). 2015; 4(4): 235-249, the contents of which are incorporated herein by reference in their full text.

[0149] For example, proteins that can interact directly or indirectly with the extracellular domain of CD138 include, but are not limited to, matrix proteins (e.g., laminin, fibronectin, thromboretin, collagen, fibrin, HB-GAM, tendinin, fibronectin, fibrin, or elastin), proteases (e.g., MMP7, MMP9, ADAMTS4, MT1-PPT, neutrophil elastase, cathepsin G, or carboxypeptidase), and receptors (e.g., integrins, α-receptors). v β3, α v β5, α6β4, α2β1, α3β1, or α Mβ2), cytokines or growth factors (e.g., morphogenetic proteins (e.g., activin, BMP-2, BMP-4, tendinin, sound hedgehog factor, curl-related protein, budding peptide, any one of Wnt1 to Wnt13), anti-angiogenic factors (e.g., angiogenic statin or endostatin), growth factors (e.g., bimodalin, batacillin, HB-EGF, neuromodulatory proteins, any one of FGF1 to FGF23, PDGF, GDNF, VEGF, HGF, TGF β1, TGF) β2, TPA or PAI-1), or cytokines (e.g., GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-7, IL-12, interferon, TNF-α, CC chemokine or CXC chemokine), energy balance-related proteins (e.g., ApoB, ApoE or lipoprotein lipase), complement or clotting proteins (e.g., antithrombin II, tissue factor (TF), pathway inhibitors, factor IX, factor X, factor XI or factor XII), or viral or parasitic capsid proteins (e.g., HIV-1-tat, HIV-1 gp41, HIV-1 gp120, HSV gB, HSV gC, HSV gD, HHV-6 or HHV-8 capsid proteins or RSV G-proteins).

[0150] CD138 expressed on the cell surface can be cleaved by specific proteases, while shed CD138 is responsible for mediating paracrine and autocrine functions. Shed CD138 is a soluble and secreted extracellular domain (ECD) in blood and matrix. Shed CD138 is an indicator of poor prognosis in multiple myeloma patients and enhanced tumor progression in mouse models of myeloma. Generally, shed CD138 is not considered a major cause of the disease. Translocation of CD138 to the nucleus may be associated with the differentiation and proliferation of certain tumor cells. In one embodiment, the anti-CD138 antibody molecule described herein preferentially targets membrane-associated CD138 compared to soluble CD138.

[0151] CD138 is generally absent from B lymphocytes and is expressed after plasma cell differentiation begins. CD138 is highly expressed on malignant plasma cells (myeloma) and plays a causal role in disease progression. CD138 is involved in a variety of biological functions. For example, it can bind to extracellular proteins, growth factors, and chemokines; upon aggregation, it binds to and activates αVβ3 and αVβ5 integrins; regulates exon biogenesis; and modulates the bone marrow microenvironment that supports myeloma growth and metastasis. Several signals can be attenuated by targeting CD138.

[0152] CD138 is upregulated in multiple myeloma (Tassone et al. Blood. 104(12): 3688-3696). It is overexpressed on malignant plasma cells. Multiple myeloma cells typically express CD138 at levels 50-200 times higher. The level of soluble CD138 (sCD138) typically ranges from 60 ng / mL in normal serum to 200-1500 ng / mL in the serum of multiple myeloma patients. CD138 is overexpressed in approximately 80% of multiple myeloma patients.

[0153] CD138 can be used as a major diagnostic marker for multiple myeloma. Elevated levels of exfoliated CD138 in serum are associated with increased tumor burden and poor prognosis. CD138+ myeloma cells exhibit high proliferation, while patients with CD138+ myeloma have low overall survival. CD138+ myeloma cells aberrantly express angiogenic factors such as HGF, IL-15, ANG, APRIL, CTGF, or TGFA (Hose et al. Blood. 2009; 114(1): 128-143). The expression level of CD138 and its released extracellular domains are associated with tumor malignancy, phenotype, and metastatic potential in solid tumors and hematologic malignancies. CD138 expression varies by cancer type, but differential expression profiles between normal cells and cancer cells in epithelial and stromal compartments are directly associated with tumor invasiveness and patient clinical outcomes and survival.

[0154] Exemplary amino acid and nucleotide sequences of human CD138 are described in, for example, Mali et al. J Biol Chem. 1990; 265(12): 6884-6889; Lories et al. J Biol Chem. 1992; 267(2): 1116-1122; and Figure 1 middle.

[0155] An exemplary amino acid sequence (SEQ ID NO: 1) of the human CD138 precursor is provided below.

[0156] MRRAALWLWLCALALSLQPALPQIVATNLPPEDQDGSGDDSDNFSGSGAGALQDITLSQQTPSTWKDTQLLTAIPTSPEPTGLEATAASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEATPRPRETTQLPTTHQASTTTATTAQEPATSHPHR DMQPGHHETSTPAGPSQADLHTPHTEDGGPSATERAAEDGASSQLPAAEGSGEQDFTFETSGENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLGGVIAGGLVGLIFAVCLVGFMLYRMKKKDEGSYSLEEPKQANGGAYQKPTKQEEFYA

[0157] An exemplary human CD138 precursor variant (Q136L) amino acid sequence (SEQ ID NO: 2) is provided below.

[0158] MRRAALWLWLCALALSLQPALPQIVATNLPPEDQDGSGDDSDNFSGSGAGALQDITLSQQTPSTWKDTQLLTAIPTSPEPTGLEATAASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEATPRPRETTQLPTTHLASTTTATTAQEPATSHPHR DMQPGHHETSTPAGPSQADLHTPHTEDGGPSATERAAEDGASSQLPAAEGSGEQDFTFETSGENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLGGVIAGGLVGLIFAVCLVGFMLYRMKKKDEGSYSLEEPKQANGGAYQKPTKQEEFYA

[0159] An exemplary human CD138 precursor variant (T76M) amino acid sequence (SEQ ID NO: 3) is provided below.

[0160] MRRAALWLWLCALALSLQPALPQIVATNLPPEDQDGSGDDSDNFSGSGAGALQDITLSQQTPSTWKDTQLLTAIPMSPEPTGLEATAASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEATPRPRETTQLPTTHQASTTTATTAQEPATSHPHR DMQPGHHETSTPAGPSQADLHTPHTEDGGPSATERAAEDGASSQLPAAEGSGEQDFTFETSGENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLGGVIAGGLVGLIFAVCLVGFMLYRMKKKDEGSYSLEEPKQANGGAYQKPTKQEEFYA

[0161] The signal peptide comprises amino acids 1-22 of any one of SEQ ID NO: 1-3. The mature peptide comprises amino acids 23-310 of any one of SEQ ID NO: 1-3. The extracellular domain comprises amino acids 23-254 of any one of SEQ ID NO: 1-3. The transmembrane domain comprises amino acids 255-275 of any one of SEQ ID NO: 1-3. The cytoplasmic domain comprises amino acids 276-310 of any one of SEQ ID NO: 1-3.

[0162] An exemplary encoding nucleotide sequence of human CD138 (SEQ ID NO: 4) is provided below. This nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 1.

[0163] ATGAGGCGCGCGGCGCTCTGGCTCTGGCTGTGCGCGCTGGCGCTGAGCCTGCAGCCGGCCCTGCCGCAAATTGTGGCTACTAATTTGCCCCCTGAAGATCAAGATGGCTCTGGGGATGACTCTGACAACTTCTCCGGCTCAGGTGCAGGTGCTTTGCAAGATATCACCTTGTCACAGCAGACCCCCTCCACTTGGAAGGACACGCAGCTCCTGACGGCTATTCCCACGTCTCCAGAACCCACCGGCCTGGAGGCTACAGCTGCCTCCACCTCCACCCTGCCGGCTGGAGAGGGGCCCAAGGAGGGAGAGGCTGTAGTCCTGCCAGAAGTGGAGCCTGGCCTCACCGCCCGGGAGCAGGAGGCCACCCCCCGACCCAGGGAGACCACACAGCTCCCGACCACTCATCAGGCCTCAACGACCACAGCCACCACGGCCCAGGAGCCCGCCACCTCCCACCCCCACAGGGACATGCAGCCTGGCCACCATGAGACCTCAACCCCTGCAGGACCCAGCCAAGCTGACCTTCACACTCCCCACACAGAGGATGGAGGTCCTTCTGCCACCGAGAGGGCTGCTGAGGATGGAGCCTCCAGTCAGCTCCCAGCAGCAGAGGGCTCTGGGGAGCAGGACTTCACCTTTGAAACCTCGGGGGAGAATACGGCTGTAGTGGCCGTGGAGCCTGACCGCCGGAACCAGTCCCCAGTGGATCAGGGGGCCACGGGGGCCTCACAGGGCCTCCTGGACAGGAAAGAGGTGCTGGGAGGGGTCATTGCCGGAGGCCTCGTGGGGCTCATCTTTGCTGTGTGCCTGGTGGGTTTCATGCTGTACCGCATGAAGAAGAAGGACGAAGGCAGCTACTCCTTGGAGGAGCCGAAACAAGCCAACGGCGGGGCCTACCAGAAGCCCACCAAACAGGAGGAATTCTATGCCTGA

[0164] Another exemplary encoding nucleotide sequence of human CD138 (SEQ ID NO: 5) is provided below. This nucleotide sequence also encodes the amino acid sequence of SEQ ID NO: 1.

[0165] ATGAGGCGCGCGGCGCTCTGGCTCTGGCTGTGCGCGCTGGCGCTGAGCCTGCAGCCGGCCCTGCCGCAAATTGTGGCTACTAATTTGCCCCCTGAAGATCAAGATGGCTCTGGGGATGACTCTGACAACTTCTCCGGCTCAGGTGCAGGTGCTTTGCAAGATATCACCTTGTCACAGCAGACCCCCTCCACTTGGAAGGACACGCAGCTCCTGACGGCTATTCCCACGTCTCCAGAACCCACCGGCCTGGAGGCTACAGCTGCCTCCACCTCCACCCTGCCGGCTGGAGAGGGGCCCAAGGAGGGAGAGGCTGTAGTCCTGCCAGAAGTGGAGCCTGGCCTCACCGCCCGGGAGCAGGAGGCCACCCCCCGACCCAGGGAGACCACACAGCTCCCGACCACTCATCAGGCCTCAACGACCACAGCCACCACGGCCCAGGAGCCCGCCACCTCCCACCCCCACAGGGACATGCAGCCTGGCCACCATGAGACCTCAACCCCTGCAGGACCCAGCCAAGCTGACCTTCACACTCCCCACACAGAGGATGGAGGTCCTTCTGCCACCGAGAGGGCTGCTGAGGATGGAGCCTCCAGTCAGCTCCCAGCAGCAGAGGGCTCTGGGGAGCAGGACTTCACCTTTGAAACCTCGGGGGAGAATACGGCTGTAGTGGCCGTGGAGCCTGACCGCCGGAACCAGTCCCCAGTGGATCAGGGGGCCACGGGGGCCTCACAGGGCCTCCTGGACAGGAAAGAGGTGCTGGGAGGGGTCATTGCCGGAGGCCTCGTGGGGCTCATCTTTGCTGTGTGCCTGGTGGGTTTCATGCTGTACCGCATGAAGAAGAAGGACGAAGGCAGCTACTCCTTGGAGGAGCCGAAACAAGCCAACGGCGGGGCCTACCAGAAGCCCACCAAACAGGAGGAATTCTATGCCTGA

[0166] As used herein, when an anti-CD138 antibody molecule binds or substantially binds to human CD138, it binds or substantially binds to one or more isotypes of human CD138. In one embodiment, the antibody molecule binds or substantially binds to human CD138 having the amino acid sequence described herein or encoded by the nucleotide sequence described herein. In one embodiment, the antibody molecule binds or substantially binds to human CD138 comprising amino acids 23-254 of any one of SEQ ID NO: 1-3.

[0167] Exemplary amino acid and nucleotide sequences of mouse CD138 are described in, for example, Saunders et al. J Cell Biol. 1989; 108(4): 1547-1556; and Vihinen et al. J Biol Chem. 1993; 268(23): 17261-17269.

[0168] An exemplary amino acid sequence (SEQ ID NO: 6) of the mouse CD138 precursor is provided below.

[0169] MRRAALWLWLCALALRLQPALPQIVAVNVPPEDQDGSGDDSDNFSGSGTGALPDTLSRQTPSTWKDVWLLTATPTAPEPTSSNTETAFTSVLPAGEKPEEGEPVLHVEAEPGFTARDKEKEVTTRPRETVQLPITQRASTVRVTTAQAAVTSHPH GGMQPGLHETSAPTAPGQPDHQPPRVEGGGTSVIKEVVEDGTANQLPAGEGSGEQDFTFETSGENTAVAAVEPGLRNQPPVDEGATGASQSLLDRKEVLGGVIAGGLVGLIFAVCLVAFMLYRMKKKDEGSYSLEEPKQANGGAYQKPTKQEEFYA

[0170] The signal peptide comprises amino acids 1-22 of SEQ ID NO: 6. The mature peptide comprises amino acids 23-311 of SEQ ID NO: 6. The extracellular domain comprises amino acids 23-255 of SEQ ID NO: 6. The transmembrane domain comprises amino acids 256-276 of SEQ ID NO: 4. The cytoplasmic domain comprises amino acids 277-311 of SEQ ID NO: 6.

[0171] An exemplary encoding nucleotide sequence of mouse CD138 (SEQ ID NO: 7) is provided below.

[0172] ATGAGACGCGCGGCGCTCTGGCTCTGGCTCTGCGCGCTGGCGCTGCGCCTGCAGCCTGCCCTCCCGCAAATTGTGGCTGTAAATGTTCCTCCTGAAGATCAGGATGGCTCTGGGGATGACTCTGACAACTTCTCTGGCTCTGGCACAGGTGCTTTGCCAGATACTTTGTCACGGCAGACACCTTCCACTTGGAAGGACGTGTGGCTGTTGACAGCCACGCCCACAGCTCCAGAGCCCACCAGCAGCAACACCGAGACTGCTTTTACCTCTGTCCTGCCAGCCGGAGAGAAGCCCGAGGAGGGAGAGCCTGTGCTCCATGTAGAAGCAGAGCCTGGCTTCACTGCTCGGGACAAGGAAAAGGAGGTCACCACCAGGCCCAGGGAGACCGTGCAGCTCCCCATCACCCAACGGGCCTCAACAGTCAGAGTCACCACAGCCCAGGCAGCTGTCACATCTCATCCGCACGGGGGCATGCAACCTGGCCTCCATGAGACCTCGGCTCCCACAGCACCTGGTCAACCTGACCATCAGCCTCCACGTGTGGAGGGTGGCGGCACTTCTGTCATCAAAGAGGTTGTCGAGGATGGAACTGCCAATCAGCTTCCCGCAGGAGAGGGCTCTGGAGAACAAGACTTCACCTTTGAAACATCTGGGGAGAACACAGCTGTGGCTGCCGTAGAGCCCGGCCTGCGGAATCAGCCCCCGGTGGACGAAGGAGCCACAGGTGCTTCTCAGAGCCTTTTGGACAGGAAGGAAGTGCTGGGAGGTGTCATTGCCGGAGGCCTAGTGGGCCTCATCTTTGCTGTGTGCCTGGTGGCTTTCATGCTGTACCGGATGAAGAAGAAGGACGAAGGCAGCTACTCCTTGGAGGAGCCCAAACAAGCCAATGGCGGTGCCTACCAGAAACCCACCAAGCAGGAGGAGTTCTACGCCTGA

[0173] As used herein, when an anti-CD138 antibody molecule binds or substantially binds to mouse CD138, it binds or substantially binds to one or more isotypes of mouse CD138. In one embodiment, the antibody molecule binds or substantially binds to human CD138 having the amino acid sequence described herein or encoded by the nucleotide sequence described herein. In one embodiment, the antibody molecule binds or substantially binds to mouse CD138 comprising amino acids 23-255 of SEQ ID NO: 6.

[0174] Epitope

[0175] The humanized antibody molecules described herein can bind to epitopes on CD138 (e.g., human CD138). For example, the epitopes to which the humanized antibody molecules described herein bind may include one or more epitope contacts described herein.

[0176] Without being intended to limit oneself, it is believed that in one embodiment, antibodies binding to any region of the membrane remote from IBD (e.g., residues 88-122 of any one of SEQ ID NO: 1-3 or 450) or CD138 may be ineffective for NK cell activation signal transduction and / or may not efficiently deliver molecules (perforin and / or granzymes) for cytotoxicity. In one embodiment, the antibody molecule binds to a CD138 epitope comprising a proximal membrane region. In one embodiment, the antibody molecule binds to a CD138 epitope comprising at least two distinct peptide regions (e.g., comprising peptide 2A and / or 6A and / or portions thereof). In one embodiment, the antibody molecule binds to a CD138 epitope that is different from the epitope bound by antibody BB4.

[0177] In one embodiment, the antibody molecule binds to CD138 (e.g., human CD138) with an affinity at least 10% greater than that of a reference anti-CD138 antibody (e.g., antibody BB4) (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 70%, 80%, or 90%), for example, as determined by cell binding assays as described herein. In one embodiment, CD138 is membrane-associated. In one embodiment, the antibody molecule binds to soluble CD138, such as the extracellular domain of soluble CD138 (e.g., the sequence having amino acids 18-251 of SEQ ID NO: 1). In one embodiment, the antibody molecule binds to peptide 2A of human CD138. In some embodiments, the antibody molecule binds to peptide 6A of human CD138.

[0178] In some embodiments, the anti-CD138 antibody molecules described herein have one, two, or all of the following properties: optimal distance between the epitope and the cell membrane (e.g., not at the N-terminus of the IDB); suitable orientation of the Fc region for CD16 binding; or, appropriate CD138 binding that allows CD16 to cluster on NK cells (e.g., to overcome excessive glycosylation of the CD138 molecule, which may limit NK cell access).

[0179] Without being bound by theory, it is believed that in one implementation, altering the location of an antibody epitope can modify certain effector mechanisms involved. For example, antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may favor epitopes closer to the membrane (compared to epitopes distal to the membrane) (Cleary et al. J Immunol. 2017; 198(10): 3999-4011). In one implementation, antibodies designed to remove target cells via specific effector mechanisms can be selected by altering the location of the antibody epitope (e.g., the distance of the epitope from the membrane).

[0180] In one implementation, the binding mode may affect the antibody's ability to mediate effector function. For example, between antibodies that bind to the same peptide epitope, the angle of the antibody-binding extracellular loop relative to the membrane surface may differ (e.g., parallel or perpendicular to the membrane surface).

[0181] In one embodiment, the anti-CD138 antibody molecule described herein binds to an epitope having one, two, or all of the following characteristics: proximal to the cell membrane; not restricted or blocked by glycosaminoglycan (GAG) chains; or preferentially present on membrane-associated CD138. In one embodiment, the anti-CD138 antibody molecule described herein can bind to a desired epitope region and bind in an optimal posture relative to the membrane. In one embodiment, the epitope is a linear epitope. In one embodiment, the antibody molecule binds to an extracellular region of CD138 remote from the transmembrane region. In one embodiment, the epitope is a discontinuous or conformational epitope.

[0182] Peptides used to recognize the epitopes required for anti-CD138 antibodies, such as PCT Publication No. WO 2019 / 070726 or U.S. Patent Application Publication No. US 2019 / 0100588. Figure 2 As shown. Not intended to be theoretically limited, it is believed that in one embodiment, the anti-CD138 antibody molecule described herein targets the peptide region of human CD138 between residues Gly217 and Glu251, for example, as described in PCT Publication No. WO 2019 / 070726 or U.S. Patent Application Publication No. US 2019 / 0100588. Figure 1As shown. It is desirable that this region have a linear random coil conformation. In one embodiment, an anti-CD138 antibody molecule binds to at least one linear tetrapeptide in the aforementioned region. In another embodiment, an anti-CD138 antibody molecule binds to a combination of linear tetrapeptides in the aforementioned region (e.g., two, three, four, or more adjacent tetrapeptides).

[0183] The amino acid sequences of the above peptides are shown in Table 3.

[0184] Table 3. Peptides used to identify CD138 epitopes

[0185]

[0186] In Table 3, overlapping amino acids between peptides are shown in bold; BB4 epitope residues are shown in italics; and glycosaminoglycan chains containing serine residues (heparin sulfate, chondroitin sulfate) are underlined. The terms “peptide” and “Pep” are used interchangeably in this document. For peptide names, lowercase and uppercase letters are intended to have the same meaning. For example, the terms peptide “1A,” “peptide 1a,” “Pep1A,” and “Pep1a” can be used to refer to the same peptide.

[0187] Other exemplary peptides for recognizing the epitopes required for anti-CD138 antibodies include PCT Publication No. WO 2019 / 070726 or U.S. Patent Application Publication No. US 2019 / 0100588. Figure 13 As shown in 22C.

[0188] In one embodiment, the antibody molecule contacts (e.g., binds to or substantially binds to) CD138 in Table 3 of PCT Publication No. WO 2019 / 070726 or U.S. Patent Application Publication No. US 2019 / 0100588. Figure 13 Or the region corresponding to one or more peptides described in 22C. In one embodiment, the peptide is Pep6. In one embodiment, the peptide is Pep6a. In one embodiment, the peptide is Pep5. In one embodiment, the peptide is Pep4. In one embodiment, the antibody molecule contacts Pep6 or Pep6a but not Pep4. In one embodiment, the antibody molecule does not contact any of Pep1a, Pep1b, Pep2a, Pep2b, Pep3, Pep4, or Pep5. In one embodiment, the antibody molecule does not contact Pep2a. In one embodiment, the antibody molecule contacts Pep2a but does not bind to the same epitope as BB4.

[0189] In one embodiment, the antibody molecule contacts Pep2a and Pep6. In one embodiment, the antibody molecule contacts Pep2a and Pep2c. In one embodiment, the antibody molecule contacts Pep6b. In one embodiment, the antibody molecule contacts Pep2a, Pep2c, and Pep6b. In one embodiment, the antibody molecule does not contact Pep6e. In one embodiment, the antibody molecule contacts Pep6b but not Pep6e. In one embodiment, the antibody molecule contacts Pep2a and Pep2c but not Pep6e. In one embodiment, the antibody molecule contacts Pep2a, Pep2c, and Pep6b but not Pep6e.

[0190] In one embodiment, the antibody molecule contacts Pep2a and Pep2d. In one embodiment, the antibody molecule contacts Pep6b and Pep6f. In one embodiment, the antibody molecule contacts Pep2a, Pep2d, Pep6b, and Pep6f.

[0191] In one embodiment, the antibody molecule binds to or substantially binds to CD138 in the extracellular region near the transmembrane domain of CD138. In one embodiment, the C-terminus of the extracellular region near the transmembrane domain is located within 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 amino acids from the N-terminus of the transmembrane domain. In one embodiment, the N-terminus of the extracellular region near the transmembrane domain is located within 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 amino acids from the N-terminus of the transmembrane domain.

[0192] In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more) consecutive amino acid residues in an extracellular region near a transmembrane domain.

[0193] In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising five or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising six or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising seven or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising eight or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising nine or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising ten or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising eleven or more consecutive amino acid residues in an extracellular region near the transmembrane domain. In another embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising twelve or more consecutive amino acid residues in an extracellular region near the transmembrane domain.

[0194] In one embodiment, the extracellular region near the transmembrane domain corresponds to (e.g., includes or constitutes thereof) Pep6. In one embodiment, the extracellular region near the transmembrane domain corresponds to (e.g., includes or constitutes thereof) Pep6a, 6b, 6e, and / or 6f. In one embodiment, the extracellular region near the transmembrane domain corresponds to (e.g., includes or constitutes thereof) Pep5.

[0195] In one embodiment, the antibody molecule contacts four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41) consecutive amino acid residues in Pep6. In one embodiment, the antibody molecule contacts four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26) consecutive amino acid residues in Pep6a.

[0196] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep6a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37): DFTF (SEQ ID NO: 18); FTFE (SEQ ID NO: 19); TFET (SEQ ID NO: 20); FETS (SEQ ID NO: 21); ETSG (SEQ ID NO: 22); TSGE (SEQ ID NO: 23); SGEN (SEQ ID NO: 24); GENT (SEQ ID NO: 25); ENTA (SEQ ID NO: 26); NTAV (SEQ ID NO: 27); TAVV (SEQ ID NO: 28). NO:28); AVVA (SEQ ID NO:29); VVAV (SEQ ID NO:30); VAVE (SEQ ID NO:31); AVEP (SEQ ID NO:32); VEPD (SEQ ID NO:33); EPDR (SEQ ID NO:34); PDRR (SEQ ID NO:35); DRRN (SEQ ID NO:36); RRNQ (SEQ ID NO:36); NO: 37); RNQS (SEQ ID NO: 38); NQSP (SEQ ID NO: 39); QSPV (SEQ ID NO: 40); SPVD (SEQ ID NO: 41); PVDQ (SEQ ID NO: 42); VDQG (SEQ ID NO: 43); DQGA (SEQ ID NO: 44); NO: 46); ATGA (SEQ ID NO: 47); TGAS (SEQ ID NO: 48); GASQ (SEQ ID NO: 49); ASQG (SEQ ID NO: 50); SQGL (SEQ ID NO: 51); QGLL (SEQ ID NO: 52); GLLD (SEQ ID NO: 53); LLDR (SEQ ID NO: 54); or LDRK (SEQ ID NO: 55).

[0197] In one embodiment, the antibody molecule is contacted with five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41) consecutive amino acid residues in Pep6a.

[0198] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep6a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37): DFTFE (SEQ ID NO: 56); FTFET (SEQ ID NO: 57); TFETS (SEQ ID NO: 58); FETSG (SEQ ID NO: 59); ETSGE (SEQ ID NO: 60); TSGEN (SEQ ID NO: 61); SGENT (SEQ ID NO: 62); GENTA (SEQ ID NO: 63); ENTAV (SEQ ID NO: 64); NTAVV (SEQ ID NO: 65); TAVVA (SEQ ID NO: 67). NO: 66); AVVAV (SEQ ID NO: 67); VVAVE (SEQ ID NO: 68); VAVEP (SEQ ID NO: 69); AVEPD (SEQ ID NO: 70); VEPDR (SEQ ID NO: 71); EPDRR (SEQ ID NO: 72); PDRRN (SEQ ID NO: 73); DRRNQ (SEQ ID NO: 74); NO:75); RNQSP (SEQ ID NO:76); NQSPV (SEQ ID NO:77); QSPVD (SEQ ID NO:78); SPVDQ ​​(SEQ ID NO:79); PVDQG (SEQ ID NO:80); VDQGA (SEQ ID NO:81); DQGAT (SEQ ID NO:82); QGATG (SEQ ID NO:82); NO: 83); GATGA (SEQ ID NO: 84); ATGAS (SEQ ID NO: 85); TGASQ (SEQ ID NO: 86); GASQG (SEQ ID NO: 87); ASQGL (SEQ ID NO: 88); SQGLL (SEQ ID NO: 89); QGLLD (SEQ ID NO: 90); GLLDR (SEQ ID NO: 91); or LLDRK (SEQ ID NO: 92).

[0199] In one embodiment, the antibody molecule is contacted with six or more (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 or 41) consecutive amino acid residues in Pep6a.

[0200] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep6a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36): DFTFET (SEQ ID NO: 93); FTFETS (SEQ ID NO: 94); TFETSG (SEQ ID NO: 95); FETSGE (SEQ ID NO: 96); ETSGEN (SEQ ID NO: 97); TSGENT (SEQ ID NO: 98); SGENTA (SEQ ID NO: 99); GENTAV (SEQ ID NO: 100); ENTAVV (SEQ ID NO: 101); NTAVVA (SEQ ID NO: 99). NO: 102); TAVVAV (SEQ ID NO: 103); AVVAVE (SEQ ID NO: 104); VVAVEP (SEQ ID NO: 105); VAVEPD (SEQ ID NO: 106); AVEPDR (SEQ ID NO: 107); VEPDRR (SEQ ID NO: 108); NO: 110); DRRNQS (SEQ ID NO: 111); RRNQSP (SEQ ID NO: 112); RNQSPV (SEQ ID NO: 113); NQSPVD (SEQ ID NO: 114); QSPVDQ ​​(SEQ ID NO: 115); SPVDQG (SEQ ID NO: 116); PVDQGA (SEQ ID NO: 117); VDQGAT (SEQ ID NO: 118); DQGATG (SEQ ID NO: 119); QGATGA (SEQ ID NO: 120); GATGAS (SEQ ID NO: 121); ATGASQ (SEQ ID NO: 122); TGASQG (SEQ ID NO: 123); GASQGL (SEQ ID NO: 124); ASQGLL (SEQ ID NO: 125); SQGLLD (SEQ ID NO: 126); QGLLDR (SEQ ID NO: 127); or GLLDRK (SEQ ID NO: 128).

[0201] In one embodiment, the antibody molecule contacts four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36) consecutive amino acid residues in Pep5.

[0202] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep5) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36): HTPH (SEQ ID NO: 129), TPHT (SEQ ID NO: 130), PHTE (SEQ ID NO: 131), HTED (SEQ ID NO: 132), TEDG (SEQ ID NO: 133), EDGG (SEQ ID NO: 134), DGGP (SEQ ID NO: 135), GGPS (SEQ ID NO: 136), GPSA (SEQ ID NO: 137), PSAT (SEQ ID NO: 138), SATE (SEQ ID NO: 139). NO: 139), ATER (SEQ ID NO: 140), TERA (SEQ ID NO: 141), ERAA (SEQ ID NO: 142), RAAE (SEQ ID NO: 143), AAED (SEQ ID NO: 144), AEDG (SEQ ID NO: 145), EDGA (SEQ ID NO: 146), DGAS (SEQ ID NO: 147), GASS (SEQ ID NO: 147) NO: 148), ASSQ (SEQ ID NO: 149), SSQL (SEQ ID NO: 150), SQLP (SEQ ID NO: 151), QLPA (SEQ ID NO: 152), LPAA (SEQ ID NO: 153), PAAE (SEQ ID NO: 154), AAEG (SEQ ID NO: 155), AEGS (SEQ ID NO: 156), EGSG (SEQ ID NO: 153) NO: 157), GSGE (SEQ ID NO: 158), SGEQ (SEQ ID NO: 159), GEQD (SEQ ID NO: 160), EQDF (SEQ ID NO:161), QDFT (SEQ ID NO:162), DFTF (SEQ ID NO:18) or FTFE (SEQ ID NO:19).

[0203] In one embodiment, the antibody molecule is contacted with five or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) consecutive amino acid residues in Pep5.

[0204] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep5) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35): HTPHT (SEQ ID NO: 163), TPHTE (SEQ ID NO: 164), PHTED (SEQ ID NO: 165), HTEDG (SEQ ID NO: 166), TEDGG (SEQ ID NO: 167), EDGGP (SEQ ID NO: 168), DGGPS (SEQ ID NO: 169), GGPSA (SEQ ID NO: 170), GPSAT (SEQ ID NO: 171), PSATE (SEQ ID NO: 172), SATER (SEQ ID NO: 173). NO: 173), ATERA (SEQ ID NO: 174), TERAA (SEQ ID NO: 175), ERAAE (SEQ ID NO: 176), RAAED (SEQ ID NO: 177), AAEDG (SEQ ID NO: 178), AEDGA (SEQ ID NO: 179), EDGAS (SEQ ID NO: 180), DGASS (SEQ ID NO: 181), GASSQ (SEQ ID NO: 182), ASSQL (SEQ ID NO: 183), SSQLP (SEQ ID NO: 184), SQLPA (SEQ ID NO: 185), QLPAA (SEQ ID NO: 186), LPAAE (SEQ ID NO: 187), PAAEG (SEQ ID NO: 188), AAEGS (SEQ ID NO: 189), AEGSG (SEQ ID NO: 190), EGSGE (SEQ ID NO: 191), GSGEQ (SEQ ID NO: 192), SGEQD (SEQ ID NO:193), GEQDF (SEQ ID NO:194), EQDFT (SEQ ID NO:195), QDFTF (SEQ ID NO:196) or DFTFE (SEQ ID NO:56).

[0205] In one embodiment, the antibody molecule is contacted with six or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34) consecutive amino acid residues in Pep5.

[0206] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep5) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34): HTPHTE (SEQ ID NO: 197), TPHTED (SEQ ID NO: 198), PHTEDG (SEQ ID NO: 199), HTEDGG (SEQ ID NO: 200), TEDGGP (SEQ ID NO: 201), EDGGPS (SEQ ID NO: 202), DGGPSA (SEQ ID NO: 203), GGPSAT (SEQ ID NO: 204), GPSATE (SEQ ID NO: 205), PSATER (SEQ ID NO: 206), SATERA (SEQ ID NO: 207). NO: 207), ATERAA (SEQ ID NO: 208), TERAAE (SEQ ID NO: 209), ERAAED (SEQ ID NO: 210), RAAEDG (SEQ ID NO: 211), AAEDGA (SEQ ID NO: 212), AEDGAS (SEQ ID NO: 213), EDGASS (SEQ ID NO: 214), DGASSQ (SEQ ID NO: 215), GASSQL (SEQ ID NO: 216), ASSQLP (SEQ ID NO: 217), SSQLPA (SEQ ID NO: 218), SQLPAA (SEQ ID NO: 219), QLPAAE (SEQ ID NO: 220), LPAAEG (SEQ ID NO: 221), PAAEGS (SEQ ID NO: 222), AAEGSG (SEQ ID NO: 223), AEGSGE (SEQ ID NO: 224), EGSGEQ (SEQ ID NO: 225), GSGEQD (SEQ ID NO: 226), SGEQDF (SEQID NO:227), GEQDFT (SEQ ID NO:228), EQDFTF (SEQ ID NO:229) or QDFTFE (SEQ ID NO:230).

[0207] In one embodiment, the antibody molecule does not bind to or binds with low affinity to the extracellular region of CD138 remote from the transmembrane domain. In one embodiment, the antibody molecule does not bind to a CD138 epitope comprising four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region remote from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region remote from the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids from the N-terminus of the transmembrane domain. In one embodiment, the extracellular region remote from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4 or combinations thereof. In one embodiment, the antibody molecule does not bind to or binds with low affinity to the integrin-binding domain (IBD) of CD138. In one embodiment, the antibody molecule does not bind to or binds with low affinity to the N-terminal region of the IBD of CD138.

[0208] In one embodiment, the antibody molecule binds or substantially binds to an extracellular region of CD138 remote from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region remote from the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids from the N-terminus of the transmembrane domain. In one embodiment, the extracellular region remote from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4, or combinations thereof. In one embodiment, the antibody molecule binds or substantially binds to the integrin-binding domain (IBD) of CD138. In one embodiment, the antibody molecule binds or substantially binds to the N-terminal region of the IBD of CD138. In one embodiment, the antibody molecule does not bind or binds with low affinity to the epitope of BB4.

[0209] In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more) consecutive amino acid residues in an extracellular region away from the transmembrane domain.

[0210] In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising five or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising six or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising seven or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising eight or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising nine or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising ten or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising eleven or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain. In another embodiment, the antibody molecule binds to an epitope on CD138, the epitope comprising twelve or more consecutive amino acid residues in an extracellular region remote from the transmembrane domain.

[0211] In one implementation, the extracellular region remote from the transmembrane domain corresponds to (e.g., contains or is composed of) Pep2a.

[0212] In one embodiment, the antibody molecule is contacted with four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, or 34) consecutive amino acid residues in Pep2a.

[0213] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep2a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31): ASTS (SEQ ID NO: 231), STST (SEQ ID NO: 232), TSTL (SEQ ID NO: 233), STLP (SEQ ID NO: 234), TLPA (SEQ ID NO: 235), LPAG (SEQ ID NO: 236), PAGE (SEQ ID NO: 237), AGEG (SEQ ID NO: 238), GEGP (SEQ ID NO: 239), EGPK (SEQ ID NO: 240), GPKE (SEQ ID NO: 241), PKEG (SEQ ID NO: 242), KEGE (SEQ ID NO: 239). (SEQ ID NO: 243), EGEA (SEQ ID NO: 244), GEAV (SEQ ID NO: 245), EAVV (SEQ ID NO: 246), AVVL (SEQ ID NO: 247), VVLP (SEQ ID NO: 248), VLPE (SEQ ID NO: 249), LPEV (SEQ ID NO: 250), PEVE (SEQ ID NO: 251), EVEP (SEQ ID NO: 252), VEPG (SEQ ID NO: 253), EPGL (SEQ ID NO: 254), PGLT (SEQ ID NO: 255), GLTA (SEQ ID NO: 256), LTAR (SEQ ID NO: 257), TARE (SEQ ID NO: 258), AREQ (SEQ ID NO: 259), REQE (SEQ ID NO: 260), or EQEA (SEQ ID NO: 261). In one embodiment, the antibody molecule does not contact LPEV (SEQ ID NO: 250).

[0214] In one embodiment, the antibody molecule contacts five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) consecutive amino acid residues in Pep2a.

[0215] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep2a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33): ASTS (SEQ ID NO: 231), STST (SEQ ID NO: 232), TSTL (SEQ ID NO: 233), STLP (SEQ ID NO: 234), TLPA (SEQ ID NO: 235), LPAG (SEQ ID NO: 236), PAGE (SEQ ID NO: 237), AGEG (SEQ ID NO: 238), GEGP (SEQ ID NO: 239), EGPK (SEQ ID NO: 240), GPKE (SEQ ID NO: 241), PKEG (SEQ ID NO: 239). The antibody molecules include (SEQ ID NO: 242), KEGE (SEQ ID NO: 243), EGEA (SEQ ID NO: 244), GEAV (SEQ ID NO: 245), EAVV (SEQ ID NO: 246), AVVL (SEQ ID NO: 247), VVLP (SEQ ID NO: 248), VLPE (SEQ ID NO: 249), LPEV (SEQ ID NO: 250), PEVE (SEQ ID NO: 251), EVEP (SEQ ID NO: 252), VEPG (SEQ ID NO: 253), EPGL (SEQ ID NO: 254), PGLT (SEQ ID NO: 255), GLTA (SEQ ID NO: 256), LTAR (SEQ ID NO: 257), TARE (SEQ ID NO: 258), AREQ (SEQ ID NO: 259), REQE (SEQ ID NO: 260), or EQEA (SEQ ID NO: 261). In one embodiment, the antibody molecule does not contact the peptide containing LPEV (SEQ ID NO: 250).

[0216] In one embodiment, the antibody molecule is contacted with six or more (e.g., 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29) consecutive amino acid residues in Pep2a.

[0217] In one embodiment, the antibody molecule contacts one or more of the following peptides (e.g., from Pep2a) (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, or 32): ASTS (SEQ ID NO: 231), STST (SEQ ID NO: 232), TSTL (SEQ ID NO: 233), STLP (SEQ ID NO: 234), TLPA (SEQ ID NO: 235), LPAG (SEQ ID NO: 236), PAGE (SEQ ID NO: 237), AGEG (SEQ ID NO: 238), GEGP (SEQ ID NO: 239), EGPK (SEQ ID NO: 240), GPKE (SEQ ID NO: 241), PKEG (SEQ ID NO: 239). The antibody molecules, including SEQ ID NO: 242), KEGE (SEQ ID NO: 243), EGEA (SEQ ID NO: 244), GEAV (SEQ ID NO: 245), EAVV (SEQ ID NO: 246), AVVL (SEQ ID NO: 247), VVLP (SEQ ID NO: 248), VLPE (SEQ ID NO: 249), LPEV (SEQ ID NO: 250), PEVE (SEQ ID NO: 251), EVEP (SEQ ID NO: 252), VEPG (SEQ ID NO: 253), EPGL (SEQ ID NO: 254), PGLT (SEQ ID NO: 255), GLTA (SEQ ID NO: 256), LTAR (SEQ ID NO: 257), TARE (SEQ ID NO: 258), AREQ (SEQ ID NO: 259), REQE (SEQ ID NO: 260), and EQEA (SEQ ID NO: 261), do not contact the peptide containing LPEV (SEQ ID NO: 250) in one embodiment.

[0218] In one embodiment, the antibody molecule binds or substantially binds to both the extracellular region of CD138 near the transmembrane domain (e.g., the extracellular region described herein) and the extracellular region of CD138 far from the transmembrane domain (e.g., the extracellular region described herein). In one embodiment, the binding affinity of the antibody molecule to the extracellular region of CD138 near the transmembrane domain is higher (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, or 500 times higher) than the binding affinity to the extracellular region of CD138 far from the transmembrane domain. In one embodiment, the binding affinity of the antibody molecule to the extracellular region of CD138 far from the transmembrane domain is higher (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, or 500 times higher) than the binding affinity to the extracellular region of CD138 near the transmembrane domain.

[0219] antibody molecules

[0220] This article discloses humanized antibody molecules that bind to CD138 (such as the CD138 molecule disclosed herein).

[0221] As used herein, the term "antibody molecule" refers to a protein containing at least one immunoglobulin variable domain sequence, such as an immunoglobulin chain or fragment thereof. The term "antibody molecule" includes, for example, full-length, mature antibodies, and antigen-binding fragments of antibodies. For example, an antibody molecule may contain a heavy (H) chain variable region sequence (abbreviated as VH herein) and a light (L) chain variable region sequence (abbreviated as VL herein). In another example, an antibody molecule contains two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites, such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (e.g., scFv), single variable domain antibodies, bivalent (Dab) antibodies (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which can be produced by modifying complete antibodies or by de novo synthesis using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments can be derived from any antibody type (including, but not limited to, IgG, IgA, IgM, IgD, and IgE) and from any antibody subtype (e.g., IgG1, IgG2, IgG3, and IgG4). Antibody molecules can be monoclonal or polyclonal. Antibody molecules can also be human, humanized, CDR-transplanted, or in vitro generated antibodies. Antibody molecules may have a heavy chain constant region selected from IgG1, IgG2, IgG3, or IgG4. Antibody molecules may also have a light chain selected from κ or λ. The term “immunoglobulin (Ig)” is used interchangeably with the term “antibody” as used herein.

[0222] Examples of antigen-binding fragments include: (i) Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab′)2 fragments, bivalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of an antibody arm; (v) diabody (dAb) fragments consisting of a VH domain; (vi) camel or camel-derived variable domains; (vii) single-chain Fv (scFv), see, for example, Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; (viii) single-domain antibodies. These antibody fragments can be obtained by any suitable method (including a variety of conventional techniques known to those skilled in the art), and fragments that have the same applications as the intact antibody are screened.

[0223] The term "antibody" includes the complete molecule and its functional fragments. Antibody constant regions can be altered (e.g., mutated) to modify the antibody's properties, such as increasing or decreasing one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function.

[0224] Antibody molecules can be single-chain antibodies. Single-chain antibodies (scFVs) can be engineered (see, for example, Colcher et al. (1999) Ann NY Acad Sci 880: 263-280; and Reiter and Pastan (1996) Clin Cancer Res2: 245-252). Single-chain antibodies can be dimerized or polymerized to produce multivalent antibodies specific to different epitopes on the same target protein.

[0225] The antibody molecules described herein may also be single-domain antibodies. Single-domain antibodies may include antibodies whose complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to: heavy chain antibodies, naturally occurring antibodies lacking a light chain, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain backbones not derived from antibodies. Single-domain antibodies may be any single-domain antibody in the art or any future single-domain antibody. Single-domain antibodies may be derived from any species, including but not limited to: mice, humans, camels, llamas, fish, sharks, sheep, rabbits, and cattle. According to some aspects, single-domain antibodies are naturally occurring single-domain antibodies known to be heavy chain antibodies lacking a light chain. Such single-domain antibodies are disclosed, for example, in WO94 / 04678. For clarity, the variable domain derived from naturally occurring heavy chain antibodies lacking a light chain is referred to herein as a VHH or nanobody to distinguish it from the conventional VH of a four-chain immunoglobulin. The VHH molecule may be derived from antibodies grown in species of the Camelidae family, such as camels, llamas, dromedaries, alpacas, and packhorses. Besides camelids, other species can also produce naturally occurring heavy chain antibodies that lack the light chain; these VHHs are also included in this article.

[0226] The VH and VL regions can be further subdivided into hypervariable regions, called "complementarity-determining regions (CDRs)," and the more conserved regions interspersed between them are called "frame regions (FRs or FWs)." As used in this paper, "complementarity-determining region" and "CDR" refer to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. The terms "frame," "FW," and "FR" are used interchangeably in this paper.

[0227] Several methods have been employed to precisely delineate the scope of the framework region and CDR (see Kabat, EA, et al., (1991) Sequences of Proteins Of Immunological Interest, 5th ed., US Public Health Service, NIH, 91-3242; Chothia, C. et al., (1987) J. Mol. Biol. 196: 901-917; and the AbM definition used with Oxford Molecular's AbM antibody modeling software. See also, for example, "Protein Sequence and Structure Analysis of Antibody Variable Domains" in: Antibody Engineering Lab. (Manual, edited by Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). In one embodiment, the following definitions are used: the AbM definition for the heavy chain variable domain CDR1 and the Kabat definition for the other CDRs. In one embodiment, the Kabat definition is applied to all CDRs. Furthermore, embodiments described using Kabat or AbM CDRs can also be implemented using the Chothia hypervariable ring. Each VH and VL typically contains three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0228] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence that can form the variable domain structure of an immunoglobulin. For example, the sequence may include all or part of a naturally occurring variable domain amino acid sequence. For example, the sequence may contain or exclude one, two or more N- or C-terminal amino acids, or may contain other modifications compatible with protein structure formation.

[0229] The term "antigen-binding region" refers to a portion of an antibody molecule that contains a determinant cluster that forms an interface with an antigen (e.g., CD138) or its epitope. In the case of a protein (or protein mimic), the antigen-binding region typically contains one or more loops (e.g., loops of at least four amino acids or amino acid mimics) that form the antigen (e.g., CD138) binding interface. Typically, the antigen-binding region of an antibody molecule contains at least one or two CDRs and / or hypervariable loops, or more typically at least three, four, five, or six CDRs and / or hypervariable loops.

[0230] The terms “competition” or “cross-competition” are used interchangeably herein to refer to the ability of an antibody molecule to interfere with the binding of an anti-CD138 antibody molecule (e.g., the anti-CD138 antibody molecule provided herein) to a target (e.g., CD138). Interference with binding can be direct or indirect (e.g., through allosteric regulation of the antibody molecule or the target). The extent to which an antibody molecule interferes with the binding of other antibody molecules to the target, and thus whether it can be described as competitive, can be determined using a competitive binding assay (e.g., FACS, ELISA, or BIACORE assay). In one embodiment, the competitive binding assay is a quantitative competitive assay. In one implementation, in a competitive binding assay (such as the competitive assay described herein), the first anti-CD138 antibody molecule is considered to competitively bind to the target when the binding of the first anti-CD138 antibody molecule to the target is reduced by 10% or more, for example, 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more.

[0231] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to antibody molecules having a single molecular composition. Monoclonal antibody compositions exhibit single binding specificity and affinity for a specific epitope. Monoclonal antibodies can be prepared using hybridoma techniques or methods that do not employ hybridoma techniques (e.g., recombinant methods).

[0232] "Effectively human" proteins are those that do not elicit a neutralizing antibody response (e.g., a human anti-mouse antibody (HAMA) response). HAMA can cause problems in many situations, such as when antibody molecules are repeatedly administered to treat symptoms of chronic or relapsing diseases. HAMA responses can cause repeated antibody administration to be ineffective due to increased serum antibody clearance (see, for example, Saleh et al., Cancer Immunol. Immunother. 32: 180-190 (1990)) and also due to potential allergic reactions (see, for example, LoBuglio et al., Hybridoma, 5: 5117-5123 (1986)).

[0233] Antibody molecules can be polyclonal or monoclonal antibodies. In some embodiments, antibodies can be generated through recombination, for example, by any suitable phage display or recombination method.

[0234] Various phage display and combination methods for generating antibodies are known in the art (as described below, for example, Ladner et al., U.S. Patent No. 5,223,409; Kang et al., International Publication No. WO 92 / 18619; Dower et al., International Publication No. WO 91 / 17271; Winter et al., International Publication No. WO 92 / 20791; Markland et al., International Publication No. WO 92 / 15679; Breitling et al., International Publication No. WO 93 / 01288; McCafferty et al., International Publication No. WO 92 / 01047; Garrard et al., International Publication No. WO 92 / 09690; Ladner et al., International Publication No. WO 90 / 02809; Fuchs et al., (1991) Bio / Technology 9:1370-1372; Hay et al., (1992) Hum Antibod Hybridomas 3:81-85; Huse et al., (1989) Science 246:1275-1281; Griffths et al., (1993) ibid.; Hawkins et al., (1992) J Mol Biol 226:889; Clackson et al., (1991) Nature 352:624; Gram et al., (1992) PNAS 89:3576-3580; Garrad et al., (1991) Bio / Technology 9:1373-1377; Hoogenboom et al., (1991) Nuc Acid Res 19:4133-4137; and Barbas et al., (1991) PNAS 88:7978-7982, the contents of which are incorporated herein by reference in their entirety.

[0235] In one embodiment, the antibody molecule is a fully human antibody (e.g., an antibody produced by a mouse that has been genetically engineered to produce antibodies derived from human immunoglobulin sequences) or a non-human antibody, such as rodent (mouse or rat), sheep, primate (e.g., monkey), or camel antibodies. In one embodiment, the non-human antibody is a rodent antibody (mouse or rat antibody). Methods for preparing rodent antibodies are known in the art.

[0236] Human monoclonal antibodies can be produced using transgenic mice carrying human immunoglobulin genes instead of a mouse system. Spleen cells from these transgenic mice immunized with antigens of interest were used to generate hybridomas that secrete human mAbs, which are specific for binding to epitopes derived from human proteins (see, for example, Wood et al., International Application No. WO 91 / 00906; Kucherlapati et al., PCT Publication No. WO 91 / 10741; Lonberg et al., International Application No. WO 92 / 03918; Kay et al., International Application No. 92 / 03917; Lonberg et al., 1994 Nature 368: 856-859; Green, LL et al., 1994 Nature Genet. 7: 13-21; Morrison, SL et al., 1994 Proc. Natl. Acad. Sci. USA 81: 6851-6855; Bruggeman et al., 1993 Year Immunol 7: 33-40; Tuaillon et al., 1993 PNAS). 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol 21:1323-1326).

[0237] Antibodies can be antibodies generated in non-human organisms (e.g., rats or mice) for the variable region or a portion thereof (e.g., CDR). Chimeric, CDR transplantation, and humanized antibodies are all included in this invention. This invention includes antibodies generated in non-human organisms (e.g., rats or mice) and subsequently modified (e.g., in the variable frame or constant region) to reduce antigenicity in humans.

[0238] Chimeric antibodies can be generated using any suitable recombinant DNA technology. Various methods are known in the art (see Robinson et al., International Patent Publication No. PCT / US86 / 02269; Akira et al., European Patent Application Publication No. 184,187; Taniguchi, M., European Patent Application Publication No. 171,496; Morrison et al., European Patent Application Publication No. 173,494; Neuberger et al., International Patent Application Publication No. WO 86 / 01533; Cabilly et al., US Patent No. 4,816,567; Cabilly et al., European Patent Application Publication No. 125,023; Better et al., (1988 Science 240: 1041-1043); Liu et al., (1987) PNAS 84: 3439-3443; Liu et al., 1987, J. Immunol. 139: 3521-3526; Sun et al., (1987) PNAS). 84:214-218; Nishimura et al., 1987, Canc. Res. 47:999-1005; Wood et al., (1985) Nature 314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

[0239] In humanized or CDR-transplanted antibodies, at least one or two, but typically all three, recipient CDRs (of the immunoglobulin heavy or light chain) are replaced by donor CDRs. The antibody may be replaced with at least a portion of non-human CDRs, or only some CDRs may be replaced with non-human CDRs. Only the number of CDRs required for the humanized antibody to bind to lipopolysaccharide needs to be replaced. In one embodiment, the donor may be a rodent antibody, such as a rat or mouse antibody, and the recipient may be a human frame or a human common frame. Typically, the immunoglobulin providing the CDR is referred to as the "donor," and the immunoglobulin providing the frame region is referred to as the "recipient." In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The recipient frame is typically a naturally occurring (e.g., human) frame or a common frame, or a sequence with approximately 85% or higher, such as 90%, 95%, 99%, or higher, sequence identity.

[0240] As used herein, the term "shared sequence" refers to a sequence consisting of the most frequently occurring amino acid (or nucleotide) in a related sequence family (see, for example, Winnaker, From Genes to Clones, Verlagsgesellschaft, Weinheim, Germany, 1987). Within a protein family, each position in the shared sequence represents the most frequently occurring amino acid at that position in that family. If two amino acids have the same frequency, either one can be included in the shared sequence. A "shared frame" refers to the frame region in a shared immunoglobulin sequence.

[0241] Antibodies can be humanized by any suitable method, and many such methods are known in the art (see, for example, Morrison, SL, 1985, Science 229:1202-1207, Oi et al., 1986, BioTechniques 4:214, and Queen et al., US 5,585,089, US 5,693,761 and US 5,693,762, the entire contents of which are incorporated herein by reference).

[0242] Humanized or CDR-transplanted antibodies can be generated by CDR transplantation or CDR replacement, which can replace one, two, or all of the CDRs in the immunoglobulin chain. See, for example, U.S. Patent No. 5,225,539; Jones et al., 1986 Nature 321:552-525; Verhoeyan et al., 1988 Science 239:1534; Beidler et al., 1988 J. Immuno1.141:4053-4060; Winter US5,225,539, the entire contents of which are incorporated herein by reference. Winter describes a CDR transplantation method that can be used to prepare humanized antibodies (UK Patent Application GB 2188638A, filed March 26, 1987; Winter US5,225,539), the entire contents of which are incorporated herein by reference.

[0243] Humanized antibodies in which specific amino acids are substituted, deleted, or inserted are also provided. A standard description of the selection of amino acids from the donor is provided, for example, in columns 12-16 of US 5,585,089, the contents of which are incorporated herein by reference. Other techniques for humanizing antibodies are described in Padlan et al. EP519596 A1 (published December 23, 1992).

[0244] In one embodiment, the heavy chain constant region of the antibody molecule is selected from, for example, the heavy chain constant regions of IgG1, IgG2 (e.g., IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; specifically, from, for example, the heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4 (e.g., human). In one embodiment, the antibody molecule includes the heavy chain constant region of IgG (e.g., m3 allotype). In another embodiment, the light chain constant region of the antibody molecule is selected from, for example, the light chain constant regions of κ or λ (e.g., human). In one embodiment, the antibody molecule also includes the light chain constant region of κ (e.g., κ constant *01). In one embodiment, the antibody molecule includes the heavy chain constant region of IgG1 and the light chain constant region of κ. The constant regions can be altered (e.g., mutated) to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, and / or complement function). In one embodiment, the antibody molecule has effector function and is capable of immobilizing complement. In another embodiment, the antibody molecule does not recruit effector cells or fix complement. In some embodiments, the antibody molecule has a reduced or absent ability to bind to the Fc receptor. For example, the antibody may be an isotype or subtype, fragment, or other mutant that does not support binding to the Fc receptor, such as having a mutagenized Fc receptor-binding region or lacking an Fc receptor-binding region.

[0245] In one embodiment, the constant region of the antibody molecule is altered. Methods for altering the constant region of an antibody are known in the art. Antibody molecules with altered functions (e.g., altered affinity for effector ligands (such as FcRs on cells) or the C1 component of complement) can be generated by replacing at least one amino acid residue in the constant region of the antibody with a different residue (see, for example, EP388,15iA1, U.S. Patent Nos. 5,624,821 and 5,648,260, the entire contents of which are incorporated herein by reference). Amino acid mutations that stabilize the antibody structure are also included, such as S228P in human IgG4 (S241P in the EU nomenclature and Kabat nomenclature). Similar types of alterations can be described that would attenuate or eliminate these functions if applied to mouse or other species immunoglobulins.

[0246] In one embodiment, the antibody molecule includes one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more) of the mutations or combinations of mutations described in Table 9.

[0247] Table 9. Exemplary Fc mutations

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265] In one embodiment, the Fc region includes FcMut001. In one embodiment, the Fc region includes FcMut002. In one embodiment, the Fc region includes FcMut003. In one embodiment, the Fc region includes FcMut004. In one embodiment, the Fc region includes FcMut005. In one embodiment, the Fc region includes FcMut006. In one embodiment, the Fc region includes FcMut007. In one embodiment, the Fc region includes FcMut008. In one embodiment, the Fc region includes FcMut009. In one embodiment, the Fc region includes FcMut010. In one embodiment, the Fc region includes FcMut011. In one embodiment, the Fc region includes FcMut012. In one embodiment, the Fc region includes FcMut013. In one embodiment, the Fc region includes FcMut014. In one embodiment, the Fc region includes FcMut015. In one embodiment, the Fc region includes FcMut016. In one embodiment, the Fc region includes FcMut017. In one embodiment, the Fc region includes FcMut018. In one embodiment, the Fc region includes FcMut019. In one embodiment, the Fc region includes FcMut020. In one embodiment, the Fc region includes FcMut021. In one embodiment, the Fc region includes FcMut022. In one embodiment, the Fc region includes FcMut023. In one embodiment, the Fc region includes FcMut024. In one embodiment, the Fc region includes FcMut026. In one embodiment, the Fc region includes FcMut027. In one embodiment, the Fc region includes FcMut028. In one embodiment, the Fc region includes FcMut029. In one embodiment, the Fc region includes FcMut030. In one embodiment, the Fc region includes FcMut031. In one embodiment, the Fc region includes FcMut032. In one embodiment, the Fc region includes FcMut033. In one embodiment, the Fc region includes FcMut034. In one embodiment, the Fc region includes FcMut035. In one embodiment, the Fc region includes FcMut036. In one embodiment, the Fc region includes FcMut037. In one embodiment, the Fc region includes FcMut038. In one embodiment, the Fc region includes FcMut039. In one embodiment, the Fc region includes FcMut040. In one embodiment, the Fc region includes FcMut041. In one embodiment, the Fc region includes FcMut042. In one embodiment, the Fc region includes FcMut043. In one embodiment, the Fc region includes FcMut044.In one embodiment, the Fc region includes FcMut045. In one embodiment, the Fc region includes FcMut046. In one embodiment, the Fc region includes FcMut047. In one embodiment, the Fc region includes FcMut048. In one embodiment, the Fc region includes FcMut049. In one embodiment, the Fc region includes FcMut050. In one embodiment, the Fc region includes FcMut051. In one embodiment, the Fc region includes FcMut052. In one embodiment, the Fc region includes FcMut053. In one embodiment, the Fc region includes FcMut067. In one embodiment, the Fc region includes FcMut068. In one embodiment, the Fc region includes FcMut069. In one embodiment, the Fc region includes FcMut070. In one embodiment, the Fc region includes FcMut071. In one embodiment, the Fc region includes FcMut072. In one embodiment, the Fc region includes FcMut073. In one embodiment, the Fc region includes FcMut074. In one embodiment, the Fc region includes FcMut075. In one embodiment, the Fc region includes FcMut076. In one embodiment, the Fc region includes FcMut077. In one embodiment, the Fc region includes FcMut078. In one embodiment, the Fc region includes FcMut079. In one embodiment, the Fc region includes FcMut080. In one embodiment, the Fc region includes FcMut081. In one embodiment, the Fc region includes FcMut082. In one embodiment, the Fc region includes FcMut083. In one embodiment, the Fc region includes FcMut084. In one embodiment, the Fc region includes FcMut085. In one embodiment, the Fc region includes FcMut086. In one embodiment, the Fc region includes FcMut087. In one embodiment, the Fc region includes FcMut088. In one embodiment, the Fc region includes FcMut089. In one embodiment, the Fc region includes FcMut090. In one embodiment, the Fc region includes FcMut091. In one embodiment, the Fc region includes FcMut093. In one embodiment, the Fc region includes FcMut094. In one embodiment, the Fc region includes FcMut095. In one embodiment, the Fc region includes FcMut096. In one embodiment, the Fc region includes FcMut097. In one embodiment, the Fc region includes FcMut098. In one embodiment, the Fc region includes FcMut099. In one embodiment, the Fc region includes FcMut100. In one embodiment, the Fc region includes FcMut101.In one embodiment, the Fc region includes FcMut102. In one embodiment, the Fc region includes FcMut103. In one embodiment, the Fc region includes FcMut104. In one embodiment, the Fc region includes FcMut105. In one embodiment, the Fc region includes FcMut106. In one embodiment, the Fc region includes FcMut107. In one embodiment, the Fc region includes FcMut108. ​​In one embodiment, the Fc region includes FcMut109. In one embodiment, the Fc region includes FcMut110. In one embodiment, the Fc region includes FcMut111. In one embodiment, the Fc region includes FcMut112. In one embodiment, the Fc region includes FcMut113. In one embodiment, the Fc region includes FcMut114. In one embodiment, the Fc region includes FcMut115. In one embodiment, the Fc region includes FcMut116. In one embodiment, the Fc region includes FcMut117. In one embodiment, the Fc region includes FcMut118. In one embodiment, the Fc region includes FcMut119. In one embodiment, the Fc region includes FcMut120. In one embodiment, the Fc region includes FcMut121. In one embodiment, the Fc region includes FcMut122. In one embodiment, the Fc region includes FcMut123. In one embodiment, the Fc region includes FcMut124. In one embodiment, the Fc region includes FcMut125. In one embodiment, the Fc region includes FcMut126. In one embodiment, the Fc region includes FcMut127. In one embodiment, the Fc region includes FcMut128. In one embodiment, the Fc region includes FcMut129. In one embodiment, the Fc region includes FcMut130. In one embodiment, the Fc region includes FcMut131. In one embodiment, the Fc region includes FcMut132. In one embodiment, the Fc region includes FcMut133. In one embodiment, the Fc region includes FcMut134. In one embodiment, the Fc region includes FcMut135. In one embodiment, the Fc region includes FcMut136. In one embodiment, the Fc region includes FcMut137. In one embodiment, the Fc region includes FcMut138. In one embodiment, the Fc region includes FcMut139. In one embodiment, the Fc region includes FcMut140. In one embodiment, the Fc region includes FcMut141. In one embodiment, the Fc region includes FcMut142. In one embodiment, the Fc region includes FcMut143. In one embodiment, the Fc region includes FcMut144.In one embodiment, the Fc region includes FcMut145. In one embodiment, the Fc region includes FcMut146. In one embodiment, the Fc region includes FcMut147. In one embodiment, the Fc region includes FcMut148. In one embodiment, the Fc region includes FcMut149. In one embodiment, the Fc region includes FcMut150. In one embodiment, the Fc region includes FcMut151. In one embodiment, the Fc region includes FcMut152. In one embodiment, the Fc region includes FcMut153. In one embodiment, the Fc region includes FcMut154. In one embodiment, the Fc region includes FcMut155. In one embodiment, the Fc region includes FcMut156. In one embodiment, the Fc region includes FcMut157. In one embodiment, the Fc region includes FcMut158. In one embodiment, the Fc region includes FcMut159. In one embodiment, the Fc region includes FcMut160. In one embodiment, the Fc region includes FcMut161. In one embodiment, the Fc region includes FcMut162. In one embodiment, the Fc region includes FcMut163. In one embodiment, the Fc region includes FcMut164. In one embodiment, the Fc region includes FcMut165. In one embodiment, the Fc region includes FcMut166. In one embodiment, the Fc region includes FcMut167. In one embodiment, the Fc region includes FcMut168. In one embodiment, the Fc region includes FcMut169. In one embodiment, the Fc region includes FcMut170. In one embodiment, the Fc region includes FcMut171. In one embodiment, the Fc region includes FcMut172. In one embodiment, the Fc region includes FcMut173. In one embodiment, the Fc region includes FcMut174. In one embodiment, the Fc region includes FcMut175. In one embodiment, the Fc region includes FcMut176. In one embodiment, the Fc region includes FcMut177. In one embodiment, the Fc region includes FcMut178. In one embodiment, the Fc region includes FcMut179. In one embodiment, the Fc region includes FcMut180. In one embodiment, the Fc region includes FcMut181. In one embodiment, the Fc region includes FcMut182. In one embodiment, the Fc region includes FcMut183. In one embodiment, the Fc region includes FcMut184. In one embodiment, the Fc region includes FcMut185. In one embodiment, the Fc region includes FcMut186. In one embodiment, the Fc region includes FcMut187.In one embodiment, the Fc region includes FcMut188. In one embodiment, the Fc region includes FcMut189. In one embodiment, the Fc region includes FcMut190. In one embodiment, the Fc region includes FcMut191. In one embodiment, the Fc region includes FcMut192. In one embodiment, the Fc region includes FcMut193. In one embodiment, the Fc region includes FcMut194. In one embodiment, the Fc region includes FcMut195. In one embodiment, the Fc region includes FcMut196. In one embodiment, the Fc region includes FcMut197. In one embodiment, the Fc region includes FcMut198. In one embodiment, the Fc region includes FcMut199. In one embodiment, the Fc region includes FcMut200. In one embodiment, the Fc region includes FcMut201. In one embodiment, the Fc region includes FcMut202. In one embodiment, the Fc region includes FcMut203. In one embodiment, the Fc region includes FcMut 204. In one embodiment, the Fc region includes FcMut 205. In one embodiment, the Fc region includes FcMut 206. In one embodiment, the Fc region includes FcMut 207. In one embodiment, the Fc region includes FcMut 208. In one embodiment, the Fc region includes FcMut 209. In one embodiment, the Fc region includes FcMut 210. In one embodiment, the Fc region includes FcMut 211. In one embodiment, the Fc region includes FcMut 212. In one embodiment, the Fc region includes FcMut 213. In one embodiment, the Fc region includes FcMut 214. In one embodiment, the Fc region includes FcMut 215. In one embodiment, the Fc region includes FcMut 216. In one embodiment, the Fc region includes FcMut 217. In one embodiment, the Fc region includes FcMut 218. In one embodiment, the Fc region includes FcMut 219. In one embodiment, the Fc region includes FcMut 220. In one embodiment, the Fc region includes FcMut 221. In one embodiment, the Fc region includes FcMut 222. In one embodiment, the Fc region includes FcMut 223. In one embodiment, the Fc region includes FcMut 224. In one embodiment, the Fc region includes FcMut 225. In one embodiment, the Fc region includes FcMut 226. In one embodiment, the Fc region includes FcMut 227. In one embodiment, the Fc region includes FcMut 228. In one embodiment, the Fc region includes FcMut 229. In one embodiment, the Fc region includes FcMut 230.In one embodiment, the Fc region includes FcMut231. In one embodiment, the Fc region includes FcMut232. In one embodiment, the Fc region includes FcMut233. In one embodiment, the Fc region includes FcMut234. In one embodiment, the Fc region includes FcMut242. In one embodiment, the Fc region includes FcMut243. In one embodiment, the Fc region includes FcMut244.

[0266] Other exemplary Fc mutations are described in, for example, International Application Publication No. WO2018 / 052556, U.S. Patent Application Publication No. US2018 / 0037634, and Booth et al., MAbs. 2018; 10(7): 1098-1110, the entire contents of which are incorporated herein by reference.

[0267] In one implementation, the Fc region is modified to extend the half-life. For example, the Fc region may contain one or more of the following: FcMut183 (T256D-Q311V-A378V), FcMut197 (H285N-T307Q-N315D), FcMut213 (H285D-T307Q-A378V), FcMut215 (T307Q-Q311V-A378V), or FcMut228 (T256D-N286D-T307R-Q311V-A378V) (all according to EU designations).

[0268] In one implementation, the Fc region is modified to enhance ADCC. For example, the Fc region may contain one or more of the following: A330L-I332E-S239D, F243L-R292P-Y300L-V305I-P396L, or S298A-E333A-K334A. In one implementation, defucosylation can be achieved by expression in a cell line (such as CHO) that knocks out fucosyltransferase (FucT8).

[0269] In one implementation, the Fc region is modified to enhance CDC. For example, the Fc region contains S267E-H268F-S324T.

[0270] In one implementation, the Fc region is modified to enhance antibody-dependent phagocytosis (ADCP). For example, the Fc region contains S239D-I332E-A330L.

[0271] In one embodiment, the amino acids in the antibody molecule are only standard amino acids. In another embodiment, the antibody molecule comprises naturally occurring amino acids; their analogs, derivatives, and congeners; amino acid analogs with variant side chains; and / or any of the stereoisomers mentioned above. The antibody molecule may comprise peptide mimics and D- or L-optical isomers of amino acids.

[0272] The peptides of the antibody molecules described herein can be linear or branched, and may contain modified amino acids and intercalated non-amino acids. Antibody molecules can also be modified; for example, by disulfide bond formation, glycosylation, esterification, acetylation, phosphorylation, or any other manipulation, such as coupling with a labeled component. The peptides can be isolated from natural sources, produced from prokaryotic or eukaryotic hosts using recombinant techniques, or may be products of synthetic methods.

[0273] The antibody molecules described herein can be used alone in an unconjugated form or can be bound to certain substances, such as toxins or portions (e.g., therapeutic agents; radioactive compounds; plant, fungal, or bacterial molecules; or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles (e.g., via viral coating proteins)). For example, anti-CD138 antibodies can be conjugated to radioactive isotopes (e.g., α-, β-, or γ-radioactive materials, or β- and γ-radioactive materials).

[0274] Antibody molecules can be derivatized into or linked to other functional molecules (e.g., another peptide or protein). As used herein, a “derivatively modified” antibody molecule is an antibody molecule that has been modified. Methods of derivatization include, but are not limited to, adding a fluorescent moiety, a radioactive nucleotide, a toxin, an enzyme, or an affinity ligand (such as biotin). Thus, antibody molecules include derivatized and other modified forms of antibodies as described herein, including immunoadhesion molecules. For example, antibody molecules can be functionally linked (through chemical coupling, genetic fusion, non-covalent association, or others) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a biantibody), a detection agent, a toxin, a pharmaceutical agent, and / or a protein or peptide that mediates the association of the antibody or antibody moiety with other molecules (such as the streptavidin core region or a polyhistidine tag).

[0275] Certain types of derivatized antibody molecules can be generated by crosslinking two or more antibodies (of the same or different types, for example, to produce bispecific antibodies). Suitable crosslinking agents include heterobifunctional crosslinking agents (e.g., m-maleimide benzoyl-N-hydroxysuccinimide ester) or homobifunctional crosslinking agents (e.g., disuccinimide octanoate) having two different reactive groups separated by suitable spacers. Such crosslinking agents are available from Pierce Chemical Company (Rockford, Illinois).

[0276] Useful detectable agents for derivatizing (or labeling) anti-CD138 antibody molecules include fluorescent compounds, various enzymes, prosthetic groups, luminescent materials, bioluminescent materials, fluorescent emitting metal atoms (e.g., europium (Eu) and other lanthanides), and radioactive materials (described below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, chloro5-dimethylamine-1-naphthalenesulfonate, phycoerythrin, etc. Antibodies can also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, etc. When antibodies are derivatized with detectable enzymes, other reagents added to the enzyme to generate a detectable reaction product can be used to detect the antibody. For example, when the detectable agent horseradish peroxidase is present, hydrogen peroxide and diaminobenzidine are added to generate a detectable color reaction product. Prosthetic groups (e.g., streptavidin / biotin and avidin / biotin) can also be used to derivatize antibody molecules. For example, biotin-derived antibodies can be used, and the antibodies can be detected by indirect assays of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, luciferin, luciferin isothiocyanate, rhodamine, dichlorotriazineamine luciferin, dansyl chloride, or phycoerythrin; examples of luminescent materials include luminol; examples of bioluminescent materials include luciferase, luciferin, and jellyfish luminescent protein.

[0277] Labeled antibody molecules may be used, for example, diagnostically and / or experimentally, including (i) for isolating predetermined antigens by standard techniques such as affinity chromatography or immunoprecipitation; (ii) for detecting predetermined antigens (e.g., in cell lysates or cell supernatants) to evaluate protein expression patterns and abundance; and (iii) for monitoring protein levels in tissues as part of clinical trials, for example, to determine the efficacy of a given treatment regimen.

[0278] Antibody molecules can be conjugated to other molecular entities, typically markers or therapeutic agents (e.g., antimicrobial agents, antibacterial agents or bactericides), immunomodulators, immunostimulants, cytotoxic agents, or cell inhibitors) or portions thereof. Radioactive isotopes can be used in detection or therapeutic applications. Radioactive isotopes that can be conjugated to antibody molecules include, but are not limited to, α-, β-, or γ-radioactive bodies, or β- and γ-radioactive bodies. Such radioactive isotopes include, but are not limited to, iodine (…). 131 I or 125 I), yttrium ( 90 Y), Lutetium ( 177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth 212 Bior 213 Bi), indium ( 111 In), Technetium (99 mTc), phosphorus ( 32 P), rhodium 188 Rh), sulfur ( 35 S), carbon ( 14 C), Tritium ( 3 H), chromium 51 Cr), chlorine ( 36 Cl), cobalt ( 57 Co or 58 Co), iron ( 59 Fe), selenium ( 75 Se) or gallium ( 67 Radioisotopes that can be used as therapeutic agents include: yttrium (Ga). 90 Y), Lutetium ( 177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth 212 Bior 213 Bi) and rhodium ( 188 Rh). Radioactive isotopes that can be used as markers, such as those used for diagnosis, include: iodine ( 131 I or 125 I), indium ( 111 In), Technetium ( 99 mTc), phosphorus ( 32 P), carbon ( 14 C) and tritium ( 3 H), or one or more of the therapeutic isotopes listed above.

[0279] This disclosure provides radiolabeled antibody molecules and labeling methods thereof. In one embodiment, a method for labeling antibody molecules is disclosed. The method includes contacting the antibody molecules with a chelating agent to generate a conjugated antibody. The conjugated antibody is then coated with a radioactive isotope (e.g., 111 indium, 90 Yttrium and 177 Lutetium is used for radiolabeling to produce labeled antibody molecules.

[0280] In one aspect, this disclosure provides a method for preparing the humanized antibody molecule disclosed herein. The method includes: providing an antigen (e.g., CD138) or a fragment thereof; obtaining a humanized antibody molecule that specifically binds to the antigen; and evaluating the efficacy of the antibody molecule in regulating the activity of the antigen and / or biological expression of the antigen (e.g., CD138). The method may further include administering the antibody molecule, including derivatives thereof (e.g., human), to a subject (e.g., a human).

[0281] This disclosure provides isolated nucleic acid molecules encoding the aforementioned antibody molecules, their vectors, and host cells. Nucleic acid molecules include, but are not limited to, RNA, genomic DNA, and cDNA.

[0282] Table 1 describes the amino acid sequences of exemplary antibody molecules. Table 2 describes the amino acid and nucleotide sequences of exemplary VH and VL. Any VH described in Table 2 may be paired with any VL described in Table 2 to form exemplary humanized anti-CD138 antibody molecules. Antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422 are sometimes also referred to herein as mAbs 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422.

[0283] Other exemplary antibody molecules are described in PCT Publication No. WO 2019 / 070726 or U.S. Patent Application Publication No. US2019 / 0100588, the full text of which is incorporated herein by reference.

[0284] Table 1. Exemplary anti-CD138 antibodies. The amino acid sequences of the heavy chain variable region (VH) and light chain variable region (VL) are provided below. The CDRs are indicated according to the Kabat or Chothia system.

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297] Table 2. Exemplary amino acid and nucleotide sequences of heavy chain variable regions (VH) and light chain variable regions (VL). CDRs defined according to the Kabat system are underlined and bolded, while CDRs defined according to the Chothia system are italicized.

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] In one embodiment, the antibody molecule includes one, two, or three CDRs (using the CDR definitions of Kabat or Chothia) of the VH region of the antibody molecule as described herein (e.g., in Table 1 or 2). In one embodiment, the antibody molecule includes one, two, or three CDRs (using the CDR definitions of Kabat or Chothia) of the VL region of the antibody molecule as described herein (e.g., in Table 1 or 2). In one embodiment, using the CDR definitions of Kabat or Chothia, the antibody molecule includes one or more (e.g., two or three) CDRs of the VH region and one or more (e.g., two or three) CDRs of the VL region of the antibody molecule as described herein (e.g., in Table 1 or 2).

[0308] In one embodiment, the antibody molecule comprises one, two, or three HCDRs as described in Table 1 or 2. In one embodiment, the antibody molecule comprises one, two, or three LCDRs as described in Table 1 or 2. In one embodiment, the antibody molecule comprises one or more (e.g., two or three) HCDRs and one or more (e.g., two or three) LCDRs as described in Table 1 or 2.

[0309] In one embodiment, the antibody molecule includes one, two, three, or four frames of the VH region of the antibody molecule described in Table 1 or 2. In one embodiment, the antibody molecule includes one, two, three, or four frames of the VL region of the antibody molecule described in Table 1 or 2. In one embodiment, the antibody molecule includes one or more (e.g., two, three, or four) frames of the VH region and one or more (e.g., two, three, or four) frames of the VL region of the antibody molecule described in Table 1 or 2.

[0310] In one embodiment, the antibody molecule comprises the VH of the antibody molecule described herein (e.g., in Table 1 or 2). In one embodiment, the antibody molecule comprises the VL of the antibody molecule described herein (e.g., in Table 1 or 2). In one embodiment, the antibody molecule comprises both the VH and VL of the antibody molecule described herein (e.g., in Table 1 or 2).

[0311] In one embodiment, the antibody molecule comprises a VH having the amino acid sequence described in Table 1 or 2 or a substantially identical amino acid sequence thereon (e.g., differing from it by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or having at least 85, 90, 95, or 99% similarity). In one embodiment, the antibody molecule comprises a VL having the amino acid sequence described in Table 1 or 2 or a substantially identical amino acid sequence thereon (e.g., differing from it by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or having at least 85, 90, 95, or 99% similarity). In one embodiment, the antibody molecule comprises a VH having the amino acid sequence described in Table 1 or 2 (or a substantially identical amino acid sequence thereon) and a VL having the amino acid sequence described in Table 1 or 2 (or a substantially identical amino acid sequence thereon).

[0312] In one embodiment, the antibody molecule comprises a VH encoded by a nucleotide sequence described in Table 2 or a substantially identical nucleotide sequence thereof (e.g., differing from it by no more than 3, 6, 15, 30, or 45 nucleotides, or being at least about 85%, 90%, 95%, or 99% identical). In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence described in Table 2 or a substantially identical nucleotide sequence thereof (e.g., differing from it by no more than 3, 6, 15, 30, or 45 nucleotides, or being at least about 85%, 90%, 95%, or 99% identical). In one embodiment, the antibody molecule comprises a VH encoded by a nucleotide sequence described in Table 2 (or a substantially identical nucleotide sequence thereof) and a VL encoded by a nucleotide sequence described in Table 2 (or a substantially identical nucleotide sequence thereof).

[0313] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0314] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0315] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466, and VL comprises the amino acid sequence SEQ ID NO: 475.

[0316] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0317] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0318] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0319] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0320] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0321] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466, and VL comprises the amino acid sequence SEQ ID NO: 481.

[0322] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0323] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0324] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 470. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 470, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0325] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0326] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0327] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 470. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 470, and VL comprises the amino acid sequence SEQ ID NO: 481.

[0328] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0329] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0330] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471, and VL comprises the amino acid sequence SEQ ID NO: 475.

[0331] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0332] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0333] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0334] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0335] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0336] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471, and VL comprises the amino acid sequence SEQ ID NO: 477.

[0337] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0338] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0339] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 471, and VL comprises the amino acid sequence SEQ ID NO: 481.

[0340] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYTFTSY (SEQ ID NO: 322); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFTSY (SEQ ID NO: 322); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0341] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0342] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 472. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 472, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0343] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0344] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0345] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473, and VL comprises the amino acid sequence SEQ ID NO: 475.

[0346] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0347] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0348] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0349] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYNFASY (SEQ ID NO: 517); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0350] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0351] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 473, and VL comprises the amino acid sequence SEQ ID NO: 481.

[0352] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 356); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 356); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0353] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYIH (SEQ ID NO: 518); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYIH (SEQ ID NO: 518); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0354] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 463. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 463, and VL comprises the amino acid sequence SEQ ID NO: 477.

[0355] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0356] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYIH (SEQ ID NO: 518); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYAQKFQG (SEQ ID NO: 519); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYIH (SEQ ID NO: 518); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYAQKFQG (SEQ ID NO: 519); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2, comprising the amino acid sequence VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3, comprising the amino acid sequence QQLVQYPYT (SEQ ID NO: 511).

[0357] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 464. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 464, and VL comprises the amino acid sequence SEQ ID NO: 476.

[0358] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0359] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0360] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466, and VL comprises the amino acid sequence SEQ ID NO: 477.

[0361] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYSFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2, comprising the amino acid sequence VLSTRAS (SEQ ID NO: 521); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFSSY (SEQ ID NO: 355); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2, comprising the amino acid sequence VLSTRAS (SEQ ID NO: 521); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0362] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2, comprising the amino acid sequence VLSTRAS (SEQ ID NO: 521); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2, comprising the amino acid sequence VLSTRAS (SEQ ID NO: 521); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0363] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 480. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 466, and VL comprises the amino acid sequence SEQ ID NO: 480.

[0364] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence GYTFTSY (SEQ ID NO: 322); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence GYTFTSY (SEQ ID NO: 322); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO: 351); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0365] In one embodiment, VH comprises one, two, or all of the following: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises one, two, or all of the following: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1, comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2, comprising the amino acid sequence TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3, comprising the amino acid sequence FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1, comprising the amino acid sequence RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2, comprising the amino acid sequence VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3, comprising the amino acid sequence QQLVEYPYT (SEQ ID NO: 354).

[0366] In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 472. In one embodiment, VL comprises the amino acid sequence SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence SEQ ID NO: 472, and VL comprises the amino acid sequence SEQ ID NO: 477.

[0367] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0368] (a) Heavy chain variable region (VH), wherein the VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH contains one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH38, VH43, or VH45 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or is at least 85, 90, 95, 99, or 100% homologous. (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0369] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL20 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0370] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0371] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0372] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0373] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0374] In one embodiment, the antibody molecule comprises:

[0375] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0376] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0377] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0378] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VH38, VH43, or VH45. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH38, VH43, or VH45.

[0379] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VL20, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL20.

[0380] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH38, VH43, or VH45 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL20 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0381] In one embodiment, VH contains the amino acid sequence of VH38, VH43, or VH45 and VL contains the amino acid sequence of VL20.

[0382] In one implementation, the antibody molecule includes an Fc region.

[0383] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0384] (a) Heavy chain variable region (VH), wherein the VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH contains one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH38, VH42, VH43, VH44, VH45, or VH36 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or at least 85, 90, 95, 99, or 99 amino acid residues. 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0385] (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL21 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0386] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0387] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0388] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0389] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0390] In one embodiment, the antibody molecule comprises:

[0391] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0392] (a) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0393] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0394] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequences of VH38, VH42, VH43, VH44, VH45, or VH36. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36.

[0395] In one embodiment, the amino acid sequence contained in VL differs from the amino acid sequence of VL21 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL21.

[0396] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequences of VH38, VH42, VH43, VH44, VH45, or VH36 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL21 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0397] In one embodiment, VH comprises the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36, and VL comprises the amino acid sequence of VL21.

[0398] In one implementation, the antibody molecule includes an Fc region.

[0399] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0400] (a) Heavy chain variable region (VH), wherein the VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH contains one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH38, VH42, VH43, or VH45 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or by at least 85, 90, 95, 99, or 100%. Homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0401] (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL26 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0402] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0403] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0404] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0405] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0406] In one embodiment, the antibody molecule comprises:

[0407] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0408] (a) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0409] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0410] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VH38, VH42, VH43, or VH45. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH38, VH42, VH43, or VH45.

[0411] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VL26, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL26.

[0412] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequences of VH38, VH42, VH43, or VH45 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL26 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0413] In one embodiment, VH comprises the amino acid sequence of VH38, VH42, VH43 or VH45 and VL comprises the amino acid sequence of VL26.

[0414] In one implementation, the antibody molecule includes an Fc region.

[0415] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0416] (a) Heavy chain variable region (VH), wherein the VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH contains one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH43, VH35, VH38, or VH44 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or by at least 85, 90, 95, 99, or 100%. Homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0417] (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL22 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0418] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0419] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0420] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0421] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0422] In one embodiment, the antibody molecule comprises:

[0423] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0424] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0425] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0426] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VH43, VH35, VH38, or VH44. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH43, VH35, VH38, or VH44.

[0427] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VL22, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL22.

[0428] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequences of VH43, VH35, VH38, or VH44 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL22 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0429] In one embodiment, VH comprises the amino acid sequence of VH43, VH35, VH38 or VH44 and VL comprises the amino acid sequence of VL22.

[0430] In one implementation, the antibody molecule includes an Fc region.

[0431] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0432] (a) Heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH38 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0433] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL20, VL21, or VL26 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0434] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0435] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0436] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0437] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0438] In one embodiment, the antibody molecule comprises:

[0439] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0440] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0441] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0442] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VH38, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH38.

[0443] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VL20, VL21, or VL26. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0444] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH38 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL20, VL21 or VL26 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0445] In one embodiment, VH contains the amino acid sequence of VH38 and VL contains the amino acid sequence of VL20, VL21, or VL26.

[0446] In one implementation, the antibody molecule includes an Fc region.

[0447] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0448] (a) Heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH42 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0449] (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL26 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0450] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0451] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0452] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0453] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0454] In one embodiment, the antibody molecule comprises:

[0455] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0456] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0457] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0458] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VH42, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH42.

[0459] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VL21 or VL26, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL21 or VL26.

[0460] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH42 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL21 or VL26 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0461] In one embodiment, VH contains the amino acid sequence of VH42 and VL contains the amino acid sequence of VL21 or VL26.

[0462] In one implementation, the antibody molecule includes an Fc region.

[0463] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0464] (a) Heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH43 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0465] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL20, VL21, VL26, or VL22 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0466] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0467] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0468] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0469] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0470] In one embodiment, the antibody molecule comprises:

[0471] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0472] (a) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0473] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0474] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VH43, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH43.

[0475] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequences of VL20, VL21, VL26, or VL22. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, VL26, or VL22.

[0476] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH43 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL20, VL21, VL26 or VL22 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0477] In one embodiment, VH contains the amino acid sequence of VH43 and VL contains the amino acid sequence of VL20, VL21, VL26 or VL22.

[0478] In one implementation, the antibody molecule includes an Fc region.

[0479] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0480] (a) Heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH45 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0481] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL20, VL21, or VL26 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0482] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0483] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0484] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0485] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0486] In one embodiment, the antibody molecule comprises:

[0487] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0488] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0489] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0490] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VH45, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH45.

[0491] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from, or at least 85, 90, 95, 99, or 100% homology with, the amino acid sequence of VL20, VL21, or VL26. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0492] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH45 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL20, VL21 or VL26 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0493] In one embodiment, VH contains the amino acid sequence of VH45 and VL contains the amino acid sequence of VL20, VL21, or VL26.

[0494] In one implementation, the antibody molecule includes an Fc region.

[0495] On the one hand, this disclosure is characterized by a humanized anti-CD138 antibody molecule comprising one or both of the following:

[0496] (a) Heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH38 (e.g., as listed in Table 1 or 2) by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of the VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or

[0497] (b) Light chain variable region (VL), wherein the VL comprises three light chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR1 of VL22 or VL25 by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; or (iii) LCDR3, wherein the amino acid sequence therein differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0498] In one embodiment, VH comprises: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0499] In one embodiment, VH comprises: (i) HCDR1, which contains the amino acid sequence of HCDR1 of VH; (ii) HCDR2, which contains the amino acid sequence of HCDR2 of VH; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of VH.

[0500] In one embodiment, VL comprises: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of VL by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0501] In one embodiment, VL comprises: (i) LCDR1, which contains the amino acid sequence of LCDR1 of VL; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of VL; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of VL.

[0502] In one embodiment, the antibody molecule comprises:

[0503] (a) VH, comprising: (i) HCDR1, the amino acid sequence of which differs from the amino acid sequence of HCDR1 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; (ii) HCDR2, the amino acid sequence of which differs from the amino acid sequence of HCDR2 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology; and (iii) HCDR3, the amino acid sequence of which differs from the amino acid sequence of HCDR3 of VH by no more than 1, 2, or 3 amino acid residues or has at least 85, 90, 95, 99, or 100% homology.

[0504] (b) VL, comprising: (i) LCDR1, the amino acid sequence of which differs from the amino acid sequence of LCDR1 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; (ii) LCDR2, the amino acid sequence of which differs from the amino acid sequence of LCDR2 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (iii) LCDR3, the amino acid sequence of which differs from the amino acid sequence of LCDR3 of the VL by no more than 1, 2 or 3 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0505] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of the VH; (ii) HCDR2, which comprises the amino acid sequence of HCDR2 of the VH; and (iii) HCDR3, which comprises the amino acid sequence of HCDR3 of the VH; and (b) VL, which comprises: (i) LCDR1, which comprises the amino acid sequence of LCDR1 of the VL; (ii) LCDR2, which comprises the amino acid sequence of LCDR2 of the VL; and (iii) LCDR3, which comprises the amino acid sequence of LCDR3 of the VL.

[0506] In one embodiment, the amino acid sequence contained in VH has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VH38, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, the antibody molecule VH comprises the amino acid sequence of VH38.

[0507] In one embodiment, the amino acid sequence contained in VL has no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues different from the amino acid sequence of VL22 or VL25, or has at least 85, 90, 95, 99, or 100% homology. In one embodiment, VL comprises the amino acid sequence of VL22 or VL25.

[0508] In one embodiment, (a) the amino acid sequence contained in VH differs from the amino acid sequence of VH38 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology; and (b) the amino acid sequence contained in VL differs from the amino acid sequence of VL22 or VL25 by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or has at least 85, 90, 95, 99 or 100% homology.

[0509] In one embodiment, VH contains the amino acid sequence of VH38 and VL contains the amino acid sequence of VL22 or VL25.

[0510] In one implementation, the antibody molecule includes an Fc region.

[0511] In one embodiment, the anti-CD138 antibody molecule includes:

[0512] (a) Heavy chain variable region (VH), wherein the VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH contains one, two, or all of the following: (i) HCDR1 containing the amino acid sequence GYN / S / TFA / S / TSY (SEQ ID NO: 438); (ii) HCDR2 containing the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3 containing the amino acid sequence FVY (SEQ ID NO: 508); and

[0513] (b) Light chain variable region (VL), wherein the VL contains three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), wherein the VL contains one, two or all of the following: (i) LCDR1, which contains the amino acid sequence K / RA / SSK / QSLLYKDGKTYLN (SEQ ID NO: 522); (ii) LCDR2, which contains the amino acid sequence VL / VSS / TL / RA / QS (SEQ ID NO: 523); or (iii) LCDR3, which contains the amino acid sequence QQLVE / QYPYT (SEQ ID NO: 524).

[0514] In one embodiment, the anti-CD138 antibody molecule includes:

[0515] (a) Heavy chain variable region (VH), wherein VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein VH contains one, two, or all of the following: (i) HCDR1 containing the amino acid sequence SYYI / MH (SEQ ID NO: 525); (ii) HCDR2 containing the amino acid sequence TIHPSDSTA / TNYA / NQKFK / QG (SEQ ID NO: 526); or (iii) HCDR3 containing the amino acid sequence FVY (SEQ ID NO: 508); and

[0516] (b) Light chain variable region (VL), wherein the VL contains three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), wherein the VL contains one, two or all of the following: (i) LCDR1, which contains the amino acid sequence K / RA / SSK / QSLLYKDGKTYLN (SEQ ID NO: 522); (ii) LCDR2, which contains the amino acid sequence VL / VSS / TL / RA / QS (SEQ ID NO: 523); or (iii) LCDR3, which contains the amino acid sequence QQLVE / QYPYT (SEQ ID NO: 524).

[0517] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises a common amino acid sequence, or a subgroup thereof, of the HCDR1 sequences of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, and 4422; and (ii) HCDR2, which comprises the HCDR1 sequence of the same antibody. The common amino acid sequence of sequence 2; and (iii) HCDR3, which contains the common amino acid sequence of the HCDR3 sequence of the same antibody; and (b) VL, which contains: (i) LCDR1, which contains the common amino acid sequence of the amino acid sequence of LCDR1 of the same antibody; (ii) LCDR2, which contains the common amino acid sequence of the amino acid sequence of LCDR2 of the same antibody; and (iii) LCDR3, which contains the common amino acid sequence of the amino acid sequence of LCDR3 of the same antibody.

[0518] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises a common amino acid sequence of the HCDR1 sequences of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, and 4422; and (ii) HCDR2, which comprises the HCDR2 sequence of the same antibody. (i) the shared amino acid sequence of the same antibody; and (ii) HCDR3, which contains the shared amino acid sequence of the HCDR3 sequence of the same antibody; and (b) VL, which contains: (i) LCDR1, which contains the shared amino acid sequence of the LCDR1 sequence of the same antibody; (ii) LCDR2, which contains the shared amino acid sequence of the LCDR2 sequence of the same antibody; and (iii) LCDR3, which contains the shared amino acid sequence of the LCDR3 sequence of the same antibody.

[0519] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the anti-CD138 antibody described herein (e.g., selected from antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422), or the amino acid sequence of HCDR1 as listed in Table 1; (ii) HCDR2, It comprises (iii) HCDR2, which contains the amino acid sequence of the anti-CD138 antibody; and (b) HCDR3, which contains the amino acid sequence of the anti-CD138 antibody; and (c) VL, which comprises: (i) LCDR1, which contains the amino acid sequence of the anti-CD138 antibody LCDR1; (ii) LCDR2, which contains the amino acid sequence of the anti-CD138 antibody LCDR2; and (iii) LCDR3, which contains the amino acid sequence of the anti-CD138 antibody LCDR3.

[0520] In one embodiment, the anti-CD138 antibody molecule includes:

[0521] (a) Heavy chain variable region (VH), wherein VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein VH contains one, two, or all of the following: (i) HCDR1 containing the amino acid sequence GYN / S / TFA / S / TSY (SEQ ID NO: 438); (ii) HCDR2 containing the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3 containing the amino acid sequence FVY (SEQ ID NO: 508); and

[0522] (b) Light chain variable region (VL), wherein the VL contains three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), wherein the VL contains one, two or all of the following: (i) LCDR1, which contains the amino acid sequence K / RA / SSK / QSLLYKDGKTYLN (SEQ ID NO: 522); (ii) LCDR2, which contains the amino acid sequence VL / VSS / TL / RA / QS (SEQ ID NO: 523); or (iii) LCDR3, which contains the amino acid sequence QQLVE / QYPYT (SEQ ID NO: 524).

[0523] In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 355, 322, 517, or 356, HCDR2 comprises the amino acid sequence of SEQ ID NO: 351, and HCDR3 comprises the amino acid sequence of FVY (SEQ ID NO: 508). In one embodiment, LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515, or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516, or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511. In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 355, 322, 517 or 356, HCDR2 comprises the amino acid sequence of SEQ ID NO: 351, and HCDR3 comprises the amino acid sequence of FVY (SEQ ID NO: 508), LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511.

[0524] In one embodiment, the anti-CD138 antibody molecule includes:

[0525] (a) Heavy chain variable region (VH), wherein VH contains three heavy chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), wherein VH contains one, two, or all of the following: (i) HCDR1 containing the amino acid sequence SYYI / MH (SEQ ID NO: 525); (ii) HCDR2 containing the amino acid sequence TIHPSDSTA / TNYA / NQKFK / QG (SEQ ID NO: 526); or (iii) HCDR3 containing the amino acid sequence FVY (SEQ ID NO: 508); and

[0526] (b) Light chain variable region (VL), wherein the VL contains three light chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), wherein the VL contains one, two or all of the following: (i) LCDR1, which contains the amino acid sequence K / RA / SSK / QSLLYKDGKTYLN (SEQ ID NO: 522); (ii) LCDR2, which contains the amino acid sequence VL / VSS / TL / RA / QS (SEQ ID NO: 523); or (iii) LCDR3, which contains the amino acid sequence QQLVE / QYPYT (SEQ ID NO: 524).

[0527] In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 380 or 518, HCDR2 comprises the amino acid sequence of SEQ ID NO: 382, ​​509, 513, 514 or 519, and HCDR3 comprises the amino acid sequence of FVY (SEQ ID NO: 508). In one embodiment, LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511. In one embodiment, HCDR1 contains the amino acid sequence of SEQ ID NO: 380 or 518, HCDR2 contains the amino acid sequence of SEQ ID NO: 382, ​​509, 513, 514 or 519, and HCDR3 contains the amino acid sequence of FVY (SEQ ID NO: 508), LCDR1 contains the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 contains the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 contains the amino acid sequence of SEQ ID NO: 354 or 511.

[0528] In one embodiment, the antibody molecule comprises: (a) VH, which comprises: (i) HCDR1, which comprises the anti-CD138 antibody described herein, for example, the amino acid sequence of HCDR1 selected from antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422; (ii) HCDR2, which comprises the anti-CD138 antibody described herein, for example, the amino acid sequence of HCDR1 selected from antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422; The amino acid sequence of HCDR2 of the CD138 antibody; and (iii) HCDR3, which contains the amino acid sequence of HCDR3 of the anti-CD138 antibody; and (b) VL, which contains: (i) LCDR1, which contains the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2, which contains the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3, which contains the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0529] In one embodiment, VH comprises the amino acid sequence of VH containing the anti-CD138 antibody, while VL comprises the amino acid sequence of VL containing the anti-CD138 antibody.

[0530] In one implementation, the antibody molecule comprises two VHs and two VLs.

[0531] In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule. In one embodiment, the antibody molecule is a humanized antibody molecule. In one embodiment, the antibody molecule comprises one or more frame regions derived from human frame germline sequences.

[0532] In one embodiment, the antibody molecule includes a VH region containing one or more mutations relative to the anti-CD138 antibody described herein (e.g., antibody 2810, 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0533] In one embodiment, the antibody molecule binds to the extracellular domain of CD138. In one embodiment, the antibody molecule binds to the extracellular region of CD138 near the transmembrane domain. In one embodiment, the antibody molecule is capable of binding to one or more (e.g., two, three, or all) of the following peptides: a peptide comprising the amino acid sequence ENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 440), a peptide comprising the amino acid sequence TAVVAVEPDRRNQSPVDQGATGASQ (SEQ ID NO: 441), a peptide comprising the amino acid sequence ENTAVVAVEPDRRNQSPVDQGATG (SEQ ID NO: 442), or a peptide comprising the amino acid sequence ENTAVVAVEPDRRNQ (SEQ ID NO: 443). In one embodiment, the antibody molecule is capable of binding one or more (e.g., two or all) of the following peptides: a peptide containing the amino acid sequence ENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 440), a peptide containing the amino acid sequence RNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 444), or a peptide containing the amino acid sequence ENTAVVAVEPDRRNQ (SEQ ID NO: 443).

[0534] In one embodiment, the antibody molecule also binds to an extracellular region of CD138 that is distant from the transmembrane domain, for example, a region corresponding to or near the integrin-binding domain (IBD) of CD138. In one embodiment, the antibody molecule is capable of binding to one or both of the following peptides: a peptide containing the amino acid sequence ASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEA (SEQ ID NO: 10), or a peptide containing the amino acid sequence GEAVVLPEVEPGLTA (SEQ ID NO: 445).

[0535] In one embodiment, the antibody molecule is a synthetic antibody molecule. In one embodiment, the antibody molecule is an isolated antibody molecule. In one embodiment, the antibody molecule is a humanized antibody molecule. In one embodiment, the antibody molecule comprises one or more frame regions derived from human frame germline sequences.

[0536] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule includes a heavy chain constant region of IgG selected from IgG1, IgG2, IgG3, or IgG4. In one embodiment, the antibody molecule includes a light chain constant region of the κ or λ light chain.

[0537] In one embodiment, the antibody molecule includes an Fc region containing one or more mutations to increase binding affinity to the nascent receptor FcRn and / or the half-life of the antibody molecule. In another embodiment, the antibody molecule includes an Fc region containing one or more mutations as described herein, such as to increase half-life, ADCC, CDC, or ADCP, or one or more of these mutations.

[0538] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule includes a heavy chain constant region of IgG selected from IgG1, IgG2, IgG3, or IgG4. In one embodiment, the antibody molecule includes a light chain constant region of the κ or λ light chain.

[0539] In one embodiment, the antibody molecule includes an Fc region containing one or more mutations to increase binding affinity to the nascent receptor FcRn and / or the half-life of the antibody molecule. In one embodiment, the antibody molecule includes an Fc region containing one or more mutations as described herein, for example, to increase one or more of ADCC, CDC, or ADCP. In one embodiment, for example, as determined by the methods described herein, the antibody molecule induces ADCC activity that is at least 10% greater (e.g., at least 15%, 20%, 25%, 30%, 35%, or 40%) than a reference anti-CD138 antibody (e.g., antibody BB4).

[0540] In one embodiment, the antibody molecule further comprises a heavy chain constant region. In one embodiment, the heavy chain constant region is an IgG1 constant region or a functional portion thereof. In another embodiment, the heavy chain constant region is an IgG2 constant region or a functional portion thereof. In one embodiment, the antibody molecule further comprises a light chain constant region. In one embodiment, the antibody molecule further comprises both a heavy chain constant region and a light chain constant region. In one embodiment, the antibody molecule comprises the heavy chain constant region, the light chain constant region, and the heavy and light chain variable regions of the antibody molecules described in Table 1 or 2 herein. In some embodiments, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and a variable region, which comprises one, two, three, four, five, or six CDRs of the antibody molecules described in Table 1 or 2.

[0541] An exemplary heavy chain constant region is described below.

[0542] IgG1 HC constant region:

[0543] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:446)

[0544] IgG2 HC constant region:

[0545] ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHN AKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:447)

[0546] In one embodiment, the antibody molecule comprises a heavy chain sequence (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity) listed in Table 6. In one embodiment, the antibody molecule comprises a heavy chain containing one or more (e.g., 1, 2, 3, 4, or 5) of the sequences listed in Table B, or one or more amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity. In one embodiment, the antibody molecule comprises a light chain sequence (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity) listed in Table 6. In one embodiment, the antibody molecule comprises a light chain containing one or more (e.g., 1, 2, or 3) of the sequences listed in Table 8, or one or more amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with it.

[0547] In one embodiment, the antibody molecule comprises one, two, or all of the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule comprises all of the CH1, CH2, and CH3 sequences listed in Table 7 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule also comprises the heavy chain constant hinge region sequences listed in Table 7 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them).

[0548] In one embodiment, the antibody molecule comprises a light chain constant region sequence (e.g., CL) listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith). In one embodiment, the antibody molecule further comprises a light chain constant hinge region sequence (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith) listed in Table 8.

[0549] In one embodiment, the antibody molecule comprises one, two, or all of the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them), and the light chain constant region sequences (e.g., CL) listed in Table 8 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule comprises all the CH1, CH2, and CH3 sequences listed in Table 7 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them), and the light chain constant hinge region sequence listed in Table 8 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule comprises the heavy chain constant hinge region sequence (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity) listed in Table 7, and the light chain constant hinge region sequence (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity) listed in Table 8.

[0550] In one embodiment, the antibody molecule comprises one, two, or all of the amino acid sequences of SEQ ID NO: 529, 531, or 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule comprises all of the amino acid sequences of SEQ ID NO: 529, 531, and 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with them). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 530 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with it).

[0551] In one embodiment, the antibody molecule comprises the amino acid sequence of SEQ ID NO: 534 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 533 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith).

[0552] In one embodiment, the antibody molecule comprises one, two, or all of the amino acid sequence of SEQ ID NO: 534 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith) and the amino acid sequences of SEQ ID NO: 529, 531, or 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith). In one embodiment, the antibody molecule comprises all of the amino acid sequence of SEQ ID NO: 534 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith) and the amino acid sequences of SEQ ID NO: 529, 531, and 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 530 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith) and / or the amino acid sequence of SEQ ID NO: 533 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity therewith).

[0553] In one embodiment, the antibody molecule comprises one, two, three, four, five, or all of the amino acid sequence of SEQ ID NO: 529-534.

[0554] Table 6. Heavy and light chain sequences of mAb 4320

[0555]

[0556]

[0557] Table 7. Notes on the heavy chain sequence of mAb 4320

[0558]

[0559] The CDR band is underlined in the variable region (VH) as defined by Chothia. The heavy chain constant region is the constant γ1 (m3 allotype) of the human immunoglobulin heavy chain. Any humanized anti-CD138 antibody molecule described herein (e.g., antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422) may contain constant CH1, hinge, CH2, and / or CH3 sequences as described in Table 7.

[0560] Table 8. Notes on the light chain sequence of mAb 4320

[0561]

[0562] The CDR is underlined in the variable region (VL) as defined by Chothia. The light chain is Homo sapiens κ constant *01. Any humanized anti-CD138 antibody molecule described herein (e.g., antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422) may contain constant CL and / or hinge sequences as described in Table 8.

[0563] In one embodiment, the antibody molecule is a multivalent (e.g., bivalent, trivalent, or tetravalent) antibody molecule. In one embodiment, the antibody molecule binds to two or more (e.g., three or four) different regions of CD138. For example, the antibody molecule may contain two or more sets of identical or substantially identical VH-VL pairs, wherein each VH-VL pair binds to two or more different regions of CD138. As another example, the antibody molecule may contain two or more sets of different VH-VL pairs, wherein each VH-VL pair binds to a different region of CD138.

[0564] In one embodiment, the antibody molecule is a multispecific (e.g., bispecific, trispecific, or tetraspecific) antibody molecule. In one embodiment, the antibody molecule has a first binding specificity for CD138 and a second binding specificity different from CD138. For example, the antibody molecule may contain two or more sets of identical or substantially identical VH-VL pairs, wherein each VH-VL pair has a first binding specificity and a second binding specificity. As another example, the antibody molecule may contain two or more sets of different VH-VL pairs, wherein each VH-VL pair has a different binding specificity.

[0565] In one embodiment, as determined by the methods described herein, the humanized antibody molecule is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times more stable in vitro than a reference antibody molecule, such as an associated non-humanized antibody molecule. In one embodiment, the humanized antibody molecule has a first thermal transition temperature of at least about 62°C, for example, about 65°C to about 70°C (e.g., about 65°C, 66°C, 67°C, 68°C, 69°C, or 70°C), determined, for example, by differential scanning calorimetry (DSF). In one embodiment, the humanized antibody molecule has a second thermal transition temperature of at least about 70°C, for example, about 75°C to about 80°C (e.g., about 75°C, 76°C, 77°C, 78°C, 79°C, or 80°C), determined, for example, by DSF.

[0566] In one embodiment, as determined by the methods described herein, the humanized antibody molecule is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times more stable in vivo than a reference antibody molecule, such as a related non-humanized antibody molecule. In one embodiment, as determined by the methods described herein, the serum half-life (in humans or animal models) of the antibody molecule is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times longer than a reference antibody molecule, such as a related non-humanized antibody molecule.

[0567] Antibody-drug conjugates

[0568] As used herein, the term "antibody-drug conjugate" or ADC refers to an antibody molecule conjugated to a non-antibody moiety, such as a therapeutic agent or a marker (e.g., a cytotoxic agent). Antibody molecules can be conjugated to non-antibody moieties directly or indirectly, such as through a linker.

[0569] In one embodiment, the antibody molecule is covalently coupled to the non-antibody portion. In one embodiment, the antibody molecule is coupled to the non-antibody portion via a peptide bond. In one embodiment, the antibody molecule is coupled to the non-antibody portion via a non-peptide bond. In one embodiment, the antibody molecule is not coupled to the non-antibody portion via a non-peptide bond. In one embodiment, the non-antibody portion is also referred to as the "carrier".

[0570] In one embodiment, the non-antibody portion is coupled to the backbone of the antibody molecule. In another embodiment, the non-antibody portion is coupled to the side chain of the antibody molecule. In one embodiment, two or more (e.g., three, four, five, six, seven, eight or more) non-antibody portions are coupled to the antibody molecule.

[0571] In one implementation, the ADC comprises an antibody molecule that binds to CD138, such as the humanized anti-CD138 antibody molecule described herein.

[0572] In one implementation, the ADC comprises one, two, or three CDRs of the VH region of the antibody molecules described in Table 1 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422), using the CDR definitions of Kabat or Chothia. In one implementation, the ADC comprises one, two, or three CDRs of the VL region of the antibody molecules described in Table 1 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422), using the CDR definitions of Kabat or Chothia. In one implementation, the ADC comprises one or more (e.g., two or three) CDRs of the VH region and / or one or more (e.g., two or three) CDRs of the VL region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422), using the CDR definition of Kabat or Chothia.

[0573] In one embodiment, the ADC includes one, two, or three VH CDRs as described in Table 1 or 2. In one embodiment, the ADC includes one, two, or three VL CDRs as described in Table 1 or 2. In one embodiment, the ADC includes one or more (e.g., two or three) VH CDRs and / or one or more (e.g., two or three) VL CDRs as described in Table 1 or 2.

[0574] In one embodiment, the ADC includes one, two, three, or four frame regions of the VH region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422). In one embodiment, the ADC includes one, two, three, or four frame regions of the VL region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422). In one implementation, the ADC includes one or more (e.g., two, three, or four) frame regions of the VH region and / or one or more (e.g., two, three, or four) frame regions of the VL region of antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0575] In one embodiment, the ADC includes the heavy chain variable region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422). In one embodiment, the ADC includes the light chain variable region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422). In one embodiment, the ADC includes a heavy chain variable region and a light chain variable region of the antibody molecule described in Table 1 or 2 (e.g., any one of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0576] In one embodiment, the ADC includes a heavy chain variable region having the amino acid sequence described in Table 1 or 2. In one embodiment, the ADC includes a light chain variable region having the amino acid sequence described in Table 1 or 2. In one embodiment, the ADC includes a heavy chain variable region having the amino acid sequence described in Table 1 or 2 and a light chain variable region having the amino acid sequence described in Table 1 or 2.

[0577] In one embodiment, the antibody molecule includes a heavy chain variable region encoded by the nucleotide sequences described in Table 2. In one embodiment, the antibody molecule includes a light chain variable region encoded by the nucleotide sequences described in Table 2. In one embodiment, the antibody molecule includes both a heavy chain variable region encoded by the nucleotide sequences described in Table 2 and a light chain variable region encoded by the nucleotide sequences described in Table 2.

[0578] In one embodiment, the ADC includes a heavy chain constant region. In one embodiment, the ADC includes a light chain constant region. In one embodiment, the ADC includes both a heavy chain constant region and a light chain constant region. In one embodiment, the ADC includes the heavy chain constant region, the light chain constant region, and the heavy and light chain variable regions of the antibody molecule described in Table 1 or 2 herein. In some embodiments, the ADC includes a heavy chain constant region, a light chain constant region, and a variable region, which includes one, two, three, four, five, or six CDRs of the antibody molecule described in Table 1 or 2.

[0579] In one embodiment, the ADC includes one, two, or all of the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7. In one embodiment, the ADC includes all of CH1, CH2, and CH3 listed in Table 7. In one embodiment, the ADC also includes the heavy chain constant hinge region sequences listed in Table 7. In one embodiment, the ADC includes the light chain constant region sequences (e.g., CL) listed in Table 8. In one embodiment, the ADC also includes the light chain constant hinge region sequences listed in Table 8.

[0580] In one embodiment, the ADC comprises one, two, or all of the light chain constant region sequences (e.g., CL) listed in Table 8 and the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7. In one embodiment, the ADC comprises all of the light chain constant hinge region sequences listed in Table 8 and CH1, CH2, and CH3 listed in Table 7. In one embodiment, the ADC further comprises the heavy chain constant hinge region sequences listed in Table 7 and / or the light chain constant hinge region sequences listed in Table 8.

[0581] In one embodiment, the ADC comprises a heavy chain containing the amino acid sequences described in Table 6 or 8. In one embodiment, the ADC comprises a light chain containing the amino acid sequences described in Table 6 or 7. In one embodiment, the ADC comprises a heavy chain containing the amino acid sequences described in Table 6 or 8 and a light chain containing the amino acid sequences described in Table 6 or 7.

[0582] In one embodiment, the non-antibody molecule comprises a cytotoxic agent (e.g., any cytotoxic agent active against cancer). In one embodiment, the cytotoxic agent is selected from microtubule polymerase inhibitors (e.g., retoxetine), agents associated with microtubule depolymerization (e.g., maytansine), agents associated with DNA cleavage (e.g., galiceramycin), DNA minor groove alkylating agents (e.g., ducamycin), DNA minor groove cross-linking agents (e.g., PBD dimer), or RNA polymerase II inhibitors (e.g., α-amanitin).

[0583] In one embodiment, the cytotoxic agent is α-amanitin. α-Amanitin is a bicyclic octapeptide belonging to a large class of protoplasmic mushroom toxins called amatoxins. α-Amanitin binds to the bridging helix of RNA polymerase II, inhibiting the translocation of RNA and DNA required to clear the site for the next round of synthesis, thereby reducing the transcription rate. α-Amanitin and its use in ADCs are described, for example, Moldenhauer et al. J Natl Cancer Inst. 2012; 104(8): 622-634. The structure of α-Amanitin is as follows:

[0584]

[0585] In one embodiment, the cytotoxic agent is a nostocin analogue. Nostocins are a group of cyanobacterial condensates that exhibit significant biological activity against multidrug-resistant (MDR) cancer cells. Nostocins prevent cell division by consuming microtubules through interaction with tubulin. They can induce apoptosis, possibly through other mechanisms besides microtubule inhibition-mediated apoptosis. Nostocins, analogues, and their use in ADCs are described, for example, in Shih and Teicher. Curr Pharm Des. 2001; 7(13): 1259-1276; Eggen and Georg. Med Res Rev. 2002; 22(2): 85-101. The structures of nostocin analogues are as follows:

[0586]

[0587] In one embodiment, the cytotoxic agent is galicariin (also known as LL-E33288). Galicariin contacts DNA and induces Bergman circularization, leading to DNA cleavage and thus cell destruction. Galicariin and its use in ADCs are described, for example, in Maiese et al. J Antibiot (Tokyo). 1989; 42(4): 558-563; Watanabe et al. ChemBiol. 2002; 9(2): 245-251; Ricart and Tolcher. Nat Clin Pract Oncol. 2007; 4: 245-255. The structure of galicariin is as follows.

[0588]

[0589] In one embodiment, the cytotoxic agent is centanamycin. Centanamycin is also known as ML-970, AS-1-145, NSC 716970, or N-[4-amino-1-(2-chloroethyl)-2-naphthyl]-5,6,7-trimethoxy-1H-indole-2-carboxamide. Centanamycin binds to AT-rich DNA minor grooves and alkylates the DNA. Centanamycin and its use in ADCs are described, for example, Rayburn et al. Cancer Chemother Pharmacol. 2012; 69(6): 1423-31.

[0590] In one embodiment, the cytotoxic agent is dolastatin. In one embodiment, the dolastatin is dolastatin 10 or dolastatin 15. Dolastatin class noncompetitively inhibits the binding of vincristine to tubulin in the vinca / peptide region. Analogs of dolastatin include, for example, symplostatin 1, symplostatin 3, and retinoxetine. Dolastatin, analogs, and their uses are described in, for example, Amador et al. Annals of Oncology. 2003; 14: 1607-1615; Kijjoa and Sawangwong. Mar Drugs. 2004; 2(2): 73-82; Luesch et al. J Nat Prod. 2001; 64(7): 907-910; Luesch et al. J Nat Prod. 2002; 65(1): 16-20. The structure of dolastatin 10 is as follows:

[0591]

[0592] The structure of saccharin 15 is as follows:

[0593]

[0594] In one embodiment, the cytotoxic agent is a duocarmycin analog. Duocarmycin analogs are DNA minor groove, AT sequence selectors, and adenine N3 alkylating agents. Duocarmycin, analogs, and their use in ADCs are described, for example, Tietze and Krewer. Chem Biol Drug Des. 2009; 74(3): 205-211; Cacciari et al. Expert Opinion on Therapeutic Patents. 2000; 10(12): 1853-1871; Tercel et al. AngewChem Int Ed Engl. 2013; 52(21): 5442-5446. Exemplary duocarmycins and analogs include, for example, duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, and CC-1065. The structure of duocarmycin A is as follows:

[0595]

[0596] In one embodiment, the cytotoxic agent is maytansine. Maytansine (a benzoadamantane lactone) is a highly effective microtubule-targeting compound that induces mitotic arrest and kills tumor cells at sub-nanomolar concentrations. Maytansine and its analogues (matansine compounds DM1 and DM4) are effective microtubule-targeting compounds that inhibit cell proliferation during mitosis. Maytansine is described in, for example, Lopus et al. Mol Cancer Ther. 2010; 9(10): 2689-2699; Widdison et al. J Med Chem. 2006; 49(14): 4392-4408; Liu et al. J Mass Spectrom. 2005; 40(3): 389-399; Tassone et al. Cancer Res. 2004; 64(13): 4629-4636; Sawada et al. Bioconjug Chem. 1993; 4(4): 284-289. The structure of maytansine is as follows:

[0597]

[0598] In one embodiment, the cytotoxic agent is monomethylreoxetine E (MMAE, vedotin). MMAE is a potent antimitotic agent that inhibits cell division by preventing the polymerization of tubulin. MMAE and its use in ADCs are described, for example, Francisco et al. Blood. 2003; 102(4): 1458-1465; Junutula et al. Nat Biotechnol. 2008; 26(8): 925-932; Asundi et al. Clin Cancer Res. 2011; 17(5): 965-975; Younes et al. J Clin Oncol. 2012; 30(18): 2183-2189; Pettit et al. Anticancer Drug Des. 1995; 10(7): 529-544; Doronina et al. Nat Biotechnol. 2003; 21(7): 778-784. The structure of MMAE is as follows:

[0599]

[0600] In one embodiment, the cytotoxic agent is monomethylreoxetine F (MMAF). MMAF is an anti-tubulin agent that inhibits cell division by preventing the polymerization of tubulin. It is a reoxetine derivative with a charged C-terminal phenylalanine residue, exhibiting reduced cytotoxic activity compared to its uncharged counterpart, monomethylreoxetine E (MMAE). MMAF can induce potent antitumor activity when conjugated to monoclonal antibodies targeting internalized tumor-specific cell surface antigens via protease-cleaving linkers. For example, the linker to the monoclonal antibody is stable in the extracellular fluid, but once the conjugate enters tumor cells, cathepsins can cleave it, thereby activating antimitotic mechanisms. MMAF and its use in ADCs are described in, for example, Smith et al. Mol Cancer Ther. 2006 5; 1474-1482; Doronina et al. Bioconjug Chem. 2006; 17(1): 114-24; Oflazoglu et al. Clin Cancer Res. 2008; 14(19): 6171-6180; Nilsson et al. Cancer. 2010; 116(4 Supplement): 1033-1042. The structure of MMAF is as follows:

[0601]

[0602] In one embodiment, the cytotoxic agent is pyrrolobenzodiazepine (PBD). PBD is a class of sequence-selective DNA minor groove binding cross-linking agents. The mechanism of action of PBD is related to its ability to form adducts in the minor groove, thereby interfering with DNA processing. Exemplary agents belonging to the class of pyrrolobenzodiazepine antibiotics include, but are not limited to, anthramycin, gibberellin, gecirammycin, DC-81, methylaminopicrin, neopicrin A, neopicrin B, roxithromycin, prothracarcin, sibanomicin (DC-102), sibiromycin, and tomamycin. PBD and its use in ADCs are described in, for example, Antonow and Thurston DE. Chem Rev. 2011; 111: 2815-2864; Cipolla et al. Anticancer Agents Med Chem. 2009; 9: 1-31; Geratana. Med Res Rev. 2012; 32: 254-293; Li et al. Appl Environ Microbiol. 2009; 75(9): 2869-2878; Rahman et al. Org. Biomol. Chem. 2011; 9: 1632-1641; Saunders et al. Sci Transl Med. 2015; 7(302): 302ra136; Hu et al. Chem Biol. 2007; 14(6): 691-701. The structure of PBD is as follows:

[0603]

[0604] In one embodiment, the ADC further includes a linker, for exam...

Claims

1. An anti-CD138 antibody molecule comprising: (a) a heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises: (i) an HCDR1 consisting of the amino acid sequence of SEQ ID NO: 355, an HCDR2 consisting of the amino acid sequence of SEQ ID NO: 351, and an HCDR3 consisting of the amino acid sequence of SEQ ID NO: 508, according to the Chothia numbering system; or (ii) an HCDR1 consisting of the amino acid sequence of SEQ ID NO: 380, an HCDR2 consisting of the amino acid sequence of SEQ ID NO: 514, and an HCDR3 consisting of the amino acid sequence of SEQ ID NO: 508, according to the Kabat numbering system; and (b) a light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises: (i) an LCDR1 consisting of the amino acid sequence of SEQ ID NO: 510, an LCDR2 consisting of the amino acid sequence of SEQ ID NO: 353, and an LCDR3 consisting of the amino acid sequence of SEQ ID NO: 354, according to the Chothia numbering system; or (ii) an LCDR1 consisting of the amino acid sequence of SEQ ID NO: 510, an LCDR2 consisting of the amino acid sequence of SEQ ID NO: 353, and an LCDR3 consisting of the amino acid sequence of SEQ ID NO: 354, according to the Kabat numbering system.

2. The antibody molecule of claim 1, wherein: (a) the VH comprises an amino acid sequence having no more than 15 amino acid residues difference or at least 85% homology to the amino acid sequence of SEQ ID NO: 471 or 466; and / or (b) the VL comprises an amino acid sequence having no more than 15 amino acid residues difference or at least 85% homology to the amino acid sequence of SEQ ID NO:

475.

3. The antibody molecule of claim 1, wherein, the VH comprises the amino acid sequence of SEQ ID NO: 471, and / or the VL comprises the amino acid sequence of SEQ ID NO:

475.

4. The antibody molecule of claim 1, wherein, the VH comprises the amino acid sequence of SEQ ID NO: 466, and / or the VL comprises the amino acid sequence of SEQ ID NO:

475.

5. The antibody molecule of claim 1, comprising a Fc region.

6. The antibody molecule of claim 1, comprising: (a) a heavy chain (HC) comprising an amino acid sequence having no more than 15 amino acid residues difference or at least 85% homology to the amino acid sequence of SEQ ID NO: 527; and / or (b) a light chain (LC) comprising an amino acid sequence having no more than 15 amino acid residues difference or at least 85% homology to the amino acid sequence of SEQ ID NO:

528. (b) a light chain (LC) comprising an amino acid sequence that differs in no more than 15 amino acid residues or has at least 85% homology to the amino acid sequence of SEQ ID NO:

528.

7. The antibody molecule of claim 1, wherein, HC comprises the amino acid sequence of SEQ ID NO: 527, and / or LC comprises the amino acid sequence of SEQ ID NO:

528.

8. The antibody molecule of claim 1, comprising two VH and two VL.

9. The antibody molecule of claim 1, which is a synthetic antibody molecule or an isolated antibody molecule.

10. The antibody molecule of claim 1, which is a monovalent antibody molecule, a multivalent antibody molecule, or a monospecific antibody molecule.

11. The antibody molecule of claim 1, which is a humanized antibody molecule.

12. The antibody molecule of claim 1, comprising one or more framework regions derived from a human framework germline sequence.

13. The antibody molecule of claim 1, which is an IgG antibody.

14. The antibody molecule of claim 1, comprising a heavy chain constant region of an IgG selected from IgGl, IgG2, IgG3, or IgG4.

15. The antibody molecule of claim 1, comprising a light chain constant region of a kappa or lambda light chain.

16. The antibody molecule of claim 1, comprising a heavy chain constant region of IgGl and a light chain constant region of a kappa light chain.

17. The antibody molecule of claim 1, comprising an Fc region comprising one or more mutations to increase binding affinity to the neonatal receptor FcRn and / or half-life of the antibody molecule.

18. The antibody molecule of claim 1, comprising an Fc region comprising one or more mutations to increase one or more of half-life, ADCC, CDC, or ADCP.

19. A pharmaceutical composition comprising the antibody molecule of any one of claims 1-18, and a pharmaceutically acceptable carrier.

20. A nucleic acid molecule encoding a heavy chain variable region (VH) and a light chain variable region (VL) of the antibody molecule of any one of claims 1-18.

21. A vector comprising the nucleic acid molecule of claim 20.

22. A cell comprising the nucleic acid molecule of claim 20.

23. The cell of claim 22, wherein the cell is an isolated cell.

24. A kit comprising the antibody molecule of any one of claims 1-18, and instructions for use of the antibody molecule or composition.

25. A container comprising the antibody molecule of any one of claims 1-18, or a pharmaceutical composition comprising the antibody molecule.

26. A method of producing an anti-CD138 antibody molecule, the method comprising culturing the cell of claim 22 under conditions that allow production of the antibody molecule, thereby producing the antibody molecule.

27. The method of claim 26, further comprising isolating or purifying the antibody molecule.

28. Use of an antibody molecule as defined in any one of claims 1-18 in the manufacture of a medicament for a method of treating a CD138-associated cancer in a subject, wherein the cancer is multiple myeloma.

29. The use of claim 28, wherein the antibody molecule is combined with a second therapeutic agent or treatment method.

30. The use of claim 29, wherein the second therapeutic agent or treatment method comprises a proteasome inhibitor.

31. The use of claim 30, wherein the proteasome inhibitor comprises bortezomib.

32. Use of an antibody molecule as defined in any one of claims 1-18 in the manufacture of a medicament for preventing a CD138-associated cancer, wherein the cancer is multiple myeloma.

33. A non-diagnostic method of detecting a CD138 molecule, the method comprising contacting a cell or a subject in vitro or ex vivo with an antibody molecule as defined in any one of claims 1-18, thereby detecting a CD138 molecule.

34. The method of claim 33, wherein, The antibody molecule is coupled to a detectable label.

Images