CD138 antibody molecules and uses thereof

Abstract

Antibody molecules that specifically bind to CD138 are disclosed. The antibody molecules may 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 benefit of U.S. Provisional Application No. 62 / 566,936, filed on October 2, 2017, and U.S. Provisional Application No. 62 / 725,880, filed on August 31, 2018. The contents of the above applications are incorporated herein by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing, which has been submitted electronically in ASCII format, and its entire contents are incorporated herein by reference. The ASCII copy created on September 26, 2018 is named P2029-7017WO_SL.txt and is 171,304 bytes in size. Background Art

[0005] Multiple myeloma (MM) is a cancer that develops from malignant plasma cells. These tumors usually develop in the bones but are occasionally found in other tissues. The 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, there were an estimated 30,000 new cases in 2017, with an estimated 10,000+ deaths. Despite therapeutic advances in the treatment of multiple myeloma, multiple myeloma remains an incurable disease in the majority of patients.

[0006] There is a need to develop new approaches 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, an antibody molecule bound to CD138 (e.g., human CD138), comprising one or more functions and structural properties disclosed herein. In one embodiment, the antibody molecule can cause effector functions (e.g., antibody-dependent cellular toxicity (ADCC) activity) on cells expressing CD138. In one embodiment, compared to soluble CD138, the antibody molecule preferentially binds to membrane-bound CD138. In one embodiment, the antibody molecule binds to an epitope in the extracellular region of CD138, which is near 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 is not only bound to the IBD of CD138. It is not intended to be limited by theory, it is believed that in one embodiment, by targeting certain extracellular regions on the membrane-bound CD138 near the cell membrane, improved or optimal cytotoxicity can be achieved.

[0008] In one embodiment, the antibody molecule is selected from Table 1, or competes with an anti-CD138 monoclonal antibody selected from Table 1 for binding to CD138. In one embodiment, the antibody molecule binds to an epitope that is identical to or overlaps with 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 and / or one or more light chain variable regions described in Table 1. 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.

[0009] In one embodiment, antibody molecules-drug conjugates (ADCs), nucleic acid molecules encoding antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, containers, and methods for preparing antibody molecules are also provided. The antibody molecules disclosed herein can be used (alone or in combination with other agents or treatments) to treat, prevent and / or diagnose diseases associated with CD138, such as cancer or precancerous conditions (e.g., multiple myeloma or smoldering myeloma).

[0010] Thus, in certain aspects, the disclosure provides antibody molecules, e.g., 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):

[0011] a) with high affinity (e.g., dissociation constant (K D ) is 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, such as less than about 80, 70, 60, 50, 40, 30, 20,

[0012] 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001

[0013] nM) binds to CD138 (e.g., human CD138),

[0014] b) with high affinity (e.g., dissociation constant (K D ) is 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, such as less than about 80, 70, 60, 50, 40, 30, 20,

[0015] 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001

[0016] nM) binds to membrane-bound CD138,

[0017] c) i) 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, such as 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) with low affinity (e.g., dissociation constant (K D ) is greater than about 100 nM, such as greater than about 200, 300, 400 or 500 nM) binds to soluble CD138,

[0018] d) binds to membrane-bound CD138 or the complete extracellular domain of CD138, i) preferably better than soluble CD138, e.g., the binding affinity to membrane-bound CD138 or the complete extracellular domain of CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the binding affinity to soluble CD138; or ii) binds with an affinity similar to the binding affinity to soluble CD138, e.g., the binding affinity to membrane-bound CD138 or the complete extracellular domain of CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the binding affinity to soluble CD138,

[0019] 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, for example, 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,

[0020] f) i) binds to an extracellular region of CD138 distal to the transmembrane domain, e.g., the C-terminus of the region is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids away from the N-terminus of the transmembrane domain; or ii) does not bind or binds with low affinity to an extracellular region of CD138 distal to the transmembrane domain, e.g., the C-terminus of the region is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids away from the N-terminus of the transmembrane domain,

[0021] g) binds to the integrin binding domain (IBD) of CD138 or the N-terminal region of the IDB; or ii)

[0022] does not bind or binds with low affinity to the N-terminal region of the IBD or IDB of CD138,

[0023] h) binds to a CD138 epitope that comprises 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 that is proximal to the transmembrane domain (e.g., a region that comprises 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 an extracellular region that is distal to the transmembrane domain (e.g., a region that comprises amino acids 176-250 (e.g., 176-214 or 210-250) of any one of SEQ ID NOs: 1-3 or 450). NO: 1-3 or 450) in the region of amino acids 23-50, 51-95, 88-121, 88-102, or 111-150 of any one of NO: 1-3 or 450,

[0024] i) a multivalent (e.g., bivalent, trivalent, or tetravalent) antibody molecule that binds to two or more different regions of CD138, e.g., 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 different regions,

[0025] j) does not bind to an extracellular region comprising a region distal to the transmembrane domain (e.g., comprising SEQ ID NO:

[0026] 1-3 or 450) in the region of amino acids 23-50, 51-95, 88-121, 88-101, or 111-150 of any of

[0027] 15, 15, 20, 25, 30, 35 or more) consecutive amino acid residues of a CD138 epitope, k) binds with high affinity to a cancer cell or precancerous cell (e.g., a myeloma cell) expressing CD138,

[0028] l) binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte, or an eosinophil),

[0029] m) induce effector functions (e.g. ADCC activity) on target cells expressing CD138,

[0030] n) binds to C1q and induces complement-dependent cytotoxicity (CDC) on target cells expressing CD138,

[0031] o) mediating homotypic adhesion of one or more CD138-expressing cells,

[0032] p) inhibiting the action of proteases on membrane-bound CD138, such as reducing the shedding of CD138;

[0033] q) reducing (e.g., inhibiting) one or more biological activities of CD138-expressing cells in vitro, ex vivo, or in vivo,

[0034] r) reducing (e.g., inhibiting) one or more functions of CD138 (e.g., binding of CD138 to a ligand) in vitro, ex vivo, or in vivo,

[0035] s) reducing (e.g., inhibiting) the proliferation of CD138-expressing cancer cells or precancerous cells,

[0036] t) binds to an epitope on CD138 that is identical, similar, or overlapping with the epitope recognized by the anti-CD138 monoclonal antibodies described herein,

[0037] u) exhibits the same or similar binding affinity or specificity, or both, as the anti-CD138 monoclonal antibodies described herein,

[0038] v) exhibits the same or similar binding affinity or specificity, or both, as an antibody molecule comprising a heavy chain variable region and / or a light chain variable region described herein (e.g., a heavy chain variable region and / or a light chain variable region of any anti-CD138 monoclonal antibody described herein),

[0039] w) exhibits a similar appearance to that described herein comprising one or more (e.g., two or three) heavy chain CDRs and

[0040] 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 any anti-CD138 monoclonal antibody described herein).

[0041] or one or more (two or three) light chain CDRs) of an antibody molecule having the same or similar binding affinity or specificity, or both,

[0042] x) exhibits the same or similar binding affinity or specificity, or both, as an antibody molecule comprising the amino acid sequence described herein,

[0043] y) exhibits the same or similar binding affinity or specificity, or both, as an antibody molecule comprising the amino acid sequence encoded by the nucleotide sequence described herein,

[0044] z) inhibiting (e.g., competitively inhibiting) the binding of a second antibody molecule to CD138, wherein the second antibody molecule is an antibody molecule described herein, such as any anti-CD138 monoclonal antibody described herein,

[0045] aa) competing with a second antibody molecule for binding to CD138, wherein the second antibody molecule is an anti-CD138 monoclonal antibody described herein,

[0046] bb) has one or more biological properties of the anti-CD138 monoclonal antibodies described herein, cc) has one or more structural properties of the anti-CD138 monoclonal antibodies described herein, or

[0047] dd) possesses one or more pharmacokinetic properties of the anti-CD138 monoclonal antibodies described herein.

[0048] In one aspect, the disclosure features an anti-CD138 antibody molecule that: (i) binds or binds substantially to an extracellular region of CD138 proximal to the transmembrane domain; and (ii) induces antibody-dependent cellular cytotoxicity (ADCC) activity on cells expressing CD138.

[0049] In one embodiment, the C-terminus of the extracellular region near the transmembrane domain is 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 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.

[0050] In one embodiment, the antibody molecule binds to a CD138 epitope comprising five or more (e.g., 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 the extracellular region.

[0051] In one embodiment, the extracellular region proximal to the transmembrane domain comprises or consists of amino acids 210-250 or 220-245 of any one of SEQ ID NOs: 1-3 or 450.

[0052] In one embodiment, the antibody molecule binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte, or an eosinophil).

[0053] In one embodiment, the cell expressing CD138 is a cancer cell or a precancerous cell. In one embodiment, the cancer cell or the precancerous cell is a myeloma cell.

[0054] In one embodiment, the antibody molecule is also combined with or is bound to the CD138 extracellular region away from the transmembrane domain with higher affinity.In one embodiment, the antibody molecule is bound to the CD138 epitope comprising five or more (for example, 6,7,8,9,10,11,12,13,14,15,20,25,30,35 or more) continuous amino acid residues in the extracellular region away from the transmembrane domain.In one embodiment, the C-terminal of the extracellular region away from the transmembrane domain is at least 100,110,120,130,140,150,160,170,180,190 or 200 amino acids from the N-terminal of the transmembrane domain.In one embodiment, the extracellular region away from the transmembrane domain includes SEQ ID NO:1-3 or 450 any one of amino acid 23-50,51-95,88-121 or 111-150. In some embodiments, the extracellular region distal to the transmembrane domain comprises amino acids 88-121 or 101-121 of any one of SEQ ID NOs: 1-3 or 450.

[0055] In one embodiment, the antibody molecule also binds or binds with higher affinity to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule also binds or binds with high affinity to the N-terminal region of the IBD of CD138.

[0056] In one embodiment, the antibody molecule is not bound to or is bound to the extracellular region of CD138 away from the transmembrane domain with low affinity.In one embodiment, the antibody molecule is not bound to the CD138 epitope comprising five or more (for example, 6,7,8,9,10,11,12,13,14,15,20,25,30,35 or more) continuous amino acid residues in the extracellular region away from the transmembrane domain.In one embodiment, the C-terminal of the extracellular region away from the transmembrane domain is at least 100,110,120,130,140,150,160,170,180,190 or 200 amino acids from the N-terminal of the transmembrane domain.In one embodiment, the extracellular region away from the transmembrane domain includes SEQ ID NO:1-3 or 450 any one of amino acid 23-50,51-95,88-121 or 111-150.

[0057] In one embodiment, the antibody molecule does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule does not bind or binds with low affinity to the N-terminal region of the IBD of CD138.

[0058] In one embodiment, the antibody molecule binds to CD138 with a dissociation constant (KD) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM.

[0059] In one embodiment, the antibody molecule has a binding affinity for membrane-bound CD138 that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, or 500 times greater than the binding affinity for soluble CD138. In one embodiment, the antibody molecule has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D Binds to membrane-bound CD138.

[0060] In one embodiment, the antibody molecule has a binding affinity for membrane-bound CD138 that is similar to its binding affinity for soluble CD138, for example, the binding affinity for membrane-bound CD138 is within about ±10%, ±20%, ±30%, ±40%, ±50%, ±60%, ±70%, ±80%, ±90%, ±100% of the affinity for soluble CD138, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% greater than the affinity for soluble CD138. In one embodiment, the antibody molecule has a K 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, such as 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. D In one embodiment, the antibody molecule binds to soluble CD138 with a K of greater than about 100, 200, 300, 400 or 500 nM. D Binds to soluble CD138.

[0061] In one embodiment, the antibody molecule binds better to membrane-bound CD138 than to soluble CD138, e.g., the binding affinity to membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the binding affinity to soluble CD138. In one embodiment, the antibody molecule binds better to soluble CD138 than to membrane-bound CD138, e.g., the binding affinity to soluble CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the binding affinity to membrane-bound CD138. In one embodiment, the antibody molecule binds to both soluble CD138 and membrane-bound CD138.

[0062] In one embodiment, the antibody molecule binds to C1q and causes complement dependent cytotoxicity (CDC) activity on cells expressing CD138. In one embodiment, the antibody molecule reduces (e.g., inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, in vitro or in vivo. In one embodiment, the antibody molecule mediates homotypic adhesion of one or more CD138 expressing cells. In one embodiment, the antibody molecule inhibits the effect of proteases on membrane-bound CD138, for example, to reduce the shedding of CD138. In one embodiment, the antibody molecule reduces (e.g., inhibits) the proliferation of cancer cells or precancerous cells expressing CD138.

[0063] In one embodiment, the antibody molecule comprises 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 an anti-CD138 monoclonal antibody as described herein. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) and / or a light chain variable region (VL) of an anti-CD138 monoclonal antibody as described herein. In one embodiment, the antibody molecule comprises an Fc region.

[0064] In one aspect, the disclosure features an anti-CD138 antibody molecule that binds or binds substantially 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) consecutive amino acid residues in the extracellular region proximal to the transmembrane domain of CD138.

[0065] In one embodiment, the C-terminus of the extracellular region near the transmembrane domain is 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 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. In one embodiment, the extracellular region near the transmembrane domain comprises or consists of amino acids 176-250 of any one of SEQ ID NOs: 1-3 or 450.

[0066] In one embodiment, the antibody molecule is bound to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte or an eosinophil). In one embodiment, the antibody molecule can cause (e.g., promote or induce) ADCC activity on cells expressing CD138. In one embodiment, the antibody molecule can cause (e.g., promote or induce) antibody-dependent cellular phagocytosis (ADCP) activity on cells expressing CD138. In one embodiment, the cells expressing CD138 are cancer cells or precancerous cells. In one embodiment, cancer cells or precancerous cells are myeloma cells.

[0067] In one embodiment, the antibody molecule is also combined with or is bound to the CD138 extracellular region away from the transmembrane domain with higher affinity.In one embodiment, the antibody molecule is bound to the CD138 epitope comprising five or more (for example, 6,7,8,9,10,11,12,13,14,15,20,25,30,35 or more) continuous amino acid residues in the extracellular region away from the transmembrane domain.In one embodiment, the C-terminal of the extracellular region away from the transmembrane domain is at least 100,110,120,130,140,150,160,170,180,190 or 200 amino acids from the N-terminal of the transmembrane domain.In one embodiment, the extracellular region away from the transmembrane domain includes SEQ ID NO:1-3 or 450 any one of amino acid 23-50,51-95,88-121 or 111-150.

[0068] In one embodiment, the antibody molecule also binds or binds with higher affinity to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule also binds or binds with high affinity to the N-terminal region of the IBD of CD138.

[0069] In one embodiment, the antibody molecule does not bind or binds with low affinity to an extracellular region of CD138 distal to the transmembrane domain.

[0070] In one embodiment, the epitope does not include five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region away 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 away from the transmembrane domain includes amino acids 23-50, 51-95, 88-121 or 111-150 of any one of SEQ ID NO: 1-3 or 450.

[0071] In one embodiment, the antibody molecule does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule does not bind or binds with low affinity to the N-terminal region of the IBD of CD138.

[0072] In one embodiment, the antibody molecule has a dissociation constant (K) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D ) binds to CD138.

[0073] In one embodiment, the antibody molecule has a binding affinity for membrane-bound CD138 that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, or 500 times greater than the binding affinity for soluble CD138. In one embodiment, the antibody molecule has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D In one embodiment, the antibody molecule binds to membrane-bound CD138 with a K of greater than about 100, 200, 300, 400, or 500 nM. D Binds to soluble CD138.

[0074] In one embodiment, the antibody molecule has a binding affinity for membrane-bound CD138 that is similar to its binding affinity for soluble CD138, for example, the binding affinity for membrane-bound CD138 is within about ±10%, ±20%, ±30%, ±40%, ±50%, ±60%, ±70%, ±80%, ±90%, ±100% of the affinity for soluble CD138, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% greater than the affinity for soluble CD138. In one embodiment, the antibody molecule has a K 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, such as 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. D In one embodiment, the antibody molecule binds to soluble CD138 with a K of greater than about 100, 200, 300, 400 or 500 nM. DBinds to soluble CD138.

[0075] In one embodiment, the antibody molecule binds better to membrane-bound CD138 than to soluble CD138, e.g., the binding affinity to membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the binding affinity to soluble CD138. In one embodiment, the antibody molecule binds better to soluble CD138 than to membrane-bound CD138, e.g., the binding affinity to soluble CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 times higher than the binding affinity to membrane-bound CD138. In one embodiment, the antibody molecule binds to both soluble CD138 and membrane-bound CD138.

[0076] In one embodiment, the antibody molecule binds to C1q and causes complement dependent cytotoxicity (CDC) activity on cells expressing CD138. In one embodiment, the antibody molecule reduces (e.g., inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, in vitro or in vivo. In one embodiment, the antibody molecule mediates homotypic adhesion of one or more CD138 expressing cells. In one embodiment, the antibody molecule inhibits the effect of proteases on membrane-bound CD138, for example, to reduce the shedding of CD138. In one embodiment, the antibody molecule reduces (e.g., inhibits) the proliferation of cancer cells or precancerous cells expressing CD138.

[0077] In one embodiment, the antibody molecule comprises 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 an anti-CD138 monoclonal antibody as described herein. In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) and / or a light chain variable region (VL) of an anti-CD138 monoclonal antibody as described herein. In one embodiment, the antibody molecule comprises an Fc region.

[0078] In one aspect, the disclosure features an anti-CD138 antibody molecule comprising one or both of:

[0079] (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 the following: (i) HCDR1 comprising an amino acid sequence identical to that of an anti-CD138 monoclonal antibody disclosed herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910 or 1409); (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from, or is at least 85, 90, 95, 99 or 100% homologous to, the amino acid sequence of 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 from, or is at least 85, 90, 95, 99 or 100% homologous to, the amino acid sequence of HCDR3 of the anti-CD138 antibody; or

[0080] (b) a light chain variable region (VL), wherein VL comprises three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from, or is at least 85, 90, 95, 99 or 100% homologous to, the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from, or is at least 85, 90, 95, 99 or 100% homologous to, the amino acid sequence of LCDR2 of the anti-CD138 antibody; or (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from, or is at least 85, 90, 95, 99 or 100% homologous to, the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0081] In one embodiment, VH comprises: (i) HCDR1, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of HCDR2 of the anti-CD138 antibody; (ii) HCDR2, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of HCDR3 of the anti-CD138 antibody; and (iii) HCDR3, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of HCDR3 of the anti-CD138 antibody.

[0082] 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.

[0083] In one embodiment, VL comprises: (i) LCDR1, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; (ii) LCDR2, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody; and (iii) LCDR3, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0084] 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.

[0085] In one embodiment, the antibody molecule comprises:

[0086] (a) VH, which comprises: (i) HCDR1, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of the anti-CD138 antibody; (ii) HCDR2, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of the anti-CD138 antibody; and (iii) HCDR3, which comprises an amino acid sequence that 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 is at least 85, 90, 95, 99 or 100% homologous to that of the anti-CD138 antibody, and

[0087] (a) a VL comprising: (i) a LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from the amino acid sequence of LCDR1 of the anti-CD138 antibody, or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; (ii) a LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from the amino acid sequence of LCDR2 of the anti-CD138 antibody, or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody; and (iii) a LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues from the amino acid sequence of LCDR3 of the anti-CD138 antibody, or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0088] 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.

[0089] 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 compared to the amino acid sequence of VH of anti-CD138 antibody or at least 85,90,95,99 or 100% homology.In one embodiment, antibody molecule VH comprises the amino acid sequence of VH of described anti-CD138 antibody.

[0090] 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 or at least 85,90,95,99 or 100% homology compared to the amino acid sequence of VL of anti-CD138 antibody.In one embodiment, VL comprises the amino acid sequence of VL of anti-CD138 antibody.

[0091] In one embodiment, (a) VH comprises an amino acid sequence that 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) VL comprises an amino acid sequence that 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.

[0092] In one embodiment, VH comprises the amino acid sequence of VH of an anti-CD138 antibody, and VL comprises the amino acid sequence of VL of an anti-CD138 antibody.

[0093] In one embodiment, the antibody molecule comprises an Fc region.

[0094] In one aspect, the disclosure features an antibody molecule that competes with an anti-CD138 monoclonal antibody described herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409) for binding to CD138.

[0095] In one aspect, the disclosure features an antibody molecule that binds or substantially binds to an epitope that completely or partially overlaps with an epitope of an anti-CD138 monoclonal antibody described herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

[0096] In one aspect, the disclosure features an antibody-molecule drug conjugate (ADC) comprising an antibody molecule described herein, optionally comprising a cytotoxic agent, and optionally comprising a linker.

[0097] In one aspect, the disclosure features a composition comprising an antibody molecule described herein or an ADC described herein, optionally wherein the composition is a pharmaceutical composition.

[0098] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0099] In one aspect, the disclosure features nucleic acid molecules encoding the heavy chain variable region (VH), the light chain variable region (VL), or both, of the antibody molecules described herein.

[0100] In one aspect, the disclosure features a vector comprising a nucleic acid molecule described herein.

[0101] In one aspect, the disclosure features a cell comprising a nucleic acid molecule described herein or a vector described herein, optionally wherein the cell is an isolated cell.

[0102] In one aspect, the disclosure features a kit comprising an antibody molecule described herein, an ADC described herein, or a composition described herein, and instructions for use of the antibody molecule or composition.

[0103] In one aspect, the disclosure features a container comprising an antibody molecule described herein, an ADC described herein, or a composition described herein.

[0104] In one aspect, the disclosure features a method of producing an anti-CD138 antibody molecule, the method comprising culturing a cell described herein under conditions that permit production of the antibody molecule, thereby producing the antibody molecule.

[0105] In one embodiment, the method further comprises isolating or purifying the antibody molecule.

[0106] In one aspect, the disclosure features an antibody molecule described herein, an ADC described herein, or a composition described herein, for use in a method of treating cancer in a subject.

[0107] 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 a solid tumor described herein.

[0108] In one embodiment, the antibody molecule, ADC or composition is administered to a subject intravenously.

[0109] In one embodiment, the antibody molecule, ADC or composition is administered to a subject at a dose of 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.

[0110] In one embodiment, the antibody molecule, ADC or composition is administered to a subject at a fixed dose of 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.

[0111] In one embodiment, 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.

[0112] In one embodiment, the use further comprises determining the level of CD138 in a sample from the subject. In one embodiment, the use further comprises administering a second therapy for cancer to the subject.

[0113] In one aspect, the disclosure features an antibody molecule described herein, an ADC described herein, or a composition described herein, for use in a method of treating a precancerous condition or preventing cancer.

[0114] In one embodiment, the precancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS). In one embodiment, the cancer is multiple myeloma.

[0115] In one aspect, the disclosure features a method of inducing ADCC activity, the method comprising contacting a cell or a subject with an antibody molecule described herein, an ADC described herein, or a composition described herein, thereby inducing ADCC activity.

[0116] In one aspect, the disclosure features a method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule described herein, an ADC described herein, or a composition described herein, thereby treating the cancer.

[0117] In one aspect, the disclosure features a method of treating a precancerous condition or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule described herein, an ADC described herein, or a composition described herein, thereby treating the precancerous condition or preventing cancer.

[0118] In one aspect, the disclosure features a method of detecting an anti-CD138 molecule, the method comprising contacting a cell or a subject with an antibody molecule described herein, thereby detecting the CD138 molecule.

[0119] In one embodiment, the antibody molecule is coupled to a detectable label. In one embodiment, the CD138 molecule is detected in vitro, ex vivo or in vivo.

[0120] The present disclosure encompasses all combinations of any one or more of the foregoing aspects and / or embodiments, as well as combinations with any one or more of the embodiments provided in the detailed description and examples.

[0121] Other features, objects, and advantages of the compositions and methods herein will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0122] The patent or application file contains at least one drawing printed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0123] Figure 1An exemplary amino acid sequence of human CD138 is described (UniProt number: P18827). The signal peptide comprises residues 1-22 (shown in italics); the extracellular domain comprises residues 23-254; the transmembrane domain comprises residues 255-275; and the cytoplasmic domain comprises residues 276-310. The integrin binding domain (IBD) comprises residues 88-122. Known O-linked heparin sulfate chains are located at residues 37, 45, and 47 (underlined); known O-linked chondroitin sulfate chains are located at residues 206 and 216 (underlined). Possible N-linked glycans are located at residue 43. The inferred B-B4 antibody hotspot epitope residues are Leu107, Pro108, Glu109, and Val110 (shown in bold). Exemplary peptide regions that can be targeted by anti-CD138 antibody molecules described herein include residues Gly217 to Glu251 (shown in bold and italics). Figure 1 SEQ ID NO: 450 is disclosed.

[0124] Figure 2 Peptides used to identify anti-CD138 antibodies that bind to a desired epitope are described.

[0125] Figure 3 The characterization of complement-dependent cytotoxicity (CDC) of the anti-CD138 antibody B-B4 in human myeloma RPMI 8226 cells is described.

[0126] Figure 4 The characterization of antibody-dependent cellular cytotoxicity (ADCC) of anti-CD138 antibody B-B4 in human myeloma RPMI 8226 cells is described.

[0127] Figure 5 The ability of rabbit polyclonal anti-CD138 antibody to induce ADCC in human multiple myeloma U266 cells is demonstrated.

[0128] Fig. 6A Depicted are transposed constructs including the B-B4 epitope at various positions.

[0129] Figure 6B The amino acid sequences of mutated CD138 in clones 1-3 are illustrated. Figure 6B SEQ ID NOs: 451-453 are disclosed respectively in order of appearance.

[0130] Figure 6C The amino acid sequences of mutated CD138 in clones 4 and 5 are illustrated. Figure 6C SEQ ID NOs: 454-455 are disclosed respectively in order of appearance.

[0131] Fig. 7AThe line graph shows the ability of B-B4 to induce ADCC activity as the epitope moves closer to the cell membrane.

[0132] Figure 7B The bar graph shows the ability of B-B4 to induce ADCC activity when the epitope moves closer to the cell membrane. BB4-Mid: hCD138 with the BB-4 epitope in the midway of the extracellular domain. BB4-MP: hCD138 with the BB-4 epitope in the membrane-proximal region. CD138: human CD138 wild type. R-PAb: rabbit polyclonal anti-CD138 antibody.

[0133] Figure 7C This indicates that the ADCC potential can be further enhanced by Fc engineering.

[0134] Figure 8 The graph shows the binding of various anti-CD138 antibodies to the soluble form of the extracellular domain of CD138 (amino acids 23-250, SEQ ID NO: 1) as measured by ELISA.

[0135] Figures 9A-9C A series of graphs show the binding of various anti-CD138 antibodies to peptide fragments of CD138 as measured by ELISA: (A) peptide 2a, (B) peptide 5, (C) peptide 6.

[0136] Fig.9D The structure of the CD138 polypeptide is shown. The positions of peptides 2a, 5 and 6 are indicated.

[0137] Fig.10 Graph showing binding of anti-CD138 antibodies 1610, 624 and B-B4 (also referred to herein as BB4) to peptides 2a and 6 of CD138 as measured by ELISA under higher stringency conditions for antibody-antigen binding.

[0138] Figures 11A-11C A series of graphs showing the binding of antibody 1610 to cell surface CD138 expressed on U266 multiple myeloma cells (A) or to the soluble CD138 extracellular domain (B). (C) EC50 values ​​for the binding of antibody 1610 to soluble or membrane-bound (cell surface) CD138.

[0139] Fig.12 The series of graphs show the binding kinetics of anti-CD138 antibodies 1610, 624 and BB4 to the recombinant CD138 extracellular domain measured by bio-layer interferometry.

[0140] Fig.13A series of graphs show the binding kinetics of anti-CD138 antibody 1610 to CD138 peptide fragments (upper panel: peptides 2A (SEQ ID NO: 10), 2C (SEQ ID NO: 449); lower panel: peptides 6B (SEQ ID NO: 440), 6E (SEQ ID NO: 444)), as measured by biolayer interferometry using biotinylated peptides.

[0141] Figures 14A-14B A series of graphs showing the comparative binding kinetics of anti-CD138 antibodies 1610 (A) and B-B4 (B) to CD138 peptide fragments (peptides 2A and 6B) measured by biolayer interferometry. Note the ability of mAb 1610 (but not B-B4) to bind to peptides 2A and 6B with different kinetics.

[0142] Figures 15A-15C A series of graphs show competition between biotinylated test antibodies (anti-CD138 antibodies 1610, 624 and B-B4) and the corresponding unlabeled antibodies at different concentrations for binding to cell surface CD138. The differential profiles by epitope binning are indicated.

[0143] Fig.16 The graph shows that defucosylated anti-CD138 antibodies 1610, 624 and B-B4 induce ADCC activity in U266 cells.

[0144] Fig.17 The table shows the mutations generated in anti-CD138 antibody variants 2510, 2610, 2710, 2810 and 2910 relative to the parent antibody 1610. Also shown are the protein titers produced by each of these antibodies from transiently transfected HEK293 cells.

[0145] Figures 18A-18D A series of graphs showing the binding of antibody 1610 and its variants 2510, 2610 and 2810 to the recombinant CD138 extracellular domain (A), peptide 2a (B) and peptide 6 (C) measured by ELISA. The EC50 values ​​of each antibody variant are shown in Fig.18D Note the improved binding of the mAb 1610 variants (relative to the parent antibody 1610) to membrane proximal regions (as indicated by peptide 6).

[0146] Fig.19A The figure shows the defucosylated form of antibody 1610 and its variants binding to cell surface CD138 expressed by U266 cells.

[0147] Fig.19B A series of graphs showing Fig.18A Representative flow cytometry results of the cell binding assay summarized in .

[0148] Fig. 20 The graph shows that the defucosylated form of antibody 1610 and its variants induce ADCC activity in CD138+U266 cells. Rabbit polyclonal (PAb) anti-CD138 antibody was used as an assay control.

[0149] Fig.21 The graph shows the binding of antibody 2810 compared to BB4 to CD138 peptide fragments (peptide 2A and peptide 6B). Binding was measured by a modified format of ELISA in which the antibody was captured directly on the ELISA plate and the binding of CD138 peptide at different concentrations was measured.

[0150] Figures 22A-22C A series of graphs showing that antibody variant 2810 (A) binds to a different part of CD138 compared to antibody B-B4 (B). The peptide sequence is depicted in C. Fig. 22C SEQ ID NOs: 456, 10, 449, 445, 457, 440, 444, 443, 443 and 449 are disclosed in order of appearance, respectively. DETAILED DESCRIPTION

[0151] Disclosed herein are antibody molecules that bind to CD138 (e.g., human CD138). Advantageously, at least several antibody molecules described herein have improved ability to inhibit cells expressing CD138, such as by initiating effector functions. Without intending to be limited by theory, it is believed that in one embodiment, anti-CD138 antibodies that bind to the desired epitopes described herein have enhanced effector functions and preferential binding to membrane-associated forms of CD138. Effectively targeting CD138 can lead to extensive activity and favorable therapeutic indexes for myeloma and other cancers. 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. Antibody molecules and pharmaceutical compositions disclosed herein (alone or in combination with other agents or treatments) can be used to treat, prevent, and / or diagnose diseases and conditions, such as diseases and conditions associated with CD138, such as cancer or precancerous conditions.

[0152] definition

[0153] The articles "a" and "an" are used herein to refer to one or more than one (ie, to at least one) of the grammatical object of the article.

[0154] As used herein, the term "or / or" means, and is used interchangeably with, "and / or" unless the context clearly indicates otherwise.

[0155] "About" and "approximately" should generally represent an acceptable degree of error of the measured amount in consideration of the nature or precision of the measurement. An exemplary degree of error is within 20% of a given value or numerical range, typically within 10%, and more typically within 5%. When "about" or "approximately" is present before a series of numbers or ranges, it should be understood that "about" or "approximately" can modify each number in the series or range. Similarly, when "at least", "greater than", "not greater than", "less than", "not less than", or "within..." appears before a series of numbers or ranges, it should be understood that "at least", "greater than", "not greater than", "less than", "not less than", or "within..." can modify each number in the series or range. As used herein, ranges include upper and lower limits.

[0156] The compositions and methods described herein include polypeptides and nucleic acids having a specified sequence, or a sequence substantially identical or similar to a specified sequence (e.g., at least 85%, 90%, 95% or more identical to a specified sequence).

[0157] In the context of describing an amino acid sequence, 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) conservative substitutions of the aligned amino acid residues in the second amino acid sequence, so that the first and second amino acid sequences can have a common domain and / or a common functional activity. For example, an amino acid sequence comprising 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., a sequence provided herein).

[0158] In the case of describing nucleotide sequences, the term "substantially identical" as used herein means that the first nucleic acid sequence comprises a sufficient or minimum number of nucleotides identical to the aligned nucleotides in the second nucleic acid sequence, so that the first and second nucleotide sequences encode polypeptides with the same functional activity, or encode the same structural polypeptide domain or the same functional polypeptide activity. For example, comprising a nucleotide sequence having at least about 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence (e.g., a sequence provided herein).

[0159] The term "functional variant" refers to a polypeptide having substantially the same amino acid sequence as a native sequence or encoded by substantially the same nucleotide sequence and capable of having one or more activities of the native sequence.

[0160] Calculations of homology or sequence identity (the terms are used interchangeably herein) between sequences are performed as follows.

[0161] In order to determine the percent identity of 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 length of the reference sequence used for comparison purposes is at least 30% of the length of the reference sequence, such as at least 40%, 50%, 60%, such as at least 70%, 80%, 90%, 100%. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When the amino acid residue or nucleotide occupied at a position in the first sequence is the same as the corresponding position in the second sequence, then the molecules are identical at that position.

[0162] The percent identity between two sequences is related to the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.

[0163] Mathematical algorithms can be used to compare sequences and determine percent identity between two sequences. In some embodiments, percent 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 http: / / www.gcg.com), using a Blossum 62 matrix or a PAM250 matrix, a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In certain embodiments, percent identity between two nucleotide sequences is calculated using the GAP program in the GCG software package (available from http: / / www.gcg.com), using the NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. A suitable set of parameters (and the set of parameters that should be used unless otherwise stated) 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.

[0164] The percent identity 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 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0165] The nucleic acid and protein sequences disclosed herein can also be used as a "query sequence" to search public databases, for example, to identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al., 1990, J. Mol. Biol., 215:403-10. BLAST nucleotide searches can be performed using the NBLAST program with score = 100 and word length = 12 to obtain nucleotide sequences homologous to the nucleic acids described herein. BLAST protein searches can be performed using the XBLAST program with score = 50 and word length = 3 to obtain amino acid sequences homologous to the protein molecules described herein. In order to obtain gapped alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al., 1997, Nucleic Acids Res., 25:3389-3402. When using BLAST and Gapped BLAST programs, the default parameters of each program (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.

[0166] As used herein, the term "hybridization under low stringency, medium stringency, high stringency or very high stringency conditions" refers to the conditions for hybridization and washing. Guidance for conducting hybridization reactions can be found in Current Protocols in Molecular Biology (John Wiley & Sons, New York (1989), 6.3.1-6.3.6), which is incorporated herein by reference. Aqueous and nonaqueous methods are described in this reference, and either method can be used. Specific hybridization conditions contemplated herein are as follows: 1) low stringency hybridization conditions in 6X sodium chloride / sodium citrate (SSC) at about 45°C, followed by two washes in 0.2X SSC, 0.1% SDS at at least 50°C (under low stringency conditions, the washing temperature can be raised to 55°C); 2) moderate stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 60°C; 3) high stringency hybridization conditions in 6X SSC at about 45°C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 65°C; and preferably 4) very high stringency hybridization conditions are 0.5M sodium phosphate, 7% SDS at 65°C, followed by one or more washes in 0.2X SSC and 1% SDS at 65°C. Very high stringency conditions 4) are suitable conditions and are the conditions that should be used (unless otherwise specified).

[0167] It is understood that the molecules described herein may have additional conservative or non-essential amino acid substitutions that do not substantially affect the function of the molecule.

[0168] The term "amino acid" encompasses all molecules, whether natural or synthetic, that contain an amino functional group and an acid functional group and that can be included in a polymer formed by naturally occurring amino acids. Exemplary amino acids include naturally occurring amino acids; analogs, derivatives, and congeners thereof; amino acid analogs with variant side chains; and all stereoisomers of any of the foregoing. As used herein, the term "amino acid" includes D- and L-mirror image isomers and peptidomimetics.

[0169] A "conservative amino acid substitution" is a situation where one amino acid residue is replaced 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, histidine), amino acids with acidic side chains (such as aspartic acid, glutamic acid), amino acids with uncharged polar side chains (such as glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), amino acids with non-polar side chains (such as alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), amino acids with beta-branched side chains (such as threonine, valine, isoleucine) and amino acids with aromatic side chains (such as tyrosine, phenylalanine, tryptophan, histidine).

[0170] The terms "polypeptide," "peptide," and "protein" (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acids. The term also includes amino acid polymers that have been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as coupling with a labeling component. The polypeptide may be isolated from a natural source, may be produced by a prokaryotic or eukaryotic host using recombinant technology, or may be the product of a synthetic process.

[0171] The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably herein. They refer to a polymeric form of nucleotides of any length, whether deoxyribonucleotides or ribonucleotides or their analogs. Polynucleotides can be single-stranded or double-stranded, and if single-stranded, can be a coding strand or a non-coding (antisense) strand. Polynucleotides can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The nucleotide sequence may be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by coupling with a labeling component. Nucleic acids can be recombinant polynucleotides, or genomic polynucleotides, cDNA, semisynthetic or synthetic in origin, i.e., non-naturally occurring or associated with another polynucleotide in a non-natural arrangement.

[0172] 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 produced). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the polynucleotide or polypeptide separated from some or all coexisting materials in the natural system is isolated. Such a polynucleotide can be part of a vector and / or such a polynucleotide or polypeptide can be part of a composition, but it is still isolated because the vector or composition is not part of the environment in which the polynucleotide or polypeptide naturally occurs.

[0173] As used herein, the term "treating" a disorder (e.g., myeloma) means that, in one embodiment, a subject (e.g., human) with a disorder (e.g., myeloma) and / or experiencing symptoms of a disorder (e.g., myeloma) will experience a less severe symptom and / or recover faster than if the antibody molecule had not been received, when the antibody molecule has been received. In one embodiment, when treating myeloma, after the myeloma is effectively treated, a bone marrow biopsy will show fewer clonal plasma cells. For example, after administering the antibody molecule described herein to effectively treat myeloma, a diagnostic assay will detect fewer clonal plasma cells in the biological sample of the subject. Other assays, urine tests or blood tests can also be used to monitor the treatment of a patient, or to detect the presence of myeloma symptoms in a subject after treating myeloma, such as a reduction (or absence). In one embodiment, when treating myeloma, after the myeloma is effectively treated, the level of β2 microglobulin (β2M) in serum or urine will be reduced. Treatment can be, for example, partially or completely alleviating, improving, alleviating, inhibiting or reducing the severity of the disease and / or reducing the incidence rate, and optionally delaying the manifestation or onset of one or more consequences or symptoms, characteristics and / or causes of the disease (e.g., myeloma). In one embodiment, treatment is performed for an object that does not show certain signs of a disease (e.g., myeloma) and / or only shows early signs of a disease (e.g., nephropathy). In one embodiment, treatment is performed for an object with one or more established signs of a disease (e.g., myeloma). In one embodiment, treatment is performed for an object diagnosed with a disease (e.g., myeloma).

[0174] As used herein, the term "preventing" a disease (eg, myeloma) means that a subject (eg, human) is less likely to develop the disease (eg, myeloma) if the subject (eg, human) receives the antibody molecule.

[0175] Various aspects of the compositions and methods described herein are described in further detail below. Additional definitions are provided throughout the specification.

[0176] CD138

[0177] CD138 is a protein that is encoded by the SDC1 gene in humans. CD138 is also known as Syndecan 1, Syndecan 1, CD138 antigen, SYND1, SDC, Syndecan-1 or Syndecan.

[0178] CD138 is a transmembrane (type I) heparan sulfate proteoglycan and a member of the syndecan proteoglycan family. Syndecan mediates cell binding, cell signaling, and cytoskeletal organization, while the syndecan receptor is required for the internalization of the HIV-1 tat protein. CD138 functions as an integral membrane protein and participates in cell proliferation, cell migration, and cell-matrix interactions through its receptors for extracellular matrix proteins. Changes in CD138 expression have been detected in several different tumor types.

[0179] The core of CD138 includes three main domains: 1) a short cytoplasmic domain; 2) a hydrophobic domain that spans the plasma membrane; 3) a long extracellular domain. The functions of the CD138 domains are described in, for example, Stepp et al. Adv Wound Care (New Rochelle). 2015; 4(4): 235-249). The cytoplasmic domain can transmit signals and can also bind to anchor molecules (including PDZ family members). The heparan sulfate chain of CD138 also has important biological functions. In mammals, CD138 is the main heparan sulfate proteoglycan (HSPG) with high levels of expression on epithelial cells (Fuki et al. J Clin Invest. 1997; 100(6): 1611-1622). Without intending to be limited by theory, it is believed that the HSPG of CD138 allows the proteoglycan 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).

[0180] For example, for a human CD138 protein (e.g., any one of SEQ ID NOs: 1-3 or 450), the signal peptide comprises residues 1-22; the extracellular domain comprises residues 23-254; the transmembrane domain comprises residues 255-275; the cytoplasmic domain comprises residues 276-310; or the integrin binding domain (IBD) comprises residues 88-122.

[0181] In one embodiment, the anti-CD138 antibody molecules described herein can regulate (e.g., inhibit) CD138 and the combination of one or more proteins that interact (e.g., directly or indirectly bind) with the extracellular domain of CD138. In one embodiment, the anti-CD138 antibody molecules described herein can regulate (e.g., inhibit) and interact (e.g., directly or indirectly bind) with the extracellular domain of CD138. The protein that interacts with CD138 directly binds to the extracellular domain of CD138. In one embodiment, the protein that interacts with CD138 is bound to the extracellular domain of CD138 through a glycosaminoglycan (GAG) chain.

[0182] Examples of proteins that interact with CD138 and their functions are described, for example, in Stepp et al. Adv Wound Care (New Rochelle). 2015; 4(4): 235-249, the contents of which are incorporated herein by reference in their entirety.

[0183] For example, proteins that can directly or indirectly interact with the extracellular domain of CD138 include, but are not limited to, matrix proteins (e.g., laminin, fibronectin, thrombospondin, collagen, fibrin, HB-GAM, tenascin, vitronectin, fibrillin or tropoelastin), proteases (e.g., MMP7, MMP9, ADAMTS4, MT1-PPT, neutrophil elastase, cathepsin G or carboxypeptidase), receptors (e.g., integrins, α v β3, α v β5, α6β4, α2β1, α3β1 or α Mβ2), cytokines or growth factors (e.g., morphogens (e.g., activin, BMP-2, BMP-4, tenascin, sonic hedgehog, frizzled-related protein, Sprouty peptide, any of Wnt1 to Wnt13, anti-angiogenic factors (e.g., angiotensin or endostatin), growth factors (e.g., amphiregulin, batacellulin, HB-EGF, neuregulin, any of FGF1 to FGF23, PDGF, GDNF, VEGF, HGF, TGFβ1, TGFβ2, TPA or PAI-1), or cytokines ( For example, GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-7, IL-12, interferon, TNF-α, CC chemokine or CXC chemokine), a protein associated with energy balance (such as ApoB, ApoE or lipoprotein lipase), a complement or coagulation protein (such as antithrombin II, tissue factor (TF), a pathway inhibitor, factor IX, factor X, factor XI or factor XII), or a viral or parasite coat protein (for example, HIV-1-tat, HIV-1 gp41, HIV-1 gp120, HSV gB, HSV gC, HSV gD, a coat protein of HHV-6 or HHV-8 or the G-protein of RSV).

[0184] CD138 expressed on the cell surface can be cleaved by specific proteases, and the CD138 that comes off is responsible for mediating paracrine and autocrine functions. CD138 that comes off is soluble and secreted extracellular domain (ECD) in blood and matrix. CD138 that comes off is an indicator of enhanced tumor progression in multiple myeloma patients with poor prognosis and myeloma mouse models. Generally, it is not believed that CD138 that comes off is the main cause of the disease. The translocation of CD138 to the nucleus can be related to the differentiation and proliferation of some tumor cells. In one embodiment, compared with soluble CD138, the anti-CD138 antibody molecules described herein preferentially target the CD138 associated with membrane.

[0185] CD138 is not normally present on B lymphocytes and is expressed after the onset of plasma cell differentiation. CD138 is highly expressed on malignant plasma cells (myeloma) and has a causal role in disease progression. CD138 has been associated with a variety of biological functions. For example, it can bind extracellular proteins, growth factors, and chemokines; engage and activate αVβ3 and αVβ5 integrins when clustered; regulate the biogenesis of exosomes; and regulate the bone marrow microenvironment that supports myeloma growth and metastasis. Multiple signals can be attenuated by targeting CD138.

[0186] 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 50-200-fold higher levels of CD138. 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.

[0187] CD138 can be used as a primary diagnostic marker for multiple myeloma. Elevated levels of CD138 shed in serum are associated with increased tumor burden and poor prognosis. CD138+ myeloma cells show higher proliferation, while the overall survival rate of CD138+ myeloma patients is lower. CD138+ myeloma cells abnormally 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 domain are related to tumor malignancy, phenotype and metastatic potential of solid tumors and hematological tumors. The expression of CD138 varies depending on the type of cancer, but the differential expression characteristics between normal cells and cancer cells in the epithelial and stromal compartments are directly associated with the aggressiveness of the tumor and the clinical outcome and survival rate of the patient.

[0188] Exemplary amino acid and nucleotide sequences of human CD138 are described in, e.g., 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.

[0189] The amino acid sequence of an exemplary human CD138 precursor (SEQ ID NO: 1) is provided below.

[0190]

[0191] The amino acid sequence (SEQ ID NO: 2) of an exemplary human CD138 precursor variant (Q136L) is provided below.

[0192]

[0193] The amino acid sequence (SEQ ID NO: 3) of an exemplary human CD138 precursor variant (T76M) is provided below.

[0194]

[0195] The signal peptide includes amino acids 1-22 of any one of SEQ ID NOs: 1-3. The mature peptide includes amino acids 23-310 of any one of SEQ ID NOs: 1-3. The extracellular domain includes amino acids 23-254 of any one of SEQ ID NOs: 1-3. The transmembrane domain includes amino acids 255-275 of any one of SEQ ID NOs: 1-3. The cytoplasmic domain includes amino acids 276-310 of any one of SEQ ID NOs: 1-3.

[0196] 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.

[0197]

[0198] 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.

[0199]

[0200] 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 isoforms of human CD138. In one embodiment, the antibody molecule binds or substantially binds to human CD138 having an amino acid sequence described herein or encoded by a 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 NOs: 1-3.

[0201] 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.

[0202] The amino acid sequence of an exemplary mouse CD138 precursor (SEQ ID NO: 6) is provided below.

[0203]

[0204] The signal peptide includes amino acids 1-22 of SEQ ID NO: 6. The mature peptide includes amino acids 23-311 of SEQ ID NO: 6. The extracellular domain includes amino acids 23-255 of SEQ ID NO: 6. The transmembrane domain includes amino acids 256-276 of SEQ ID NO: 4. The cytoplasmic domain includes amino acids 277-311 of SEQ ID NO: 6.

[0205] An exemplary encoding nucleotide sequence of mouse CD138 (SEQ ID NO: 7) is provided below.

[0206]

[0207] CCGGAGAGAAGCCCGAGGAGGGAGAGCCTGTGCTCCATGTAGAAGCAGAGCCTGGCTTCACTGCTCGGGA

[0208] CAAGGAAAAGGAGGTCACCACCAGGCCCAGGGAGACCGTGCAGCTCCCCATCACCCAACGGGCCTCAACA

[0209] GTCAGAGTCACCACAGCCCAGGCAGCTGTCACATCTCATCCGCACGGGGGCATGCAACCTGGCCTCCATG

[0210] AGACCTCGGCTCCCACAGCACCTGGTCAACCTGACCATCAGCCTCCACGTGTGGAGGGTGGCGGCACTTC

[0211] TGTCATCAAAGAGGTTGTCGAGGATGGAACTGCCAATCAGCTTCCCGCAGGAGAGGGCTCTGGAGAACAA

[0212] GACTTCACCTTTGAAACATCTGGGGAGAACACAGCTGTGGCTGCCGTAGAGCCCGGCCTGCGGAATCAGC

[0213] CCCCGGTGGACGAAGGAGCCACAGGTGCTTCTCAGAGCCTTTTGGACAGGAAGGAAGTGCTGGGAGGTGT

[0214] CATTGCCGGAGGCCTAGTGGGCCTCATCTTTGCTGTGTGCCTGGTGGCTTTCATGCTGTACCGGATGAAG

[0215] AAAGAAGGACGAAGGCAGCTACTCCTTGGAGGAGCCCAAACAAGCCAATGGCGGTGCCTACCAGAAACCCA

[0216] CCAAGCAGGAGGAGTTCTACGCCTGA

[0217] 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 isoforms of mouse CD138. In one embodiment, the antibody molecule binds or substantially binds to human CD138 having an amino acid sequence described herein or encoded by a 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.

[0218] Epitope

[0219] The antibody molecules described herein can bind to an epitope on CD138 (eg, human CD138). For example, the epitope to which the antibody molecules described herein bind can include one or more epitope contact points described herein.

[0220] Without intending to be limited by theory, it is believed that in one embodiment, antibodies that bind to the IBD (e.g., residues 88-122 of any of SEQ ID NOs: 1-3 or 450) or any region of CD138 that is distal to the membrane may be ineffective in signaling NK cell activation and / or may not be able to efficiently deliver molecules (perforin and / or granzymes) for cytotoxicity.

[0221] In some embodiments, the anti-CD138 antibody molecules described herein possess one, two, or all of the following properties: optimal distance of the epitope from the cell membrane (e.g., not at the N-terminus of the IDB); appropriate orientation of the Fc region for CD16 engagement; or, appropriate CD138 engagement that allows CD16 clustering on NK cells (e.g., to overcome extensive glycosylation on the CD138 molecule, which may limit access by NK cells).

[0222] Without intending to be limited by theory, it is believed that in one embodiment, changing the position of the antibody epitope can change certain effector mechanisms involved. For example, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may be more favorable to epitopes near the membrane (compared to epitopes distal to the membrane) (Cleary et al. J Immunol. 2017; 198 (10): 3999-4011). In one embodiment, antibodies designed to remove target cells by a specific effector mechanism can be selected by changing the position of the antibody epitope (e.g., the distance between the epitope and the membrane).

[0223] In one embodiment, the mode of binding may affect the ability of the antibody to mediate effector function. For example, the angle at which the antibody binds to the extracellular loop relative to the membrane surface may be different (e.g., parallel or perpendicular to the membrane surface) between antibodies that bind to the same peptide epitope.

[0224] In one embodiment, the anti-CD138 antibody molecules described herein bind to epitopes having one, two or all of the following characteristics: near 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 molecules described herein can bind to the desired epitope region and engage with the membrane in an optimal posture. In one embodiment, the epitope is a linear epitope. In one embodiment, the antibody molecule binds to the extracellular region of CD138 away from the transmembrane region. In one embodiment, the epitope is a discontinuous or conformational epitope.

[0225] Figure 2 Peptides for identifying desired epitopes of anti-CD138 antibodies are shown. Without intending to be limited by theory, it is believed that in one embodiment, the anti-CD138 antibody molecules described herein target a peptide region between residues Gly217 to Glu251 of human CD138, e.g. Figure 1 As shown. It is expected that this region has a linear random coil conformation. In one embodiment, the anti-CD138 antibody molecule is bound to at least one linear tetrapeptide in the aforementioned region. In one embodiment, the anti-CD138 antibody molecule is bound to a combination of linear tetrapeptides in the aforementioned region (e.g., two, three, four or more adjacent tetrapeptides).

[0226] The amino acid sequences of the above peptides are shown in Table 3.

[0227] Table 3. Peptides used to identify CD138 epitopes

[0228]

[0229] In Table 3, overlapping amino acids between peptides are shown in bold; BB4 epitope residues are shown in italics; glycosaminoglycan (heparan sulfate, chondroitin sulfate) chains with serine residues are underlined. The terms "peptide" and "Pep" are used interchangeably herein. 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.

[0230] Other exemplary peptides for identifying desired epitopes of anti-CD138 antibodies are described herein, e.g. Fig.13 and 22C middle.

[0231] In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) CD138 and is associated with a protein in Table 3, Fig.13 or a 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 does not contact 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.

[0232] 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 and does not contact Pep6e. In one embodiment, the antibody molecule contacts Pep2a and Pep2c and does not contact Pep6e. In one embodiment, the antibody molecule contacts Pep2a, Pep2c, and Pep6b and does not contact Pep6e.

[0233] 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.

[0234] 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 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 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.

[0235] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 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 the extracellular region proximal to the transmembrane domain.

[0236] In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises five or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises six or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises seven or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises eight or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises nine or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, which comprises ten or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises eleven or more continuous amino acid residues in the extracellular region near the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises twelve or more continuous amino acid residues in the extracellular region near the transmembrane domain.

[0237] In one embodiment, the extracellular region proximal to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep6. In one embodiment, the extracellular region proximal to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep6a, 6b, 6e and / or 6f. In one embodiment, the extracellular region proximal to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep5.

[0238] 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.

[0239] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 or 38) of the following peptides (e.g., from Pep6a): 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).

[0240] 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41) consecutive amino acid residues in Pep6a.

[0241] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36 or 37) of the following peptides (e.g., from Pep6a): 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:66); 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: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).

[0242] In one embodiment, the antibody molecule contacts 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.

[0243] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or 36) of the following peptides (e.g., from Pep6a): 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: 102). 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); EPDRRN (SEQ ID NO:109); 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).

[0244] 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.

[0245] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36) of the following peptides (e.g., from Pep5): 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: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).

[0246] In one embodiment, the antibody molecule contacts 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.

[0247] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) of the following peptides (e.g., from Pep5): 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).

[0248] In one embodiment, the antibody molecule contacts 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.

[0249] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, 33, or 34) of the following peptides (e.g., from Pep5): 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).

[0250] In one embodiment, the antibody molecule does not bind or is bound to the extracellular region of CD138 away from the transmembrane domain with low affinity. In one embodiment, the antibody molecule does not bind to the 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) continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the C-terminal of the extracellular region away from the transmembrane domain is at least 100,110,120,130,140,150,160,170,180,190 or 200 amino acids from the N-terminal of the transmembrane domain. In one embodiment, the extracellular region away from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4 or a combination thereof. In one embodiment, the antibody molecule does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule does not bind or binds with low affinity to the N-terminal region of the IBD of CD138.

[0251] In one embodiment, the antibody molecule binds or substantially binds to the extracellular region of CD138 away from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region away 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 away from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4 or a combination 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 to the epitope of BB4 with low affinity.

[0252] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 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 the extracellular region distal to the transmembrane domain.

[0253] In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes five or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes six or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes seven or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes eight or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes nine or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138, and the epitope includes ten or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises eleven or more continuous amino acid residues in the extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises twelve or more continuous amino acid residues in the extracellular region away from the transmembrane domain.

[0254] In one embodiment, the extracellular region distal to the transmembrane domain corresponds to (eg, comprises or consists of) Pep2a.

[0255] 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, or 34) consecutive amino acid residues in Pep2a.

[0256] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, or 31) of the following peptides (e.g., from Pep2a): 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: 243), 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).

[0257] 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.

[0258] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, 32, or 33) of the following peptides (e.g., from Pep2a): 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), 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 a peptide comprising LPEV (SEQ ID NO: 250).

[0259] In one embodiment, the antibody molecule contacts 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.

[0260] In one embodiment, the antibody molecule contacts 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, 26, 27, 28, 29, 30, 31, or 32) of the following peptides (e.g., from Pep2a): 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), 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), EQEA (SEQ ID NO:261). In one embodiment, the antibody molecule does not contact a peptide comprising LPEV (SEQ ID NO:250).

[0261] In one embodiment, the antibody molecule binds or substantially binds to a CD138 extracellular region (e.g., an extracellular region described herein) near the transmembrane domain and a CD138 extracellular region (e.g., an extracellular region described herein) away from the transmembrane domain. In one embodiment, the binding affinity of the antibody molecule to the CD138 extracellular region near the transmembrane domain is higher than (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400 or 500 times) the binding affinity to the CD138 extracellular region away from the transmembrane domain. In one embodiment, the antibody molecule binds to the extracellular region of CD138 distal to the transmembrane domain with greater (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, or 500-fold greater) affinity than it binds to the extracellular region of CD138 proximal to the transmembrane domain.

[0262] Antibody molecules

[0263] Disclosed herein are antibody molecules that bind to CD138 (eg, the CD138 molecules disclosed herein).

[0264] As used herein, the term "antibody molecule" refers to a protein comprising at least one immunoglobulin variable domain sequence, such as an immunoglobulin chain or a 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 include a heavy (H) chain variable region sequence (abbreviated herein as VH) and a light (L) chain variable region sequence (abbreviated herein as VL). In another example, an antibody molecule includes 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 (such as scFv), single variable domain antibodies, double antibodies (Dab) (divalent and bispecific) and chimeric (such as humanized) antibodies, and can be produced by modifying complete antibodies or synthesizing them from scratch using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their corresponding antigens or receptors. Antibodies and antibody fragments can be 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 produced antibodies. Antibody molecules can have a heavy chain constant region selected from IgG1, IgG2, IgG3 or IgG4. Antibody molecules can also have a light chain selected from κ or λ. The term "immunoglobulin (Ig)" is used interchangeably with the term "antibody" herein.

[0265] Examples of antigen-binding fragments include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment, which consists of the VH and CH1 domains; (iv) a Fv fragment, which consists of the VL and VH domains of a single arm of an antibody; (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) camelid or camelized variable domains; (vii) a single-chain Fv (scFv), see, e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) a single-domain antibody. These antibody fragments can be obtained by any suitable method, including a variety of conventional techniques known to those of ordinary skill in the art, and the fragments screened for the same utility as intact antibodies.

[0266] The term "antibody" includes complete molecules and functional fragments thereof. The antibody constant region can be altered (e.g., mutated) to modify the performance of the antibody, such as to increase or improve or decrease or reduce one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine ​​residues, effector cell function, or complement function.

[0267] The antibody molecule may be a single-chain antibody. Single-chain antibodies (scFV) may be engineered (see, e.g., Colcher et al. (1999) Ann NY Acad Sci 880:263-280; and Reiter and Pastan (1996) Clin Cancer Res 2:245-252). Single-chain antibodies may be dimerized or multimerized to produce multivalent antibodies specific for different epitopes on the same target protein.

[0268] The antibody molecules described herein may also be single-domain antibodies. Single-domain antibodies may include antibodies whose complementary determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally lacking light chains, single-domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and single-domain skeletons not derived from antibodies. Single-domain antibodies may be any single-domain antibody or any future single-domain antibody in the art. 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 as heavy chain antibodies lacking light chains. Such single-domain antibodies are disclosed in, for example, WO94 / 04678. For clarity, the variable domains derived from the heavy chain antibodies naturally lacking light chains are referred to herein as VHH or nanobodies to distinguish them from the conventional VH of four-chain immunoglobulins. The VHH molecules may be derived from antibodies grown in species of the Camelidae family, such as camels, llamas, dromedaries, alpacas, and pack horses. In addition to Camelidae, other species also produce heavy chain antibodies that are naturally devoid of light chains; these VHHs are also included in this article.

[0269] The VH and VL regions can be further subdivided into hypervariable regions, called "complementarity determining regions (CDR)", interspersed with more conservative regions called "framework regions (FR or FW)". As used herein, the terms "complementarity determining regions" and "CDR" refer to the amino acid sequences within the variable regions of antibodies that confer antigen specificity and binding affinity. As used herein, the terms "framework", "FW" and "FR" can be used interchangeably.

[0270] A variety of methods have been used to precisely define the boundaries of the framework regions and CDRs (see Kabat, EA, et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed., U.S. Public Health Service, National Institutes of Health, Publication No. 91-3242; Chothia, C., et al., (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See generally, for example, "Protein Sequence and Structure Analysis of Antibody Variable Domains" in "Antibody Engineering Lab Manual", Duebel, S. and Kontermann, R., eds., Springer-Verlag, Heidelberg). Domains"). In one embodiment, the following definitions are used: the AbM definition of heavy chain variable domain CDR1 and the Kabat definition of other CDRs. In one embodiment, the Kabat definition is used for all CDRs. In addition, embodiments described with Kabat or AbM CDRs can also be implemented using Chothia hypervariable loops. Each VH and VL typically includes three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4.

[0271] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence that can form an immunoglobulin variable domain structure. For example, the sequence may include all or part of a naturally occurring variable domain amino acid sequence. For example, the sequence may or may not include one, two or more N- or C-terminal amino acids, or may include other changes that are compatible with protein structure formation.

[0272] The term "antigen binding region" refers to the portion of an antibody molecule that comprises a determinant that forms an interface with an antigen (e.g., CD138) or an epitope thereof. In the case of a protein (or protein mimetic), the antigen binding region typically comprises one or more loops (e.g., loops of at least 4 amino acids or amino acid mimics) that form an antigen (e.g., CD138) binding interface. Typically, the antigen binding region of an antibody molecule comprises 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.

[0273] The terms "competition" or "cross-competition" are used interchangeably herein and refer to the ability of an antibody molecule to interfere with the binding of an anti-CD138 antibody molecule (e.g., an anti-CD138 antibody molecule provided herein) to a target (e.g., CD138). The interference with binding can be direct or indirect (e.g., by allosteric regulation of an antibody molecule or target). The degree to which an antibody molecule interferes with the binding of other antibody molecules to a target and whether it can be referred to as competition can be determined using a competitive binding assay (e.g., a FACS assay, an ELISA or a BIACORE assay). In one embodiment, a competitive binding assay is a quantitative competitive assay. In one embodiment, a first anti-LPS antibody molecule is considered to compete with a second anti-CD138 antibody molecule for binding to a target when binding of the first anti-CD138 antibody molecule to the target is reduced by 10% or more, e.g., 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 in a competitive binding assay (e.g., a competitive assay described herein).

[0274] The term "monoclonal antibody" or "monoclonal antibody composition" as used herein refers to a preparation of antibody molecules having a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a specific epitope. Monoclonal antibodies can be prepared using hybridoma technology or methods that do not use hybridoma technology (e.g., recombinant methods).

[0275] An "effectively human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can cause problems in many situations, such as if the antibody molecule is repeatedly administered, such as in the treatment of chronic or recurrent disease symptoms. A HAMA response can cause repeated administration of an antibody to lose effectiveness due to increased serum antibody clearance (see, e.g., Saleh et al., Cancer Immunol. Immunother. 32: 180-190 (1990)) and potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma, 5: 5117-5123 (1986)).

[0276] The antibody molecule may be a polyclonal or monoclonal antibody.In some embodiments, the antibody may be produced recombinantly, for example by any suitable phage display or recombinant method.

[0277] Various phage display and combinatorial methods for generating antibodies are known in the art (described, for example, in Ladner et al., U.S. Pat. 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 3:81-82). -85; Huse et al., (1989) Science 246:1275-1281; Griffths et al., (1993) supra; 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).

[0278] 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 a rodent (mouse or rat), sheep, primate (e.g., monkey), camel antibody. 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.

[0279] Human monoclonal antibodies can be produced using transgenic mice carrying human immunoglobulin genes rather than mouse systems. Splenocytes from these transgenic mice immunized with an antigen of interest are used to generate hybridomas that secrete human mAbs with binding specificity for epitopes from human proteins (see, e.g., 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).

[0280] The antibody may be one in which the variable region or a portion thereof (e.g., CDR) is produced in a non-human organism (e.g., rat or mouse). Chimeric, CDR-grafted, and humanized antibodies are all included in the present invention. The present invention includes antibodies produced in a non-human organism (e.g., rat or mouse) and subsequently modified (e.g., in the variable framework or constant region) to reduce antigenicity in humans.

[0281] Chimeric antibodies can be produced using any suitable recombinant DNA technology. A variety of 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., U.S. Pat. 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).

[0282] In a humanized or CDR-grafted antibody, at least one or two but usually all three recipient CDRs (of an immunoglobulin heavy or light chain) are replaced by donor CDRs. At least a portion of non-human CDRs may be substituted in an antibody, or only a portion of CDRs may be substituted 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 framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is referred to as a "donor," and the immunoglobulin providing the framework region is referred to as a "recipient." In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The recipient framework is typically a naturally occurring (e.g., human) framework or consensus framework, or a sequence having about 85% or more identity thereto, such as 90%, 95%, 99% or more.

[0283] As used herein, the term "consensus sequence" refers to a sequence consisting of the most frequently occurring amino acids (or nucleotides) in a family of related sequences (see, e.g., Winnaker, From Genes to Clones, Verlagsgesellschaft, Weinheim, Germany, 1987). In a family of proteins, at each position in the consensus sequence is the amino acid that occurs most frequently at that position in the family. If two amino acids occur with the same frequency, either one may be included in the consensus sequence. "Consensus framework" refers to the framework region in a consensus immunoglobulin sequence.

[0284] Antibodies can be humanized using any suitable method, many of which are known in the art (see, e.g., 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).

[0285] CDR transplantation or CDR substitution can be used to produce humanized or CDR transplanted antibodies, and one, two or all CDRs in the immunoglobulin chain can be replaced. 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. Immunol. 141:4053-4060; Winter US 5,225,539, the entire contents of which are incorporated herein by reference. Winter describes a CDR transplantation method that can be used to prepare humanized antibodies (British Patent Application GB 2188638A, filed on March 26, 1987; Winter US 5,225,539), the entire contents of which are incorporated herein by reference.

[0286] Also provided are humanized antibodies in which specific amino acids are substituted, deleted or inserted. The criteria for selecting amino acids from donors are described in, for example, US 5,585,089, such as 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 EP519596A1 such as Padlan (published on December 23, 1992).

[0287] In one embodiment, the heavy chain constant region possessed by the antibody molecule is selected from, for example, the heavy chain constant region of IgG1, IgG2 (e.g., IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; specifically, selected from, for example, the heavy chain constant region of IgG1, IgG2, IgG3, and IgG4 (e.g., human). In another embodiment, the light chain constant region possessed by the antibody molecule is selected from, for example, the light chain constant region of κ or λ (e.g., human). The constant region can be changed (e.g., mutated) to modify the performance 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 fixing complement. In another embodiment, the antibody molecule does not recruit effector cells or fix complement. In certain embodiments, the ability of the antibody molecule to bind to the Fc receptor is reduced or does not have this ability. For example, the antibody may be an isotype or subtype, fragment or other mutant that does not support binding to an Fc receptor, such as one that has a mutagenized Fc receptor binding region or has deleted the Fc receptor binding region.

[0288] In one embodiment, the constant region of the antibody molecule is changed. The method of changing the constant region of the antibody is known in the art. The antibody molecule with the function of change (for example, the affinity of the C1 component of the effector ligand (such as FcR on the cell) or complement) can be produced by replacing at least one amino acid residue in the constant part of the antibody with different residues (see, for example, EP388,151A1, U.S. Patent No. 5,624,821 and U.S. Patent No. 5,648,260, all of which are incorporated herein by reference). It also includes amino acid mutations that stabilize the antibody structure, such as S228P (EU nomenclature, S241P in Kabat nomenclature) in human IgG4. Similar types of changes can be described, which will weaken or eliminate these functions if applied to mouse or other species immunoglobulins.

[0289] In one embodiment, the Fc region is altered to extend the half-life. For example, the Fc region may include 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).

[0290] In one embodiment, the Fc region is altered to enhance ADCC. For example, the Fc region may comprise one or more of the following: A330L-I332E-S239D, F243L-R292P-Y300L-V305I-P396L, or S298A-E333A-K334A. In one embodiment, defucosylation can be achieved by expression in a knockout fucosyltransferase (FucT8) cell line (e.g., CHO).

[0291] In one embodiment, the Fc region is altered to enhance CDC. For example, the Fc region comprises S267E-H268F-S324T.

[0292] In one embodiment, the Fc region is altered to enhance antibody-dependent cellular phagocytosis (ADCP). For example, the Fc region comprises S239D-I332E-A330L.

[0293] In one embodiment, the amino acids in the antibody molecule are only standard amino acids. In one embodiment, the antibody molecule comprises naturally occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs with variant side chains; and / or all stereoisomers of any of the foregoing. The antibody molecule may comprise peptide mimetics and D- or L- optical isomers of amino acids.

[0294] The polypeptides of the antibody molecules described herein may be linear or branched, may contain modified amino acids, and may be interspersed with non-amino acids. The antibody molecules may also be modified; for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as coupling with a labeling component. The polypeptides may be isolated from natural sources, may be produced by prokaryotic or eukaryotic hosts using recombinant technology, or may be the product of synthetic methods.

[0295] The antibody molecules described herein can be used alone in an unconjugated form, or can be conjugated to certain substances, such as toxins or moieties (e.g., therapeutic drugs; compounds that emit radiation; plant, fungal or bacterial derived molecules; or biological proteins (e.g., protein toxins) or particles (e.g., recombinant viral particles (e.g., via viral envelope proteins)). For example, an anti-CD138 antibody can be conjugated to a radioactive isotope (e.g., α-, β-, or γ-radiator or β- and γ-radiator).

[0296] Antibody molecules can be derivatized or linked to other functional molecules (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is an antibody molecule that has been modified. Methods of derivatization include, but are not limited to, adding fluorescent moieties, radionucleotides, toxins, enzymes, or affinity ligands (e.g., biotin). Therefore, antibody molecules include derivatized and other modified forms of antibodies described herein, including immunoadhesion molecules. For example, antibody molecules can be functionally linked (by chemical coupling, genetic fusion, non-covalent association, or other) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detection agent, a toxin, a pharmaceutical agent, and / or a protein or peptide that can mediate the association of the antibody or antibody portion with other molecules (e.g., a streptavidin core region or a polyhistidine tag).

[0297] Certain types of derivatized antibody molecules can be produced by cross-linking two or more antibodies (of the same type or of different types, e.g., to produce bispecific antibodies). Suitable cross-linking agents include heterobifunctional cross-linking agents (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate) cross-linking agents having two different reactive groups separated by a suitable spacer. Such cross-linking agents are available from Pierce Chemical Company (Rockford, Illinois).

[0298] Useful detectable agents that can be used for derivatization (or labeling) of 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 lanthanide atoms), and radioactive materials (as described below). Exemplary fluorescent detection agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonic acid chloride, phycoerythrin, and the like. Antibodies can also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, β-galactosidase, acetylcholinesterase, glucose oxidase, and the like. When antibodies are derivatized with detectable enzymes, other reagents that are added to the enzyme to produce detectable reaction products can be used to detect the antibody. For example, when the detection agent horseradish peroxidase is present, hydrogen peroxide and diaminobenzidine are added to produce a detectable color reaction product. Antibody molecules can also be derivatized with prosthetic groups (e.g., streptavidin / biotin and avidin / biotin). For example, the antibody can be derivatized with biotin and detected by indirect assay of avidin or streptavidin binding. Examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; examples of luminescent materials include luminol; examples of bioluminescent materials include luciferase, luciferin and aequorin.

[0299] Labeled antibody molecules can be used, for example, diagnostically and / or experimentally, including (i) for isolating a predetermined antigen by standard techniques (such as affinity chromatography or immunoprecipitation); (ii) for detecting a predetermined antigen (e.g., in cell lysates or cell supernatants) to assess the expression pattern and abundance of the protein; (iii) for monitoring protein levels in tissues as part of a clinical trial, for example, to determine the efficacy of a given treatment regimen.

[0300] Antibody molecules may be coupled to other molecular entities, which are typically markers or therapeutic agents (e.g., antimicrobial agents (e.g., antibacterial or bactericides), immunomodulators, immunostimulants, cytotoxic or cytostatic agents) or moieties. Radioactive isotopes may be used in detection or therapeutic applications. Radioactive isotopes that may be coupled to antibody molecules include, but are not limited to, α-, β-, or γ-emitters, or β- and γ-emitters. 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、Bi( 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 Ga). Radioactive isotopes that can be used as therapeutic agents include: yttrium ( 90 Y), Lutetium ( 177 Lu), Actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re、Bi( 212 Bior 213 Bi) and rhodium ( 188 Rh). Radioactive isotopes useful as labels, for example for diagnostic purposes, 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.

[0301] The present disclosure provides radiolabeled antibody molecules and methods for labeling the same. In one embodiment, a method for labeling an antibody molecule is disclosed. The method comprises contacting the antibody molecule with a chelating agent to produce a conjugated antibody. The conjugated antibody is labeled with a radioisotope (e.g. 111 indium, 90 Yttrium and 177 The antibody is radiolabeled with lutetium to produce a labeled antibody molecule.

[0302] In some aspects, the present disclosure provides a method for preparing an antibody molecule disclosed herein. The method includes: providing an antigen (e.g., CD138) or a fragment thereof; obtaining an antibody molecule that specifically binds to the antigen; evaluating the effectiveness 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 its derivatives (e.g., humanized antibody molecules), to a subject (e.g., a human).

[0303] The present disclosure provides isolated nucleic acid molecules encoding the above antibody molecules, and vectors and host cells thereof. Nucleic acid molecules include but are not limited to RNA, genomic DNA and cDNA.

[0304] The amino acid and nucleotide sequences of exemplary antibody molecules are described in Tables 1 and 2, respectively.

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318] In one embodiment, the antibody molecule comprises one, two or three CDRs in the VH region of the antibody molecule described herein (e.g., in Table 1) (using the CDR definition of Kabat or Chothia). In one embodiment, the antibody molecule comprises one, two or three CDRs in the VL region of the antibody molecule described herein (e.g., in Table 1) (using the CDR definition of Kabat or Chothia). In one embodiment, using the CDR definition of Kabat or Chothia, the antibody molecule comprises one or more (e.g., two or three) CDRs in the VH region of the antibody molecule described herein (e.g., in Table 1) and one or more (e.g., two or three) CDRs in the VL region.

[0319] In one embodiment, the antibody molecule comprises one, two or three HCDRs described in Table 1. In one embodiment, the antibody molecule comprises one, two or three LCDRs described in Table 1. 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 described in Table 1.

[0320] In one embodiment, the antibody molecule comprises one, two, three or four frameworks of the VH region of the antibody molecule described in Table 1. In one embodiment, the antibody molecule comprises one, two, three or four frameworks of the VL region of the antibody molecule described in Table 1. In one embodiment, the antibody molecule comprises one or more (e.g., two, three or four) frameworks of the VH region and one or more (e.g., two, three or four) frameworks of the VL region of the antibody molecule described in Table 1.

[0321] In one embodiment, the antibody molecule comprises a VH of an antibody molecule described herein (e.g., in Table 1). In one embodiment, the antibody molecule comprises a VL of an antibody molecule described herein (e.g., in Table 1). In one embodiment, the antibody molecule comprises a VH and a VL of an antibody molecule described herein (e.g., in Table 1).

[0322] In one embodiment, the antibody molecule comprises a VH having an amino acid sequence as described in Table 1 or an amino acid sequence substantially identical thereto (e.g., differing by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues therefrom, or having at least 85, 90, 95, or 99% identity thereto). In one embodiment, the antibody molecule comprises a VL having an amino acid sequence as described in Table 1 or an amino acid sequence substantially identical thereto (e.g., differing by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues therefrom, or having at least 85, 90, 95, or 99% identity thereto). In one embodiment, the antibody molecule comprises a VH having an amino acid sequence as described in Table 1 (or an amino acid sequence substantially identical thereto) and a VL having an amino acid sequence as described in Table 1 (or an amino acid sequence substantially identical thereto).

[0323] In one embodiment, the antibody molecule comprises a VH encoded by a nucleotide sequence described in Table 2, or a nucleotide sequence substantially identical thereto (e.g., differing by no more than 3, 6, 15, 30, or 45 nucleotides therefrom, or at least about 85%, 90%, 95%, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VL encoded by a nucleotide sequence described in Table 2, or a nucleotide sequence substantially identical thereto (e.g., differing by no more than 3, 6, 15, 30, or 45 nucleotides therefrom, or at least about 85%, 90%, 95%, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VH encoded by a nucleotide sequence described in Table 2 (or a nucleotide sequence substantially identical thereto) and a VL encoded by a nucleotide sequence described in Table 2 (or a nucleotide sequence substantially identical thereto).

[0324] In one embodiment, VH comprises one, two or all of the following: (i) HCDR1 comprising the amino acid sequence GYNFSSY (SEQ ID NO:350); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO:351); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 GYNFSSY (SEQ ID NO:350); (ii) HCDR2, comprising the amino acid sequence HPSDST (SEQ ID NO:351); and (iii) HCDR3, comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1, comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0325] 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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 the amino acid sequence of SEQ ID NO: 291. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 291, and VL comprises the amino acid sequence of SEQ ID NO: 292.

[0327] In one embodiment, VH comprises one, two or all of the following: (i) HCDR1 comprising the amino acid sequence GYNFSSY (SEQ ID NO:350); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO:351); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 GYNFSSY (SEQ ID NO:350); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO:351); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0328] 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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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, the VH comprises the amino acid sequence of SEQ ID NO: 293. In one embodiment, the VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 293 and the VL comprises the amino acid sequence of SEQ ID NO: 292.

[0330] 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; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 GYSFSSY (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; and VL comprises three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3), wherein VL comprises: (i) LCDR1, comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0331] 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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0332] In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 294. In one embodiment, the VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 294 and the VL comprises the amino acid sequence of SEQ ID NO: 292.

[0333] 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; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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:356); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO:351); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0334] 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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIHPSDSTTNCNQKFKG (SEQ ID NO:381); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0335] In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 295. In one embodiment, the VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 295 and the VL comprises the amino acid sequence of SEQ ID NO: 292.

[0336] 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; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 GYSFSSY (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; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0337] 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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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, the VH comprises the amino acid sequence of SEQ ID NO: 296. In one embodiment, the VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, the VH comprises the amino acid sequence of SEQ ID NO: 296, and the VL comprises the amino acid sequence of SEQ ID NO: 292.

[0339] 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; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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:356); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO:351); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0340] 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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); or (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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 TIPSDSTTNYNQKFKG (SEQ ID NO:382); and (iii) HCDR3 comprising the amino acid sequence FVY; and VL comprises: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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).

[0341] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 297. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 292. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 297 and VL comprises the amino acid sequence of SEQ ID NO: 292.

[0342] In one embodiment, VH comprises one, two or all of the following: (i) HCDR1 comprising the amino acid sequence of GFTFNTY (SEQ ID NO:357); (ii) HCDR2 comprising the amino acid sequence of RSKSSNYA (SEQ ID NO:358); or (iii) HCDR3 comprising the amino acid sequence of ELRLRYAMDY (SEQ ID NO:359); and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYTNGKTYLN (SEQ ID NO:360); (ii) LCDR2 comprising the amino acid sequence of LVSKLDS (SEQ ID NO:304); or (iii) LCDR3 comprising the amino acid sequence of LQSTHFPLT (SEQ ID NO:361). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence GFTFNTY (SEQ ID NO:357); (ii) HCDR2 comprising the amino acid sequence RSKSSNYA (SEQ ID NO:358); and (iii) HCDR3 comprising the amino acid sequence ELRLRYAMDY (SEQ ID NO:359); and VL comprises: (i) LCDR1 comprising the amino acid sequence KSSQSLLYTNGKTYLN (SEQ ID NO:360); (ii) LCDR2 comprising the amino acid sequence LVSKLDS (SEQ ID NO:304); and (iii) LCDR3 comprising the amino acid sequence LQSTHFPLT (SEQ ID NO:361).

[0343] In one embodiment, VH comprises one, two or all of the following: (i) HCDR1 comprising the amino acid sequence TYAMH (SEQ ID NO:383); (ii) HCDR2 comprising the amino acid sequence RIRSKSSNYATYYADSVKD (SEQ ID NO:384); or (iii) HCDR3 comprising the amino acid sequence ELRLRYAMDY (SEQ ID NO:359); and VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence KSSQSLLYTNGKTYLN (SEQ ID NO:360); (ii) LCDR2 comprising the amino acid sequence LVSKLDS (SEQ ID NO:304); or (iii) LCDR3 comprising the amino acid sequence LQSTHFPLT (SEQ ID NO:361). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence TYAMH (SEQ ID NO:383); (ii) HCDR2 comprising the amino acid sequence RIRSKSSNYATYYADSVKD (SEQ ID NO:384); and (iii) HCDR3 comprising the amino acid sequence ELRLRYAMDY (SEQ ID NO:359); and VL comprises: (i) LCDR1 comprising the amino acid sequence KSSQSLLYTNGKTYLN (SEQ ID NO:360); (ii) LCDR2 comprising the amino acid sequence LVSKLDS (SEQ ID NO:304); and (iii) LCDR3 comprising the amino acid sequence LQSTHFPLT (SEQ ID NO:361).

[0344] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 291. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 298. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 298, and VL comprises the amino acid sequence of SEQ ID NO: 292.

[0345] In one embodiment, the anti-CD138 antibody molecule comprises:

[0346] (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 the following: (i) HCDR1 comprising the amino acid sequence GF / YS / TFT / IA / T / S / R / T / DH / Y / F; (ii) HCDR2 comprising the amino acid sequence D / H / Y / NPN / S / YT / D / S / YG / SS / A / V; or (iii) HCDR3 comprising the amino acid sequence N / S / EW / Y / GH / XD / XY / XT / Y / XD / E / A / XG / F / M / XP / A / L / DY / H (X = absent); and

[0347] (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence KSSQ / HSLLD / H / YG / S / TD / NGK / ETYLN (SEQ ID NO:435); (ii) LCDR2 comprising the amino acid sequence LVSK / NLDS (SEQ ID NO:436); or (iii) LCDR3 comprising the amino acid sequence W / LQG / STHFPR / QT (SEQ ID NO:437).

[0348] In one embodiment, the anti-CD138 antibody molecule comprises:

[0349] (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 the following: (i) a HCDR1 comprising the amino acid sequence of A / T / S / R / D / NH / Y / FH / W / N / GMH / N / S; (ii) a HCDR2 comprising the amino acid sequence of E / R / N / WID / H / Y / NP / TN / S / YT / D / S / YG / SS / A / V / D / YT / S / PT / Q / N / GYN / D / T / AQ / E / DK / R / N / DFR / K / EA / T / N / S / G; or (iii) a HCDR3 comprising the amino acid sequence of N / S / EW / Y / GH / XD / XY / XT / Y / XD / E / A / XG / F / M / XP / A / L / DY / H (X = absent); and

[0350] (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence KSSQ / HSLLD / H / YG / S / TD / NGK / ETYLN (SEQ ID NO:435); (ii) LCDR2 comprising the amino acid sequence LVSK / NLDS (SEQ ID NO:436); or (iii) LCDR3 comprising the amino acid sequence W / LQG / STHFPR / QT (SEQ ID NO:437).

[0351] In one embodiment, the antibody molecule comprises: (i) HCDR1, which comprises the amino acid sequence of HCDR1 of an anti-CD138 antibody described herein (e.g., selected from antibody CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619 or 623); (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.

[0352] In one embodiment, the anti-CD138 antibody molecule comprises:

[0353] (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 three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the VH comprises one, two, or all of the following: (i) HCDR1 comprising the amino acid sequence GYN / S / TFSSY (SEQ ID NO: 438); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence FVY; and

[0354] (b) a light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence of RSSKSLLYKDGKTYLN (SEQ ID NO:352); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO:353); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO:354).

[0355] In one embodiment, HCDR1 comprises an amino acid sequence selected from any one of SEQ ID NO: 350, 355 or 356, HCDR2 comprises an amino acid sequence of SEQ ID NO: 351, and HCDR3 comprises an amino acid sequence of FVY. In one embodiment, LCDR1 comprises an amino acid sequence of SEQ ID NO: 352; LCDR2 comprises an amino acid sequence of SEQ ID NO: 353; and LCDR3 comprises an amino acid sequence of SEQ ID NO: 354.

[0356] In one embodiment, the anti-CD138 antibody molecule comprises:

[0357] (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 three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), wherein the 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 TIHPSDSTTNC / YNQKFKG (SEQ ID NO: 439); or (iii) HCDR3 comprising the amino acid sequence FVY; and

[0358] (b) a light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence of RSSKSLLYKDGKTYLN (SEQ ID NO:352); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO:353); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO:354).

[0359] In one embodiment, HCDR1 comprises an amino acid sequence selected from any one of SEQ ID NO: 380, HCDR2 comprises an amino acid sequence of SEQ ID NO: 381 or 382, ​​and HCDR3 comprises an amino acid sequence of FVY. In one embodiment, LCDR1 comprises an amino acid sequence of SEQ ID NO: 352; LCDR2 comprises an amino acid sequence of SEQ ID NO: 353; and LCDR3 comprises an amino acid sequence of SEQ ID NO: 354.

[0360] In one embodiment, the antibody molecule comprises: (a) VH comprising: (i) HCDR1 comprising the amino acid sequence of HCDR1 of an anti-CD138 antibody described herein (e.g., from antibody 1610, 2510, 2610, 2710, 2810, 2910 or 1409); (ii) HCDR2 comprising the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) HCDR3 comprising the amino acid sequence of HCDR3 of the anti-CD138 antibody; and (b) VL comprising: (i) LCDR1 comprising the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3 comprising the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0361] In one embodiment, VH comprises the amino acid sequence of VH of an anti-CD138 antibody, and VL comprises the amino acid sequence of VL of an anti-CD138 antibody.

[0362] In one embodiment, the antibody molecule comprises two VHs and two VLs.

[0363] 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 framework regions derived from human framework germline sequences.

[0364] In one embodiment, the antibody molecule comprises a VH region comprising one or more mutations relative to an anti-CD138 antibody described herein (e.g., antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409). In one embodiment, the mutation comprises one or more substitutions relative to the VH sequence of antibody 1610. In one embodiment, the substitution is C60Y. In one embodiment, the substitution is N28S. In one embodiment, the substitution is N28T. In one embodiment, the substitution is N28S and C60Y. In one embodiment, the substitution is N28T and C60Y. In one embodiment, the mutated antibody molecule is expressed at a level equal to or greater than antibody 1610 in transiently transfected HEK293 cells.

[0365] In one embodiment, the antibody molecule is bound to the extracellular domain of CD138. In one embodiment, the antibody molecule is bound to the extracellular region of CD138 near the transmembrane domain. In one embodiment, the antibody molecule can be bound 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 comprising the amino acid sequence ENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO:440), a peptide comprising the amino acid sequence RNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO:444), or a peptide comprising the amino acid sequence ENTAVVAVEPDRRNQ (SEQ ID NO:443).

[0366] In one embodiment, the antibody molecule also binds to an extracellular region of CD138 distal to the transmembrane domain, e.g., a region corresponding to or proximal to 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 comprising the amino acid sequence ASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEA (SEQ ID NO: 10), or a peptide comprising the amino acid sequence GEAVVLPEVEPGLTA (SEQ ID NO: 445).

[0367] 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 framework regions derived from human framework germline sequences.

[0368] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule comprises a heavy chain constant region of an IgG selected from IgG1, IgG2, IgG3 or IgG4. In one embodiment, the antibody molecule comprises a light chain constant region of a kappa or lambda light chain.

[0369] In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations to increase binding affinity to the neonatal receptor FcRn and / or the half-life of the antibody molecule. In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations described herein, e.g., to increase one or more of half-life, ADCC, CDC or ADCP.

[0370] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule comprises a heavy chain constant region of an IgG selected from IgG1, IgG2, IgG3 or IgG4. In one embodiment, the antibody molecule comprises a light chain constant region of a kappa or lambda light chain.

[0371] In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations to increase binding affinity to the neonatal receptor FcRn and / or the half-life of the antibody molecule. In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations described herein, e.g., to increase one or more of half-life, ADCC, CDC or ADCP.

[0372] 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 a heavy chain constant region and a light chain constant region. In one embodiment, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and a heavy chain and light chain variable region of the antibody molecule described in Table 1 herein. In certain 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 molecule described in Table 1.

[0373] Exemplary heavy chain constant regions are described below.

[0374] IgG1 HC constant region:

[0375] ASTKGPSVFPLAPSSKSTSGGTAALGCLVK D YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPK DTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:446)

[0376] IgG2 HC constant region:

[0377] ASTKGPSVFPLAPCSRSTSESTAALGCLVK D YFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPK D TLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYT LPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:447)

[0378] 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 in CD138. For example, the antibody molecule may comprise two or more identical or substantially identical VH-VL pairs, wherein each VH-VL pair binds to two or more different regions in CD138. As another example, the antibody molecule may comprise two or more different VH-VL pairs, wherein each VH-VL pair binds to different regions in CD138.

[0379] 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 comprise two or more 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 comprise two or more different VH-VL pairs, wherein each VH-VL pair has a different binding specificity.

[0380] Antibody-drug conjugates

[0381] As used herein, the term "antibody molecule-drug conjugate" or ADC refers to an antibody molecule coupled to a non-antibody portion, such as a therapeutic agent or a marker (e.g., a cytotoxic agent). The antibody molecule can be coupled to the non-antibody portion directly or indirectly, such as via a linker.

[0382] In one embodiment, the antibody molecule is coupled to the non-antibody portion via a covalent bond. 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 a "cargo."

[0383] In one embodiment, the non-antibody moiety is coupled to the main chain of an antibody molecule. In another embodiment, the non-antibody moiety is coupled to the side chain of an antibody molecule. In one embodiment, two or more (e.g., three, four, five, six, seven, eight or more) non-antibody moieties are coupled to an antibody molecule.

[0384] In one embodiment, the ADC comprises an antibody molecule that binds to CD138, such as an anti-CD138 antibody molecule described herein.

[0385] In one embodiment, the ADC comprises one, two or three CDRs of the VH region of an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409) using the CDR definitions of Kabat or Chothia. In one embodiment, the ADC comprises one, two or three CDRs of the VL region of an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409), using the CDR definitions of Kabat or Chothia. In one embodiment, 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 an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409), using the CDR definitions of Kabat or Chothia.

[0386] In one embodiment, the ADC comprises one, two or three VH CDRs described in Table 1. In one embodiment, the ADC comprises one, two or three VL CDRs described in Table 1. In one embodiment, the ADC comprises one or more (e.g., two or three) VH CDRs and / or one or more (e.g., two or three) VL CDRs described in Table 1.

[0387] In one embodiment, the ADC comprises one, two, three or four frameworks of the VH region of an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910 or 1409). In one embodiment, the ADC comprises one, two, three or four frameworks of the VL region of an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910 or 1409). In one embodiment, the ADC comprises one or more (e.g., two, three, or four) frameworks of the VH region and / or one or more (e.g., two, three, or four) frameworks of the VL region of an antibody molecule described in Table 1 (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

[0388] In one embodiment, the ADC comprises a heavy chain variable region of an antibody molecule described in Table 1 (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409). In one embodiment, the ADC comprises a light chain variable region of an antibody molecule described in Table 1 (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409). In one embodiment, the ADC comprises the heavy chain variable region and the light chain variable region of the antibody molecule described in Table 1 (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

[0389] In one embodiment, the ADC comprises a heavy chain variable region having an amino acid sequence described in Table 1. In one embodiment, the ADC comprises a light chain variable region having an amino acid sequence described in Table 1. In one embodiment, the ADC comprises a heavy chain variable region having an amino acid sequence described in Table 2 and a light chain variable region having an amino acid sequence described in Table 1.

[0390] In one embodiment, the antibody molecule comprises a heavy chain variable region encoded by a nucleotide sequence described in Table 2. In one embodiment, the antibody molecule comprises a light chain variable region encoded by a nucleotide sequence described in Table 2. In one embodiment, the antibody molecule comprises a heavy chain variable region encoded by a nucleotide sequence described in Table 2 and a light chain variable region encoded by a nucleotide sequence described in Table 2.

[0391] In one embodiment, the ADC comprises a heavy chain constant region. In one embodiment, the ADC comprises a light chain constant region. In one embodiment, the ADC comprises a heavy chain constant region and a light chain constant region. In one embodiment, the ADC comprises a heavy chain constant region, a light chain constant region, and a heavy chain and light chain variable region of an antibody molecule described in Table 1 herein. In certain embodiments, the ADC 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 an antibody molecule described in Table 1.

[0392] 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 a tubulin polymerase inhibitor (e.g., riocetin), an agent associated with tubulin depolymerization (e.g., maytansine), an agent associated with DNA cleavage (e.g., calicheamicin), a DNA minor groove alkylating agent (e.g., dukamycin), a DNA minor groove cross-linking agent (e.g., a PBD dimer), or an RNA polymerase II inhibitor (e.g., α-amanitin).

[0393] In one embodiment, the cytotoxic agent is α-amanitin. α-amanitin is a bicyclic octapeptide that belongs to a large group of protoplasmic mushroom toxins called atomoxins. 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 in, for example, Moldenhauer et al. J Natl Cancer Inst. 2012; 104(8): 622-634. The structure of α-amanitin is as follows:

[0394]

[0395] In one embodiment, the cytotoxic agent is a scutellarin analog. Scutellarin is a group of cyanobacterial decapeptides that have significant biological activity against multidrug resistant (MDR) cancer cells. Scutellarin consumes microtubules by interacting with tubulin, thereby preventing cell division. They are able to induce apoptosis, possibly through other mechanisms in addition to apoptosis mediated by microtubule inhibition. Scutellarin, analogs 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 scutellarin analogs are as follows:

[0396]

[0397] In one embodiment, the cytotoxic agent is calicheamicin (also known as LL-E33288). Calicheamicin contacts DNA and causes Bergman cyclization, resulting in DNA cleavage, thereby destroying cells. Calicheamicin 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 calicheamicin is as follows.

[0398]

[0399] 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 the AT-rich minor groove of DNA and alkylates the DNA. Centanamycin and its use in ADCs are described, for example, in Rayburn et al. Cancer Chemother Pharmacol. 2012; 69(6): 1423-31.

[0400] In one embodiment, the cytotoxic agent is dolastatin. In one embodiment, the dolastatin is dolastatin 10 or dolastatin 15. Dolastatins non-competitively inhibit vincristine binding to tubulin in the periwinkle / peptide region. Analogs of dolastatin include, for example, symplostatin 1, symplostatin 3, and ruiocetin. Dolastatin, analogs, and uses thereof 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:

[0401]

[0402] The structure of Aplysia 15 is as follows:

[0403]

[0404] In one embodiment, the cytotoxic agent is a duocarmycin analog. Ducarmycin analogs are DNA minor groove, AT sequence selective and adenine N3 alkylating agents. Ducarmycin, analogs and their use in ADCs are described in, 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. Angew Chem 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:

[0405]

[0406] In one embodiment, the cytotoxic agent is maytansine. Maytansine (a benzoadamantanyl lactone) is a highly effective microtubule-targeting compound that can induce mitotic arrest and kill tumor cells at subnanomolar concentrations. Maytansine and its analogs (maytansine compounds DM1 and DM4) are effective microtubule-targeting compounds that can 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:

[0407]

[0408] In one embodiment, the cytotoxic agent is monomethylreoxetine E (MMAE, vedotin). MMAE is a highly effective antimitotic agent that inhibits cell division by preventing the polymerization of tubulin. MMAE and its use in ADCs are described in, 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:

[0409]

[0410] In one embodiment, the cytotoxic agent is monomethyl ruoxetine F (MMAF). MMAF is an anti-tubulin agent that inhibits cell division by preventing the polymerization of tubulin. It is a ruoxetine derivative with a charged C-terminal phenylalanine, and its cytotoxic activity is weakened compared to its uncharged counterpart, monomethyl ruoxetine E (MMAE). When coupled to a monoclonal antibody targeting internalized, tumor-specific cell surface antigens through a protease cleavage linker, MMAF can induce effective anti-tumor effects. For example, the linker connected to the monoclonal antibody is stable in the extracellular fluid, but once the conjugate enters the tumor cell, it can be cleaved by cathepsins, thereby activating the anti-mitotic mechanism. MMAF and its use in ADCs are described, for example, in 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 Suppl): 1033-1042. The structure of MMAF is as follows:

[0411]

[0412] In one embodiment, the cytotoxic agent is a 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 pyrrolobenzodiazepine antibiotics include but are not limited to anthramycin, gibberellins, ciprofloxacin, DC-81, methyl anthramycin, neothramycin A, neothramycin B, roxithromycin, prothracarcin, sibanomicin (DC-102), sibiromycin and tomamycin. PBDs and their use in ADCs are described, for example, in Antonow and Thurston DE. Chem Rev. 2011; 111: 2815-2864; Cipolla et al. Anticancer Agents Med Chem. 2009; 9: 1-31; Gerratana. 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:

[0413]

[0414] In one embodiment, the ADC further comprises a linker, for example, a linker that couples the antibody molecule to a non-antibody moiety. In one embodiment, the linker comprises a hydrazone, a disulfide bond, a peptide or a thioether bond.

[0415] In one embodiment, the linker is a non-cleavable linker. Exemplary non-cleavable linkers include, for example, a non-cleavable thioether linker (e.g., N-succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC)) or a non-cleavable maleimidocaproyl linker.

[0416] In one embodiment, the linker is a cleavable linker. In one embodiment, the cleavable linker is a chemically unstable linker, for example, an acid-cleavable linker (for example, an acid-cleavable hydrazone) or a reducible linker (for example, a disulfide bond). In one embodiment, the cleavable linker is an enzyme-cleavable linker, such as a peptide-based linker (for example, a dipeptide linker (for example, a valine-citrulline (Val-Cit) linker or a phenylalanine-lysine (Phe-Lys) dipeptide linker)) or a β-glucuronic acid linker. Other linkers and their use in ADC are described in, for example, Lu et al. Int J Mol Sci. 2016; 17 (4): 561, the contents of which are incorporated herein by reference in their entirety.

[0417] In one embodiment, the linker is a poly(ethylene glycol) (PEG) linker.

[0418] Animal models

[0419] The antibody molecules described herein can be evaluated in vivo, for example, using various animal models. For example, animal models can be used to test the efficacy of the antibody molecules described herein in inhibiting CD138 and / or treating or preventing the conditions described herein, such as myeloma (e.g., multiple myeloma). Animal models can also be used, for example, to study side effects, measure the concentration of antibody molecules in situ, and demonstrate the correlation between CD138 function and diseases described herein, such as myeloma (e.g., multiple myeloma). Exemplary types of animals that can be used to evaluate the antibody molecules described herein include, but are not limited to, mice, rats, rabbits, guinea pigs, and monkeys.

[0420] Exemplary animal models of myeloma (e.g., multiple myeloma) that can be used to evaluate the antibody molecules described herein include, but are not limited to, immunocompetent mouse models, such as the 5TMM (5T Rad1), 5T2, T33, and 5TGMA models (Radl et al. Am J Pathol. 1988; 132:593-597); immunocompromised mouse models, such as the RAG-2 model (Fowler et al. DisModel Mech. 2009; 2:604-611), xenograft mouse myeloma models, such as the SCID and NOD / SCID models (Huang et al. Cancer Res. 1993; 53:1392-1396; Tsunenari et al. Blood. 1997; 90:2437-2444; Torcia et al. Exp Hematol. 1996; 24:868-874; Hjorth-Hansen et al. J Bone Miner Res. 1999; 14: 256–263); SCID-Hu and SCID-Rab models (Urashima et al. Blood. 1997; 90: 754–765; Yaccoby et al. Blood. 1998; 92: 2908–2913; Yata and Yaccoby. Leukemia. 2004; 18: 1891–1897); genetically engineered models, e.g., IL-6- and MYC-driven models (Kovalchuk et al. Proc Natl Acad Sci USA. 2002; 99: 1509–1514; Adams et al. Nature. 1985; 318: 533–538; Chesi et al. Blood. 2012; 120: 376–385); Eμ-xbp-1s model (Carrasco et al. Cancer Cell. 2007; 11(4): 349-360); L-GP130 model (Dechow et al. J Clin Invest. 2014; 124(12): 5263-5274).

[0421] Various mouse and human myeloma cell lines and primary human myeloma cells can be used for preclinical in vivo models. Exemplary mouse and human myeloma cell lines that can be used for transplantation include, but are not limited to, 5T myeloma cells (Radl et al. Am J Pathol. 1988; 132: 593–597), human lymphoblastoid ARH-77 cells (Huang et al. Cancer Res. 1993; 53 (6): 1392-1396), human JJN3 myeloma cell line (Hjorth-Hansen et al. J Bone Miner Res. 1999; 14 (2): 256-263), and IL-6 dependent myeloma cell line (Tsunenari et al. Blood. 1997; 90 (6): 2437-2444). The desired cell line can be selected based on, for example, the speed of tumor implantation, the characteristics of a particular tumor type (e.g., the tendency to lytic bone lesions), or the type of monoclonal protein produced.

[0422] Other animal models of myeloma (eg, multiple myeloma) are described in, for example, Lwin et al. Bonekey Rep. 2016; 5:772; Libouban et al. Morphologie. 2015; 99(325):63-72; Campbell et al. Curr Protoc Pharmacol. 2008; Chapter 14, Unit 14.9.

[0423] Pharmaceutical compositions and kits

[0424] In some aspects, the disclosure provides compositions, e.g., pharmaceutically acceptable compositions, comprising an anti-CD138 antibody molecule described herein (e.g., a humanized antibody molecule described herein), formulated together with a pharmaceutically acceptable carrier.

[0425] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, isotonic agents and absorption delaying agents, etc. that are physiologically compatible. The carrier may be suitable for intravenous, intramuscular, subcutaneous, parenteral, rectal, spinal or epidermal administration (e.g., by injection or infusion). In certain embodiments, less than about 5% (e.g., less than about 4%, 3%, 2% or 1%) of the antibody molecules in the pharmaceutical composition exist in aggregate form. In other embodiments, at least about 95% (e.g., at least about 96%, 97%, 98%, 98.5%, 99%, 99.5%, 99.8% or more) of the antibody molecules in the pharmaceutical composition exist in monomeric form. In some embodiments, aggregate or monomer levels are determined by chromatography (e.g., high performance size exclusion chromatography (HP-SEC)).

[0426] Compositions described herein can be in various forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. Suitable forms depend on the target mode of administration and therapeutic application. Usually suitable compositions are in the form of injectable or infusible solutions. One of suitable modes of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In some embodiments, the antibody molecule is administered by intravenous infusion or injection. In certain embodiments, the antibody is administered by intramuscular or subcutaneous injection.

[0427] As used herein, the terms "parenteral administration" and "administered parenterally" refer to forms of administration other than enteral and topical administration, usually by injection, such as, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraocular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0428] The therapeutic composition should generally be sterile and stable under the conditions of preparation and storage. The composition can be formulated into a solution, microemulsion, dispersion, liposome or other ordered structure suitable for high antibody concentration. The required amount of active compound (i.e., antibody or antibody portion) in a suitable solvent can be blended with one or a combination of the above components as needed, and then filtered and sterilized to prepare a sterile injection. Usually, the active activator is mixed into a sterile carrier containing an alkaline dispersion medium and the above-mentioned other required ingredients to prepare a dispersant. When preparing sterile powders for sterile injection, the preferred preparation method is vacuum drying and freeze drying, and the powder of the active ingredient and any other required components is obtained from the previously sterile filtered solution. The appropriate fluidity of the solution can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersant, and by using a surfactant. Including agents that delay absorption such as monostearate and gelatin in the composition can prolong the absorption of the injectable composition.

[0429] The antibody molecules described herein can be administered by a variety of methods. Several are known in the art, and for many therapeutic, prophylactic or diagnostic applications, the appropriate route / mode of administration is intravenous injection or infusion. For example, the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg / min; preferably less than or equal to 5 mg / min to achieve a dose of about 1 to 100 mg / m2, preferably about 5 to 50 mg / m2, about 7 to 25 mg / m2, and more preferably about 10 mg / m2. It will be understood by those skilled in the art that the route and / or mode of administration varies depending on the desired results. In certain embodiments, the active compound can be prepared with a carrier that will protect the compound from rapid release, such as a controlled release formulation, including an implant, a transdermal patch, and a microencapsulation delivery system. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Many methods for preparing such preparations have been patented or are well known to those skilled in the art. See, eg, Sustained and Controlled Release Drug Delivery Systems, JR Robinson, ed., Marcel Dekker, Inc., New York, 1978.

[0430] In certain embodiments, the antibody molecule may be administered orally (e.g., with an inert diluent or an absorbable edible carrier). The antibody molecule (and other components as needed) may also be contained in a hard or soft shell gelatin capsule, compressed into a tablet, or directly incorporated into the subject's diet. For oral therapeutic administration, the antibody molecule may be mixed with an excipient and used in the form of an ingestible tablet, buccal tablet, lozenge, capsule, elixir, suspension, syrup, wafer, or the like. In order to administer the antibody molecule by other forms of non-parenteral administration, it may be necessary to coat the compound with a material or co-administer a material with the compound to prevent the compound from being inactivated. Therapeutic, prophylactic, or diagnostic compositions may also be administered using medical devices, several of which are known in the art.

[0431] The dosage regimen is adjusted to provide the desired response (e.g., a therapeutic, preventive, or diagnostic response). For example, it may be a single bolus, divided doses over time, or the dose may be reduced or increased proportionally according to the urgency of the treatment situation. Particularly advantageous are parenteral compositions formulated in unit dosage form for ease of administration and dosage uniformity. Unit dosage form herein refers to physically discrete units used as a single dose for a subject to be treated, each unit containing a predetermined amount of active compound and a desired drug carrier, which is calculated to produce the desired therapeutic effect. The specifications of the dosage unit form of the present invention depend on or are directly dependent on (a) the unique characteristics of the antibody and the specific therapeutic, preventive, or diagnostic effect to be achieved, and (b) the inherent limitations of the field of preparation of this antibody molecule in dealing with individual sensitivity.

[0432] An exemplary non-limiting range of a therapeutically, prophylactically or diagnostically effective amount of an antibody molecule is about 0.1 to 50 mg / kg of subject body weight, for example, about 0.1 to 30 mg / kg, for example, about 1 to 30, 1 to 15, 1 to 10, 1 to 5, 5 to 10 or 1 to 3 mg / kg, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40 or 50 mg / kg. For example, the antibody molecule can be administered by intravenous infusion at a rate of less than 10 mg / minute, for example, less than or equal to 5 mg / minute to achieve a dose of about 1 to 100 mg / m2, for example, about 5 to 50 mg / m2, about 7 to 25 mg / m2, about 10 mg / m2. It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated. It should be understood that for each particular subject, the specific dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the dosage ranges listed herein are merely exemplary and are not intended to limit the scope or embodiment of the claimed composition.

[0433] The pharmaceutical compositions herein may comprise a "therapeutically effective amount", "prophylactically effective amount" or "diagnostically effective amount" of the antibody molecules described herein.

[0434] "Therapeutically effective amount" refers to an amount that can achieve the desired therapeutic effect according to a certain dose and necessary schedule. The therapeutically effective amount of an antibody molecule may vary according to factors such as the disease state, age, sex and weight of the individual and the ability of the antibody or antibody portion to cause the desired response in the individual. Therapeutically effective amount, the therapeutic beneficial effects of the antibody molecule outweigh any toxic or harmful effects. Relative to an untreated subject, a "therapeutically effective dose" generally suppresses a measurable parameter by at least about 20%, such as at least about 40%, at least about 60% or at least about 80%. Measurable parameters can be, for example, hematuria, urine color, urine foam, pain, swelling of the hands and feet (edema) or high blood pressure. The ability of an antibody molecule to suppress a measurable parameter can be assessed in an animal model system for predicting the efficacy of treating or preventing myeloma. Alternatively, the ability of an antibody molecule to inhibit CD138 can be examined (e.g., by in vitro assays) to assess this property of the composition.

[0435] "Prophylactically effective amount" refers to an amount that can effectively achieve the desired preventive effect according to a certain dosage and necessary schedule. Generally speaking, since the preventive dose is used for the subject in the early stage of the disease or before the disease occurs, the preventive effective amount will be less than the therapeutic effective amount.

[0436] "Diagnostically effective amount" refers to an amount that, at a certain dosage and for a certain period of time, can achieve the desired diagnostic effect. Generally, a diagnostically effective amount is an amount in which a disorder, such as a disorder described herein (eg, myeloma), can be diagnosed in vitro, ex vivo, or in vivo.

[0437] The present disclosure also includes a kit containing the antibody molecules described herein. The kit may include one or more other elements, including: instructions for use; other reagents, such as markers, therapeutic agents, reagents that can be used to chelate or couple the antibody molecules to markers or therapeutic agents, radiation protection compositions / components; devices or other materials for preparing the antibody molecules for administration; pharmaceutically acceptable carriers; and devices or other materials for administering to a subject.

[0438] Nucleic Acids

[0439] As described herein, the invention also features nucleic acids comprising nucleotide sequences encoding anti-CD138 antibody molecules (eg, heavy and light chain variable regions and CDRs of the antibody molecule).

[0440] For example, the disclosure features a first and second nucleic acid encoding a heavy chain and a light chain variable region, respectively, of an antibody molecule selected from one or more antibody molecules disclosed herein (e.g., an antibody molecule of Table 2) or a portion of an antibody molecule (e.g., a variable region of Table 2). The nucleic acid can comprise a nucleotide sequence encoding any one of the amino acid sequences in the tables herein, or a sequence substantially identical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical to a sequence shown in the tables herein, or differing therefrom by no more than 3, 6, 15, 30 or 45 nucleotides).

[0441] In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs from a heavy chain variable region having an amino acid sequence listed in the table herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, such as conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two or three CDRs from a light chain variable region having an amino acid sequence listed in the table herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, such as conservative substitutions). In some embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five or six CDRs from a heavy and light chain variable region having an amino acid sequence listed in the table herein, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or having one or more substitutions, such as conservative substitutions).

[0442] In certain embodiments, the nucleic acid may include a nucleotide sequence encoding at least one, two or three CDRs from a heavy chain variable region, the nucleic acid having a nucleotide sequence shown in Table 2, a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under stringent conditions described herein). In some embodiments, the nucleic acid may include a nucleotide sequence encoding at least one, two or three CDRs from a light chain variable region, the nucleic acid having a nucleotide sequence shown in Table 2, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under stringent conditions described herein). In certain embodiments, the nucleic acid may include a nucleotide sequence encoding at least one, two, three, four, five or six CDRs from heavy and light chain variable regions, the nucleic acid having a nucleotide sequence shown in Table 2, or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under stringent conditions described herein).

[0443] In certain embodiments, the nucleic acid comprises a nucleotide sequence shown in Table 2 or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under stringent conditions as described herein). In some embodiments, the nucleic acid comprises a portion of a nucleotide sequence shown in Table 2 or a sequence substantially homologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or more identical thereto, and / or capable of hybridizing under stringent conditions as described herein). The portion may encode, for example, a variable region (e.g., VH or VL); one, two, or three or more CDRs; or one, two, three, four or more framework regions.

[0444] Nucleic acids as described herein include deoxyribonucleotides or ribonucleotides or their analogs. Polynucleotides can be single-stranded or double-stranded, and if single-stranded, can be coding strands or non-coding (antisense) strands. Polynucleotides can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. Nucleotide sequences can be interspersed with non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by coupling with a labeling component. Nucleic acids can be recombinant polynucleotides, or polynucleotides of genomic, cDNA, semisynthetic or synthetic origin, i.e., non-naturally occurring or associated with another polynucleotide in a non-natural arrangement.

[0445] In certain aspects, the features of the present application include host cells and vectors comprising nucleic acids described herein. The nucleic acids may be present in a single vector or in separate multiple vectors in the same host cell or in non-same host cells, as described below.

[0446] Carrier

[0447] Further provided herein are vectors comprising a nucleotide sequence encoding an anti-CD138 antibody molecule described herein.

[0448] In one embodiment, the vector comprises a nucleotide encoding an antibody molecule described herein (e.g., as described in Table 1). In another embodiment, the vector comprises a nucleotide sequence described herein (e.g., in Table 2). Vectors include, but are not limited to, viruses, plasmids, cosmids, lambda phages, or yeast artificial chromosomes (YACs).

[0449] Many vector systems can be used. For example, one class of vectors utilizes DNA elements derived from animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retrovirus (Rous sarcoma virus, MMTV or MOMLV) or SV40 virus. Another class of vectors utilizes RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern equine encephalitis virus and flaviviruses.

[0450] In addition, by introducing one or more markers that can select transfected host cells, the cells that have been stably integrated into their chromosomes can be selected. The marker can provide, for example, auxotrophic, biocide (such as antibiotic) resistance or resistance to heavy metals such as copper to auxotrophic hosts. The selective marker gene can be directly connected to the DNA sequence to be expressed, or introduced into the same cell by co-transformation. The optimization synthesis of mRNA may also require other elements. These elements may include splicing signals, as well as transcriptional promoters, enhancers and termination signals.

[0451] Once an expression vector or DNA sequence containing a construct for expression is prepared, the expression vector can be transfected or introduced into a suitable host cell. This can be achieved using a variety of techniques, such as protoplast fusion, calcium phosphate precipitation, electroporation, retroviral transduction, viral transfection, gene gun, lipid-based transfection or other conventional techniques. In the case of protoplast fusion, the cells can be grown in culture and screened for appropriate activity.

[0452] Methods and conditions for culturing the resulting transfected cells and recovering the produced antibody molecules are known to those of skill in the art and can be modified or optimized based on the description herein according to the particular expression vector and mammalian host cell used.

[0453] cell

[0454] The present disclosure also provides cells (e.g., host cells) comprising nucleic acids encoding anti-CD138 antibody molecules as described herein. For example, the host cell may comprise a nucleotide sequence described in Table 2, a sequence substantially homologous thereto (e.g., a sequence having at least about 85%, 90%, 95%, 99% or more identity thereto, and / or a sequence capable of hybridizing under stringent conditions as described herein) or a portion of one of the nucleic acids. In addition, the host cell may comprise a nucleic acid molecule encoding the amino acid sequence in Table 1, a sequence substantially homologous thereto (e.g., a sequence at least about 80%, 85%, 90%, 95%, 99% or more identical thereto), or a portion of one of the sequences.

[0455] In some embodiments, the host cell is genetically engineered to contain a nucleic acid encoding an antibody molecule described herein.

[0456] In certain embodiments, an expression cassette is used to genetically engineer a host cell. The term "expression cassette" refers to a nucleotide sequence that can affect gene expression in a host compatible with such a sequence. Such an expression cassette may include a promoter, an open reading frame with or without introns, and a termination signal. Other factors necessary or helpful for expression may also be used, such as an inducible promoter.

[0457] The present disclosure also provides host cells comprising the vectors described herein.

[0458] The cell may be, but is not limited to, a eukaryotic cell, a bacterial cell, an insect cell or a human cell. Suitable eukaryotic cells include, but are not limited to, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cells include, but are not limited to, Sf9 cells. In one embodiment, the cell (e.g., a host cell) is an isolated cell.

[0459] Uses of Antibody Molecules

[0460] The antibody molecules described herein, as well as the pharmaceutical compositions described herein, have in vitro, ex vivo and in vivo therapeutic, prophylactic and / or diagnostic uses.

[0461] In one embodiment, the antibody molecule causes (e.g., induces or increases) effector function on cells expressing CD138. For example, the antibody molecule can be administered to a subject (e.g., a human subject) to produce antibody-dependent cellular toxicity to diseased cells (e.g., cancer cells or precancerous cells) bound thereto. In one embodiment, the antibody molecule causes complement-dependent cytotoxic activity on cells expressing CD138. In one embodiment, the antibody molecule reduces (e.g., inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138. In one embodiment, the antibody molecule inhibits the effect of proteases on membrane-bound CD138, for example, to reduce the shedding of CD138. For example, these antibody molecules can be administered to cells in culture in vitro or in vitro, or, for example, administered to a subject, such as a human subject, in vivo to reduce (e.g., inhibit, block or neutralize) one or more biological activities of the cell.

[0462] Therefore, on the one hand, the present disclosure provides a method for treating, preventing or diagnosing a disease in a subject, such as a disease described herein (e.g., multiple myeloma), the method comprising administering the anti-CD138 antibody molecule to the subject, thereby treating, preventing or diagnosing the disease. For example, the present disclosure provides a method comprising contacting the antibody molecule described herein with cells in culture, such as in vitro or ex vivo, or administering the antibody molecule described herein to a subject, for example, to treat, prevent or diagnose a disease, such as a disease associated with CD138 (e.g., multiple myeloma).

[0463] The term "subject" as used herein is intended to include humans and non-human animals. In some embodiments, the subject is a human subject, such as a human patient suffering from a disease described herein (e.g., multiple myeloma) or at risk of suffering from a disease described herein (e.g., multiple myeloma). The term "non-human animal" includes mammals and non-mammals, such as non-human primates. In some embodiments, the subject is a human. The methods and compositions described herein are suitable for treating a disease described herein (e.g., multiple myeloma) in a human patient. Patients with a disease described herein include, for example, those patients suffering from a disease described herein but (at least temporarily) asymptomatic, patients who have shown symptoms of a disease described herein, and patients suffering from a disease related or associated with a disease described herein.

[0464] Methods of treating or preventing disease

[0465] The antibody molecules described herein can be used to treat or prevent diseases associated with CD138 or symptoms thereof.

[0466] Exemplary diseases or conditions that may be associated with CD138 include, but are not limited to, cancer (e.g., blood cancer (e.g., myeloma, such as multiple myeloma) or solid tumors, and precancerous conditions (e.g., smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS)). In one embodiment, the disease is associated with abnormal expression of CD138. In one embodiment, the antibody molecule is used to treat a subject having a disease described herein or at risk of developing a disease described herein. In one embodiment, the antibody molecule is used to reduce the progression of a disease, e.g., to reduce the progression of a precancerous condition to cancer.

[0467] The frequency of administration of the antibody molecules described herein should generally maintain a therapeutically effective level of the antibody molecules in the patient's system until the patient recovers. For example, the antibody molecules can be administered at a frequency sufficient to achieve a serum concentration of at least about 1, 2, 5, 10, 20, 30 or 40 antibody molecules bound to each CD138 molecule. In one embodiment, the antibody molecules are administered every 1, 2, 3, 4, 5, 6 or 7 days, every 1, 2, 3, 4, 5 or 6 weeks, or every 1, 2, 3, 4, 5 or 6 months.

[0468] Methods of administering various antibody molecules are known in the art and are described below. The appropriate dosage of the antibody molecule used will depend on the age and weight of the subject and the specific drug used.

[0469] In one embodiment, the antibody molecule is administered intravenously to a subject (e.g., a human subject). In one embodiment, the antibody molecule is administered to a subject at a dosage of 0.1 mg / kg-50 mg / kg, e.g., 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 is administered to a subject at a fixed dose of 10 mg-1000 mg, e.g., 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. In one embodiment, the antibody molecule is administered once a week, twice a week, once every two weeks, once every three weeks, once every four weeks, once every eight weeks, once a month, once every two months, or once every three months. In one embodiment, the antibody molecule is administered at 0.5 mg / kg-3 mg / kg or 50 mg-150 mg once a week, twice a week, once every two weeks or once every four weeks.

[0470] The antibody molecule can be used alone or coupled to a second agent, such as a bacterial agent, a toxin or a protein (e.g., a second anti-CD138 antibody molecule). The method includes administering a single antibody molecule or an antibody molecule coupled to a second agent to a subject in need of the treatment. The antibody molecule can be delivered with a variety of therapeutic agents (e.g., toxins or mixtures thereof).

[0471] cancer

[0472] The anti-CD138 antibody molecules described herein can be used to treat or prevent cancer or a precancerous condition.

[0473] CD138 expression is dysregulated in many cancers, such as prostate cancer, breast cancer, pancreatic cancer, ovarian cancer, colon cancer, lung cancer and myeloma (Kiviniemi et al. APMIS. 2004; 112(2):89-97; Lendorf et al. J Histochem Cytochem. 2011; 59(6):615-629; Juuti et al. Oncology. 2005; 68(2-3):97-106; Kusumoto et al. Oncol Rep. 2010; 23(4):917-25; Hashimoto et al. BMC Cancer. 2008; 8:185; Joensuu et al. Cancer Res. 2002; 62(18):5210-5217; Seidel et al. Blood. 2000; 95(2):388-392). CD138 regulates several key processes of tumorigenesis, such as cancer cell proliferation, apoptosis and angiogenesis (Teng et al. Matrix Biol. 2012; 31(1): 3-16). The molecular and clinical characteristics of CD138 in solid cancers and hematological cancers are described in, for example, Akl et al. Oncotarget. 2015; 6(30): 28693-28715.

[0474] CD138 can affect tumorigenesis by regulating mediators (e.g., oncogenes or growth factors) of tumor cell survival and proliferation. For example, Sdc1- / - mice are protected from Wnt-1-induced mammary tumorigenesis (Alexander et al. Nat Genet. 2000; 25(3): 329-32). Hepatocyte growth factor (HGF) binds to CD138 on myeloma cells (Derksen et al. Blood. 2002; 99(4): 1405-1410). The interaction of HGF with CD138-enhanced Met signaling is involved in the growth, survival, and spread of many cancers (Birchmeier et al. Nat Rev Mol Cell Biol. 2003; 4(12): 915-925; Derksen et al. Blood. 2002; 99(4): 1405-1410). CD138 expression is elevated in reactive stroma of breast cancer tissue (Stanley et al. Am J Clin Pathol. 1999; 112(3):377-383). CD138-expressing MEFs enhance the growth of breast cancer cell lines in co-culture and promote breast cancer development in vivo (Maeda et al. Cancer Res. 2004; 64(2):612-621).

[0475] CD138 can regulate tumor cell apoptosis. Knockdown of CD138 in myeloma cells induces growth arrest and apoptosis (Khotskaya et al. J Biol Chem. 2009; 284(38): 26085-26095). Recombinant CD138 extracellular domain induces apoptosis in MCF-7 breast cancer cells and cultured human prostate cancer cells (Sun et al. Cancer Res. 2008; 68(8): 2912-2919; Hu et al. Neoplasia. 2010; 12(10): 826-836).

[0476] CD138 can bind to pro-angiogenic factors (such as FGF-2 and VEGF) and present these factors to their respective receptors on endothelial cells to initiate endothelial invasion and sprouting (Teng et al. Matrix Biol. 2012; 31(1): 3-16). Increased CD138 expression in stromal fibroblasts has been observed in several cancers, such as breast cancer, gastric cancer, and thyroid cancer (Stanley et al. Am J Clin Pathol. 1999; 112(3): 377-383; Wiksten et al. Int J Cancer. 2001; 95(1): 1-6; Barbareschi et al. Cancer. 2003; 98(3): 474-483). In a xenograft model in mice implanted with human breast cancer cells and CD138-transfected fibroblasts, stromal CD138 expression was associated with significantly increased microvessel density and larger vascular area (Maeda et al. Oncogene. 2006; 25(9): 1408-1412).

[0477] Exemplary cancers that can be treated or prevented by the antibody molecules described herein include, but are not limited to, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma, AIDS-related lymphoma, primary central nervous system (CNS) lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid / humanoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (e.g., Ewing's sarcoma or osteosarcoma and malignant fibrous histiocytoma), brain tumors (e.g., astrocytoma, brain stem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, CNS system embryonal tumors, central nervous system germ cell tumors, craniopharyngioma or ependymoma), breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid (e.g., gastrointestinal carcinoid), cardiac (heart) tumors, embryonal tumors, germ cell tumors, lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), chronic myeloproliferative neoplasms, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer, ependymoma, esophageal cancer, nasal glioma, Ewing sarcoma, extracranial genital tract cancer cell tumors, extragonadal germ cell tumors, eye cancer (e.g., intraocular melanoma or retinoblastoma), fallopian tube cancer, fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid, gastrointestinal stromal tumor (GIST), germ cell tumors (e.g., central nervous system tumors, extracranial tumors, extragonadal tumors, ovarian cancer, or testicular cancer), gestational trophoblastic disease, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, Kaposi's sarcoma, kidney cancer (e.g., renal cell carcinoma or Wi lms tumor), Langerhans cell histiocytosis (LCH), laryngeal cancer, leukemia (e.g., acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), or hairy cell leukemia), lip and oral cancer, liver cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC) or small cell lung cancer), lymphoma (e.g., AIDS-related Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or primary central nervous system (CNS) lymphoma), Waldenstrom Macroglobulinemia, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma (e.g., intraocular (eye) melanoma), Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma, midline carcinoma, oral cancer, multiple endocrine neoplasms, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, chronic myelin proliferative neoplasms, nasal and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, lip and oral cavity cancer, oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer (e.g., epithelial ovarian cancer or germ cell ovarian tumor), pancreatic cancer, pancreatic neuroendocrine tumors (islet cell tumors) ), papilloma, paraganglioma, carcinoma of the paranasal sinuses and nasal cavity, parathyroid carcinoma, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, pleuropulmonary blastoma, peritoneal cancer, prostate cancer, rectal cancer, retina, rhabdomyosarcoma, salivary gland cancer, sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, soft tissue sarcoma, or uterine sarcoma), Sézary syndrome, skin cancer (e.g., melanoma, Merkel cell carcinoma, or non-melanoma skin cancer), small intestine cancer, squamous cell carcinoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid carcinoid, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, endometrial cancer, vaginal cancer, vulvar cancer, or metastatic lesions thereof.

[0478] In one embodiment, the cancer is a hematological cancer, such as a myeloma, lymphoma, or leukemia. In one embodiment, the cancer is a myeloma. In one embodiment, the cancer is multiple myeloma.

[0479] In another embodiment, the cancer is a solid tumor. In one embodiment, the cancer is cervical cancer (e.g., cervical squamous cell carcinoma or endocervical adenocarcinoma), uterine cancer (e.g., endometrioid carcinoma), brain cancer (e.g., glioblastoma), lung cancer (e.g., lung squamous cell carcinoma) or breast cancer (e.g., invasive breast carcinoma).

[0480] In one embodiment, the cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, glioma, head and neck cancer, laryngeal cancer, liver cancer, lung cancer, mesothelioma, nasopharyngeal cancer, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer or thyroid cancer.

[0481] In one embodiment, the cancer is bladder cancer. CD138 is expressed in bladder cancer (Kim and Park. Hum Pathol. 2014; 45: 1830-1838). In one embodiment, bladder cancer is urothelial carcinoma, squamous cell carcinoma or adenocarcinoma. In one embodiment, bladder cancer is non-invasive, non-muscle invasive or muscle invasive. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat bladder cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery (e.g., transurethral resection of bladder tumors (TURBT) or cystectomy), intravesical therapy (e.g., intravesical immunotherapy (e.g., bacillus Calmette-Guérin (BCG) therapy) or intravesical chemotherapy (e.g., mitomycin, valfloxacin, docetaxel, thiotepa or gemcitabine)), chemotherapy (e.g., intravesical chemotherapy or systemic chemotherapy (e.g., cisplatin, fluorouracil (5-FU), mitomycin, gemcitabine, methotrexate, vinblastine, doxorubicin, carboplatin, paclitaxel, docetaxel, ifosfamide or pemetrexed), radiotherapy or immunotherapy (e.g., intravesical BCG, immune checkpoint inhibitors (e.g., PD-L1 inhibitors (e.g., atezolizumab, durvalumab, or avelumab) or PD-1 inhibitors (e.g., nivolumab or pembrolizumab).

[0482] In one embodiment, the cancer is breast cancer. CD138 is expressed in breast cancer (Akl et al. Oncotarget. 2015; 6(30):28693-28715; Barbareschi et al. Cancer. 2003; 98:474-483; Lim et al. Singapore Med J. 2014; 55:468-472; Nguyen et al. Am J Clin Pathol. 2013; 140:468-474; Lendorf et al. J Histochem Cytochem. 2011; 59:615-629; Gotte et al. Breast Cancer Res. 2007; 9(1):R8; Tsanou et al. J Exp Clin Cancer Res. 2004; 23(4):641-650). In one embodiment, the breast cancer is ductal carcinoma (e.g., ductal carcinoma in situ (DCIS) or invasive ductal carcinoma (IDC) (e.g., tubular carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma or cribriform carcinoma), lobular carcinoma (e.g., lobular carcinoma in situ (LCIS) or invasive lobular carcinoma (ILC)) or inflammatory breast cancer. In one embodiment, the breast cancer is ER positive, PR positive, HER2 positive or triple negative (ER-, PR- and HER2-). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, procedure or therapy to treat bladder cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery (e.g., breast conserving surgery or mastectomy), radiation therapy, chemotherapy (e.g., anthracyclines (e.g., doxorubicin, liposomal doxorubicin, epirubicin), taxanes (e.g., paclitaxel, albumin-bound paclitaxel (e.g., nab-paclitaxel or docetaxel), 5-fluorouracil (5-FU), cyclophosphamide, platinum agents (e.g., cisplatin or carboplatin), vinorelbine, capecitabine, gemcitabine, mitoxantrone, ixabepilone or eribulin), hormone therapy (e.g., tamoxifen, toremifene, fulvestrant, aromatase inhibitors (e.g., letrozole, anastrozole or exemestane), ovarian ablation (e.g., oophorectomy, luteinizing hormone-releasing hormone (LHRH) analogs or chemotherapy drugs), targeted therapy (e.g., trastuzumab, pertuzumab, ado-trastuzumab amitriptyline, lapatinib, neratinib, CDK4 / 6 inhibitors (e.g., palbociclib or levitra), mTOR inhibitors (e.g., everolimus), or a combination thereof.

[0483] In one embodiment, the cancer is cervical cancer. CD138 is expressed in cervical cancer (Akl et al. Oncotarget. 2015; 6 (30): 28693-28715). In one embodiment, cervical cancer is microinvasive cervical cancer or invasive cervical cancer. In one embodiment, cervical cancer is squamous cell carcinoma or adenocarcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat cervical cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery (e.g., cryosurgery, laser surgery, conization, simple hysterectomy, radical hysterectomy, tracheectomy or pelvic resection), chemotherapy (e.g., cisplatin, carboplatin, paclitaxel, topotecan, gemcitabine, docetaxel, ifosfamide, 5-fluorouracil (5-FU), irinotecan or mitomycin), targeted therapy (e.g., angiogenesis inhibitors (e.g., bevacizumab)) or a combination thereof.

[0484] In one embodiment, the cancer is endometrial cancer. CD138 is expressed in endometrial cancer (Hasengaowa et al. Ann Oncol. 2005; 16: 1109-1115). In one embodiment, endometrial cancer is endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, mixed or undifferentiated carcinoma, squamous cell carcinoma, transitional cell carcinoma or endometrial stromal sarcoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat endometrial cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery, radiation therapy, hormonal therapy (e.g., a progestin (e.g., medroxyprogesterone acetate) or progesterone acetate), tamoxifen, a luteinizing hormone-releasing hormone (LHRH) agonist (e.g., goserelin or leuprolide), an aromatase inhibitor (e.g., letrozole, anastrozole or exemestane), chemotherapy (e.g., paclitaxel, carboplatin, doxorubicin, liposomal doxorubicin or cisplatin), or a combination thereof.

[0485] In one embodiment, the cancer is gallbladder cancer. CD138 is overexpressed in gallbladder cancer (Roh et al. EurSurg Res. 2008; 41 (2): 245-250). In one embodiment, gallbladder cancer is adenocarcinoma or papillary adenocarcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat gallbladder cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., gemcitabine, cisplatin, 5-fluorouracil (5-FU), capecitabine or oxaliplatin), or palliative therapy (e.g., biliary stent, biliary catheter, biliary bypass, alcohol injection, analgesics) or a combination thereof.

[0486] In one embodiment, the cancer is gastric cancer. Strong matrix CD138 expression is associated with gastric cancer (Wiksten et al. Int J Cancer. 2001; 95 (1): 1-6). In one embodiment, gastric cancer is adenocarcinoma (ACA). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat gastric cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, chemotherapy (e.g., 5-FU (fluorouracil), capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, irinotecan, oxaliplatin or paclitaxel) or a combination thereof.

[0487] In one embodiment, the cancer is brain cancer (e.g., glioma). CD138 is expressed in glioma (Xu et al. Mol Biol Rep. 2012; 39(9): 8979-8985). In one embodiment, the glioma is an astrocytoma, a meningocytoma, or an oligodendroglioma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation, or therapy to treat glioma. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., carboplatin, carmustine (BCNU), cisplatin, cyclophosphamide, etoposide, irinotecan, lomustine (CCNU), methotrexate, procarbazine, temozolomide, or vincristine), targeted therapy (e.g., bevacizumab or everolimus), corticosteroids (e.g., dexamethasone), antiepileptic drugs or hormones, or a combination thereof.

[0488] In one embodiment, the cancer is laryngeal cancer. CD138 is expressed in laryngeal cancer (Klatka et al. Otolaryngol Pol. 2004; 58: 933-940). In one embodiment, laryngeal cancer is squamous cell carcinoma or adenocarcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat laryngeal cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., cisplatin, carboplatin, 5-fluorouracil (5-FU), docetaxel, paclitaxel, bleomycin, methotrexate or ifosfamide), targeted therapy (e.g., EGFR inhibitors (e.g., cetuximab)) or a combination thereof. In one embodiment, the cancer is liver cancer. In one embodiment, liver cancer is hepatocellular carcinoma (HCC), cholangiocarcinoma, angiosarcoma or secondary liver cancer. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat liver cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery, tumor ablation, tumor embolization, radiation therapy, targeted therapy (e.g., sorafenib or regorafenib), chemotherapy (e.g., doxorubicin, 5-fluorouracil (5-FU) or cisplatin), or a combination thereof.

[0489] In one embodiment, the cancer is lung cancer. CD138 is expressed in lung cancer (Anttonen et al. Lung Cancer. 2001; 32: 297-305). In one embodiment, lung cancer is non-small cell lung cancer (NSCLC) (e.g., adenocarcinoma, squamous cell carcinoma, large cell carcinoma or large cell neuroendocrine tumor) or small cell lung cancer (SCLC). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat lung cancer. In one embodiment, the anti-CD138 antibody molecule is administered with surgery, radiofrequency ablation (RFA), radiation therapy, chemotherapy (cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine or pemetrexed), targeted therapy (angiogenesis inhibitors (e.g., bevacizumab or ramucirumab), EGFR inhibitors (e.g., erlotinib, afatinib, gefitinib, osimertinib or netotuzumab), ALK inhibitors (e.g., In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery, radiation therapy, chemotherapy (cisplatin, etoposide, carboplatin, or irinotecan), or a combination thereof, for example, to treat small cell lung cancer.

[0490] In one embodiment, the cancer is mesothelioma. CD138 is expressed in mesothelioma (Kumar-singh et al. J Pathol. 1998; 186: 300-305). In one embodiment, mesothelioma is epithelioid mesothelioma, sarcomatoid mesothelioma or biphasic mesothelioma. In one embodiment, mesothelioma is pleural mesothelioma, peritoneal mesothelioma or pericardial mesothelioma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat mesothelioma. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., pemetrexed, cisplatin, carboplatin, gemcitabine, methotrexate, vinorelbine, mitomycin or doxorubicin), or a combination thereof.

[0491] In one embodiment, the cancer is nasopharyngeal carcinoma. CD138 is expressed in nasopharyngeal carcinoma (Anttonen et al. Lung Cancer. 2001; 32: 297-305). In one embodiment, nasopharyngeal carcinoma is keratinizing squamous cell carcinoma, non-keratinizing differentiated carcinoma or undifferentiated carcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat nasopharyngeal carcinoma. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., carboplatin, doxorubicin, epirubicin, paclitaxel, docetaxel, gemcitabine, bleomycin or methotrexate), targeted therapy (e.g., cetuximab) or a combination thereof.

[0492] In one embodiment, the cancer is nasopharyngeal carcinoma. CD138 is expressed in oral cancer (Al-Otaibi et al. J Oral Pathol Med. 2013; 42: 186-193). In one embodiment, oral cancer is squamous cell carcinoma, verrucous carcinoma or mild salivary gland cancer. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat oral cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., cisplatin, carboplatin, 5-fluorouracil (5-FU), paclitaxel, docetaxel, methotrexate, ifosfamide or bleomycin), targeted therapy (e.g., cetuximab) or a combination thereof.

[0493] In one embodiment, the cancer is ovarian cancer. CD138 is expressed in ovarian cancer (Kusumoto et al. Oncol Rep. 2010; 23: 917-925; Davies et al. Clin Cancer Res. 2004; 10: 5178-5186). In one embodiment, ovarian cancer is epithelial cancer, germ cell cancer, stromal cancer or small cell cancer. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat ovarian cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery, chemotherapy (e.g., cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel (nab-paclitaxel), docetaxel, atiradimine, capecitabine, cyclophosphamide, etoposide, gemcitabine, ifosfamide, irinotecan, liposomal doxorubicin, melphalan, pemetrexed, topotecan or vinorelbine), hormone therapy (e.g., luteinizing hormone-releasing hormone (LHRH) agonists (e.g., goserelin or leuprolide), tamoxifen, or aromatase inhibitors (e.g., letrozole, anastrozole or exemestane), targeted therapy (e.g., angiogenesis inhibitors (e.g., bevacizumab), PARP inhibitors (e.g., olaparib, rucaparib or niraparib), radiation therapy, or a combination thereof.

[0494] In one embodiment, the cancer is pancreatic cancer. CD138 is expressed in pancreatic cancer (Juuti et al. Oncology. 2005; 68: 97-106). In one embodiment, pancreatic cancer is an exocrine tumor or an endocrine tumor. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat pancreatic cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, ablation, embolization, radiotherapy or chemotherapy (cicitabine, 5-fluorouracil (5-FU), irinotecan, oxaliplatin, albumin-bound paclitaxel, capecitabine, cisplatin, paclitaxel, docetaxel or irinotecan liposomes.

[0495] In one embodiment, the cancer is prostate cancer. CD138 is expressed in prostate cancer (Ledezma et al. Asian J Androl. 2011; 13: 476-480; Shariat et al. BJU Int. 2008; 101: 232-237; Kiviniemi et al. Apmis. 2004; 112: 89-97; Zellweger et al. Prostate. 2003; 55: 20-29). In one embodiment, prostate cancer is adenocarcinoma, transitional cell (or urothelial) carcinoma, squamous cell carcinoma or small cell prostate cancer. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat prostate cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with surgery, radiotherapy, cryotherapy, hormonal therapy (e.g., orchiectomy, LHRH agonists (e.g., leuprolide, goserelin, triptorelin or histones), LHRH antagonists (e.g., degarelix), CYP17 inhibitors (e.g., abiraterone), anti-androgens (e.g., flutamide, bicalutamide, nilutamide or enzalutamide), estrogen or ketoconazole), chemotherapy (e.g., docetaxel, cabazitaxel, mitoxantrone or estramustine), vaccine therapy (e.g., Sipuleucel-T), or bone-directed therapy (e.g., bisphosphonates (e.g., zoledronic acid), denosumab, corticosteroids (e.g., prednisone or dexamethasone), external beam radiation therapy, radiopharmaceuticals (e.g., strontium-89, samarium-153 or radium-223), or a combination thereof.

[0496] In one embodiment, the cancer is head and neck cancer. CD138 is expressed in head and neck cancer (Anttonen et al. Br J Cancer. 1999; 79: 558-564; Inki et al. Br J Cancer. 1994; 70: 319-323). In one embodiment, head and neck cancer is squamous cell carcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat head and neck cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radiotherapy, chemotherapy (e.g., methotrexate, bleomycin or docetaxel), targeted therapy (e.g., cetuximab), immunotherapy (e.g., PD-1 inhibitors (e.g., nivolumab or pembrolizumab) or a combination thereof.

[0497] In one embodiment, the cancer is thyroid cancer. CD138 is expressed in thyroid cancer (Oh and Park. J Korean Med Sci. 2006; 21: 397-405). In one embodiment, thyroid cancer is papillary carcinoma, follicular carcinoma, Hürthle cell carcinoma, medullary thyroid carcinoma or anaplastic carcinoma. The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat thyroid cancer. In one embodiment, the anti-CD138 antibody molecules are used in combination with surgery, radioiodine therapy, thyroid hormone therapy, radiotherapy, chemotherapy, targeted therapy (e.g., kinase inhibitors (e.g., sorafenib or lenvatinib)) or a combination thereof.

[0498] In one embodiment, the cancer is chronic lymphocytic leukemia (CLL). CD138 is expressed in chronic lymphocytic leukemia cancer (Jilani et al. Int J Lab Hematol. 2009; 31: 97-105). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, procedure or therapy to treat thyroid cancer. In one embodiment, the anti-CD138 antibody molecule is used in combination with chemotherapy (e.g., a purine analog (e.g., fludarabine, pentostatin or cladribine), an alkylating agent (e.g., chlorambucil, cyclophosphamide or bendamustine), a corticosteroid (e.g., prednisone, methylprednisolone or dexamethasone), doxorubicin, methotrexate, oxaliplatin, vincristine, etoposide and cytarabine), an anti-CD20 antibody (rituximab, obenutuzumab or ofatumumab), an anti-CD52 antibody (e.g., alemtuzumab), a targeted therapy (e.g., ibrutinib, edaracibin or venetoclax), a stem cell transplant (SCT), or a combination thereof.

[0499] In one embodiment, the cancer is a lymphoma (e.g., diffuse large B-cell lymphoma (DLBCL)). CD138 is expressed in DLBCL (Oh and Park. J Korean Med Sci. 2006; 21: 397-405; Bodoor et al. Asian Pac J Cancer Prev. 2012; 13: 3037-3046). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat DLBCL. In one embodiment, the anti-CD138 antibody molecule is administered with chemotherapy (e.g., an alkylating agent (e.g., cyclophosphamide, chlorambucil, bendamustine or ifosfamide), a corticosteroid (e.g., prednisone or dexamethasone), a platinum drug (cisplatin, carboplatin or oxaliplatin), a purine analog (e.g., fludarabine, pentostatin or cladribine), an antimetabolite (e.g., cytarabine, gemcitabine, methotrexate or pranilalast), vincristine, doxorubicin, mitoxantrone, etoposide, etoposide, immunotherapy (e.g., anti-CD 20 antibodies (rituximab, obinutuzumab, or ofatumumab), anti-CD52 antibodies (e.g., alemtuzumab), anti-CD30 antibodies (e.g., belentuzumab-vedotin), interferons, immunomodulatory drugs (e.g., thalidomide or lenalidomide), targeted therapies (e.g., proteasome inhibitors (e.g., bortezomib), histone deacetylase (HDAC) inhibitors (e.g., romidepsin or belinstat), or kinase inhibitors (e.g., ibrutinib or edaracibinib)), radiation therapy, stem cell transplantation (SCT), or a combination thereof.

[0500] In one embodiment, the cancer is Hodgkin's lymphoma. CD138 is expressed in Hodgkin's lymphoma (Gharbaran et al. J Hematol Oncol. 2013; 6: 62; Vassilakopoulos et al. Anticancer Res. 2005; 25: 4743-4746). The anti-CD138 antibody molecules described herein can be used alone or in combination with a second therapeutic agent, operation or therapy to treat Hodgkin's lymphoma. In one embodiment, the anti-CD138 antibody molecules are used in combination with chemotherapy (e.g., doxorubicin, bleomycin, vinblastine, dacarbazine, etoposide, cyclophosphamide, vincristine, prucarbazine, prednisone, methoxyethylamine, vincristine or vinblastine), immunotherapy (e.g., anti-CD30 antibodies (e.g., berentuzumab-vedotin)), stem cell transplantation or a combination thereof.

[0501] In one embodiment, the antibody molecule is used to treat or prevent precancerous conditions. Precancerous conditions, also known as premalignant conditions, potential precancerous conditions or potential premalignant conditions, refer to a state of disordered cell morphology associated with an increased risk of cancer. If not treated in time, precancerous conditions may lead to cancer. In one embodiment, premalignant lesions are morphologically atypical tissues that appear abnormal under microscopic examination and are more likely to develop cancer than in their apparently normal cancers. In one embodiment, the precancerous condition is a smoldering myeloma or an asymptomatic myeloma. In one embodiment, the precancerous condition is monoclonal gammopathy of unknown significance (MGUS). Other examples of precancerous conditions include, but are not limited to, actinic keratosis, Barrett's esophagus, atrophic gastritis, ductal carcinoma in situ, congenital dyskeratosis, dysphagia, dysphagia, lichen planus, oral submucous fibrosis, solar elastosis, cervical atypical hyperplasia, leukoplakia and mucosal erythema.

[0502] Multiple Myeloma

[0503] The antibody molecules described herein can be used to treat or prevent multiple myeloma.

[0504] Multiple myeloma, also known as plasma cell myeloma, is a cancer of plasma cells, which are normally responsible for producing antibodies (Raab et al. Lancet. 2009; 374(9686):324-39).

[0505] Signs or symptoms of multiple myeloma include, for example, bone pain, anemia (e.g., normocytic and / or normochromic anemia), renal failure (e.g., acute or chronic renal failure), infection (e.g., pneumonia or pyelonephritis), neurologic symptoms (e.g., weakness, confusion, fatigue, headache, vision changes, retinopathy, radicular pain, loss of bowel or bladder control, carpal tunnel syndrome, or paraplegia).

[0506] Risk factors for multiple myeloma include, for example, smoldering myeloma (also known as asymptomatic myeloma), monoclonal gammopathy of undetermined significance (MGUS), obesity or familial susceptibility. In one embodiment, the anti-CD138 antibody molecules described herein can be used to reduce (e.g., prevent) the development of smoldering myeloma or MGUS into multiple myeloma.

[0507] Diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS are described, for example, in Kyle and Rajkumar Leukemia. 2009; 23(1):3-9.

[0508] The diagnostic criteria for symptomatic myeloma (all three criteria must be met) include, for example, >10% clonal plasma cells in a bone marrow biopsy or a biopsy of (any number of) other tissues (plasmacytoma), monoclonal protein (myeloma protein) in serum or urine (except for true non-secretory myeloma), and evidence of end-organ destruction associated with plasma cell disease (organ or tissue damage associated, often abbreviated as "CRAB"): hypercalcemia (corrected calcium >2.75 mmol / l, >11 mg / dL), renal insufficiency (attributable to myeloma), anemia (hemoglobin <10 g / dL), bone lesions (lytic lesions or osteoporosis with compression fractures). The diagnostic criteria for asymptomatic / smoldering myeloma include, for example, serum M-protein >30 g / l (3 g / dL) and / or clonal plasma cells >10% on bone marrow biopsy, and no myeloma-related organ or tissue damage. Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) include, for example, serum paraprotein <30 g / l (3 g / dL) and <10% clonal plasma cells in bone marrow biopsy in the absence of myeloma-related organ or tissue damage or associated B-cell lymphoproliferative disorder.

[0509] Associated conditions include, for example, solitary plasmacytoma, plasma cell dysplasia (eg, AL amyloidosis) and peripheral neuropathies, organomegaly, endocrinopathies, monoclonal plasma cell disorders, and skin changes.

[0510] The International Staging System (ISS) for myeloma is described in, for example, Greipp et al. J Clin Oncol. 2005; 23(15): 3412-20. For example, the ISS includes the following: Stage I: β2 microglobulin (β2M) <3.5 mg / L, albumin ≥3.5 g / dL; Stage II: β2M <3.5 mg / L and albumin <3.5 g / dL; or β2M 3.5–5.5 mg / L, regardless of serum albumin; Stage III: β2M ≥5.5 mg / L.

[0511] The ISS can be used with the Durie-Salmon staging system. The Durie-Salmon staging system is described in, for example, Durie and Salmon Cancer. 1975; 36(3): 842-54. For example, the Durie-Salmon staging system includes the following: Stage I (all Hb>10 g / dL, normal calcium, bone examination: normal or single plasmacytoma or osteoporosis, serum paraprotein level <5 g / dL if IgG, <3 g / dL if IgA, urinary light chain excretion <4 g / 24h); Stage II (does not meet the criteria for Stage I or Stage III); Stage III (Hb<8.5 g / dL, high calcium>12 mg / dL, bone examination: three or more lytic lesions, serum paraprotein>7 g / dL if IgG, >5 g / dL if IgA, urinary light chain excretion>12 g / 24h, one or more). Based on serum creatinine, the first, second, and third stages of the Durie-Salmon staging system can be divided into A or B: A: serum creatinine <2 mg / dL (<177 μmol / L); B: serum creatinine >2 mg / dL (>177 μmol / L).

[0512] Other treatments for multiple myeloma that can be used in combination with the anti-CD138 antibody molecules described herein include, for example, protease inhibitors (e.g., bortezomib Carfilzomib or ixazomib ), immunomodulators (e.g. thalidomide Lenalidomide Pomalidomide ), chemotherapy (eg, melphalan, vincristine Cyclophosphamide, etoposide, doxorubicin Liposomal doxorubicin or bendamustine ), corticosteroids (eg, prednisone or dexamethasone), histone deacetylase (HDAC) inhibitors (eg, panobinostat Anti-CD38 antibodies (eg, daratumumab ), anti-SLAMF7 antibodies (e.g., elotizumab ), interferon or bone marrow transplantation (eg, autologous stem cell transplantation (ASCT) or allogeneic stem cell transplantation), bisphosphonates (eg, pamidronate and zoledronic acid Radiation therapy, surgery, intravenous immune globulin (IVIG), treatments for low blood counts (such as erythropoietin) Darbepoetin ), plasma exchange, or a combination thereof.

[0513] Exemplary combination therapies that can be used in combination with the anti-CD138 antibody molecules described herein include, but are not limited to: melphalan and prednisone (MP), with or without thalidomide or bortezomib; and vincristine, doxorubicin and dexamethasone (VAD); thalidomide (or lenalidomide) and dexamethasone; bortezomib, doxorubicin and dexamethasone; bortezomib, dexamethasone and thalidomide (or lenalidomide); liposomal doxorubicin, vincristine and dexamethasone; carfilzomib, lenalidomide and dexamethasone; dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP); dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (DT-PACE), with or without bortezomib; panobinostat, bortezomib and dexamethasone; lenalidomide and dexamethasone, and evolozumab, lenalidomide and dexamethasone.

[0514] Combination therapy

[0515] The antibody molecules described herein can be used in combination with other therapies. For example, a combined therapy may include co-formulating and / or co-administering the antibody molecule with one or more other therapeutic agents (e.g., one or more other therapeutic agents described herein). In other embodiments, the antibody molecule and other therapeutic treatment modes (e.g., other therapeutic treatment modes described herein) are administered in combination. Such combined therapy can advantageously utilize a lower dose of the given therapeutic agent, thereby avoiding possible toxicity or complications associated with various individual treatments.

[0516] As used herein, "combined" administration refers to the delivery of two (or more) different treatments / therapies to a subject before or during the subject's illness. In one embodiment, two or more treatments are delivered prophylactically, such as before the subject suffers from the illness or is diagnosed with the illness. In another embodiment, two or more treatments are performed after the subject has developed or been diagnosed with the disease. In some embodiments, when the second treatment begins to be delivered, the delivery of the first treatment is still ongoing, thereby overlapping. This is sometimes referred to as "simultaneous" or "co-delivery". In other embodiments, after the delivery of the first treatment is terminated, the delivery of the other treatments begins. In either of these two cases, the treatment is more effective due to combined administration. For example, compared to what can be observed if only the second treatment is given without the first treatment, the second treatment is more effective (e.g., the same effect is observed with less second treatment, or the second treatment alleviates or reduces symptoms to a greater extent), or the first treatment is also true. In some embodiments, delivery alleviates or reduces or reduces symptoms or other parameters related to the illness to a greater extent than what can be observed by delivering one treatment without delivering another. The effects of the two treatments may be partially additive, fully additive, or greater than additive. The delivery may be such that the effects of delivering the first treatment are still detectable when the second treatment is delivered.

[0517] In certain embodiments, the additional agent is a second antibody molecule, e.g., a second antibody molecule that is different from the first antibody molecule. Exemplary antibody molecules that can be used in combination include, but are not limited to, any combination of the antibody molecules listed in Table 1.

[0518] In one embodiment, the antibody molecule is administered in combination with a second therapy to treat or prevent a myeloma, such as multiple myeloma.

[0519] In one embodiment, the antibody molecule is administered in combination with a protease inhibitor. Exemplary protease inhibitors include, for example, bortezomib Carfilzomib and ixazomib

[0520] In one embodiment, the antibody molecule is administered in combination with an immunomodulator. Exemplary immunomodulators include, for example, thalidomide Lenalidomide Pomalidomide

[0521] In one embodiment, the antibody molecule is administered in combination with a chemotherapeutic agent. Exemplary chemotherapeutic agents include, for example, melphalan, vincristine Cyclophosphamide, etoposide, doxorubicin Liposomal doxorubicin and bendamustine

[0522] In one embodiment, the antibody molecule is administered in combination with corticosteroids (eg, prednisone and dexamethasone).

[0523] In one embodiment, the antibody molecule is combined with a histone deacetylase (HDAC) inhibitor, such as panobinostat. Combination given.

[0524] In one embodiment, the antibody molecule is combined with an anti-CD38 antibody such as daratumumab Combination given.

[0525] In one embodiment, the antibody molecule is combined with an anti-SLAMF7 antibody, such as eloizumab Combined giving.

[0526] In one embodiment, the antibody molecule is administered in combination with an interferon.

[0527] In one embodiment, the antibody molecule is administered in conjunction with a bone marrow transplant (eg, autologous stem cell transplant (ASCT) or allogeneic stem cell transplant).

[0528] In one embodiment, the antibody molecule is combined with a bisphosphonate, such as pamidronate Zoledronic acid Combination given.

[0529] In one embodiment, the antibody molecule is administered in combination with radiation therapy.

[0530] In one embodiment, the antibody molecule is administered in combination with surgery.

[0531] In one embodiment, the antibody molecule is administered in combination with intravenous immunoglobulin (IVIG).

[0532] In one embodiment, the antibody molecule is combined with a treatment for low blood cell counts, such as erythropoietin. Darbepoetin Combination given.

[0533] In one embodiment, the antibody molecule is administered in combination with plasmapheresis.

[0534] In one embodiment, the antibody molecule is administered in combination with melphalan and prednisone (MP), with or without thalidomide or bortezomib.

[0535] In one embodiment, the antibody molecule is combined with vincristine, doxorubicin Administered in combination with dexamethasone (VAD).

[0536] In one embodiment, the antibody molecule is administered in combination with thalidomide (or lenalidomide) and dexamethasone.

[0537] In one embodiment, the antibody molecule is administered in combination with bortezomib, doxorubicin and dexamethasone.

[0538] In one embodiment, the antibody molecule is administered in combination with bortezomib, dexamethasone and thalidomide (or lenalidomide).

[0539] In one embodiment, the antibody molecule is administered in combination with liposomal doxorubicin, vincristine and dexamethasone;

[0540] In one embodiment, the antibody molecule is administered in combination with carfilzomib, lenalidomide and dexamethasone.

[0541] In one embodiment, the antibody molecule is administered in combination with dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP).

[0542] In one embodiment, the antibody molecule is administered in combination with dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (DT-PACE), with or without bortezomib.

[0543] In one embodiment, the antibody molecule is administered in combination with panobinostat, bortezomib and dexamethasone.

[0544] In one embodiment, the antibody molecule is administered in combination with ixamib, lenalidomide and dexamethasone.

[0545] In one embodiment, the antibody molecule is administered in combination with evolozumab, lenalidomide and dexamethasone.

[0546] In one embodiment, the antibody molecule is administered in combination with a second agent that targets the CD138 pathway. Exemplary agents that target the CD138 pathway include, for example, agents that target the extracellular domain of CD138 (e.g., synstatin, BT-062-DM4 (indatuximab ravtansine), B-B4, which is coupled to 131I, OC-46F2, or GLVGLIFAV (SEQ ID NO: 448)), agents targeting shed CD138 (e.g., NSC 405020, BB-94, PI-88, PG545, M402, SST00001 or pentraxin-3), and agents targeting CD138 genetic expression (e.g., all-trans retinoic acid, nimesulide, zoledronic acid or imatinib). Other agents targeting the CD138 pathway are described in, e.g., Akl et al. Oncotarget. 2015; 6(30): 28693-28715, the contents of which are incorporated herein by reference in their entirety.

[0547] In one embodiment, the antibody molecule is administered in combination with lenalidomide and / or dexamethasone, e.g., to treat multiple myeloma (e.g., relapsed multiple myeloma).

[0548] In one embodiment, the antibody molecule is administered in combination with a FGFR2 antagonist (eg, an anti-FGFR2 antibody, eg, FPA144) to treat a solid tumor (eg, an advanced solid tumor).

[0549] In one embodiment, the antibody molecule is v β3 inhibitors (eg, against integrin α v The invention relates to a method for treating Hodgkin lymphoma (eg, relapsed or refractory Hodgkin lymphoma) in combination with an ADC that targets a β3 inhibitor, such as brentuximab-vedotin.

[0550] In one embodiment, the antibody molecule is administered in combination with heparin or a heparanase inhibitor (eg, roneparstat (SST0001)), eg, to treat multiple myeloma (eg, advanced multiple myeloma).

[0551] In one embodiment, the antibody molecule is administered in combination with a VEGFR inhibitor (eg, bevacizumab or cediranib), eg, to treat cancer (eg, advanced cancer).

[0552] In one embodiment, the antibody molecule is administered in combination with a Wnt signaling pathway inhibitor, such as ipafricept (OMP-54F28), for example to treat solid tumors.

[0553] In one embodiment, the antibody molecule is administered in combination with a FAK inhibitor (eg, defactinib (VS-6063) or GSK2256098), eg, to treat a solid tumor, eg, lung cancer (eg, non-small cell lung cancer, eg, a cancer with a KRAS mutation).

[0554] In one embodiment, the antibody molecule is administered in combination with a glycosaminoglycan or heparanase inhibitor (e.g., necuparanib (M402)), optionally further administered with a chemotherapeutic agent (e.g., nab-paclitaxel or gemcitabine), e.g., to treat pancreatic cancer (e.g., metastatic pancreatic cancer).

[0555] In one embodiment, the antibody molecule is administered in combination with a mannosyl oligosaccharide or an FGF, heparanase and / or VEGF inhibitor (eg, muparfostat (PI-88)), eg, to treat cancer (eg, melanoma).

[0556] In one embodiment, the antibody molecule is administered in combination with a chemically modified heparan sulfate / heparanase inhibitor (eg, PG545), eg, to treat a solid tumor (eg, an advanced solid tumor).

[0557] In one embodiment, the antibody molecule is administered in combination with an amino acid or a matrix metalloproteinase inhibitor (eg, intrapleural batimastat (BB-94)), eg, to treat malignant pleural effusion.

[0558] In one embodiment, the antibody molecule is administered in combination with a chimeric anti-CD138 antigen receptor modified T cell, for example to treat multiple myeloma (e.g., relapsed and / or refractory multiple myeloma). Exemplary treatments / therapies that can be used in combination with the antibody molecules or compositions described herein to treat or prevent other disorders are also described in the "Methods for treating or preventing disorders" section herein.

[0559] Diagnostic Methods

[0560] In some aspects, the present disclosure provides a diagnostic method for detecting the presence of CD138 in vitro (e.g., in a biological sample, such as a biopsy or blood sample) or in vivo (e.g., imaging in a subject). The method includes: (i) contacting a sample with an anti-CD138 antibody molecule described herein, or administering the antibody molecule to a subject; (optionally) (ii) contacting a reference sample, such as a control sample (e.g., a control biological sample, such as a biopsy or blood sample) or a control subject with an antibody molecule described herein; and (iii) detecting the formation of a complex between the antibody molecule and the sample or subject or the control sample or subject, wherein a change (e.g., a statistically significant change) in the formation of the complex in the sample or subject relative to the control sample or subject indicates the presence of CD138 in the sample. The antibody molecule can be directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody molecules. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, and radioactive materials as described above and described in more detail below.

[0561] The term "sample" refers to a sample used to detect a polypeptide (eg, CD138) or a nucleic acid encoding the polypeptide, including but not limited to cells, cell lysates, protein or cell membrane extracts, body fluids such as blood, or tissue samples (eg, biopsies).

[0562] The complex formation between the antibody molecule and CD138 can be detected by measuring or observing the antibody molecule or unbound antibody molecule bound to CD138. Any suitable detection method can be used, and conventional detection methods include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA) or tissue immunohistochemistry. In addition to labeled antibody molecules, the presence of CD138 can be measured by competitive immunoassay using a standard labeled with a detectable substance and an unlabeled antibody molecule. In this test, a biological sample, a labeled standard substance and an antibody molecule are combined, and the amount of the labeled standard substance bound to the unlabeled binding molecule is determined. The amount of CD138 in the sample is inversely proportional to the amount of the labeled standard substance bound to the antibody molecule.

[0563] The anti-CD138 antibody molecules described herein can be used to diagnose diseases that can be treated or prevented by the anti-CD138 antibody molecules described herein. The detection or diagnosis methods described herein can be combined with other methods described herein to treat or prevent the disorders described herein.

[0564] This disclosure also includes any of the following numbered paragraphs:

[0565] 1. An anti-CD138 antibody molecule, which:

[0566] (i) binds or substantially binds to CD138 in the extracellular region proximal to the transmembrane domain of CD138; and

[0567] (ii) induces antibody-dependent cellular cytotoxicity (ADCC) activity on cells expressing CD138.

[0568] 2. The antibody molecule of paragraph 1, wherein the C-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0569] 3. The antibody molecule of paragraph 1 or 2, wherein the N-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0570] 4. The antibody molecule of any of paragraphs 1-3, wherein the antibody molecule binds to a CD138 epitope comprising five or more (e.g., 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 the extracellular region.

[0571] 5. The antibody molecule of any of paragraphs 1-4, wherein the extracellular region proximal to the transmembrane domain comprises or consists of amino acids 210-250 or 220-245 of any of SEQ ID NOs: 1-3 or 450.

[0572] 6. An antibody molecule as described in any of paragraphs 1-5, which binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte or an eosinophil).

[0573] 7. The antibody molecule of any of paragraphs 1 to 5, wherein the cell expressing CD138 is a cancer cell or a precancerous cell.

[0574] 8. The antibody molecule of paragraph 7, wherein the cancer cell or precancerous cell is a myeloma cell.

[0575] 9. The antibody molecule of any of paragraphs 1-8, which does not bind or binds with low affinity to the extracellular region of CD138 away from the transmembrane domain.

[0576] 10. The antibody molecule of any of paragraphs 1-9, which does not bind to a CD138 epitope comprising five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region away from the transmembrane domain.

[0577] 11. An antibody molecule as described in any of paragraphs 1-8, which binds or substantially binds to a CD138 epitope comprising five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region distal to the transmembrane domain.

[0578] 12. The antibody molecule of any of paragraphs 9-11, wherein the C-terminus of the extracellular region distal to the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids away from the N-terminus of the transmembrane domain.

[0579] 13. The antibody molecule of any of paragraphs 9-12, wherein the extracellular region distal to the transmembrane domain comprises amino acids 23-50, 51-95, 88-121 or 111-150 of any of SEQ ID NOs: 1-3 or 450.

[0580] 14. The antibody molecule of any of paragraphs 1-13, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138, the N-terminal region of the IBD of CD138, or both.

[0581] 15. The antibody molecule of any of paragraphs 1-13, which binds to the IBD of CD138, the N-terminal region of the IBD of CD138, or both.

[0582] 16. The antibody molecule of any of paragraphs 1-15, which binds to CD138 with a dissociation constant (KD) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05 or 1-0.1 nM.

[0583] 17. The antibody molecule of any of paragraphs 1-16, wherein the binding affinity of the antibody molecule to membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200 or 500 times higher than the binding affinity to soluble CD138.

[0584] 18. The antibody molecule of any of paragraphs 1-17, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D Binds to membrane-bound CD138.

[0585] 19. The antibody molecule of any of paragraphs 1-18, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D , or with a K of greater than about 100, 200, 300, 400, or 500 nM D Binds to soluble CD138.

[0586] 20. The antibody molecule of any of paragraphs 1-19, which binds membrane-bound CD138 better than soluble CD138, for example, the binding affinity for membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 times higher than the binding affinity for soluble CD138; or binds to membrane-bound CD138 and soluble CD138 with similar affinity, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher than the binding affinity for soluble CD138.

[0587] 21. The antibody molecule of any of paragraphs 1-20, which binds to C1q and induces complement dependent cytotoxicity (CDC) activity on cells expressing CD138.

[0588] 22. The antibody molecule of any of paragraphs 1-21, which reduces (eg, inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, ex vivo or in vivo.

[0589] 23. The antibody molecule of any of paragraphs 1-22, which mediates homotypic adhesion of one or more cells expressing CD138.

[0590] 24. The antibody molecule of any of paragraphs 1-23, which inhibits the action of proteases on membrane-bound CD138, such as reducing the shedding of CD138.

[0591] 25. The antibody molecule of any of paragraphs 1-24, which reduces (eg, inhibits) the proliferation of cancer cells or precancerous cells expressing CD138.

[0592] 26. The antibody molecule of any of paragraphs 1-25, comprising one or more (eg, two or three) heavy chain CDRs and / or one or more (eg, two or three) light chain CDRs of an anti-CD138 monoclonal antibody described herein.

[0593] 27. The antibody molecule of any of paragraphs 1-26, comprising the heavy chain variable region (VH) and / or the light chain variable region (VL) of the anti-CD138 monoclonal antibody described herein.

[0594] 28. The antibody molecule of any of paragraphs 1-27, comprising an Fc region.

[0595] 29. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in the extracellular region proximal to the transmembrane domain of CD138.

[0596] 30. The antibody molecule of paragraph 29, wherein the C-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0597] 31. The antibody molecule of paragraph 29 or 30, wherein the N-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0598] 32. The antibody molecule of any of paragraphs 29-31, wherein the extracellular region proximal to the transmembrane domain comprises or consists of amino acids 176-250 of any of SEQ ID NOs: 1-3 or 450.

[0599] 33. The antibody molecule of any of paragraphs 29-32, which does not bind or binds with low affinity to the extracellular region of CD138 distal to the transmembrane domain.

[0600] 34. The antibody molecule of any of paragraphs 29-33, wherein the epitope does not comprise five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region away from the transmembrane domain.

[0601] 35. The antibody molecule of paragraph 33 or 34, wherein the C-terminus of the extracellular region distal to the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids away from the N-terminus of the transmembrane domain.

[0602] 36. The antibody molecule of any of paragraphs 33-35, wherein the extracellular region distal to the transmembrane domain comprises amino acids 23-50, 51-95, 88-121 or 111-150 of any of SEQ ID NOs: 1-3 or 450.

[0603] 37. The antibody molecule of any of paragraphs 33-36, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138, the N-terminal region of the IBD of CD138, or both.

[0604] 38. The antibody molecule of any of paragraphs 33-36, which binds to the IBD of CD138, the N-terminal region of the IBD of CD138, or both.

[0605] 39. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in the extracellular region distal to the CD138 transmembrane domain, wherein the epitope does not consist of amino acid residues 107-111 of any one of SEQ ID NOs: 1-3 or 450.

[0606] 40. The antibody molecule of paragraph 39, wherein the epitope does not comprise amino acids 107-111 of any one of SEQ ID NO: 1-3 or 450.

[0607] 41. The antibody molecule of paragraph 39 or 40, wherein the C-terminus of the extracellular region distal to the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids away from the N-terminus of the transmembrane domain.

[0608] 42. The antibody molecule of any of paragraphs 39-41, wherein the extracellular region distal to the transmembrane domain comprises or consists of amino acids 88-121 of any of SEQ ID NOs: 1-3 or 450.

[0609] 43. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in an extracellular region proximal to the transmembrane domain of CD138; and 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 distal to the transmembrane domain of CD138.

[0610] 44. The antibody molecule of paragraph 43, wherein the C-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0611] 45. The antibody molecule of paragraph 43 or 44, wherein the N-terminus of the extracellular region proximal to the transmembrane domain is 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.

[0612] 46. ​​The antibody molecule of any of paragraphs 43-45, wherein the extracellular region proximal to the transmembrane domain comprises or consists of amino acids 176-250 or amino acids 210-250 of any of SEQ ID NOs: 1-3 or 450.

[0613] 47. The antibody molecule of any of paragraphs 43-46, wherein the C-terminus of the extracellular region distal to the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 amino acids away from the N-terminus of the transmembrane domain.

[0614] 48. The antibody molecule of any of paragraphs 43-47, wherein the extracellular region distal to the transmembrane domain comprises or consists of amino acids 23-50, 51-95, 88-121 or 111-150 of any of SEQ ID NOs: 1-3 or 450.

[0615] 49. The antibody molecule of any of paragraphs 43-48, wherein the extracellular region distal to the transmembrane domain comprises or consists of amino acids 88-121 of any one of SEQ ID NOs: 1-3 or 450.

[0616] 50. The antibody molecule of any of paragraphs 43-49, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138.

[0617] 51. The antibody molecule of any of paragraphs 43-50, which does not bind or binds with low affinity to the N-terminal region of the IBD of CD138.

[0618] 52. The antibody molecule of paragraph 51, wherein the epitope does not comprise amino acids 107-111 of any one of SEQ ID NO: 1-3 or 450.

[0619] 53. The antibody molecule of any of paragraphs 43-49, which binds to the IBD of CD138.

[0620] 54. The antibody molecule of any of paragraphs 43-50, which binds to the N-terminal region of the IBD of CD138.

[0621] 55. The antibody molecule of paragraph 54, wherein the epitope comprises amino acids 107-111 of any one of SEQ ID NO: 1-3 or 450.

[0622] 56. An antibody molecule as described in any of paragraphs 29-55, which binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte or an eosinophil).

[0623] 57. The antibody molecule of any of paragraphs 29-56, which is capable of inducing ADCC activity on cells expressing CD138.

[0624] 58. The antibody molecule of paragraph 57, wherein the cell expressing CD138 is a cancer cell or a precancerous cell.

[0625] 59. The antibody molecule of paragraph 58, wherein the cancer cell or precancerous cell is a myeloma cell.

[0626] 60. The antibody molecule of any of paragraphs 29-59, which has a dissociation constant (K) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D ) binds to CD138.

[0627] 61. The antibody molecule of any of paragraphs 29-60, wherein the antibody molecule has a binding affinity for membrane-bound CD138 that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200, or 500 times greater than that for soluble CD138; or binds to membrane-bound CD138 and soluble CD138 with similar binding affinity, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% greater than that for soluble CD138.

[0628] 62. The antibody molecule of any of paragraphs 29-61, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D Binds to membrane-bound CD138.

[0629] 63. The antibody molecule of any of paragraphs 29-62, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D , or with a K of greater than about 100, 200, 300, 400, or 500 nM D Binds to soluble CD138.

[0630] 64. The antibody molecule of any of paragraphs 29-63, which binds membrane-bound CD138 better than soluble CD138, for example, the binding affinity for membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 times higher than the binding affinity for soluble CD138.

[0631] 65. The antibody molecule of any of paragraphs 29-63, which binds to C1q and induces complement dependent cytotoxicity (CDC) activity on cells expressing CD138.

[0632] 66. The antibody molecule of any of paragraphs 29-65, which reduces (eg, inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, ex vivo or in vivo.

[0633] 67. The antibody molecule of any of paragraphs 29-66, which mediates homotypic adhesion of one or more cells expressing CD138.

[0634] 68. The antibody molecule of any of paragraphs 29-67, which inhibits the action of proteases on membrane-bound CD138, such as reducing the shedding of CD138.

[0635] 69. The antibody molecule of any of paragraphs 29-68, which reduces (eg, inhibits) proliferation of cancer cells or precancerous cells expressing CD138.

[0636] 70. The antibody molecule of any of paragraphs 29-69, comprising one or more (eg, two or three) heavy chain CDRs and / or one or more (eg, two or three) light chain CDRs of an anti-CD138 monoclonal antibody described herein.

[0637] 71. The antibody molecule of any of paragraphs 29-70, comprising the heavy chain variable region (VH) and / or the light chain variable region (VL) of the anti-CD138 monoclonal antibody described herein.

[0638] 72. The antibody molecule of any of paragraphs 29-71, comprising an Fc region.

[0639] 73. An anti-CD138 antibody molecule comprising one or both of the following:

[0640] (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 the following:

[0641] (i) a HCDR1 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or is at least 85, 90, 95, 99, or 100% homologous to the amino acid sequence of a HCDR1 of an anti-CD138 monoclonal antibody disclosed herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409);

[0642] (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR2 of the anti-CD138 antibody; or

[0643] (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody; or

[0644] (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:

[0645] (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody;

[0646] (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; or

[0647] (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0648] 74. The antibody molecule of paragraph 73, wherein VH comprises:

[0649] (i) HCDR1, which comprises an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of HCDR1 of the anti-CD138 antibody;

[0650] (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and

[0651] (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody.

[0652] 75. The antibody molecule of paragraph 73 or 74, wherein VH comprises: (i) HCDR1 comprising the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) HCDR2 comprising the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) HCDR3 comprising the amino acid sequence of HCDR3 of the anti-CD138 antibody.

[0653] 76. The antibody molecule of any of paragraphs 73-75, wherein VL comprises:

[0654] (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody;

[0655] (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; and

[0656] (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0657] 77. The antibody molecule of any of paragraphs 73-76, wherein VL comprises: (i) LCDR1 comprising the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3 comprising the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0658] 78. The antibody molecule of any of paragraphs 73-77, comprising:

[0659] (a) VH comprising:

[0660] (i) HCDR1, which comprises an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of HCDR1 of the anti-CD138 antibody;

[0661] (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and

[0662] (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody, and

[0663] (a) VL comprising:

[0664] (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody;

[0665] (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; and

[0666] (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0667] 79. The antibody molecule of any of paragraphs 73-78, comprising:

[0668] (a) a VH comprising: (i) a HCDR1 comprising the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) a HCDR2 comprising the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) a HCDR3 comprising the amino acid sequence of HCDR3 of the anti-CD138 antibody, and

[0669] (a) a VL comprising: (i) a LCDR1 comprising the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) a LCDR2 comprising the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) a LCDR3 comprising the amino acid sequence of LCDR3 of the anti-CD138 antibody.

[0670] 80. The antibody molecule of any of paragraphs 73-79, wherein VH comprises an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of VH of an anti-CD138 antibody.

[0671] 81. The antibody molecule of any of paragraphs 73-80, wherein VH comprises the amino acid sequence of VH of an anti-CD138 antibody.

[0672] 82. The antibody molecule of any of paragraphs 73-81, wherein VL comprises an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of VL of an anti-CD138 antibody.

[0673] 83. The antibody molecule of any of paragraphs 73-82, wherein VL comprises the amino acid sequence of VL of an anti-CD138 antibody.

[0674] 84. The antibody molecule of any of paragraphs 73-83, wherein:

[0675] (a) VH comprises an amino acid sequence that 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

[0676] (b) VL comprises an amino acid sequence that 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.

[0677] 85. The antibody molecule of any of paragraphs 73-84, wherein VH comprises the amino acid sequence of VH of an anti-CD138 antibody, and VL comprises the amino acid sequence of VL of an anti-CD138 antibody.

[0678] 86. The antibody molecule of any of paragraphs 73-85, comprising an Fc region.

[0679] 87. An anti-CD138 antibody molecule comprising:

[0680] (I) (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 three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the VH comprises: (i) HCDR1 comprising the amino acid sequence GYN / S / TFSSY (SEQ ID NO: 438); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO: 439); NO:351); or (iii) HCDR3 comprising the amino acid sequence FVY; and (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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); or

[0681] (II) (a) a heavy chain variable region (VH), wherein VH comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3), wherein VH comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3), wherein VH comprises: (i) HCDR1 comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence TIPSDSTTNC / YNQKFKG (SEQ ID NO: 439); or (iii) HCDR3 comprising the amino acid sequence FVY; and (b) a light chain variable region (VL), wherein VL comprises three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO: 352); (ii) LCDR2 comprising the amino acid sequence VVSTRAS (SEQ ID NO: 440). NO:353); or (iii) LCDR3 comprising the amino acid sequence QQLVEYPYT (SEQ ID NO:354).

[0682] 88. The antibody molecule of any of paragraphs 1-87, comprising two VHs and two VLs.

[0683] 89. The antibody molecule of any of paragraphs 1-88, which is a synthetic antibody molecule or an isolated antibody molecule.

[0684] 90. The antibody molecule of any of paragraphs 1-89, which is a monovalent antibody molecule, a multivalent (eg, bivalent, trivalent or tetravalent) antibody molecule, a monospecific molecule or a multispecific (eg, bispecific, trispecific or tetraspecific) antibody molecule.

[0685] 91. The antibody molecule of any of paragraphs 1-90, which is a humanized antibody molecule.

[0686] 92. The antibody molecule of any of paragraphs 1-91, comprising one or more framework regions derived from human framework germline sequences.

[0687] 93. The antibody molecule of any of paragraphs 1-92, which is an IgG antibody.

[0688] 94. The antibody molecule of any of paragraphs 1-93, comprising a heavy chain constant region of an IgG selected from IgG1, IgG2, IgG3 or IgG4.

[0689] 95. The antibody molecule of any of paragraphs 1-94, comprising a light chain constant region of a kappa or lambda light chain.

[0690] 96. The antibody molecule of any of paragraphs 1-95, comprising an Fc region comprising one or more mutations to increase binding affinity to the neonatal receptor FcRn and / or the half-life of the antibody molecule.

[0691] 97. The antibody molecule of any of paragraphs 1-96, comprising an Fc region comprising one or more mutations described herein, e.g., to increase one or more of half-life, ADCC, CDC or ADCP.

[0692] 98. An antibody molecule that competes for binding to CD138 with an anti-CD138 antibody molecule described herein, e.g., an anti-CD138 monoclonal antibody described herein (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

[0693] 99. An antibody molecule that binds or substantially binds to an epitope that completely or partially overlaps with an anti-CD138 antibody molecule described herein, e.g., an anti-CD138 monoclonal antibody described herein (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

[0694] 100. An antibody-molecule drug conjugate (ADC) comprising the antibody molecule of any of paragraphs 1-99, optionally comprising a cytotoxic agent, and optionally comprising a linker.

[0695] 101. A composition comprising the antibody molecule of any of paragraphs 1-99 or the ADC of paragraph 100, optionally wherein the composition is a pharmaceutical composition.

[0696] 102. The composition of paragraph 101, further comprising a pharmaceutically acceptable carrier.

[0697] 103. A nucleic acid molecule encoding the heavy chain variable region (VH), the light chain variable region (VL), or both of the antibody molecule described in any of paragraphs 1-99.

[0698] 104. A vector comprising the nucleic acid molecule of paragraph 103.

[0699] 105. A cell comprising the nucleic acid molecule of paragraph 103 or the vector of paragraph 104, optionally wherein the cell is an isolated cell.

[0700] 106. A kit comprising the antibody molecule of any of paragraphs 1-99, the ADC of paragraph 100, or the composition of paragraphs 101 or 102, and instructions for use of the antibody molecule or composition.

[0701] 107. A container comprising the antibody molecule of any of paragraphs 1-99, the ADC of paragraph 100, or the composition of paragraphs 101 or 102.

[0702] 108. A method of producing an anti-CD138 antibody molecule, the method comprising culturing the cell of paragraph 105 under conditions that allow production of the antibody molecule, thereby producing the antibody molecule.

[0703] 109. The method of paragraph 108, further comprising isolating or purifying the antibody molecule.

[0704] 110. The antibody molecule of any of paragraphs 1-99, the ADC of paragraph 100, or the composition of paragraph 101 or 102, for use in a method of treating cancer in a subject.

[0705] 111. The antibody molecule, ADC or composition for use as described in paragraph 110, wherein the cancer is a hematological cancer.

[0706] 112. The antibody molecule, ADC or composition for use as described in paragraph 110 or 111, wherein the cancer is multiple myeloma.

[0707] 113. The antibody molecule, ADC or composition for use as described in paragraph 110, wherein the cancer is a solid tumor, such as a solid tumor described herein.

[0708] 114. The antibody molecule, ADC or composition of any of paragraphs 110-113, wherein the antibody molecule, ADC or composition is administered intravenously to a subject.

[0709] 115. The antibody molecule, ADC or composition for use as described in any of paragraphs 110-114, wherein the antibody molecule, ADC or composition is administered to a subject at a dose of 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.

[0710] 116. The antibody molecule, ADC or composition for use in any of paragraphs 110-115, wherein the antibody molecule, ADC or composition is administered to a subject at a fixed dose of 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.

[0711] 117. The antibody molecule, ADC or composition for use as described in any of paragraphs 110-116, wherein 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.

[0712] 118. The antibody molecule, ADC or composition for use as described in any of paragraphs 110-117, further comprising determining the level of CD138 in a sample from the subject.

[0713] 119. The antibody molecule, ADC or composition for use as described in any of paragraphs 110-118, further comprising administering to the subject a second therapy for cancer.

[0714] 120. The antibody molecule of any of paragraphs 1-99, the ADC of paragraph 100, or the composition of paragraph 101 or 102, for use in a method of treating a precancerous condition or preventing cancer.

[0715] 121. The antibody molecule, ADC or composition for use as described in paragraph 120, wherein the precancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS).

[0716] 122. The antibody molecule, ADC or composition for use as described in paragraph 120, wherein the cancer is multiple myeloma.

[0717] 123. A method for inducing ADCC activity, the method comprising contacting a cell or a subject with the antibody molecule of any of paragraphs 1-99, such as the ADC of paragraph 100, or the composition of paragraph 101 or 102, thereby inducing ADCC activity.

[0718] 124. A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule as described in any of paragraphs 1-99, an ADC as described in paragraph 100, or a composition as described in paragraphs 101 or 102, thereby treating cancer.

[0719] 125. A method for treating a precancerous condition or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule as described in any of paragraphs 1-99, an ADC as described in paragraph 100, or a composition as described in paragraphs 101 or 102, thereby treating the precancerous condition or preventing cancer.

[0720] 126. A method for detecting an anti-CD138 molecule, the method comprising contacting a cell or an object with the antibody molecule described in any one of paragraphs 1-99, thereby detecting the CD138 molecule.

[0721] 127. The method of paragraph 126, wherein the antibody molecule is conjugated to a detectable label.

[0722] 128. The method of paragraphs 126 or 127, wherein the CD138 molecule is detected in vitro, ex vivo or in vivo.

[0723] Example

[0724] Example 1: Immunization of mice

[0725] Female CD-1 IGS (outbred) mice (Charles River Laboratories) aged 5-6 weeks were immunized intravenously (iv) with 50 μg of a plasmid encoding human CD138 (pCDNA3.1-hCD138) vector on days 0, 14, and 28. A second group of mice was immunized intraperitoneally with rCD138 (Sino Biological, Inc.) + Sigma adjuvant (1:1) or peptide 6 + Sigma adjuvant (1:1) on day 0 and boosted with the same reagents on days 14 and 30. After three rounds of DNA or protein / peptide immunization, serum titers of anti-CD138 antibodies were measured by indirect ELISA using recombinant CD138 (R&D Systems). The titers of peptide-6 binding antibodies were also evaluated by ELISA using peptide-6. Briefly, 200 ng of rCD138 or peptide-6 in PBS was coated on Maxisorp 96-well plates (NUNC #439454) at 4°C overnight. The coated plates were incubated at room temperature in 1x 5% BLOTTO TMThe cells were blocked in a blocking buffer of PBS (PBST) with 0.05% Tween-20 for 1 hour. All subsequent incubation steps were performed with 3X washing steps in PBST. Anti-CD138 (or anti-peptide-6) antibody titers were determined by multiple dilutions of mouse serum (in PBS), starting from 1:50, followed by 1:5000-1:10000 HRP-coupled goat anti-mouse IgG secondary antibody (Jackson ImmunoResearch Laboratories) at room temperature for 1 hour. Anti-CD138 (or anti-peptide-6) immunoglobulin reactivity was observed using 100 μl / well of freshly prepared TMB substrate (KPL). Colorimetric development was performed at room temperature for up to 10 minutes, and then the enzyme reaction was quenched by adding 100 μl 1N sulfuric acid and quantified by absorbance at 450 nm. Three days before sacrifice, removal of spleen and separation of spleen cell fusion, mice with strong seropositive titers against the primary immunogen (human CD138) were boosted with 5-10ug of rCD138 or peptide-6 by tail vein injection. Selected mice received two additional intraperitoneal (ip) immunizations with peptide-6 mixed with Sigma adjuvant before peptide-6 tail vein booster immunization. Mice with better species cross-reactivity in the serum profile were noted.

[0726] Example 2: Hybridoma Development

[0727] P3X63Ag8.653 plasmacytoma (ATCC #CRL-1580), referred to herein as P3X cells, were used as the source of fusion partner myeloma. Spleen-derived B cell clones were immortalized using a modified published method. Briefly, P3X cells were cultured for at least 1 week prior to use and maintained in logarithmic phase to reach 6×10 cells per day prior to subsequent spleen fusion. 5 -1.2x10 6 The target cell density of cells / mL and 95% viability. After euthanasia and cardiac puncture, spleen cells were isolated from 2-3 mice / immunization arm and collected into DMEM+1% antibiotics (penicillin / streptomycin), and then gently washed and centrifuged (2X) to precipitate tissue fragments and clarify the suspended spleen cells. Splenocytes were then precipitated by centrifugation at 400xg for 10 minutes at 4°C, and red blood cells were lysed at room temperature for 5 minutes after the cell pellet was gently resuspended in 1X red blood cell lysis buffer. Splenocytes were diluted with ice-cold DMEM and collected by centrifugation (2X). P3X cells were also washed 3 times in DMEM and then fused.

[0728] According to the established method, mouse spleen cells and P3X cells were fused in a fusion medium (50% PEG 1450, Sigma Aldrich) at a ratio of 3:1. Briefly, preheated PEG was gradually added to the pelleted mixture of spleen cells and P3X cells (37°C, gentle resuspension), and then preheated DMEM was gradually added. The fused cells were collected by low-speed centrifugation and resuspended in hybridoma selective medium (hypoxanthine-aminopterin-thymidine, Sigma Aldrich), and then incubated at 37°C for 30 minutes. The fused cells were plated at approximately 2.0 x 10 6 The density of splenocytes (20,000 cells per well) was plated in 96-well plates. The CD138 binding of hybridoma supernatants was screened by ELISA on days 10-14 after fusion, as described. In brief, the total IgG of the supernatant from the conditioned medium was quantified by bioinferometry using the AMC anti-mouse IgG quantitative kit (Pall Biosciences). If possible, the supernatant from the hybridoma conditioned medium was standardized to 10 μg / mL and analyzed by ELISA for binding to CD138 or peptide-6. Positive hybridomas were selected for culture scale expansion, antibody purification and further ch...

Claims

1. An anti-CD138 antibody molecule, which: (i) binds or substantially binds to CD138 in the extracellular region proximal to the transmembrane domain of CD138; and (ii) induces antibody-dependent cellular cytotoxicity (ADCC) activity on cells expressing CD138.

2. The antibody molecule according to claim 1, wherein The C-terminus of the extracellular region proximal to the transmembrane domain is 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.

3. The antibody molecule according to claim 1 or 2, wherein The N-terminus of the extracellular region proximal to the transmembrane domain is 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.

4. The antibody molecule according to any one of claims 1 to 3, wherein The antibody molecule binds to an epitope of CD138 comprising five or more (e.g., 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 the extracellular region.

5. The antibody molecule according to any one of claims 1 to 4, wherein The extracellular region proximal to the transmembrane domain comprises or consists of amino acids 210-250 or 220-245 of any one of SEQ ID NOs: 1-3 or 450.

6. The antibody molecule of any one of claims 1 to 5, which binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte, or an eosinophil).

7. The antibody molecule according to any one of claims 1 to 5, wherein Cells expressing CD138 are cancer cells or precancerous cells.

8. The antibody molecule according to claim 7, wherein The cancer cell or precancerous cell is a myeloma cell.

9. The antibody molecule of any one of claims 1 to 8, which does not bind or binds with low affinity to the extracellular region of CD138 away from the transmembrane domain.

10. The antibody molecule of any one of claims 1-9, which does not bind to a CD138 epitope comprising five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region distal to the transmembrane domain.

11. An antibody molecule as described in any one of claims 1 to 8, which binds or substantially binds to a CD138 epitope comprising five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region distal to the transmembrane domain.

12. The antibody molecule according to any one of claims 9 to 11, wherein The C-terminus of the extracellular region distal to 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.

13. The antibody molecule according to any one of claims 9 to 12, wherein The extracellular region distal to the transmembrane domain comprises amino acids 23-50, 51-95, 88-121 or 111-150 of any one of SEQ ID NOs: 1-3 or 450.

14. The antibody molecule of any one of claims 1-13, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138, the N-terminal region of the IBD of CD138, or both.

15. The antibody molecule of any one of claims 1-13, which binds to the IBD of CD138, the N-terminal region of the IBD of CD138, or both.

16. The antibody molecule of any one of claims 1-15, which has a dissociation constant (K) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D ) binds to CD138.

17. The antibody molecule according to any one of claims 1 to 16, wherein The antibody molecule has a binding affinity for membrane-bound CD138 that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200 or 500 times greater than its binding affinity for soluble CD138.

18. The antibody molecule of any one of claims 1-17, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D Binds to membrane-bound CD138.

19. The antibody molecule of any one of claims 1-18, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D , or with a K of greater than about 100, 200, 300, 400, or 500 nM D Binds to soluble CD138.

20. An antibody molecule as described in any of claims 1-19, which binds membrane-bound CD138 better than soluble CD138, for example, the binding affinity for membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 times higher than the binding affinity for soluble CD138; or binds to membrane-bound CD138 and soluble CD138 with similar affinity, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher than the binding affinity for soluble CD138.

21. The antibody molecule of any one of claims 1-20, which binds to C1q and induces complement dependent cytotoxicity (CDC) activity on cells expressing CD138.

22. The antibody molecule of any one of claims 1-21, which reduces (eg, inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, ex vivo or in vivo.

23. The antibody molecule of any one of claims 1-22, which mediates homotypic adhesion of one or more cells expressing CD138.

24. The antibody molecule of any one of claims 1-23, which inhibits the action of proteases on membrane-bound CD138, such as reducing the shedding of CD138.

25. The antibody molecule of any one of claims 1-24, which reduces (eg, inhibits) the proliferation of cancer cells or precancerous cells expressing CD138.

26. The antibody molecule of any one of claims 1-25, comprising 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 an anti-CD138 monoclonal antibody described herein.

27. The antibody molecule of any one of claims 1-26, comprising the heavy chain variable region (VH) and / or the light chain variable region (VL) of the anti-CD138 monoclonal antibody described herein.

28. The antibody molecule of any one of claims 1-27, comprising an Fc region.

29. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in the extracellular region proximal to the transmembrane domain of CD138.

30. The antibody molecule according to claim 29, wherein The C-terminus of the extracellular region proximal to the transmembrane domain is 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.

31. The antibody molecule according to claim 29 or 30, wherein The N-terminus of the extracellular region proximal to the transmembrane domain is 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.

32. The antibody molecule according to any one of claims 29 to 31, wherein The extracellular region proximal to the transmembrane domain comprises or consists of amino acids 176-250 of any one of SEQ ID NOs: 1-3 or 450.

33. The antibody molecule of any one of claims 29-32, which does not bind or binds with low affinity to the extracellular region of CD138 away from the transmembrane domain.

34. The antibody molecule according to any one of claims 29 to 33, wherein The epitope does not include five or more (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region away from the transmembrane domain.

35. The antibody molecule according to claim 33 or 34, wherein The C-terminus of the extracellular region distal to 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.

36. The antibody molecule according to any one of claims 33 to 35, wherein The extracellular region distal to the transmembrane domain comprises amino acids 23-50, 51-95, 88-121 or 111-150 of any one of SEQ ID NOs: 1-3 or 450.

37. The antibody molecule of any one of claims 33-36, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138, the N-terminal region of the IBD of CD138, or both.

38. The antibody molecule of any one of claims 33-36, which binds to the IBD of CD138, the N-terminal region of the IBD of CD138, or both.

39. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in the extracellular region distal to the CD138 transmembrane domain, wherein The epitope does not consist of amino acid residues 107-111 of any of SEQ ID NOs: 1-3 or 450.

40. The antibody molecule according to claim 39, wherein The epitope does not include amino acids 107-111 of any one of SEQ ID NOs: 1-3 or 450.

41. The antibody molecule according to claim 39 or 40, wherein The C-terminus of the extracellular region distal to 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.

42. The antibody molecule of any one of claims 39 to 41, wherein The extracellular region distal to the transmembrane domain comprises or consists of amino acids 88-121 of any one of SEQ ID NOs: 1-3 or 450.

43. An anti-CD138 antibody molecule that binds or substantially 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) consecutive amino acid residues in an extracellular region proximal to the transmembrane domain of CD138; and 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 distal to the transmembrane domain of CD138.

44. The antibody molecule according to claim 43, wherein The C-terminus of the extracellular region proximal to the transmembrane domain is 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.

45. The antibody molecule according to claim 43 or 44, wherein The N-terminus of the extracellular region proximal to the transmembrane domain is 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.

46. ​​The antibody molecule of any one of claims 43 to 45, wherein The extracellular region proximal to the transmembrane domain comprises or consists of amino acids 176-250 or amino acids 210-250 of any one of SEQ ID NOs: 1-3 or 450.

47. The antibody molecule of any one of claims 43 to 46, wherein The C-terminus of the extracellular region distal to 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.

48. The antibody molecule of any one of claims 43 to 47, wherein The extracellular region distal to the transmembrane domain comprises or consists of amino acids 23-50, 51-95, 88-121 or 111-150 of any one of SEQ ID NOs: 1-3 or 450.

49. The antibody molecule of any one of claims 43 to 48, wherein The extracellular region distal to the transmembrane domain comprises or consists of amino acids 88-121 of any one of SEQ ID NOs: 1-3 or 450.

50. The antibody molecule of any one of claims 43-49, which does not bind or binds with low affinity to the integrin binding domain (IBD) of CD138.

51. The antibody molecule of any one of claims 43-50, which does not bind or binds with low affinity to the N-terminal region of the IBD of CD138.

52. The antibody molecule of claim 51, wherein The epitope does not include amino acids 107-111 of any one of SEQ ID NOs: 1-3 or 450.

53. The antibody molecule of any one of claims 43-49, which binds to the IBD of CD138.

54. The antibody molecule of any one of claims 43-50, which binds to the N-terminal region of the IBD of CD138.

55. The antibody molecule of claim 54, wherein The epitope comprises amino acids 107-111 of any one of SEQ ID NOs: 1-3 or 450.

56. An antibody molecule as described in any one of claims 29-55, which binds to an Fc receptor (FcR) (e.g., one or more of FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb) on the surface of an immune cell (e.g., a natural killer (NK) cell, a macrophage, a monocyte, or an eosinophil).

57. The antibody molecule of any one of claims 29-56, which is capable of inducing ADCC activity on cells expressing CD138.

58. The antibody molecule of claim 57, wherein Cells expressing CD138 are cancer cells or precancerous cells.

59. The antibody molecule of claim 58, wherein The cancer cell or precancerous cell is a myeloma cell.

60. The antibody molecule of any one of claims 29-59, which has a dissociation constant (K) of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D ) binds to CD138.

61. The antibody molecule of any one of claims 29-60, wherein The antibody molecule has a binding affinity for membrane-bound CD138 that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, 100, 200 or 500 times higher than that for soluble CD138; or binds to membrane-bound CD138 and soluble CD138 with similar binding affinity, for example, the binding affinity for membrane-bound CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% higher than that for soluble CD138.

62. The antibody molecule of any one of claims 29-61, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D Binds to membrane-bound CD138.

63. The antibody molecule of any one of claims 29-62, which has a K of less than about 100, 90, 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 about 10-0.001, 10-0.01, 5-0.01, 3-0.05, or 1-0.1 nM. D , or with a K of greater than about 100, 200, 300, 400, or 500 nM D Binds to soluble CD138.

64. An antibody molecule as described in any one of claims 29-63, which binds to membrane-bound CD138 better than soluble CD138, for example, the binding affinity for membrane-bound CD138 is at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 times higher than the binding affinity for soluble CD138.

65. The antibody molecule of any one of claims 29-63, which binds to C1q and induces complement dependent cytotoxicity (CDC) activity on cells expressing CD138.

66. An antibody molecule as described in any one of claims 29-65, which reduces (e.g., inhibits, blocks or neutralizes) one or more biological activities of cells expressing CD138 in vitro, ex vivo or in vivo.

67. The antibody molecule of any one of claims 29-66, which mediates homotypic adhesion of one or more cells expressing CD138.

68. The antibody molecule of any one of claims 29-67, which inhibits the action of proteases on membrane-bound CD138, such as reducing the shedding of CD138.

69. The antibody molecule of any one of claims 29-68, which reduces (eg, inhibits) the proliferation of cancer cells or precancerous cells expressing CD138.

70. The antibody molecule of any one of claims 29-69, comprising 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 an anti-CD138 monoclonal antibody described herein.

71. The antibody molecule of any one of claims 29-70, comprising the heavy chain variable region (VH) and / or the light chain variable region (VL) of the anti-CD138 monoclonal antibody described herein.

72. The antibody molecule of any one of claims 29-71, comprising an Fc region.

73. An anti-CD138 antibody molecule comprising one or both of the following: (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 the following: (i) a HCDR1 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues or is at least 85, 90, 95, 99, or 100% homologous to the amino acid sequence of a HCDR1 of an anti-CD138 monoclonal antibody disclosed herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409); (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the 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 is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody; or (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 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; or (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

74. The antibody molecule of claim 73, wherein VH comprises: (i) HCDR1, which comprises an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody.

75. An antibody molecule as described in claim 73 or 74, wherein 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.

76. The antibody molecule of any one of claims 73-75, wherein VL comprises: (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

77. The antibody molecule of any one of claims 73-76, wherein 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.

78. The antibody molecule of any one of claims 73-77, comprising: (a) VH comprising: (i) HCDR1, which comprises an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) a HCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and (iii) a HCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of the HCDR3 of the anti-CD138 antibody, and (a) VL comprising: (i) LCDR1 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) LCDR2 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) LCDR3 comprising an amino acid sequence that differs by no more than 1, 2 or 3 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of LCDR3 of the anti-CD138 antibody.

79. The antibody molecule of any one of claims 73-78, comprising: (a) a VH comprising: (i) a HCDR1 comprising the amino acid sequence of HCDR1 of the anti-CD138 antibody; (ii) a HCDR2 comprising the amino acid sequence of HCDR2 of the anti-CD138 antibody; and (iii) a HCDR3 comprising the amino acid sequence of HCDR3 of the anti-CD138 antibody, and (a) a VL comprising: (i) a LCDR1 comprising the amino acid sequence of LCDR1 of the anti-CD138 antibody; (ii) a LCDR2 comprising the amino acid sequence of LCDR2 of the anti-CD138 antibody; and (iii) a LCDR3 comprising the amino acid sequence of LCDR3 of the anti-CD138 antibody.

80. The antibody molecule of any one of claims 73-79, wherein VH comprises an amino acid sequence that differs 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 to the amino acid sequence of VH of an anti-CD138 antibody.

81. The antibody molecule of any one of claims 73-80, wherein VH comprises the amino acid sequence of VH of the anti-CD138 antibody.

82. The antibody molecule of any one of claims 73 to 81, wherein VL comprises an amino acid sequence that differs by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 amino acid residues or is at least 85, 90, 95, 99 or 100% homologous to the amino acid sequence of VL of an anti-CD138 antibody.

83. The antibody molecule of any one of claims 73-82, wherein VL comprises the amino acid sequence of VL of the anti-CD138 antibody.

84. The antibody molecule of any one of claims 73 to 83, wherein: (a) VH comprises an amino acid sequence that 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) VL comprises an amino acid sequence that 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.

85. The antibody molecule of any one of claims 73-84, wherein VH comprises the amino acid sequence of VH of the anti-CD138 antibody, and VL comprises the amino acid sequence of VL of the anti-CD138 antibody.

86. The antibody molecule of any one of claims 73-85, comprising an Fc region.

87. An anti-CD138 antibody molecule comprising: (I) (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 three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), wherein the VH comprises: (i) HCDR1 comprising the amino acid sequence GYN / S / TFSSY (SEQ ID NO: 438); (ii) HCDR2 comprising the amino acid sequence HPSDST (SEQ ID NO: 439); NO:351); or (iii) HCDR3 comprising the amino acid sequence FVY; and (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (b) a light chain variable region (VL), wherein the VL comprises three light chain complementary determining regions (LCDR1, LCDR2, and LCDR3), wherein the VL comprises one, two, or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO:352); (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); or (II) (a) a heavy chain variable region (VH), wherein VH comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3), wherein VH comprises three heavy chain complementary determining regions (HCDR1, HCDR2 and HCDR3), wherein VH comprises: (i) HCDR1 comprising the amino acid sequence SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence TIHPSDSTTNC / YNQKFKG (SEQ ID NO: 439); or (iii) HCDR3 comprising the amino acid sequence FVY; and (b) a light chain variable region (VL), wherein VL comprises three light chain complementary determining regions (LCDR1, LCDR2 and LCDR3), wherein VL comprises one, two or all of the following: (i) LCDR1 comprising the amino acid sequence RSSKSLLYKDGKTYLN (SEQ ID NO: 352); (ii) LCDR2 comprising the amino acid sequence VVSTRAS (SEQ ID NO: 440). NO:353); or (iii) LCDR3 comprising the amino acid sequence QQLVEYPYT (SEQ ID NO:354).

88. The antibody molecule of any one of claims 1-87, comprising two VHs and two VLs.

89. The antibody molecule of any one of claims 1-88, which is a synthetic antibody molecule or an isolated antibody molecule.

90. The antibody molecule of any one of claims 1-89, which is a monovalent antibody molecule, a multivalent (e.g., bivalent, trivalent or tetravalent) antibody molecule, a monospecific molecule or a multispecific (e.g., bispecific, trispecific or tetraspecific) antibody molecule.

91. The antibody molecule of any one of claims 1-90, which is a humanized antibody molecule.

92. The antibody molecule of any one of claims 1-91, comprising one or more framework regions derived from human framework germline sequences.

93. The antibody molecule of any one of claims 1-92, which is an IgG antibody.

94. The antibody molecule of any one of claims 1-93, comprising a heavy chain constant region of an IgG selected from IgG1, IgG2, IgG3 or IgG4.

95. The antibody molecule of any one of claims 1-94, comprising a light chain constant region of a kappa or lambda light chain.

96. The antibody molecule of any one of claims 1-95, comprising an Fc region comprising one or more mutations to increase the binding affinity to the neonatal receptor FcRn and / or the half-life of the antibody molecule.

97. An antibody molecule as described in any one of claims 1-96, comprising an Fc region comprising one or more mutations as described herein, e.g., to increase one or more of half-life, ADCC, CDC or ADCP.

98. An antibody molecule that competes for binding to CD138 with an anti-CD138 monoclonal antibody described herein (e.g., any one of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

99. An antibody molecule that binds or substantially binds to an epitope that completely or partially overlaps with an epitope of an anti-CD138 monoclonal antibody described herein (e.g., any of antibodies CD001, CD002, CD003, CD004, CD005, CD006, 602, 603, 604, 607, 613, 614, 617, 624, 632, 616, 619, 623, 1610, 2510, 2610, 2710, 2810, 2910, or 1409).

100. An antibody-molecule drug conjugate (ADC) comprising an antibody molecule as claimed in any one of claims 1 to 99, optionally comprising a cytotoxic agent, and optionally comprising a linker.

101. A composition comprising the antibody molecule of any one of claims 1-99 or the ADC of claim 100, optionally wherein the composition is a pharmaceutical composition.

102. The composition of claim 101, further comprising a pharmaceutically acceptable carrier.

103. A nucleic acid molecule encoding the heavy chain variable region (VH), the light chain variable region (VL), or both of the antibody molecule of any one of claims 1-99.

104. A vector comprising the nucleic acid molecule of claim 103.

105. A cell comprising the nucleic acid molecule of claim 103 or the vector of claim 104, optionally wherein the cell is an isolated cell.

106. A kit comprising the antibody molecule of any one of claims 1-99, the ADC of claim 100 or the composition of claim 101 or 102, and instructions for use of the antibody molecule or composition.

107. A container comprising the antibody molecule of any one of claims 1-99, the ADC of claim 100 or the composition of claim 101 or 102.

108. A method for producing an anti-CD138 antibody molecule, the method comprising culturing the cell of claim 105 under conditions that allow production of the antibody molecule, thereby producing the antibody molecule.

109. The method of claim 108, further comprising isolating or purifying the antibody molecule.

110. The antibody molecule of any one of claims 1-99, the ADC of claim 100, or the composition of claim 101 or 102, for use in a method of treating cancer in a subject.

111. The antibody molecule, ADC or composition for use according to claim 110, wherein the cancer is a hematological cancer.

112. The antibody molecule, ADC or composition for use as claimed in claim 110 or 111, wherein the cancer is multiple myeloma.

113. The antibody molecule, ADC or composition for use as claimed in claim 110, wherein the cancer is a solid tumor, such as a solid tumor described herein.

114. The antibody molecule, ADC or composition of any one of claims 110-113, wherein the antibody molecule, ADC or composition is administered intravenously to a subject.

115. An antibody molecule, ADC or composition for use as described in any one of claims 110 to 114, wherein: The antibody molecule, ADC or composition is administered to a subject at a dose of 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.

116. An antibody molecule, ADC or composition for use as claimed in any one of claims 110 to 115, wherein: The antibody molecule, ADC or composition is administered to a subject at a fixed dose of 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.

117. The antibody molecule, ADC or composition for use as described in any one of claims 110-116, wherein 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.

118. The antibody molecule, ADC or composition for use according to any one of claims 110 to 117, further comprising determining the level of CD138 in a sample from the subject.

119. The antibody molecule, ADC or composition for use according to any one of claims 110 to 118, further comprising administering to the subject a second therapy for cancer.

120. The antibody molecule of any one of claims 1-99, the ADC of claim 100 or the composition of claim 101 or 102 for use in a method of treating a precancerous condition or preventing cancer.

121. The antibody molecule, ADC or composition for use as claimed in claim 120, wherein: The precancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS).

122. The antibody molecule, ADC or composition for use as claimed in claim 120, wherein the cancer is multiple myeloma.

123. A method for inducing ADCC activity, the method comprising contacting a cell or a subject with the antibody molecule of any one of claims 1-99, the ADC of claim 100 or the composition of claim 101 or 102, thereby inducing ADCC activity.

124. A method of treating cancer, the method comprising administering to a subject in need thereof an effective amount of the antibody molecule of any one of claims 1-99, the ADC of claim 100, or the composition of claim 101 or 102, thereby treating cancer.

125. A method for treating a precancerous condition or preventing cancer, the method comprising administering to a subject in need thereof an effective amount of an antibody molecule as described in any one of claims 1-99, an ADC as described in claim 100, or a composition as described in claim 101 or 102, thereby treating a precancerous condition or preventing cancer.

126. A method for detecting an anti-CD138 molecule, the method comprising contacting a cell or an object with the antibody molecule according to any one of claims 1 to 99, thereby detecting the CD138 molecule.

127. The method of claim 126, wherein: The antibody molecule is coupled to a detectable label.

128. The method of claim 126 or 127, wherein: The CD138 molecule is detected in vitro, ex vivo or in vivo.

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