Humanized antibody molecules directed against CD138 and uses thereof

Abstract

Humanized antibody molecules that specifically bind to CD138 are disclosed. The humanized antibody molecules can be used to treat, prevent, and / or diagnose disorders such as multiple myeloma. The present disclosure provides, at least in part, humanized antibody molecules that bind to CD138, e.g., human CD138, and contain one or more properties, e.g., one or more functional, biophysical, and structural properties disclosed herein. For example, the humanized antibody molecules described herein may have reduced immunogenicity, greater therapeutic efficacy (e.g., lower tumor burden and / or increased overall survival), improved target binding (e.g., affinity), improved in vitro or in vivo stability, and higher mammalian recombinant expression levels.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 862,457, filed June 17, 2019, and U.S. Provisional Application No. 63 / 035,323, filed June 5, 2020, the contents of which are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on June 12, 2020, is named P2029-7029WO_SL.txt and is 128,635 bytes in size. [Background technology]

[0003] background Multiple myeloma (MM) is a cancer formed by malignant plasma cells. These tumors typically develop in the bone, but can also be found in other tissues. Disease with a single plasma cell neoplasm is known as sporadic (or solitary) plasmacytoma. When more than one plasmacytoma is present, it is known as multiple myeloma. In the United States, there are an estimated 30,000 new cases in 2017, with over 10,000 deaths. Despite advances in treatment, multiple myeloma remains incurable in most patients.

[0004] There is a need to develop new approaches to treat, prevent, and diagnose multiple myeloma and other disorders that share similar disease mechanisms. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides, at least in part, humanized antibody molecules that bind to CD138, such as human CD138, and include one or more properties, such as one or more functional, biophysical, and structural properties disclosed herein. For example, the humanized antibody molecules described herein may have reduced immunogenicity, greater therapeutic efficacy (e.g., lower tumor burden and / or increased overall survival), improved target binding (e.g., affinity), improved in vitro or in vivo stability, and higher mammalian recombinant expression levels. In one embodiment, the antibody molecule can elicit an effector function (e.g., antibody-dependent cell cytotoxicity (ADCC) activity) against cells expressing CD138. In one embodiment, the antibody molecule preferentially binds to membrane-bound CD138 as compared to soluble CD138. In one embodiment, the antibody molecule binds to an epitope in the extracellular region of CD138 adjacent to the transmembrane domain. In one embodiment, the antibody molecule does not bind to the integrin-binding domain (IBD) of CD138. In one embodiment, the antibody molecule specifically does not bind to the IBD of CD138. Without being bound by theory, in one embodiment, improved or optimal cytotoxicity may be achieved by targeting a specific extracellular region on membrane-bound CD138 adjacent to the cell membrane.

[0006] 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 the same as or overlaps with the epitope recognized by an anti-CD138 monoclonal antibody selected from Table 1. In one embodiment, the antibody molecule includes one or more heavy chain variable regions (VH) and / or one or more light chain variable regions (VL) described in Table 1. In one embodiment, the antibody molecule includes heavy chains (HC) and light chains (LC) described in Tables 6-8. In one embodiment, the antibody molecule includes one or more heavy chain CDRs and / or one or more light chain CDRs described in Table 1, 7, or 8.

[0007] In one embodiment, the antibody molecule comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from Table 2, or competes with an anti-CD138 monoclonal antibody comprising a VH comprising an amino acid sequence selected from Table 2 for binding to CD138. In one embodiment, the antibody molecule comprises a light chain variable region (VL) comprising an amino acid sequence selected from Table 2, or competes with an anti-CD138 monoclonal antibody comprising a VL comprising an amino acid sequence selected from Table 2 for binding to CD138. In one embodiment, the antibody molecule comprises a VH and a VL each comprising an amino acid sequence selected from Table 2, or competes with an anti-CD138 monoclonal antibody comprising a VH and a VL each comprising an amino acid sequence selected from Table 2 for binding to CD138. In one embodiment, the antibody molecule binds to an epitope that is identical to or overlaps with the epitope recognized by an anti-CD138 monoclonal antibody comprising a VH and / or a VL each comprising an amino acid sequence selected from Table 2. In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2, or 3) heavy chain CDRs and / or one or more (e.g., 1, 2, or 3) light chain CDRs as set forth in Table 2.

[0008] In one embodiment, the antibody molecule comprises a heavy chain (HC) comprising an amino acid sequence selected from Table 6 or 7, or competes with an anti-CD138 monoclonal antibody comprising an HC comprising an amino acid sequence selected from Table 6 or 7 for binding to CD138. In one embodiment, the antibody molecule comprises a light chain (LC) comprising an amino acid sequence selected from Table 6 or 8, or competes with an anti-CD138 monoclonal antibody comprising an LC comprising an amino acid sequence selected from Table 6 or 8 for binding to CD138. In one embodiment, the antibody molecule comprises an HC and an LC each comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8, or competes with an anti-CD138 monoclonal antibody comprising an HC and an LC each comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8 for binding to CD138. In one embodiment, the antibody molecule binds to an epitope that is identical to or overlaps with the epitope recognized by an anti-CD138 monoclonal antibody comprising an HC and / or an LC each comprising an amino acid sequence selected from Table 6 or 7 or Table 6 or 8. In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2, or 3) heavy chain CDRs and / or one or more (e.g., 1, 2, or 3) light chain CDRs as set forth in Table 7 or 8.

[0009] In one embodiment, an antibody molecule-drug conjugate (ADC), a nucleic acid molecule encoding the antibody molecule, an expression vector, a host cell, a composition (e.g., a pharmaceutical composition), a kit, a container, and a method for making the antibody molecule are also provided. The antibody molecules disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent, and / or diagnose disorders associated with CD138, such as cancer or pre-cancerous conditions (e.g., multiple myeloma or smoldering myeloma).

[0010] Thus, in certain aspects, the disclosure provides humanized antibody molecules, such as the humanized antibody molecules described herein, having the following characteristics a)-dd): a) high affinity, e.g., a dissociation constant (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, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM; D ) and binds to CD138 (e.g., human CD138), b) high affinity, e.g., a dissociation constant (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, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM; D ) and binds to membrane-bound CD138, c) i) high affinity, e.g., a dissociation constant (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, e.g., less than about 80, 70, 60, 50, 40, 30, 20, 10, 8, 6, 4, 3, 2, 1, 0.5, 0.2, 0.1, 0.05, 0.01, 0.005 or 0.001 nM; D ) or ii) with low affinity, e.g., a dissociation constant (K) of greater than about 100 nM, e.g., greater than about 200, 300, 400, or 500 nM. D ) and binds to soluble CD138. d) i) preferentially over soluble CD138 (e.g., the binding affinity to membrane-bound CD138 or the intact 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) with a binding affinity similar to that to soluble CD138 (e.g., the binding affinity to membrane-bound CD138 or the intact extracellular domain of CD138 is less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the binding affinity to soluble CD138), and binds to membrane-bound CD138 or the intact extracellular domain of CD138, 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) amino acid residues of CD138 in the extracellular region adjacent to the transmembrane domain of CD138, e.g., within 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5 amino acids from the N-terminus of the transmembrane domain, f) i) binds to the C-terminus of the extracellular region of CD138 remote from the transmembrane domain, e.g., in a region at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids from the N-terminus of the transmembrane domain; or ii) does not bind or binds with low affinity to the C-terminus of the extracellular region of CD138 remote from the transmembrane domain, e.g., in a region at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids from the N-terminus of the transmembrane domain, g) i) binds to the region N-terminal to the integrin binding domain (IBD) or IDB of CD138; or ii) does not bind or binds with low affinity to the region N-terminal to the IBD or IDB of CD138, It should be noted that there is an unclear "④" in item e of the original text, which is retained in the translation for now. You may need to check and correct it in the original source if necessary.h) CD138 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 adjacent to the transmembrane domain, for example, a region comprising amino acids 176 to 250 (e.g., 176 to 214 or 210 to 250) of any of SEQ ID NOs: 1 to 3 or 450. and optionally, the epitope further comprises four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in an extracellular region remote from the transmembrane domain, e.g., a region comprising amino acids 23-50, 51-95, 88-121, 88-102 or 111-150 of any of SEQ ID NOs: 1-3 or 450. i) binds to two or more different regions of CD138 (e.g., a multivalent (e.g., bivalent, trivalent, or tetravalent) antibody molecule comprising two sets of identical or substantially identical VH-VL pairs that each bind to the same two or more regions, or a different set of VH-VL pairs that each independently bind to a different region); j) does not bind to an epitope on CD138 that contains four or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in an extracellular region remote from the transmembrane domain, e.g., a region comprising amino acids 23 to 50, 51 to 95, 88 to 121, 88 to 101, or 111 to 150 of any of SEQ ID NOs: 1 to 3 or 450; k) binds with high affinity to cancer or pre-cancerous cells (e.g., myeloma cells) that express CD138; 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, macrophage, monocyte, or eosinophil); m) induce effector function (e.g., ADCC activity) against target cells expressing CD138; n) binds to C1q and induces complement-dependent cytotoxicity (CDC) against target cells expressing CD138; o) mediate homotypic adhesion of one or more CD138-expressing cells; p) inhibiting the action of proteases on membrane-bound CD138, e.g., reducing CD138 shedding; q) reducing (e.g., inhibiting) one or more biological activities of cells expressing CD138 in vitro, ex vivo, or in vivo; r) decreasing (e.g., inhibiting) one or more functions of CD138 (e.g., binding of CD138 to a ligand) in vitro, ex vivo, or in vivo; s) reducing (e.g., inhibiting) the proliferation of cancer or precancerous cells that express CD138; t) binds to an epitope on CD138 that is the same as, similar to, or overlaps with the epitope recognized by the anti-CD138 monoclonal antibodies described herein; u) exhibit the same or similar binding affinity or specificity or both as the anti-CD138 monoclonal antibodies described herein; v) exhibits the same or similar binding affinity or specificity, or both, as a humanized antibody molecule comprising a heavy chain variable region and / or a light chain variable region described herein, e.g., the heavy chain variable region and / or the light chain variable region of any of the anti-CD138 monoclonal antibodies described herein; w) exhibit the same or similar binding affinity or specificity, or both, as a humanized antibody molecule 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 described herein, e.g., one or more (e.g., two or three) heavy chain CDRs and / or one or more (e.g., two or three) light chain CDRs of any of the anti-CD138 monoclonal antibodies described herein, x) exhibit the same or similar binding affinity or specificity, or both, as a humanized antibody molecule comprising an amino acid sequence described herein; y) exhibits the same or similar binding affinity or specificity, or both, as a humanized antibody molecule comprising an amino acid sequence encoded by a nucleotide sequence described herein; z) inhibits, e.g., competitively inhibits, the binding of a second antibody molecule to CD138, wherein the second antibody molecule is a humanized antibody molecule described herein; aa) competes with a second antibody molecule for binding to CD138, wherein the second antibody molecule is a humanized anti-CD138 monoclonal antibody described herein; bb) has one or more biological properties of the humanized anti-CD138 monoclonal antibodies described herein; cc) has one or more structural characteristics of a humanized anti-CD138 monoclonal antibody described herein, or dd) has one or more pharmacokinetic properties of the humanized anti-CD138 monoclonal antibodies described herein; In some embodiments, the humanized antibody molecules have 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 amino acid sequences of the amino acid sequence ...

[0011] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule comprising: (a) Comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of an anti-CD138 monoclonal antibody described herein (e.g., any of antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422, e.g., those listed in Table 1 or 2) by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of the anti-CD138 antibody by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of the HCDR3s comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of the anti-CD138 antibody by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (b) Comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of the anti-CD138 antibody by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of the anti-CD138 antibody by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of the LCDR3s comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of the anti-CD138 antibody by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto Characterized by a humanized anti-CD138 antibody molecule comprising one or both of

[0012] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0013] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of an anti-CD138 antibody; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of an anti-CD138 antibody; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of an anti-CD138 antibody.

[0014] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of an anti-CD138 antibody by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0015] In one embodiment, the VL comprises (i) an LCDR1 comprising the amino acid sequence of LCDR1 of an anti-CD138 antibody; (ii) an LCDR2 comprising the amino acid sequence of LCDR2 of an anti-CD138 antibody; and (iii) an LCDR3 comprising the amino acid sequence of LCDR3 of an anti-CD138 antibody.

[0016] In one embodiment, the antibody molecule comprises: (a) a VH comprising: (i) an HCDR1 that differs by no more than 1, 2, or 3 amino acid residues from the amino acid sequence of HCDR1 of an anti-CD138 antibody or comprises an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto; (ii) an HCDR2 that differs by no more than 1, 2, or 3 amino acid residues from the amino acid sequence of HCDR2 of an anti-CD138 antibody or comprises an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto; and (iii) an HCDR3 that differs by no more than 1, 2, or 3 amino acid residues from the amino acid sequence of HCDR3 of an anti-CD138 antibody or comprises an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto; and (b) a VL comprising: (i) an LCDR1 that differs by not more than 1, 2, or 3 amino acid residues from the amino acid sequence of LCDR1 of an anti-CD138 antibody, or an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto; (ii) an LCDR2 that differs by not more than 1, 2, or 3 amino acid residues from the amino acid sequence of LCDR2 of an anti-CD138 antibody, or an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto; and (iii) an LCDR3 that differs by not more than 1, 2, or 3 amino acid residues from the amino acid sequence of LCDR3 of an anti-CD138 antibody, or an amino acid sequence that is at least 85, 90, 95, 99, or 100% identical thereto. Includes:

[0017] In one embodiment, the antibody molecule comprises (a) a VH comprising (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of an anti-CD138 antibody; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of an anti-CD138 antibody; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of an anti-CD138 antibody, and (b) a VL comprising (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of an anti-CD138 antibody; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of an anti-CD138 antibody; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of an anti-CD138 antibody.

[0018] In one embodiment, the VH comprises an amino acid sequence that differs from the amino acid sequence of the VH of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the VH of the antibody molecule comprises the amino acid sequence of the VH of the anti-CD138 antibody.

[0019] In one embodiment, the VL comprises an amino acid sequence that differs from the amino acid sequence of the VL of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the VL comprises the amino acid sequence of the VL of the anti-CD138 antibody.

[0020] In one embodiment, (a) the VH comprises an amino acid sequence that differs from the amino acid sequence of the VH of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith; and (b) the VL comprises an amino acid sequence that differs from the amino acid sequence of the VL of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith.

[0021] In one embodiment, the VH comprises the amino acid sequence of the VH of an anti-CD138 antibody, and the VL comprises the amino acid sequence of the VL of an anti-CD138 antibody.

[0022] In one embodiment, the antibody molecule comprises an Fc region (e.g., an Fc region described herein). In one embodiment, the antibody molecule comprises an IgG, e.g., IgG1, heavy chain constant region. In one embodiment, the antibody molecule comprises a kappa light chain constant region.

[0023] In one embodiment, the antibody molecule comprises a heavy chain (HC) of an anti-CD138 antibody that 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 from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the HC of an anti-CD138 antibody.

[0024] In one embodiment, the antibody molecule comprises a light chain (LC) of an anti-CD138 antibody that 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 from, or has at least 85, 90, 95, 99, or 100% identity thereto. In one embodiment, the LC comprises the amino acid sequence of the LC of an anti-CD138 antibody.

[0025] In one embodiment, the antibody molecule comprises (a) a heavy chain HC of an anti-CD138 antibody that differs from, or has at least 85, 90, 95, 99, or 100% identity with, the amino acid sequence of the HC by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues; and (b) a light chain (LC) of an anti-CD138 antibody that differs from, or has at least 85, 90, 95, 99, or 100% identity with, the amino acid sequence of the LC by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues. In one embodiment, the HC comprises the amino acid sequence of the HC of an anti-CD138 antibody, and the LC comprises the amino acid sequence of the LC of an anti-CD138 antibody.

[0026] In one embodiment, the antibody molecule comprises (a) the HC comprising 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 from, or is at least 85, 90, 95, 99, or 100% identical to, the amino acid sequence of SEQ ID NO: 527; and / or (b) the LC comprising 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 from, or is at least 85, 90, 95, 99, or 100% identical to, the amino acid sequence of SEQ ID NO: 528. In one embodiment, the HC comprises the amino acid sequence of SEQ ID NO: 527, or the LC comprises the amino acid sequence of SEQ ID NO: 528. In one embodiment, the HC comprises the amino acid sequence of SEQ ID NO: 527, or the LC comprises the amino acid sequence of SEQ ID NO: 528.

[0027] In one aspect, the disclosure features a humanized antibody molecule that competes for binding to CD138 with an anti-CD138 monoclonal antibody described herein (e.g., any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0028] In one aspect, the disclosure features an antibody molecule that binds to or substantially binds to an epitope that completely or partially overlaps with the epitope of a humanized anti-CD138 monoclonal antibody described herein (e.g., any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0029] In one aspect, the disclosure features an antibody drug conjugate (ADC) comprising a humanized antibody molecule described herein, optionally comprising a cytotoxic agent, and optionally further comprising a linker.

[0030] In one aspect, the disclosure features a composition, which is optionally a pharmaceutical composition, comprising a humanized antibody molecule described herein or an ADC described herein.

[0031] In one embodiment, the composition further comprises a pharmaceutically acceptable carrier.

[0032] In one aspect, the disclosure features a nucleic acid molecule encoding the heavy chain variable region (VH), the light chain variable region (VL), or both, of a humanized antibody molecule described herein.

[0033] In one aspect, the disclosure features a vector that includes a nucleic acid molecule described herein.

[0034] In one aspect, the disclosure features a cell, optionally an isolated cell, that includes a nucleic acid molecule described herein or a vector described herein.

[0035] In one aspect, the disclosure features a kit including a humanized antibody molecule described herein, an ADC described herein, or a composition described herein, and instructions for use of the antibody molecule or composition.

[0036] In one aspect, the present disclosure features a container comprising a humanized antibody molecule described herein, an ADC described herein, or a composition described herein.

[0037] In one aspect, the present disclosure features a method of producing a humanized anti-CD138 antibody molecule, the method comprising culturing a cell described herein under conditions that permit production of the humanized antibody molecule, thereby producing the antibody molecule.

[0038] In one embodiment, the method further comprises isolating or purifying the antibody molecule.

[0039] In one aspect, the present disclosure features a humanized antibody molecule described herein, an ADC described herein, or a composition described herein for use in a method of treating cancer in a subject.

[0040] 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. In one embodiment, the antibody molecule reduces the tumor burden in a subject, such as a subject having multiple myeloma.

[0041] In one embodiment, the antibody molecule, ADC, or composition is administered intravenously to the subject. In one embodiment, the antibody molecule is administered intraperitoneally to the subject.

[0042] In one embodiment, the antibody molecule, ADC or composition is administered to a subject at a dose of 0.1 mg / kg to 50 mg / kg, 0.2 mg / kg to 25 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 3 mg / kg, 0.5 mg / kg to 2.5 mg / kg, 0.5 mg / kg to 2 mg / kg, 0.5 mg / kg to 1.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1 mg / kg to 2 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg or 1 mg / kg to 5 mg / kg. In one embodiment, the antibody molecule, ADC or composition is administered at a dose of 1 to 50 mg / kg, such as 1 to 40 mg / kg, 1 mg / kg to 30 mg / kg, 1 mg / kg to 20 mg / kg, 1 mg / kg to 10 mg / kg or 1 mg / kg to 5 mg / kg. In one embodiment, the antibody molecule is administered at a dose of about 4 mg / kg, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / kg.

[0043] In one embodiment, the antibody molecule, ADC or composition is administered to a subject at a fixed dose of 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 250 mg, 10 mg to 150 mg, 10 mg to 100 mg, 10 mg to 50 mg, 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg, 100 mg to 200 mg or 150 mg to 250 mg.

[0044] 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.

[0045] 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 cancer treatment to the subject.

[0046] In one aspect, the disclosure features a humanized 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.

[0047] In one embodiment, the precancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS). In one embodiment, the cancer is multiple myeloma.

[0048] In one aspect, the disclosure features a method of eliciting ADCC activity, the method comprising contacting a cell or a subject with a humanized antibody molecule described herein, an ADC described herein, or a composition described herein, thereby eliciting said ADCC activity.

[0049] 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 a humanized antibody molecule described herein, an ADC described herein, or a composition described herein, thereby treating the cancer.

[0050] 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 a humanized antibody molecule described herein, an ADC described herein, or a composition described herein, thereby treating the precancerous condition or preventing said cancer.

[0051] In one aspect, the disclosure features a method of detecting an anti-CD138 molecule, the method including contacting a cell or a subject with a humanized antibody molecule described herein, thereby detecting the CD138 molecule.

[0052] 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.

[0053] This disclosure contemplates any one or more combinations of all of the above-described aspects and / or embodiments, as well as any one or more combinations with any one of the embodiments described in the detailed description and examples.

[0054] Other features, objects, and advantages of the compositions and methods of this specification will be apparent from this description, the drawings, and the claims. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. An anti-CD138 antibody molecule comprising: (a) a heavy chain variable region (VH), said VH comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), said VH comprising: (i) an HCDR1 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the HCDR1 of any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422; (ii) an HCDR2 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and (iii) an HCDR3 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the HCDR3 of the anti-CD138 antibody; a heavy chain variable region (VH) comprising: (b) a light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), and the VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% homology to, the amino acid sequence of the LCDR1 of the anti-CD138 antibody; (ii) an LCDR2 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the LCDR2 of the anti-CD138 antibody; and (iii) an LCDR3 comprising an amino acid sequence that differs by no more than 1, 2, or 3 amino acid residues from, or has at least 85, 90, 95, 99, or 100% identity to, the amino acid sequence of the LCDR3 of the anti-CD138 antibody; a light chain variable region (VL) comprising: 1. An anti-CD138 antibody molecule comprising: (Item 2) (a)(i) An HCDR1 comprising the amino acid sequence of the HCDR1 of the anti-CD138 antibody; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the anti-CD138 antibody, and a VH, (b)(i) An LCDR1 comprising the amino acid sequence of the LCDR1 of the anti-CD138 antibody; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the anti-CD138 antibody; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the anti-CD138 antibody, and a VL, The antibody molecule according to item 1, comprising (Item 3) The antibody molecule according to item 1 or 2, wherein the VH comprises an amino acid sequence that differs from the amino acid sequence of the VH of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto. (Item 4) The antibody molecule according to any one of items 1 to 3, wherein the VH comprises the amino acid sequence of the VH of the anti-CD138 antibody. (Item 5) The antibody molecule according to any one of items 1 to 4, wherein the VL comprises an amino acid sequence that differs from the amino acid sequence of the VL of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto. (Item 6) The antibody molecule according to any one of items 1 to 5, wherein the VL comprises the amino acid sequence of the VL of the anti-CD138 antibody. (Item 7) (a) The VH comprises an amino acid sequence that differs from the amino acid sequence of the VH of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; and (b) The VL comprises an amino acid sequence that differs from the amino acid sequence of the VH of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto, The antibody molecule according to any one of items 1 to 6. (Item 8) The antibody molecule according to any one of items 1 to 7, wherein the VH contains the amino acid sequence of the VH of the anti-CD138 antibody, and the VL contains the amino acid sequence of the VL of the anti-CD138 antibody. (Item 9) The antibody molecule according to any one of items 1 to 8, which contains an Fc region. (Item 10) The antibody molecule according to any one of items 1 to 9, wherein the heavy chain (HC) contains an amino acid sequence that differs from the amino acid sequence of the HC of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology therewith. (Item 11) The antibody molecule according to item 10, wherein the HC contains the amino acid sequence of the HC of the anti-CD138 antibody. (Item 12) The antibody molecule according to any one of items 1 to 11, wherein the light chain (LC) contains an amino acid sequence that differs from the amino acid sequence of the LC of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology therewith. (Item 13) The antibody molecule according to item 12, wherein the LC contains the amino acid sequence of the LC of the anti-CD138 antibody. (Item 14) (a) The HC contains an amino acid sequence that differs from the amino acid sequence of the heavy chain (HC) of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology therewith; and (b) The LC contains an amino acid sequence that differs from the amino acid sequence of the light chain (LC) of the anti-CD138 antibody by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99% or 100% homology therewith; The antibody molecule according to any one of items 1 to 13, which contains the same. (Item 15) The antibody molecule according to item 14, wherein the HC contains the amino acid sequence of the HC of the anti-CD138 antibody, and the LC contains the amino acid sequence of the LC of the anti-CD138 antibody. (Item 16) 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), and the VH comprises: (i) HCDR1 comprising the amino acid sequence of G - Y - N / S / T - F - A / S / T - S - Y (SEQ ID NO: 438); (ii) HCDR2 comprising the amino acid sequence of H - P - S - D - S - T (SEQ ID NO: 351); or (iii) a heavy chain variable region (VH) comprising one, two, or all of HCDR3 comprising the amino acid sequence of F - V - Y (SEQ ID NO: 508); and (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), and the VL comprises: (i) LCDR1 comprising the amino acid sequence of K / R - A / S - S - K / Q - S - L - L - Y - K - D - G - K - T - Y - L - N (SEQ ID NO: 522); (ii) LCDR2 comprising the amino acid sequence of V - L / V - S - S / T - L / R - A / Q - S (SEQ ID NO: 523); or (iii) a light chain variable region (VL) comprising one, two, or all of LCDR3 comprising the amino acid sequence of Q - Q - L - V - E / Q - Y - P - Y - T (SEQ ID NO: 524); or (II) (a) A heavy chain variable region (VH), wherein the VH comprises three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), and the VH comprises: (i) HCDR1 comprising the amino acid sequence of S - Y - Y - I / M - H (SEQ ID NO: 525); (ii) HCDR2 comprising the amino acid sequence of T - I - H - P - S - D - S - T - A / T - N - Y - A / N - Q - K - F - K / Q - G (SEQ ID NO: 526); or (iii) a heavy chain variable region (VH) comprising one, two, or all of HCDR3 comprising the amino acid sequence of F - V - Y (SEQ ID NO: 508); and (b) A light chain variable region (VL), wherein the VL comprises three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), and the VL comprises: (i) LCDR1 comprising the amino acid sequence of K / R - A / S - S - K / Q - S - L - L - Y - K - D - G - K - T - Y - L - N (SEQ ID NO: 522); (ii) LCDR2 comprising the amino acid sequence of V - L / V - S - S / T - L / R - A / Q - S (SEQ ID NO: 523); or (iii) a light chain variable region (VL) comprising one, two, or all of LCDR3 comprising the amino acid sequence of Q - Q - L - V - E / Q - Y - P - Y - T (SEQ ID NO: 524); An anti-CD138 antibody molecule comprising: (Item 17) 17. The antibody molecule of any of items 1 to 16, comprising two VHs and two VLs. (Item 18) 18. The antibody molecule according to any one of items 1 to 17, which is a synthetic antibody molecule or an isolated antibody molecule. (Item 19) 19. The antibody molecule according to any of items 1 to 18, 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. (Item 20) 20. The antibody molecule according to any one of items 1 to 19, which is a humanized antibody molecule. (Item 21) 21. The antibody molecule of any of items 1 to 20, comprising one or more framework regions derived from human framework germline sequences. (Item 22) 22. The antibody molecule according to any one of items 1 to 21, which is an IgG antibody. (Item 23) 23. The antibody molecule according to any of items 1 to 22, comprising a heavy chain constant region of an IgG selected from IgG1, IgG2, IgG3, or IgG4. (Item 24) 24. The antibody molecule of any of items 1 to 23, comprising a light chain constant region of a kappa or lambda light chain. (Item 25) 25. The antibody molecule of any of items 1 to 24, 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. (Item 26) 26. The antibody molecule of any of items 1 to 25, 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. (Item 27) An antibody molecule that competes with any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422 for binding to CD138. (Item 28) An antibody molecule that binds to or substantially binds to an epitope that completely or partially overlaps with the epitope of any of antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422. (Item 29) An antibody-drug conjugate (ADC) comprising an antibody molecule according to any one of items 1 to 28, optionally comprising a cytotoxic agent, and further optionally comprising a linker. (Item 30) A composition comprising an antibody molecule according to any one of items 1 to 28 or an ADC according to item 29, which is optionally a pharmaceutical composition. (Item 31) The composition according to item 30, further comprising a pharmaceutically acceptable carrier. (Item 32) A nucleic acid molecule encoding the heavy chain variable region (VH), the light chain variable region (VL), or both of the antibody molecule according to any one of items 1 to 28. (Item 33) A vector comprising the nucleic acid molecule according to item 32. (Item 34) A cell comprising the nucleic acid molecule according to item 32 or the vector according to item 33, which is optionally an isolated cell. (Item 35) A kit comprising an antibody molecule according to any one of items 1 to 28, an ADC according to item 29, or a composition according to item 30 or 31, and an instruction manual for use of the antibody molecule or composition. (Item 36) A container comprising an antibody molecule according to any one of items 1 to 28, an ADC according to item 29, or a composition according to item 30 or 31. (Item 37) A method for producing an anti-CD138 antibody molecule, comprising culturing the cell according to item 34 under conditions enabling the production of the antibody molecule, thereby producing the antibody molecule. (Item 38) The method according to item 37, further comprising isolating or purifying the antibody molecule. (Item 39) An antibody molecule according to any one of items 1 to 28, an ADC according to item 29, or a composition according to item 30 or 31 for use in a method for treating cancer in a subject. (Item 40) The antibody molecule, ADC, or composition for use according to item 39, wherein the cancer is a blood cancer. (Item 41) The antibody molecule, ADC, or composition for use according to item 39 or 40, wherein the cancer is multiple myeloma. (Item 42) The antibody molecule, ADC, or composition for use according to item 39, wherein the cancer is a solid tumor, such as a solid tumor described herein. (Item 43) The antibody molecule, ADC, or composition for use according to any one of items 39 to 42, which is administered intravenously to the subject. (Item 44) An antibody molecule, ADC or composition for use according to any of items 39 to 43, which is administered to the subject at a dose of 0.1 mg / kg to 50 mg / kg, 0.2 mg / kg to 25 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 3 mg / kg, 0.5 mg / kg to 2.5 mg / kg, 0.5 mg / kg to 2 mg / kg, 0.5 mg / kg to 1.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1 mg / kg to 2 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg or 1 mg / kg to 5 mg / kg. (Item 45) An antibody molecule, ADC or composition for use according to any of items 39 to 44, which is administered to the subject at a fixed dose of 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 250 mg, 10 mg to 150 mg, 10 mg to 100 mg, 10 mg to 50 mg, 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg, 100 mg to 200 mg or 150 mg to 250 mg. (Item 46) An antibody molecule, ADC or composition for use according to any of items 39 to 45, which is administered once a week, twice a week, once every two weeks, once every three weeks or once every four weeks. (Item 47) An antibody molecule, ADC or composition for use according to any of items 39 to 46, further comprising determining the level of CD138 in a sample from the subject. (Item 48) An antibody molecule, ADC or composition for use according to any of items 39 to 47, further comprising administering a second cancer treatment to the subject. (Item 49) An antibody molecule according to any of items 1 to 28, an ADC according to item 29, or a composition according to item 30 or 31 for use in a method of treating pre-cancerous conditions or preventing cancer. (Item 50) An antibody molecule, ADC or composition for use according to item 49, wherein the pre-cancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS). (Item 51) 50. The antibody molecule, ADC or composition for use according to item 49, wherein the cancer is multiple myeloma. (Item 52) A method for inducing ADCC activity, the method comprising contacting a cell or a subject with the antibody molecule of any of Items 1 to 28, the ADC of Item 29, or the composition of Item 30 or 31, thereby inducing the ADCC activity. (Item 53) A method for treating cancer, comprising administering to a subject in need thereof an effective amount of the antibody molecule of any of Items 1 to 28, the ADC of Item 29, or the composition of Item 30 or 31, thereby treating the cancer. (Item 54) A method for treating a precancerous condition or preventing cancer, comprising administering to a subject in need thereof an effective amount of the antibody molecule of any of Items 1 to 28, the ADC of Item 29, or the composition of Item 30 or 31, thereby treating the precancerous condition or preventing the cancer. (Item 55) 29. A method for detecting an anti-CD138 molecule, comprising contacting a cell or a subject with the antibody molecule of any of items 1 to 28, thereby detecting said CD138 molecule. (Item 56) 56. The method of claim 55, wherein the antibody molecule is coupled to a detectable label. (Item 57) 57. The method of item 55 or 56, wherein the CD138 molecule is detected in vitro, ex vivo or in vivo. (Item 58) 52. The antibody molecule, ADC or composition for use according to any of items 39 to 51, or the method according to item 53 or 54, wherein the antibody molecule is used or administered in combination with a second therapeutic agent or modality. (Item 59) 59. The antibody molecule, ADC or composition for use according to item 58, or the method according to item 58, wherein the second therapeutic agent or modality comprises a proteasome inhibitor. (Item 60) 60. The antibody molecule, ADC or composition for use according to item 59, or the method according to item 59, wherein the proteasome inhibitor comprises bortezomib.

Brief Description of the Drawings

[0055] [Figure 1] Figure 1 is a graph showing the binding of a humanized anti-CD138 antibody at various doses to the CD138+ multiple myeloma cell line U266.

[0056] [Figure 2] Figure 2 is a graph showing the ADCC activity of a humanized anti-CD138 antibody at various doses targeting CD138+ lymphoblastic myeloma cells. The ADCC activity is evaluated using a bioluminescence reporter assay to quantify the biological activity upon antibody-mediated pathway activation in an ADCC mechanism of action (MOA) assay. This bioassay includes engineered Jurkat cells stably expressing the FcγRIIIa receptor and an NFAT response element driving the expression of firefly luciferase as effector cells.

[0057] [Figure 3] Figures 3A - 3C are a series of graphs showing the dose-dependent binding of a humanized anti-CD138 antibody to three multiple myeloma cell lines: MM1.S, LP-1, and RPMI8226.

[0058] [Figure 4] Figures 4A - 4D are a series of graphs showing that a humanized anti-CD138 antibody induced ADCC in four multiple myeloma cell lines: U266, MM1.S, LP-1, and RPMI8226.

[0059] [Figure 5]Figures 5A - 5D are a series of graphs showing the in vivo efficacy of monoclonal anti - CD138 antibody 2810. The mean BLI ± 95% CI of the quantification of disseminated multiple myeloma tumors from IVIS imaging at a specific time point is shown (Figure 5A). Statistics (Bonferroni - Dunn) for comparing treatment groups by multiple t - tests. Comparison of the total tumor burden in individual mice in the vehicle group and the mAb 2810 group (mean + minimum - maximum values are also shown) (Figure 5B). Bioluminescence (BLI) of the tumor burden in skeletal tissues imaged ex vivo on day 42 post - sacrifice in the spine (Figure 5C) and hindlimbs (Figure 5D). Statistics were determined by unpaired t - tests. BLI data are plotted on a logarithmic scale.

[0060] [Figure 6-1] Figures 6A - 6C are a series of graphs showing the in vivo efficacy of monoclonal anti - CD138 antibodies. The mean BLI ± standard error of the mean of disseminated multiple myeloma tumors quantified from IVIS imaging at specific time points and dose levels is shown (Figure 6A). Statistical analysis by two - way ANOVA (Tukey's multiple comparisons). Comparison of the total tumor burden in individual mice in the vehicle control, humanized anti - CD138 antibody mAb 4320 treatment group, and murine chimeric anti - CD138 mAb 2810 treatment group (Figure 6B). Mean plus minimum - maximum values are also shown, and the median is shown as a bar. BLI data are plotted on a logarithmic scale. Percent survival of animals treated with anti - CD138 antibodies mAb 2810 and 4320 compared to animals in the vehicle group (Figure 6C). Percent survival is defined as the mice that survived to a predefined euthanasia criterion related to disease - associated morbid conditions such as weight loss exceeding 20%, severe CNS dysfunction, or severe motor impairment, or loss of righting reflex. The log - rank test (Mantel - Cox) was used for comparison of survival curves (VC vs. animals treated with anti - CD138 antibodies). [Figure 6-2] The same as above.

[0061] [Figure 7-1]Figure 7 is a series of graphs evaluating the thermal stability of the anti-CD138 antibody analyzed by differential scanning fluorimetry (DSF). The thermal melting profiles are shown as the first derivative transformation of the thermal scan (d(fluorescence) / d(temperature)). The thermal transitions (Tm1 and Tm2) are indicated by vertical lines and summarized in Table 4. [Figure 7-2] Ibid.

[0062] [Figure 8] Figure 8 is a graph showing the relative levels of the anti-CD138 antibody in mouse serum administered as a single dose in the transgenic human FcRn hemizygous mouse strain Tg276. At the 2.5 mg / kg dose level, the anti-CD138 monoclonal antibody was intravenously administered by tail vein injection. Antibody titers from serum samples collected approximately 65 hours after injection were determined by ELISA (for detection of human IgG1 Fc) and plotted as the percentage of residual antibody normalized to the serum antibody titer measured at an early time point (1 hour) after administration. The levels of the chimeric antibody mAb2810 (white bar) and the humanized anti-CD138 mAb 4320 (black bar) are indicated by dotted lines. For comparison, the anti-RSV antibody motavizumab (MVZ) was also included in this analysis.

[0063] [Figure 9] Figures 9A - 9B are a series of graphs showing the comparative dose-dependent cell binding and Fc effector-mediated ADCC activities of the humanized antibody mAb 4320 and the reference antibody BB4. Cell binding to the human lymphoblastoid cell line U266 (expressing CD138) measured by flow cytometry (Figure 9A). Antibody binding to cell surface CD138 is quantified as the mean fluorescence intensity. ADCC activity measured using a Jurkat reporter bioassay with the human FcrγIIIa transgene as the effector cell (Figure 9B). The data are normalized as fold induction compared to the minus antibody control.

[0064] [Figure 10]Figure 10 summarizes the differential binding of humanized anti-CD138 antibody mAb 4320 and reference antibody BB4 to soluble extracellular domains of human CD138 at various concentrations and selected CD138-derived peptides. Protein and peptide binding was quantified by ligand capture ELISA. CD138 peptides corresponding to the integrin-binding domain (designated peptide 2A) or the membrane-proximal region (designated peptide 6A) are noted.

[0065] [Figure 11] Figure 11 shows the in vivo multiple myeloma tumor seeding (xenograft) model used for the evaluation of mAb 4320 treatment efficacy. The experimental outline lists the mouse background (CB.17 SCID mice), human MM1.S (Luc) cell line, imaging assay (in vivo imaging / whole body luminescence for measuring tumor burden), and dosing schedule (intraperitoneal administration, twice weekly, over 8 weeks). Treatment groups (N = 8 mice / group) included vehicle control, mAb 2810 (4 mg / kg), and variable dosing of mAb 4320 (4, 8, and 16 mg / kg). The figure of the experimental design shows three phases: the staging phase, the dosing phase (with efficacy), and the survival phase. BLI, bioluminescence.

[0066] [Figure 12] Figure 12 is a graph showing the group efficacy data after treatment of mice in a multiple myeloma xenograft model with the indicated antibody molecules. The disseminated multiple myeloma tumor burden is shown as the standard error of the mean of BLI ± of the disseminated tumor, quantified from IVIS imaging at specific time points and dose levels. Efficacy is partially defined by the time to the evaluation size (BLI equal to 1 × 109 p / s), indicated by the horizontal dashed line. To compare mAb 4320 treatment with other treatment groups, statistical analysis was performed by two-way ANOVA (Tukey's multiple comparison). P-values were calculated based on the interaction as a factor of variation. BLI data are plotted on a logarithmic scale.

[0067] [Figure 13] Figure 13 is a graph showing efficacy data for individual mice in a multiple myeloma xenograft model after treatment with the indicated antibody molecules. Comparison of tumor burden in individual mice in vehicle control versus antibody-treated groups. Mean BLI values are depicted as horizontal bars.

[0068] [Figure 14] 14 is a series of images showing bioluminescence (BLI) results from a multiple myeloma xenograft study. BLI images are shown for individual mice, comparing mAb 4320, mAb 2810, and vehicle groups, as indicated, at 35 days post-tumor implantation.

[0069] [Figure 15] Figure 15 is a graph showing group survival results from a multiple myeloma xenograft study. Kaplan-Meier survival curves are shown for vehicle-treated animals versus animals treated with the anti-CD138 antibodies mAb 2810 and mAb 4320. Percent survival was defined as mice surviving until reaching a predetermined euthanasia criterion related to disease-related morbidity, such as >20% weight loss, severe CNS dysfunction, or severe motor impairment or loss of the righting reflex. P values for comparisons of VC and mAb 4320 treatment (log-rank test) were calculated by the Mantel-Cox test.

[0070] [Figure 16] Figure 16 is a graph showing changes in animal body weight in a multiple myeloma xenograft study. Percent changes in body weight are plotted as standard error of the mean. Animals corresponding to the mAb 4320 treatment group are indicated by open symbols, and animals corresponding to the vehicle control (VC) are indicated by closed circles. The greatest changes in body weight were observed in animals in the vehicle control group, demonstrating a correlation with disease progression.

[0071] [Figure 17]Figure 17 is a graph showing the pharmacokinetic (PK) results from a multiple myeloma xenograft study in the form of antibody molecule serum titers. Serum samples were collected once a week (N = 4 mouse groups). Antibody serum titers were quantified by ELISA optimized to detect human IgG1 Fc. Serum from the VC group was used as a negative control. Insert: Plot of the antibody molecule serum titer of mAb 4320 on day 13 plotted against the dose level (antibody concentration).

[0072] [Figure 18] Figures 18A - 18B are a series of graphs showing the efficacy of treatment with mAb 4320 and bortezomib. On day 0, MM1.S (Luc) cells were injected into CB17 SCID mice via the intravenous administration route, and the disease stage was classified on day 14, which also corresponded to the first day of administration of the vehicle control, mAb 4320 (4 mg / kg), bortezomib (1 mg / kg), or a combination of mAb 4320 and bortezomib. N = 9 mice / treatment group. Tumor burden was evaluated by whole - body bioluminescence (BLI) and quantified by IVIS imaging as described in the method (section 3.2). Treatment was discontinued on day 53 (administration phase), followed by a 3 - week drug - free period, and the study was terminated on day 73. (A) Group efficacy data. The seeded tumor burden was reported as bioluminescence (BLI) ± standard error of the mean at each time point. (B) Individual mice.

[0073] [Figure 19-1] Figures 19A - 19D are a series of representative bioluminescence (BLI) images of individual mice administered the indicated treatments, selected based on proximity to the median BLI on day 36. Image intensity was adjusted for normalization (minimum value of 1.0×106; maximum value of 3.0×108), but this does not imply the absence of tumor burden on day 14 (the day of disease classification and before the first administration). All animals in the vehicle control group died by day 53. [Figure 19-2] Ibid. [Figure 19-3] Ibid. [Figure 19-4] Ibid.

[0074] [Figure 20] Figure 20 is a graph showing the survival over time in treated mice as a Kaplan-Meier survival curve. Treatment was discontinued on day 53. Percent survival was defined as mice surviving to a predefined euthanasia criterion related to disease-related morbid conditions such as greater than 20% weight loss, severe CNS dysfunction, or severe motor dysfunction, or loss of the righting reflex.

[0075] [Figure 21] Figure 21 is a graph showing the change in body weight of animals after administration of the treatment. Percent change in body weight was plotted as the standard error of the mean. The greatest change in body weight was observed in animals of the vehicle control group, indicating a correspondence with disease progression. A decrease in body weight was also observed in the bortezomib monotherapy group, which may be due to drug toxicity.

Mode for Carrying Out the Invention

[0076] Detailed Description Humanized antibody molecules that bind to CD138, such as human CD138, are disclosed herein. Advantageously, at least some of the humanized antibody molecules described herein have an improved ability to inhibit cells expressing CD138, for example by inducing effector function. Without being bound by theory, in one embodiment, anti-CD138 antibodies that bind to the desired epitope described herein are thought to have increased effector function and preferentially bind to membrane-bound CD138. Effective targeting of CD138 can result in a broad spectrum of activity and favorable therapeutic indices across multiple myeloma and other cancers.

[0077] The humanized antibody molecules described herein can have one or more improved properties, e.g., one or more properties described herein, compared to, for example, the parent non-humanized antibody molecule. For example, improved properties can include, but are not limited to, therapeutic efficacy, mitigated immunogenicity, improved biophysical, physicochemical, and pharmaceutical properties, improved target binding, biological activity, and higher recombinant expression in mammalian cell lines used for antibody production. Without wishing to be bound by theory, in one embodiment, the humanized antibody molecules described herein are believed to be more suitable for therapeutic or pharmaceutical use in humans than non-humanized antibody molecules. In one embodiment, the humanized antibody molecule has greater therapeutic efficacy (e.g., smaller tumor burden and / or increased survival time). In one embodiment, the humanized antibody molecule has increased stability (in vitro and / or in vivo). In one embodiment, the humanized antibody molecule has higher expression levels (e.g., in cell lines). In one embodiment, the humanized antibody molecule has comparable or improved CD138 binding affinity, effector function (eg, ADCC activity), or both, compared to the parent non-humanized antibody.

[0078] The anti-CD138 antibody molecules (e.g., humanized anti-CD138 antibody molecules) described herein can be used to treat a variety of disorders, such as multiple myeloma and other oncological indications. Without wishing to be bound by theory, in one embodiment, the disorder is believed to involve CD138-positive cancer cells and / or CD138-mediated biological activity associated with disease pathophysiology. For example, CD138 plays an important role in the KRAS-driven pathway underlying tumorigenesis and resistance in various cancers, exemplified by pancreatic ductal adenocarcinoma.

[0079] The anti-CD138 antibody molecules (e.g., humanized anti-CD138 antibody molecules) described herein can possess biological activities that are particularly suitable for treating human disorders. For example, mAb 4320, an exemplary humanized anti-CD138 antibody molecule, exhibits potent in vitro activity associated with its immune-mediated therapeutic mechanism of action. These attributes include, for example, both subnanomolar binding to CD138+ myeloma cells and antibody-dependent cellular cytotoxicity (ADCC) against several MM cell lines, as assessed in a biologically relevant natural killer (NK) cell-based ADCC assay using, for example, human-derived NK cells. This potent cell-killing activity is dose- and target-dependent and has been shown to be highly effective against drug-resistant MM cell lines, including a number of variably expressing CD138 multiple myeloma cell lines, including stable cell lines propagated to be resistant to either bortezomib or lenalidomide, two frontline therapies commonly used in combination as standard of care in patients for induction, consolidation, or maintenance therapy. mAb 4320 effectively kills autologous myeloma cells from relapsed / refractory patients who fail to respond to such treatment. Other relevant mechanisms of action may also exist, such as antibody-dependent cellular phagocytosis (ADCP), direct inhibition of myeloma cell survival, and blockade of integrin binding. The in vivo efficacy of mAb 4320 has also been demonstrated in a mouse xenograft model of disease involving the use of disseminated MM1.S tumors in CB.17 mice, either as a single agent or in combination with proteasome inhibitors (e.g., bortezomib) to achieve synergistic effects.

[0080] Also provided are antibody-drug conjugates (ADCs), nucleic acid molecules encoding the antibody molecules, expression vectors, host cells, compositions (e.g., pharmaceutical compositions), kits, and methods for making the antibody molecules. The antibody molecules and pharmaceutical compositions disclosed herein can be used (alone or in combination with other agents or therapeutic modalities) to treat, prevent, and / or diagnose disorders and conditions, such as disorders and conditions associated with CD138, such as cancer or precancerous conditions.

[0081] definition As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.

[0082] The term "or" is used herein to mean, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0083] "About" and "approximately" generally refer to an acceptable degree of error for the quantity being measured, given the nature or precision of the measurement. Exemplary degrees of error are within 20 percent (%), typically within 10%, and more typically within 5% of a given value or range of values. When "about" or "approximately" precedes a series of numbers or ranges, it is understood that "about" or "approximately" may modify each number in the series or range. Similarly, when "at least," "greater than," "less than," "more than," or "within" precedes a series of numbers or ranges, it is understood that "at least," "greater than," "less than," "more than," or "within" may modify each number in the series or range. As used herein, a range includes both upper and lower limits.

[0084] The compositions and methods disclosed herein encompass polypeptides and nucleic acids having the designated sequences or sequences substantially identical or similar thereto, for example, sequences at least 85%, 90%, 95% or more identical to the designated sequences.

[0085] In the context of amino acid sequences, the term "substantially identical" is used herein to refer to a first amino acid sequence that contains a sufficient or minimum number of amino acid residues that are i) identical to or ii) conservative substitutions for aligned amino acid residues in a second amino acid sequence, such that the first and second amino acid sequences may have a common structural domain and / or a common functional activity. For example, an amino acid sequence containing a common structural domain that has 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.

[0086] In the context of nucleotide sequences, the term "substantially identical" is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of identical nucleotides to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode polypeptides having a common functional activity, or encode a common structural polypeptide domain or common functional polypeptide activity. For example, 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.

[0087] The term "functional variant" refers to a polypeptide that has substantially the same amino acid sequence as a naturally occurring sequence, or is encoded by substantially the same nucleotide sequence, and that can possess one or more activities of the naturally occurring sequence.

[0088] Calculations of homology or sequence identity between sequences (the terms are used interchangeably herein) are performed as follows.

[0089] To determine the percent identity between two amino acid sequences or two nucleic acid sequences, for optimal comparison, the sequences are aligned (e.g., for optimal alignment, gaps may be introduced into one or both of the first and second amino acid or nucleic acid sequences, and for comparison purposes, non-homologous sequences may be disregarded). In a typical embodiment, the length of the reference sequence aligned for comparison purposes is at least 30% of the length of the reference sequence, e.g., at least 40%, 50%, 60%, e.g., at least 70%, 80%, 90%, 100%. The amino acid residues or nucleotides at the corresponding amino acid positions or nucleotide positions are then compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position.

[0090] The percent identity between two sequences is a function of the number of identical positions the sequences share, taking into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap.

[0091] The comparison of sequences and determination of percent identity between two sequences can be achieved using a mathematical algorithm. In some embodiments, the percent identity between two amino acid sequences is determined using the algorithm by Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453) incorporated into the GAP program of the GCG software package (available at gcg.com), using either 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, the percent identity between two nucleotide sequences is determined using the GAP program of the GCG software package (available at gcg.com), using a NWSgapdna.CMP matrix, a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. One suitable parameter set (which should be used unless otherwise specified) is a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4 and a frameshift gap penalty of 5.

[0092] Percent identity between two amino acid or nucleotide sequences was calculated using the PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4, as implemented in the ALIGN program (version 2.0) by E. Meyers. and W. Miller ((1989) CABIOS, 4:11-17).

[0093] The nucleic acid and protein sequences described herein can 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 program and the XBLAST program (version 2.0) by Altschul et al. (1990) J. Mol. Biol. 215:403-10. To obtain nucleotide sequences homologous to the nucleic acids described herein, BLAST nucleotide searches can be performed with the NBLAST program, score = 100, word length = 12. To obtain amino acid sequences homologous to the protein molecules described herein, BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3. To obtain gapped alignments for comparison purposes, gapped BLAST, as described in Altschul et al. (1997) Nucleic Acids Res. 25:3389-3402, can be used. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See ncbi.nlm.nih.gov.

[0094] As used herein, the term "hybridizes under low stringency conditions, medium stringency conditions, high stringency conditions or ultra-high stringency conditions" describes the conditions for hybridization and washing. Guidelines for performing the hybridization reactions can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6 (which is incorporated by reference). Both aqueous and non-aqueous methods are described in this reference and either can be used. The specific hybridization conditions referred to herein are as follows: 1) Low stringency hybridization conditions of about 45°C in 6× sodium chloride / sodium citrate (SSC), followed by washing twice at at least 50°C in 0.2× SSC, 0.1% SDS (the washing temperature can be increased to 55°C under low stringency conditions); 2) Medium stringency hybridization conditions of about 45°C in 6× SSC, followed by washing one or more times at 60°C in 0.2× SSC, 0.1% SDS; 3) High stringency hybridization conditions of about 45°C in 6× SSC, followed by washing one or more times at 65°C in 0.2× SSC, 0.1% SDS; and preferably 4) Ultra-high stringency hybridization conditions are 0.5 M sodium phosphate, 7% SDS at 65°C, followed by washing one or more times at 65°C in 0.2× SSC, 1% SDS. Ultra-high stringency condition 4) is the appropriate condition and should be used unless otherwise specified.

[0095] The molecules described herein are understood to be capable of having additional conservative amino acid substitutions or non-essential amino acid substitutions that do not substantially affect their function.

[0096] The term "amino acid" is intended to encompass all molecules, whether natural or synthetic, that contain both amino and acid functional groups and can be included in naturally occurring amino acid polymers. Exemplary amino acids include naturally occurring amino acids; their analogs, derivatives, and congeners; amino acid analogs with variant side chains; and all stereoisomers of any of the above. As used herein, the term "amino acid" includes both D- and L-optical isomers and peptidomimetics.

[0097] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having 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 (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0098] The terms "polypeptide," "peptide," and "protein" (when single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer can be linear or branched, it can contain modified amino acids, and it can be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified, such as by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. Polypeptides can be isolated from natural sources, produced by recombinant techniques from eukaryotic or prokaryotic hosts, or can be the product of synthetic procedures.

[0099] The terms "nucleic acid", "nucleic acid sequence", "nucleotide sequence" or "polynucleotide sequence" and "polynucleotide" are used interchangeably. They refer to a polymeric form of nucleotides of any length, which can be either deoxyribonucleotides or ribonucleotides or analogs thereof. A polynucleotide can be either single-stranded or double-stranded, and if single-stranded, can be either a coding strand or a non-coding (antisense) strand. A polynucleotide can include modified nucleotides, such as methylated nucleotides and nucleotide analogs. The sequence of nucleotides can be interrupted by non-nucleotide components. A polynucleotide can be further modified after polymerization, for example, by conjugation with a labeling component. A nucleic acid can be a recombinant polynucleotide or can be a polynucleotide of genomic, cDNA, semi-synthetic or synthetic origin, which are not naturally occurring or are linked to another polynucleotide in a non-natural arrangement.

[0100] As used herein, the term "isolated" refers to a material that has been removed from its original environment or native environment (e.g., the natural environment if it occurs naturally). For example, a naturally occurring polynucleotide or polypeptide present in a living animal is not isolated, but the same polynucleotide or polypeptide that has been separated, by human intervention, from some or all of the 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 such a vector or composition is still isolated in that it is not part of the environment in which it is naturally found.

[0101] As used herein, the term "treating" a disorder, such as myeloma, means that a subject (e.g., a human) having the disorder, such as myeloma, and / or experiencing symptoms of the disorder, such as myeloma, in one embodiment, when an antibody molecule is administered, will suffer less severe symptoms and / or recover faster than when the antibody molecule is not administered. In one embodiment, when myeloma is treated, after effective treatment of the myeloma, a bone marrow biopsy will show fewer clonal plasma cells. For example, a diagnostic assay will detect fewer clonal plasma cells in a biological sample of a subject after administration of an antibody molecule described herein for effective treatment of myeloma. Other assays, such as urine or blood tests, can also be used to monitor treatment in a patient or to detect the presence, e.g., a decrease (or absence) of symptoms of myeloma after treatment of myeloma in a subject. In one embodiment, when myeloma is treated, after effective treatment of the myeloma, the level of β2-microglobulin (β2M) in serum or urine will decrease. Treatment can, for example, partially or completely alleviate, ameliorate, reduce, inhibit, or decrease the severity of, and / or decrease the incidence of, one or more manifestations of the effect, symptoms, features, and / or cause of a disorder, such as myeloma, and / or, optionally, delay its onset. In one embodiment, treatment is for a subject who does not exhibit certain signs of a disorder, such as myeloma, and / or for a subject who exhibits only early signs of a disorder, such as nephropathy. In one embodiment, treatment is for a subject who exhibits one or more established signs of a disorder, such as myeloma. In one embodiment, treatment is for a subject diagnosed with having a disorder, such as myeloma.

[0102] As used herein, the term "preventing" a disorder, such as myeloma, means that a subject (e.g., a human) is less likely to have the disorder, such as myeloma, when the subject is administered an antibody molecule.

[0103] Various aspects of the compositions and methods of this specification are described in further detail below. Additional definitions are set forth throughout this specification.

[0104] CD138 CD138 is a protein encoded by the SDC1 gene in humans. CD138 is also known as syndecan 1, syndecan proteoglycan 1, CD138 antigen, SYND1, SDC, syndecan-1, or syndecan.

[0105] CD138 is a transmembrane (type I) heparan sulfate proteoglycan (HSPG) and a member of the syndecan proteoglycan family. Highly expressed on differentiated plasma cells (PCs), CD138 is a key diagnostic biomarker for multiple myeloma (MM) and an indicator of poor clinical prognosis. CD138 is also stably and significantly overexpressed on patient-derived multiple myeloma cells during multiple stages of disease progression, with over 70% of these patients exhibiting increased CD138 cell surface expression on autologous MM cells obtained from fresh BM aspirates. CD138 gene expression is similarly increased several-fold on patient-derived MM cells compared with "normal" plasma cells from healthy patient controls. Without wishing to be bound by theory, in one embodiment, CD138 is believed to be targeted for immunotherapy against MM, including, but not limited to, smoldering myeloma, a relatively early, largely asymptomatic disease stage suitable for early therapeutic intervention. Without wishing to be bound by theory, in one embodiment, targeting CD138 may provide additional therapeutic benefits based on its important function as a promoter of myeloma cell growth, adhesion and survival, as well as other important aspects of myeloma cancer biology.Syndecans mediate cell binding, cell signaling and cytoskeleton organization, and syndecan receptors are required for the internalization of HIV-1 tat protein.CD138 functions as an integral membrane protein and is involved in cell proliferation, cell migration and cell-matrix interaction through its receptor for extracellular matrix proteins.Changes in CD138 expression have been detected in several different tumor types.

[0106] The core of CD138 contains three major domains: 1) a short cytoplasmic domain; 2) a transmembrane hydrophobic domain; and 3) a long extracellular domain. The functions of the CD138 domains are described, for example, in Stepp et al., Adv Wound Care (New Rochelle). 2015;4(4):235-249). The cytoplasmic domain transmits signals and can also bind to anchor molecules including PDZ family members. The heparan sulfate chains of CD138 also play important biological functions. In mammals, CD138 is a major heparan sulfate proteoglycan (HSPG) on epithelial cells and has high expression levels (Fuki et al., J Clin Invest. 1997;100(6):1611-1622). Without being bound by theory, the HSPG of CD138 is thought to enable 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).

[0107] For example, the signal peptide contains residues 1-22; the extracellular domain contains residues 23-254; the transmembrane domain contains residues 255-275; the cytoplasmic domain contains residues 276-310; or the integrin binding domain (IBD) contains residues 88-122 of the human CD138 protein, such as any of SEQ ID NOs: 1-3 or 450.

[0108] In one embodiment, the anti-CD138 antibody molecules described herein may modulate (e.g., inhibit) the binding of CD138 to one or more proteins that interact with (e.g., directly or indirectly bind to) the extracellular domain of CD138. In one embodiment, the anti-CD138 antibody molecules described herein may modulate (e.g., inhibit) a function associated with a protein that interacts with (e.g., directly or indirectly binds to) the extracellular domain of CD138. In one embodiment, the CD138-interacting protein directly binds to the extracellular domain of CD138. In one embodiment, the CD138-interacting protein binds to the extracellular domain of CD138 via glycosaminoglycan (GAG) chains.

[0109] Examples of CD138-interacting proteins 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 by reference in their entirety.

[0110] 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, chordin, sonic hedgehog, Frizzled-related protein, Sprouty peptide, any of Wnt1-Wnt13, anti-angiogenic factors (e.g., anguistatin or endostatin), growth factors (e.g., amphiregulin, batacellulin, HB-EGF, neuregulin, any of FGF1-FGF23, PDGF, GDNF, VEGF, HGF, TGFβ1, TGFβ2, TPA or PAI-1) or Examples include cytokines (e.g., GM-CSF, IL-2, IL-3, IL-4, IL-5, IL-7, IL-12, interferons, TNF-α, CC chemokines or CXC chemokines), proteins related to energy balance (e.g., ApoB, ApoE or lipoprotein lipase), complement or coagulation proteins (e.g., antithrombin II, tissue factor (TF), pathway inhibitors, factor IX, factor X, factor XI or factor XII) or viral or parasitic coat proteins (e.g., HIV-1 tat, HIV-1 gp41, HIV-1 gp120, HSV gB, HSV gC, HSV gD, HHV-6 or HHV-8 coat proteins or RSV G protein).

[0111] CD138 expressed on the cell surface is cleaved by specific proteases, and the shed CD138 is involved in mediating paracrine and autocrine functions. In the blood and matrix, shed CD138 is a soluble and secreted ectodomain (ECD). Shedding CD138 is an indicator of poor prognosis in multiple myeloma patients and an indicator of enhanced tumor progression in myeloma mouse models. Typically, shedding CD138 is not considered to be the primary cause of disease symptoms. Translocation of CD138 to the cell nucleus can correlate with the differentiation and proliferation of certain tumor cells. In one embodiment, the anti-CD138 antibody molecule described herein preferentially targets membrane-bound CD138 over soluble CD138.

[0112] Generally, CD138 is not present on B lymphocytes; it is expressed after the onset of plasma cell differentiation. CD138 is highly expressed on malignant plasma cells (myeloma) and plays a causal role in disease progression. CD138 is involved in various biological functions. For example, it can bind to extracellular proteins, growth factors, and chemokines; engage and activate αVβ3 and αVβ5 integrins upon clustering; regulate exosome synthesis; and regulate the bone marrow microenvironment, which supports myeloma growth and metastasis. Targeting CD138 can attenuate multiple signals.

[0113] In multiple myeloma, CD138 is upregulated (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. Soluble CD138 (sCD138) levels generally range from less than 60 ng / mL in normal serum to 200-1500 ng / mL in serum from multiple myeloma patients. CD138 is overexpressed in approximately 80% of multiple myeloma patients.

[0114] CD138 can be used as a primary diagnostic marker for multiple myeloma. Increased levels of shed CD138 in serum correlate with increased tumor burden and poor outcome. CD138+ myeloma cells exhibit higher proliferation, and CD138+ myeloma patients have a lower overall survival rate. CD138+ myeloma cells aberrantly express angiogenic factors such as HGF, IL-15, ANG, APRIL, CTGF, or TGFA (Hose et al., Blood. 2009;114(1):128-143). CD138 expression levels and its shed extracellular domain correlate with tumor grade, phenotype, and metastatic potential for both solid and hematological tumors. CD138 expression varies by cancer type, and differential expression signatures between normal and cancer cells in the epithelial and stromal compartments are directly related to tumor aggressiveness and patient clinical outcome and survival.

[0115] Exemplary amino acid and nucleotide sequences of human CD138 are described, for example, in Mali et al., J Biol Chem. 1990;265(12):6884-6889; Lories et al., J Biol Chem. 1992;267(2):1116-1122; and FIG. 1.

[0116] The amino acid sequence of an exemplary human CD138 precursor (SEQ ID NO: 1) is provided as follows.

Chem.

[0117] The amino acid sequence of an exemplary human CD138 precursor variant (Q136L) (SEQ ID NO: 2) is provided as follows.

Chem.

[0118] The amino acid sequence of an exemplary human CD138 precursor variant (T76M) (SEQ ID NO: 3) is provided as follows.

Chem.

[0119] The signal peptide contains amino acids 1-22 of any of SEQ ID NOs: 1-3. The mature peptide contains amino acids 23-310 of any of SEQ ID NOs: 1-3. The extracellular domain contains amino acids 23-254 of any of SEQ ID NOs: 1-3. The transmembrane domain contains amino acids 255-275 of any of SEQ ID NOs: 1-3. The cytoplasmic domain contains amino acids 276-310 of any of SEQ ID NOs: 1-3.

[0120] An exemplary coding nucleotide sequence of human CD138 (SEQ ID NO: 4) is provided as follows. This nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 1.

Chem.

[0121] Another exemplary coding nucleotide sequence of human CD138 (SEQ ID NO: 5) is provided as follows. This nucleotide sequence also encodes the amino acid sequence of SEQ ID NO: 1.

Chemical formula

Chemical formula

[0122] As used herein, if 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 the amino acid sequence described herein or encoded by the nucleotide sequence described herein. In one embodiment, the antibody molecule binds or substantially binds to human CD138 comprising amino acids 23-254 of any of SEQ ID NOs: 1-3.

[0123] Exemplary amino acid and nucleotide sequences of mouse CD138 are described, for example, in Saunders et al., J Cell Biol. 1989;108(4):1547-1556; and Vihinen et al., J Biol Chem. 1993;268(23):17261-17269.

[0124] An exemplary amino acid sequence of a mouse CD138 precursor (SEQ ID NO: 6) is provided as follows.

Chemical formula

[0125] The signal peptide comprises amino acids 1 to 22 of SEQ ID NO: 6. The mature peptide comprises amino acids 23 to 311 of SEQ ID NO: 6. The extracellular domain comprises amino acids 23 to 255 of SEQ ID NO: 6. The transmembrane domain comprises amino acids 256 to 276 of SEQ ID NO: 4. The cytoplasmic domain comprises amino acids 277 to 311 of SEQ ID NO: 6.

[0126] An exemplary coding nucleotide sequence for mouse CD138 (SEQ ID NO:7) is provided below: [ka] [ka]

[0127] As used herein, if an anti-CD138 antibody molecule binds or substantially binds to murine CD138, it binds or substantially binds to one or more isoforms of murine 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 murine CD138 comprising amino acids 23 to 255 of SEQ ID NO:6.

[0128] epitope The humanized antibody molecules described herein can bind to an epitope on CD138 (e.g., human CD138). For example, the epitope bound by a humanized antibody molecule described herein can include one or more of the epitope contact points described herein.

[0129] Although not bound by theory, in one embodiment, an antibody that binds to IBD of CD138 (e.g., residues 88 - 122 of any of SEQ ID NOs: 1 - 3 or 450) or any region remote from the membrane may not be effective in signaling NK cell activation and / or may not efficiently deliver molecules such as perforin and / or granzyme for cytotoxicity. In one embodiment, the antibody molecule binds to an epitope of CD138 that includes a membrane-proximal region. In one embodiment, the antibody molecule binds to an epitope of CD138 that includes at least two different peptide regions (e.g., includes peptide 2A and / or 6A and / or a portion thereof). In one embodiment, the antibody molecule binds to an epitope of CD138 that is different from the epitope bound by antibody BB4.

[0130] In one embodiment, the antibody molecule binds to CD138 (e.g., human CD138) with at least 10% (e.g., at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 50%, 55%, 60%, 70%, 80% or 90%) higher affinity compared to a reference anti-CD138 antibody (e.g., antibody BB4), as determined, for example, by the cell binding assays described herein. In one embodiment, CD138 is membrane-bound. In one embodiment, the antibody molecule binds to the extracellular domain of soluble CD138, e.g., soluble CD138 having the sequence of amino acids 18 - 251 of SEQ ID NO: 1. In one embodiment, the antibody molecule binds to peptide 2A of human CD138. In certain embodiments, the antibody molecule binds to peptide 6A of human CD138.

[0131] In some embodiments, the anti-CD138 antibody molecules described herein have one, two, or all of the following characteristics: optimal distance of the epitope from the cell membrane (e.g., not on the N-terminus of IDB); proper orientation of the Fc region for CD16 engagement; or proper CD138 engagement that allows for CD16 clustering on NK cells (e.g., to overcome the effect of extensive glycosylation on CD138 molecules that may limit access of NK cells).

[0132] Without being bound by theory, in one embodiment, it is believed that changing the location of an antibody epitope can alter the specific effector mechanism it engages. For example, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may favor membrane-proximal epitopes over membrane-distal epitopes (Cleary et al., J Immunol. 2017;198(10):3999-4011). In one embodiment, antibodies designed to delete target cells via specific effector mechanisms can be selected by varying the location of the antibody epitope (e.g., the distance of the epitope from the membrane).

[0133] In one embodiment, the mode of engagement can affect the ability of an antibody to mediate effector function. For example, the angle at which an antibody binds to an extracellular loop with respect to the membrane surface can vary between antibodies that bind to the same peptide epitope (e.g., parallel or perpendicular to the membrane surface).

[0134] In one embodiment, the anti-CD138 antibody molecule described herein binds to an epitope that has one, two, or all of the following characteristics: it is proximal to the cell membrane; it is not restricted or shielded by glycosaminoglycan (GAG) chains; or it is preferentially present on membrane-associated CD138. In one embodiment, the anti-CD138 antibody molecule described herein binds to a desired epitope region and can engage the membrane in an optimal orientation. In one embodiment, the epitope is a linear epitope. In one embodiment, the antibody molecule binds to an extracellular region of CD138 remote from the transmembrane region. In one embodiment, the epitope is a discontinuous or conformational epitope.

[0135] Peptides for specifying desired epitopes for anti-CD138 antibodies are shown, for example, in Figure 2 of WO 2019 / 070726 or U.S. Patent Application Publication No. 2019 / 0100588. Without being bound by theory, in one embodiment, the anti-CD138 antibody molecules described herein are believed to target the peptide region of human CD138 from residues Gly217 to Glu251, as shown, for example, in Figure 1 of WO 2019 / 070726 or U.S. Patent Application Publication No. 2019 / 0100588. This region is predicted to have a linear random coil conformation. In one embodiment, the anti-CD138 antibody molecule binds to at least one linear tetrapeptide in said region. In one embodiment, the anti-CD138 antibody molecule binds to a combination of linear tetrapeptides (e.g., two, three, four, or more adjacent tetrapeptides) in said region.

[0136] The amino acid sequences of the peptides are shown in Table 3. [Table 3]

[0137] 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 designations, 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.

[0138] Other exemplary peptides for use in identifying desired epitopes for anti-CD138 antibodies are described herein, e.g., in Figures 13 and 22C of WO 2019 / 070726 or U.S. Patent Application Publication No. 2019 / 0100588.

[0139] In one embodiment, the antibody molecule contacts (e.g., binds or substantially binds to) a region in CD138 corresponding to one or more peptides described in Table 3, FIG. 13, or 22C of WO 2019 / 070726 or US Patent Application Publication No. 2019 / 0100588. 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 and 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.

[0140] 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.

[0141] 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.

[0142] In one embodiment, the antibody molecule binds or substantially binds to CD138 in the extracellular region adjacent to the transmembrane domain of CD138. In one embodiment, the C-terminus of the extracellular region adjacent 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. In one embodiment, the N-terminus of the extracellular region adjacent 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.

[0143] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 4 or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more) contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain.

[0144] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises five or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises six or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises seven or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises eight or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises nine or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises ten or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises eleven or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises twelve or more contiguous amino acid residues in the extracellular region adjacent to the transmembrane domain.

[0145] In one embodiment, the extracellular region adjacent to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep6. In one embodiment, the extracellular region adjacent to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep6a, 6b, 6e and / or 6f. In one embodiment, the extracellular region adjacent to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep5.

[0146] In one embodiment, the antibody molecule contacts 4 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) contiguous amino acid residues in Pep6. In one embodiment, the antibody molecule contacts 4 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) contiguous amino acid residues in Pep6a.

[0147] In one embodiment, the antibody molecule contacts 1 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); 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: 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); QGAT (SEQ ID NO: 45); GATG (SEQ ID 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).

[0148] In one embodiment, the antibody molecule contacts 5 or more (e.g., 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) contiguous amino acid residues in Pep6a.

[0149] In one embodiment, the antibody molecule contacts 1 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., derived 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); 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); RRNQS (SEQ ID 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).

[0150] 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) contiguous amino acid residues in Pep6a.

[0151] 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); 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); PDRRNQ (SEQ ID 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).

[0152] In one embodiment, the antibody molecule contacts 4 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) contiguous amino acid residues in Pep5.

[0153] In one embodiment, the antibody molecule contacts 1 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), 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: 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).

[0154] 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.

[0155] 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), 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).

[0156] 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) contiguous amino acid residues in Pep5.

[0157] 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), 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 (SEQ ID NO: 227), GEQDFT (SEQ ID NO: 228), EQDFTF (SEQ ID NO: 229), or QDFTFE (SEQ ID NO: 230).

[0158] In one embodiment, the antibody molecule does not bind to or binds with low affinity to the extracellular region of CD138 remote from the transmembrane domain. In one embodiment, the antibody molecule does not bind to an epitope on CD138 comprising 4 or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35 or more) consecutive amino acid residues in the extracellular region remote from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region remote from the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids from the N-terminus of the transmembrane domain. In one embodiment, the extracellular region remote from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4, or 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 region N-terminal to the IBD of CD138.

[0159] In one embodiment, the antibody molecule binds or substantially binds to an extracellular region of CD138 remote from the transmembrane domain. In one embodiment, the C-terminus of the extracellular region remote from the transmembrane domain is at least 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 amino acids from the N-terminus of the transmembrane domain. In one embodiment, the extracellular region remote from the transmembrane domain corresponds to Pep1a, Pep1b, Pep2a, Pep2b, Pep2c, Pep2d, Pep3, Pep4, or 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 a region N-terminal to the IBD of CD138. In one embodiment, the antibody molecule does not bind to, or binds with low affinity to, the epitope of BB4.

[0160] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 4 or more (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or more) contiguous amino acid residues in an extracellular region remote from the transmembrane domain.

[0161] In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 5 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 6 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 7 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 8 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 9 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 10 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 11 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain. In one embodiment, the antibody molecule binds to an epitope on CD138 that comprises 12 or more contiguous amino acid residues in an extracellular region distal to the transmembrane domain.

[0162] In one embodiment, the extracellular region distal to the transmembrane domain corresponds to (e.g., comprises or consists of) Pep2a.

[0163] 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) contiguous amino acid residues in Pep2a.

[0164] 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), 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).

[0165] In one embodiment, the antibody molecule contacts five or more (e.g., 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 30) contiguous amino acid residues in Pep2a.

[0166] 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), 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 containing LPEV (SEQ ID NO: 250).

[0167] In one embodiment, the antibody molecule contacts 6 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) contiguous amino acid residues in Pep2a.

[0168] 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), 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 containing LPEV (SEQ ID NO: 250).

[0169] In one embodiment, the antibody molecule binds or substantially binds to the extracellular region of CD138 adjacent to the transmembrane domain (e.g., the extracellular region described herein) and to the extracellular region of CD138 remote from the transmembrane domain (e.g., the extracellular region described herein). In one embodiment, the antibody molecule binds to the extracellular region of CD138 adjacent to the transmembrane domain with a binding affinity that is higher (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, or 500 times higher) than the binding affinity to the extracellular region of CD138 remote from the transmembrane domain. In one embodiment, the antibody molecule binds to the extracellular region of CD138 remote from the transmembrane domain with a binding affinity that is higher (e.g., at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 100, 200, 300, 400, or 500 times higher) than the binding affinity to the extracellular region of CD138 adjacent to the transmembrane domain.

[0170] Antibody molecule Disclosed herein are humanized antibody molecules that bind to CD138, such as the CD138 molecule described herein.

[0171] As used herein, the term "antibody molecule" refers to a protein, such as an immunoglobulin chain, or a fragment thereof that includes at least one immunoglobulin variable domain sequence. The term "antibody molecule" includes, for example, full-length mature antibodies and antigen-binding fragments of antibodies. For example, an antibody molecule can include a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain 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 (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies (which can be produced by modification of whole antibodies or de novo synthesized using recombinant DNA techniques). These functional antibody fragments retain their ability to selectively bind to their respective antigens or receptors. Antibodies and antibody fragments can be derived from any class of antibody, including but not limited to IgG, IgA, IgM, IgD, and IgE, and any subclass (e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. An antibody molecule can be monoclonal or polyclonal. An antibody molecule can also be a human antibody, a humanized antibody, a CDR-grafted antibody, or an in vitro generated antibody. An antibody molecule can have a heavy chain constant region selected, for example, from IgG1, IgG2, IgG3, or IgG4. An antibody molecule can also have a light chain selected, for example, from a kappa light chain or a lambda light chain. The term "immunoglobulin" (Ig) is used interchangeably herein with the term "antibody".

[0172] Examples of antigen-binding fragments include: (i) the Fab fragment, which is a monovalent fragment consisting of the VL domain, VH domain, CL domain, and CH1 domain; (ii) the F(ab’)2 fragment, which is a divalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) the Fd fragment consisting of the VH domain and CH1 domain; (iv) the Fv fragment consisting of the VL domain and VH domain of a single arm of an antibody; (v) the diabody (dAb) fragment consisting of the VH domain; (vi) the camelid or camelized variable domain; (vii) 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); (viii) single-domain antibodies. These antibody fragments can be obtained using any suitable method, including several conventional techniques known to those skilled in the art, and the fragments can be screened for utility in the same manner as intact antibodies.

[0173] The term “antibody” includes intact molecules as well as functional fragments thereof. The constant region of an antibody can be varied, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function).

[0174] Antibody molecules can be single-chain antibodies. Single-chain antibodies (scFv) can be engineered (see, e.g., Colcher et al., (1999) Ann N Y Acad Sci 880:263-280; and Reiter & Pastan (1996) Clin Cancer Res 2:245-252). Single-chain antibodies can be dimerized or multimerized to generate multivalent antibodies having specificities for different epitopes of the same target protein.

[0175] The antibody molecules disclosed herein can also be single-domain antibodies. Single-domain antibodies can include antibodies in which the complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, heavy-chain antibodies that are naturally lacking a light chain, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. The single-domain antibodies can be of any type in the art or any future single-domain antibodies. The single-domain antibodies can be derived from any species including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cow. In some embodiments, the single-domain antibody is a naturally occurring single-domain antibody known as a heavy-chain antibody lacking a light chain. Such single-domain antibodies are disclosed, for example, in WO 94 / 04678. For reasons of clarity, this variable domain derived from a heavy-chain antibody that is naturally lacking a light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of a four-chain immunoglobulin. Such VHH molecules can be derived from antibodies raised in Camelidae species such as camel, llama, dromedary, alpaca, and guanaco. Other species besides Camelidae can produce heavy-chain antibodies that are naturally lacking a light chain; such VHHs are also contemplated.

[0176] The VH and VL regions can be further subdivided into hypervariable regions called "complementarity-determining regions" (CDRs) that are interspersed with more conserved regions called "framework regions" (FR or FW). As used herein, the terms "complementarity-determining region" and "CDR" refer to amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. As used herein, the terms "framework", "FW", and "FR" are used interchangeably.

[0177] The framework regions and the CDR ranges are defined precisely in a number of ways (see Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al., (1987) J. Mol. Biol. 196:901-917; and the AbM definitions used by Oxford Molecular's AbM antibody modeling software). In general, see, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). In one embodiment, the following definitions are used: the AbM definition of CDR1 of the heavy chain variable domain, and the Kabat definition for the other CDRs. In one embodiment, the Kabat definition is used for all CDRs. Additionally, embodiments described with respect to Kabat or AbM CDRs may also be carried out using Chothia hypervariable loops. Each VH and each VL typically contain three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0178] As used herein, "immunoglobulin variable domain sequence" refers to an amino acid sequence that can form the structure of an immunoglobulin variable domain. For example, the sequence can include all or a portion of the amino acid sequence of a naturally occurring variable domain. For example, the sequence may or may not include one, two or more N- or C-terminal amino acids, or may include other variations compatible with protein structure formation.

[0179] The term "antigen-binding region" refers to the portion of an antibody molecule that contains determinants forming an interface that binds to an antigen, such as CD138 or an epitope thereof. With respect to a protein (or protein mimetic), the antigen-binding region typically includes one or more loops (e.g., of at least 4 amino acids or amino acid mimetics) that form an interface that binds to an antigen, such as CD138. Typically, the antigen-binding region of an antibody molecule includes 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.

[0180] The terms "compete" or "cross-compete" are used interchangeably herein to refer to the ability of an antibody molecule to interfere with the binding of an anti-CD138 antibody molecule, such as the anti-CD138 antibody molecules provided herein, to a target, such as CD138. The interference with binding can be direct or indirect (e.g., via allosteric modulation of the antibody molecule or the target). Whether an antibody molecule can interfere with the binding of another antibody molecule to a target and, thus, can be said to compete can be determined using a competitive binding assay, such as a FACS assay, ELISA, or BIACORE assay. In one embodiment, the competitive binding assay is a quantitative competition assay. In one embodiment, a first anti-CD138 antibody molecule is said to compete with a second anti-CD138 antibody molecule for binding to a target if the binding of the first 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 competition assay described herein).

[0181] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope. Monoclonal antibodies may be made by hybridoma technology or by methods that do not use hybridoma technology (e.g., recombinant methods).

[0182] A "virtually human" protein is one that does not elicit a neutralizing antibody response, such as a human anti-mouse antibody (HAMA) response. HAMA can be a problem in many situations, for example, when antibody molecules are repeatedly administered in the treatment of chronic or recurrent disease symptoms. Due to increased clearance of antibodies from serum (see, e.g., Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)), and even due to potential allergic reactions (see, e.g., LoBuglio et al., Hybridoma, 5:5117-5123 (1986)), the HAMA response can potentially render repeated antibody administration ineffective.

[0183] The antibody molecule may be a polyclonal or monoclonal antibody. In some embodiments, the antibody may be recombinantly produced (e.g., produced by any suitable phage display or combinatorial method).

[0184] Various phage display and combinatorial methods for generating antibodies are known in the art (e.g., Ladner et al., U.S. Pat. No. 5,223,409; Kang et al., WO 92 / 18619; Dower et al., WO 91 / 17271; Winter et al., WO 92 / 20791; Markland et al., WO 92 / 15679; Breitling et al., WO 93 / 01288; McCafferty et al., WO 92 / 01047; Garrard et al., WO 92 / 09690; Ladner et al., WO 90 / 02809; Fuchs et al., (1991) Bio / Technology 9:1370-1372; Hay et al., (1992) Hum Antibod Hybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffths et al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628; 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 all of which are incorporated herein by reference).

[0185] In one embodiment, the antibody molecule is a fully human antibody (e.g., an antibody made in a mouse genetically engineered to produce antibodies derived from human immunoglobulin sequences) or a non-human antibody, such as a rodent (mouse or rat) antibody, a goat antibody, a primate (e.g., monkey) antibody, or a camel antibody. In one embodiment, the non-human antibody is rodent (mouse or rat antibody). Methods for producing rodent antibodies are known in the art.

[0186] Human monoclonal antibodies can be generated using transgenic mice having human immunoglobulin genes, rather than mouse strains. Spleen cells derived from these transgenic mice immunized with the antigen of interest are used to produce hybridomas that secrete human mAbs having specific affinity for epitopes derived from human proteins (see, e.g., Wood et al., WO 91 / 00906; Kucherlapati et al., WO 91 / 10741; Lonberg et al., WO 92 / 03918; Kay et al., WO 92 / 03917; Lonberg, N. et al., 1994 Nature 368:856-859; Green, L.L. et al., 1994 Nature Genet. 7:13-21; Morrison, S.L. 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).

[0187] Antibodies can be those in which the variable region or portions thereof, such as CDRs, are generated in non-human organisms, such as rats or mice. Chimeric antibodies, CDR-grafted antibodies, and humanized antibodies are within the scope of the present invention. Antibodies generated in non-human organisms, such as rats or mice, and then modified, such as in the variable framework or constant region, to reduce antigenicity in humans are within the scope of the present invention.

[0188] Chimeric antibodies can be produced by any suitable recombinant DNA technology. Some are known in the art (see Robinson et al., WO 1987 / 002671; Akira et al., EP 184,187; Taniguchi, M., EP 171,496; Morrison et al., EP 173,494; Neuberger et al., WO 86 / 01533; Cabilly et al., U.S. Pat. No. 4,816,567; Cabilly et al., EP 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).

[0189] A humanized antibody or CDR-grafted antibody will have at least one or two but generally all three recipient CDRs (of the immunoglobulin heavy and / or light chains) replaced with donor CDRs. The antibody can be replaced with at least a part of the non-human CDRs, or only a part of the CDRs can be replaced with non-human CDRs. It is only necessary to replace the number of CDRs necessary for the binding of the humanized antibody to lipopolysaccharide. In one embodiment, the donor is a rodent antibody, such as a rat antibody or a mouse antibody, and the recipient will be a human framework or a human consensus framework. Typically, the immunoglobulin providing the CDRs is referred to as the "donor", and the immunoglobulin providing the framework is referred to as the "acceptor". In some embodiments, the donor immunoglobulin is non-human (e.g., rodent). The acceptor framework is typically a naturally occurring (e.g., human) framework or consensus framework, or is identical to it by about 85% or more, e.g., 90%, 95%, 99% or more.

[0190] As used herein, the term "consensus sequence" refers to a sequence formed from the amino acids (or nucleotides) that are most frequently present in a family of related sequences (see, e.g., Winnaker, From Genes to Clones (Verlagsgesellschaft, Weinheim, Germany 1987)). In a family of proteins, each position in the consensus sequence is occupied by the amino acid that is most frequently present at that position in the family. When two amino acids are present with equal frequency, either can be included in the consensus sequence. A "consensus framework" refers to the framework region in a consensus immunoglobulin sequence.

[0191] Antibodies can be humanized by any suitable method, and several such methods are known in the art (see, e.g., Morrison, S.L., 1985, Science 229:1202-1207, by Oi et al., 1986, BioTechniques 4:214, and U.S. Patent Nos. 5,585,089, 5,693,761, and 5,693,762 by Queen et al., the contents of all of which are incorporated herein by reference).

[0192] Humanized antibodies or CDR-grafted antibodies can be produced by CDR grafting or CDR replacement, which can replace one, two, or all of the CDRs of the immunoglobulin chains. See, e.g., 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, U.S. Patent No. 5,225,539 (the contents of all of which are expressly incorporated herein by reference). Winter describes CDR grafting methods that can be used to prepare humanized antibodies (UK Patent Application Publication No. 2188638, filed Mar. 26, 1987; Winter, U.S. Patent No. 5,225,539, the contents of which are expressly incorporated by reference).

[0193] Humanized antibodies having specific amino acids substituted, deleted, or added are also provided. Criteria for selecting amino acids from the donor are described, e.g., in U.S. Patent No. 5,585,089, e.g., columns 12-16 of U.S. Patent No. 5,585,089 (the contents of which are incorporated herein by reference). Other techniques for humanizing antibodies are described in Padlan et al., EP 519596, published Dec. 23, 1992.

[0194] In one embodiment, the antibody molecule is selected from the heavy chain constant regions of, for example, IgG1, IgG2 (e.g., IgG2a), IgG3, IgG4, IgM, IgA1, IgA2, IgD and IgE; in particular, it has a heavy chain constant region selected from the (e.g., human) heavy chain constant regions of IgG1, IgG2, IgG3 and IgG are selected from the (e.g., human) light chain constant regions of kappa or lambda. In one embodiment, the antibody molecule comprises the light chain constant region of kappa (e.g., kappa constant * 01). In one embodiment, the antibody molecule comprises the heavy chain constant region of IgG1 and the light chain constant region of kappa. The constant region can be varied, e.g., mutated, to modify the properties of the antibody molecule (e.g., to increase or decrease one or more of 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 can bind to complement. In another embodiment, the antibody molecule does not recruit effector cells and does not bind to complement. In certain embodiments, the antibody molecule has a reduced or no Fc receptor binding ability. For example, it can be an isotype or subtype, fragment or other variant that does not assist in binding to the Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.

[0195] In one embodiment, the constant region of the antibody molecule is altered. Methods for altering antibody constant regions are known in the art. Antibody molecules having altered functions, such as altered effector ligands, such as altered affinities for FcRs on cells or the C1 component of complement, can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see, e.g., European Patent Application Publication No. 388,151, U.S. Patent No. 5,624,821, and U.S. Patent No. 5,648,260, all of which are incorporated herein by reference). Amino acid mutations that stabilize the antibody structure in human IgG4, such as S228P (EU nomenclature; S241P in Kabat nomenclature), are also contemplated. Similar types of changes that would decrease or eliminate these functions when applied to mouse or other species immunoglobulins can be described.

[0196] In one embodiment, the antibody molecule comprises an Fc region comprising one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more) of the mutations or combinations of mutations set forth in Table 9.

Table 9-1

Table 9-2

Table 9-3

Table 9-4

Table 9-5

[0197] In one embodiment, it includes FcMut001. In one embodiment, the Fc region includes FcMut002. In one embodiment, the Fc region includes FcMut003. In one embodiment, the Fc region includes FcMut004. In one embodiment, the Fc region includes FcMut005. In one embodiment, the Fc region includes FcMut006. In one embodiment, the Fc region includes FcMut007. In one embodiment, the Fc region includes FcMut008. In one embodiment, the Fc region includes FcMut009. In one embodiment, the Fc region includes FcMut010. In one embodiment, the Fc region includes FcMut011. In one embodiment, the Fc region includes FcMut012. In one embodiment, the Fc region includes FcMut013. In one embodiment, the Fc region includes FcMut014. In one embodiment, the Fc region includes FcMut015. In one embodiment, the Fc region includes FcMut016. In one embodiment, the Fc region includes FcMut017. In one embodiment, the Fc region includes FcMut018. In one embodiment, the Fc region includes FcMut019. In one embodiment, the Fc region includes FcMut020. In one embodiment, the Fc region includes FcMut021. In one embodiment, the Fc region includes FcMut022. In one embodiment, the Fc region includes FcMut023. In one embodiment, the Fc region includes FcMut024. In one embodiment, the Fc region includes FcMut026. In one embodiment, the Fc region includes FcMut027. In one embodiment, the Fc region includes FcMut028. In one embodiment, the Fc region includes FcMut029. In one embodiment, the Fc region includes FcMut030. In one embodiment, the Fc region includes FcMut031. In one embodiment, the Fc region includes FcMut032. In one embodiment, the Fc region includes FcMut033. In one embodiment, the Fc region includes FcMut034. In one embodiment, the Fc region includes FcMut035. In one embodiment, the Fc region includes FcMut036.In one embodiment, the Fc region comprises FcMut037. In one embodiment, the Fc region comprises FcMut038. In one embodiment, the Fc region comprises FcMut039. In one embodiment, the Fc region comprises FcMut040. In one embodiment, the Fc region comprises FcMut041. In one embodiment, the Fc region comprises FcMut042. In one embodiment, the Fc region comprises FcMut043. In one embodiment, the Fc region comprises FcMut044. In one embodiment, the Fc region comprises FcMut045. In one embodiment, the Fc region comprises FcMut046. In one embodiment, the Fc region comprises FcMut047. In one embodiment, the Fc region comprises FcMut048. In one embodiment, the Fc region comprises FcMut049. In one embodiment, the Fc region comprises FcMut050. In one embodiment, the Fc region comprises FcMut051. In one embodiment, the Fc region comprises FcMut052. In one embodiment, the Fc region comprises FcMut053. In one embodiment, the Fc region comprises FcMut067. In one embodiment, the Fc region comprises FcMut068. In one embodiment, the Fc region comprises FcMut069. In one embodiment, the Fc region comprises FcMut070. In one embodiment, the Fc region comprises FcMut071. In one embodiment, the Fc region comprises FcMut072. In one embodiment, the Fc region comprises FcMut073. In one embodiment, the Fc region comprises FcMut074. In one embodiment, the Fc region comprises FcMut075. In one embodiment, the Fc region comprises FcMut076. In one embodiment, the Fc region comprises FcMut077. In one embodiment, the Fc region comprises FcMut078. In one embodiment, the Fc region comprises FcMut079. In one embodiment, the Fc region comprises FcMut080. In one embodiment, the Fc region comprises FcMut081. In one embodiment, the Fc region comprises FcMut082. In one embodiment, the Fc region comprises FcMut083. In one embodiment, the Fc region comprises FcMut084.In one embodiment, the Fc region comprises FcMut085. In one embodiment, the Fc region comprises FcMut086. In one embodiment, the Fc region comprises FcMut087. In one embodiment, the Fc region comprises FcMut088. In one embodiment, the Fc region comprises FcMut089. In one embodiment, the Fc region comprises FcMut090. In one embodiment, the Fc region comprises FcMut091. In one embodiment, the Fc region comprises FcMut093. In one embodiment, the Fc region comprises FcMut094. In one embodiment, the Fc region comprises FcMut095. In one embodiment, the Fc region comprises FcMut096. In one embodiment, the Fc region comprises FcMut097. In one embodiment, the Fc region comprises FcMut098. In one embodiment, the Fc region comprises FcMut099. In one embodiment, the Fc region comprises FcMut100. In one embodiment, the Fc region comprises FcMut101. In one embodiment, the Fc region comprises FcMut102. In one embodiment, the Fc region comprises FcMut103. In one embodiment, the Fc region comprises FcMut104. In one embodiment, the Fc region comprises FcMut105. In one embodiment, the Fc region comprises FcMut106. In one embodiment, the Fc region comprises FcMut107. In one embodiment, the Fc region comprises FcMut108. In one embodiment, the Fc region comprises FcMut109. In one embodiment, the Fc region comprises FcMut110. In one embodiment, the Fc region comprises FcMut111. In one embodiment, the Fc region comprises FcMut112. In one embodiment, the Fc region comprises FcMut113. In one embodiment, the Fc region comprises FcMut114. In one embodiment, the Fc region comprises FcMut115. In one embodiment, the Fc region comprises FcMut116. In one embodiment, the Fc region comprises FcMut117. In one embodiment, the Fc region comprises FcMut118. In one embodiment, the Fc region comprises FcMut119. In one embodiment, the Fc region comprises FcMut120.In one embodiment, the Fc region comprises FcMut121. In one embodiment, the Fc region comprises FcMut122. In one embodiment, the Fc region comprises FcMut123. In one embodiment, the Fc region comprises FcMut124. In one embodiment, the Fc region comprises FcMut125. In one embodiment, the Fc region comprises FcMut126. In one embodiment, the Fc region comprises FcMut127. In one embodiment, the Fc region comprises FcMut128. In one embodiment, the Fc region comprises FcMut129. In one embodiment, the Fc region comprises FcMut130. In one embodiment, the Fc region comprises FcMut131. In one embodiment, the Fc region comprises FcMut132. In one embodiment, the Fc region comprises FcMut133. In one embodiment, the Fc region comprises FcMut134. In one embodiment, the Fc region comprises FcMut135. In one embodiment, the Fc region comprises FcMut136. In one embodiment, the Fc region comprises FcMut137. In one embodiment, the Fc region comprises FcMut138. In one embodiment, the Fc region comprises FcMut139. In one embodiment, the Fc region comprises FcMut140. In one embodiment, the Fc region comprises FcMut141. In one embodiment, the Fc region comprises FcMut142. In one embodiment, the Fc region comprises FcMut143. In one embodiment, the Fc region comprises FcMut144. In one embodiment, the Fc region comprises FcMut145. In one embodiment, the Fc region comprises FcMut146. In one embodiment, the Fc region comprises FcMut147. In one embodiment, the Fc region comprises FcMut148. In one embodiment, the Fc region comprises FcMut149. In one embodiment, the Fc region comprises FcMut150. In one embodiment, the Fc region comprises FcMut151. In one embodiment, the Fc region comprises FcMut152. In one embodiment, the Fc region comprises FcMut153. In one embodiment, the Fc region comprises FcMut154. In one embodiment, the Fc region comprises FcMut155.In one embodiment, the Fc region comprises FcMut156. In one embodiment, the Fc region comprises FcMut157. In one embodiment, the Fc region comprises FcMut158. In one embodiment, the Fc region comprises FcMut159. In one embodiment, the Fc region comprises FcMut160. In one embodiment, the Fc region comprises FcMut161. In one embodiment, the Fc region comprises FcMut162. In one embodiment, the Fc region comprises FcMut163. In one embodiment, the Fc region comprises FcMut164. In one embodiment, the Fc region comprises FcMut165. In one embodiment, the Fc region comprises FcMut166. In one embodiment, the Fc region comprises FcMut167. In one embodiment, the Fc region comprises FcMut168. In one embodiment, the Fc region comprises FcMut169. In one embodiment, the Fc region comprises FcMut170. In one embodiment, the Fc region comprises FcMut171. In one embodiment, the Fc region comprises FcMut172. In one embodiment, the Fc region comprises FcMut173. In one embodiment, the Fc region comprises FcMut174. In one embodiment, the Fc region comprises FcMut175. In one embodiment, the Fc region comprises FcMut176. In one embodiment, the Fc region comprises FcMut177. In one embodiment, the Fc region comprises FcMut178. In one embodiment, the Fc region comprises FcMut179. In one embodiment, the Fc region comprises FcMut180. In one embodiment, the Fc region comprises FcMut181. In one embodiment, the Fc region comprises FcMut182. In one embodiment, the Fc region comprises FcMut183. In one embodiment, the Fc region comprises FcMut184. In one embodiment, the Fc region comprises FcMut185. In one embodiment, the Fc region comprises FcMut186. In one embodiment, the Fc region comprises FcMut187. In one embodiment, the Fc region comprises FcMut188. In one embodiment, the Fc region comprises FcMut189. In one embodiment, the Fc region comprises FcMut190.In one embodiment, the Fc region comprises FcMut191. In one embodiment, the Fc region comprises FcMut192. In one embodiment, the Fc region comprises FcMut193. In one embodiment, the Fc region comprises FcMut194. In one embodiment, the Fc region comprises FcMut195. In one embodiment, the Fc region comprises FcMut196. In one embodiment, the Fc region comprises FcMut197. In one embodiment, the Fc region comprises FcMut198. In one embodiment. In an embodiment, the Fc region comprises FcMut199. In one embodiment, the Fc region comprises FcMut200. In one embodiment, the Fc region comprises FcMut201. In one embodiment, the Fc region comprises FcMut202. In one embodiment, the Fc region comprises FcMut203. In one embodiment, the Fc region comprises FcMut204. In one embodiment, the Fc region comprises FcMut205. In one embodiment, the Fc region comprises FcMut206. In one embodiment, the Fc region comprises FcMut207. In one embodiment, the Fc region comprises FcMut208. In one embodiment, the Fc region comprises FcMut209. In one embodiment, the Fc region comprises FcMut210. In one embodiment, the Fc region comprises FcMut211. In one embodiment, the Fc region comprises FcMut212. In one embodiment, the Fc region comprises FcMut213. In one embodiment, the Fc region comprises FcMut214. In one embodiment, the Fc region comprises FcMut215. In one embodiment, the Fc region comprises FcMut216. In one embodiment, the Fc region comprises FcMut217. In one embodiment, the Fc region comprises FcMut218. In one embodiment, the Fc region comprises FcMut219. In one embodiment, the Fc region comprises FcMut220. In one embodiment, the Fc region comprises FcMut221. In one embodiment, the Fc region comprises FcMut222. In one embodiment, the Fc region comprises FcMut223. In one embodiment, the Fc region comprises FcMut224. In one embodiment, the Fc region comprises FcMut225. In one embodiment, the Fc region comprises FcMut226. In one embodiment, the Fc region comprises FcMut227. In one embodiment, the Fc region comprises FcMut228. In one embodiment, the Fc region comprises FcMut229. In one embodiment, the Fc region comprises FcMut230. In one embodiment, the Fc region comprises FcMut231. In one embodiment, the Fc region comprises FcMut232. In one embodiment, the Fc region comprises FcMut233.In one embodiment, the Fc region comprises FcMut234. In one embodiment, the Fc region comprises FcMut242. In one embodiment, the Fc region comprises FcMut243. In one embodiment, the Fc region comprises FcMut244.

[0198] Other exemplary Fc mutations are described, for example, in WO 2018 / 052556, US 2018 / 0037634, and Booth et al., MAbs. 2018;10(7):1098-1110, the entire contents of which are incorporated by reference.

[0199] In one embodiment, the Fc region is altered to extend the half-life. For example, the Fc region may contain one or more of FcMut183 (T256D-Q311V-A378V), FcMut197 (H285N-T307Q-N315D), FcMut213 (H285D-T307Q-A378V), FcMut215 (T307Q-Q311V-A378V), or FcMut228 (T256D-N286D-T307R-Q311V-A378V) (all according to EU numbering).

[0200] In one embodiment, the Fc region is altered to enhance ADCC. For example, the Fc region may contain one or more of A330L-I332E-S239D, F243L-R292P-Y300L-V305I-P396L, or S298A-E333A-K334A. In one embodiment, afucosylation can be achieved by expression in a cell line in which fucosyltransferase (FucT8) is knocked out, such as CHO.

[0201] In one embodiment, the Fc region is altered to enhance CDC. For example, the Fc region contains S267E-H268F-S324T.

[0202] In one embodiment, the Fc region is altered to enhance antibody-dependent cell phagocytosis (ADCP). For example, the Fc region contains S239D-I332E-A330L

[0203] In one embodiment, only the amino acids in the antibody molecule are the reference amino acids. In one embodiment, the antibody molecule includes naturally occurring amino acids; their analogs, derivatives, and homologs; amino acid analogs having variant side chains; and / or all stereoisomers of any of the foregoing. The antibody molecule may include D- or L-enantiomers of amino acids and peptidomimetics.

[0204] The polypeptides of the antibody molecules described herein can be linear or branched, can include modified amino acids, and can be interrupted by non-amino acids. The antibody molecule can also be modified, for example, by disulfide bond formation, glycosylation, lipid addition, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling element. The polypeptide can be isolated from a natural source, produced from a eukaryotic or prokaryotic host by recombinant techniques, or be the product of synthetic procedures.

[0205] The antibody molecules described herein can be used alone in unconjugated form or can be conjugated to a substance, such as a toxin or moiety (e.g., a therapeutic agent; a compound that emits radiation; a molecule of plant, fungal, or bacterial origin; or a biological protein (e.g., a protein toxin) or a biological particle (e.g., a recombinant viral particle via a viral coat protein). For example, an anti-CD138 antibody can be coupled to a radioisotope, such as an α-, β-, or γ-emitter or a β- and γ-emitter.

[0206] Antibody molecules can be derivatized or linked to another functional molecule (e.g., another peptide or protein). As used herein, a "derivatized" antibody molecule is one that has been modified. Methods of derivatization include, but are not limited to, the addition of a fluorescent moiety, a radioactive nucleotide, a toxin, an enzyme, or an affinity ligand such as biotin. Thus, antibody molecules are intended to include derivatized forms of the antibodies described herein, including immunoadhesion molecules, and other forms modified by other methods. For example, an antibody molecule can be functionally linked (by chemical coupling, genetic fusion, non-covalent association, or other methods) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or diabody), a detectable agent, a toxin, a pharmaceutical, and / or a protein or peptide that can mediate the association of an antibody or antibody portion with another molecule (e.g., a streptavidin core region or a polyhistidine tag).

[0207] Some types of derivatized antibody molecules are produced by cross-linking two or more antibodies (of the same type or, e.g., different types to make a bispecific antibody). Suitable cross-linking linkers include heterobifunctional (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate) ones having two different reactive groups separated by a suitable spacer. Such linkers are available from Pierce Chemical Company, Rockford, Ill.

[0208] Useful detectable agents that can derivatize (or label) anti-CD138 antibody molecules include fluorescent compounds, various enzymes, families of hapten molecules, luminescent substances, bioluminescent substances, fluorescent-emitting metal atoms such as europium (Eu) and other lanthanides, and radioactive substances (described below). Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-naphthalenesulfonyl 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 an antibody is derivatized with a detectable enzyme, it can be detected by adding additional reagents used by the enzyme to produce a detectable reaction product. For example, in the presence of the detectable agent horseradish peroxidase, the addition of hydrogen peroxide and diaminobenzidine results in a detectable colored reaction product. Antibody molecules can also be derivatized with families of hapten molecules (e.g., streptavidin / biotin and avidin / biotin). For example, an antibody can be derivatized with biotin and detected via an indirect measurement of streptavidin or avidin binding. Examples of suitable fluorescent substances include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; an example of a luminescent substance is luminol; examples of bioluminescent substances include luciferase, luciferin, and aequorin.

[0209] Labeled antibody molecules can be used, for example, (i) to isolate a given antigen by standard techniques such as affinity chromatography or immunoprecipitation; (ii) to detect a given antigen (e.g., in a cell lysate or cell supernatant) in order to assess the abundance and expression pattern of a protein; (iii) as part of clinical test procedures to monitor protein levels in tissues, for example, to determine the effectiveness of a given treatment regimen, and can be used diagnostically and / or experimentally in a number of situations.

[0210] Antibody molecules can be conjugated to another molecular entity, typically a label or an agent or moiety for therapy (e.g., antimicrobial (e.g., antibacterial or bactericidal), immunomodulatory, immunostimulatory, cytotoxic or cytostatic). Radioisotopes can be used in diagnostic or therapeutic applications. Radioisotopes that can be coupled to antibody molecules include, but are not limited to, α-, β- or γ-emitters or β- and γ-emitters. Such radioisotopes include, but are not limited to, iodine ( 131 I or 125 I), yttrium ( 90 Y), lutetium ( 177 Lu), actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 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 Cl), chlorine ( 36 Cl), cobalt ( 57 Co or 58 Co), iron ( 59 Fe), selenium ( 75 Se) or gallium ( 67Examples include gallium (Ga). Radioisotopes useful as therapeutic agents include yttrium ( 90 Y), lutetium ( 177 Lu), actinium ( 225 Ac), praseodymium, astatine ( 211 At), rhenium ( 186 Re), bismuth ( 212 Bi or 213 Bi) and rhodium ( 188 Rh). For example, radioisotopes useful as labels for use in diagnosis include iodine ( 131 I or 125 I), indium ( 111 In), technetium ( 99 mTc), phosphorus ( 32 P), carbon ( 14 C) and tritium ( 3 H) or one or more of the therapeutic isotopes listed above.

[0211] The present disclosure provides radiolabeled antibody molecules and methods of labeling antibody molecules. In one embodiment, a method of labeling an antibody molecule is disclosed. The method includes contacting the antibody molecule with a chelating agent, thereby producing a conjugate antibody. Labeling the conjugate antibody with a radioisotope, such as 111 indium, 90 yttrium and 177 lutetium, thereby producing a labeled antibody molecule.

[0212] In one aspect, the present disclosure provides a method of making a humanized antibody molecule disclosed herein. The method includes providing an antigen, such as CD138 or a fragment thereof; obtaining a humanized antibody molecule that specifically binds to the antigen; and evaluating the effectiveness of the antibody molecule in modulating the activity of the antigen and / or an organism expressing the antigen, such as CD138. The method may further include administering to a subject, such as a human, an antibody molecule comprising a derivative thereof (e.g., a humanized antibody molecule).

[0213] The present disclosure provides isolated nucleic acid molecules, vectors and host cells thereof encoding the above antibody molecules. Examples of nucleic acid molecules include, but are not limited to, RNA, genomic DNA and cDNA.

[0214] The amino acid sequences of exemplary antibody molecules are set forth in Table 1. The amino acid sequences and nucleotide sequences of exemplary VH and VL are set forth in Table 2. To form an exemplary humanized anti-CD138 antibody molecule, any VH set forth in Table 2 can be paired with any VL set forth in Table 2. Antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825 or 4422 may also be referred to herein as mAb 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825 or 4422.

[0215] Other exemplary antibody molecules are described in International Publication No. WO 2019 / 070726 or US Patent Application Publication No. US 2019 / 0100588, the contents of which are incorporated herein by reference in their entirety. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

[0216] In one embodiment, the antibody molecule comprises one, two, or three CDRs of the VH region of the antibody molecules described herein, such as in Table 1 or 2, using the Kabat or Chothia definitions of CDRs. In one embodiment, the antibody molecule comprises one, two, or three CDRs of the VL region of the antibody molecules described herein, such as in Table 1 or 2, using the Kabat or Chothia definitions of CDRs. In one embodiment, the antibody molecule comprises one or more (e.g., two or three) CDRs of the VH region and one or more (e.g., two or three) CDRs of the VL region of the antibody molecules described herein, such as in Table 1 or 2, using the Kabat or Chothia definitions of CDRs.

[0217] In one embodiment, the antibody molecule comprises one, two, or three HCDRs described in Table 1 or 2. In one embodiment, the antibody molecule comprises one, two, or three LCDRs described in Table 1 or 2. In one embodiment, the antibody molecule comprises one or more (e.g., two or three) HCDRs and one or more (e.g., two or three) LCDRs described in Table 1 or 2.

[0218] In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of the VH region of the antibody molecules described in Table 1 or 2. In one embodiment, the antibody molecule comprises one, two, three, or four frameworks of the VL region of the antibody molecules described in Table 1 or 2. 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 molecules described in Table 1 or 2.

[0219] In one embodiment, the antibody molecule comprises the VH of the antibody molecules described herein, for example, in Table 1 or 2. In one embodiment, the antibody molecule comprises the VL of the antibody molecules described herein, for example, in Table 1 or 2. In one embodiment, the antibody molecule comprises the VH and VL of the antibody molecules described herein, for example, in Table 1 or 2.

[0220] In one embodiment, the antibody molecule comprises a VH having an amino acid sequence described in Table 1 or 2 or an amino acid sequence that is substantially identical thereto (e.g., that differs from it by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or that is at least 85, 90, 95, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VL having an amino acid sequence described in Table 1 or 2 or an amino acid sequence that is substantially identical thereto (e.g., that differs from it by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or that is at least 85, 90, 95, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VH having an amino acid sequence (or an amino acid sequence substantially identical thereto) described in Table 1 or 2 and a VL having an amino acid sequence (or an amino acid sequence substantially identical thereto) described in Table 1 or 2.

[0221] In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence set forth in Table 2 or a nucleotide sequence that is substantially identical thereto (e.g., that differs from it by 3, 6, 15, 30, or 45 or fewer nucleotides, or that is at least about 85%, 90%, 95%, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VL encoded by the nucleotide sequence set forth in Table 2 or a nucleotide sequence that is substantially identical thereto (e.g., that differs from it by 3, 6, 15, 30, or 45 or fewer nucleotides, or that is at least about 85%, 90%, 95%, or 99% identical thereto). In one embodiment, the antibody molecule comprises a VH encoded by the nucleotide sequence set forth in Table 2 (or a nucleotide sequence that is substantially identical thereto) and a VL encoded by the nucleotide sequence set forth in Table 2 (or a nucleotide sequence that is substantially identical thereto).

[0222] In one embodiment, the VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and the VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, the VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and the VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0223] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0224] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466 and VL comprises the amino acid sequence of SEQ ID NO: 475.

[0225] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0226] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0227] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0228] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0229] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0230] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466 and VL comprises the amino acid sequence of SEQ ID NO: 481.

[0231] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0232] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0233] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 470. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 470 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0234] In one embodiment, VH comprises one, two or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0235] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYAQKFQG (SEQ ID NO: 513); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0236] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 470. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 470 and VL comprises the amino acid sequence of SEQ ID NO: 481.

[0237] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0238] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0239] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471 and VL comprises the amino acid sequence of SEQ ID NO: 475.

[0240] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0241] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0242] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0243] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0244] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0245] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471 and VL comprises the amino acid sequence of SEQ ID NO: 477.

[0246] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0247] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0248] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 471 and VL comprises the amino acid sequence of SEQ ID NO: 481.

[0249] In one embodiment, VH comprises one, two or all of: (i) HCDR1 comprising the amino acid sequence of GYTFTSY (SEQ ID NO: 322); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYTFTSY (SEQ ID NO: 322); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0250] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0251] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 472. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 472 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0252] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0253] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0254] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 475. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473 and VL comprises the amino acid sequence of SEQ ID NO: 475.

[0255] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0256] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0257] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0258] In one embodiment, VH comprises one, two or all of: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYNFASY (SEQ ID NO: 517); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0259] In one embodiment, VH comprises one, two or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two or all of: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (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). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSQSLLYKDGKTYLN (SEQ ID NO: 512); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0260] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 481. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 473 and VL comprises the amino acid sequence of SEQ ID NO: 481.

[0261] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYTFSSY (SEQ ID NO: 356); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYTFSSY (SEQ ID NO: 356); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0262] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 518); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 518); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFQG (SEQ ID NO: 514); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0263] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 463. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 463 and VL comprises the amino acid sequence of SEQ ID NO: 477.

[0264] In one embodiment, VH comprises one, two or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0265] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 518); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYAQKFQG (SEQ ID NO: 519); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); or (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYIH (SEQ ID NO: 518); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYAQKFQG (SEQ ID NO: 519); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of KSSKSLLYKDGKTYLN (SEQ ID NO: 510); (ii) LCDR2 comprising the amino acid sequence of VVSTRAS (SEQ ID NO: 353); and (iii) LCDR3 comprising the amino acid sequence of QQLVQYPYT (SEQ ID NO: 511).

[0266] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 464. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 476. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 464 and VL comprises the amino acid sequence of SEQ ID NO: 476.

[0267] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0268] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0269] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466 and VL comprises the amino acid sequence of SEQ ID NO: 477.

[0270] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2 comprising the amino acid sequence of VLSTRAS (SEQ ID NO: 521); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYSFSSY (SEQ ID NO: 355); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2 comprising the amino acid sequence of VLSTRAS (SEQ ID NO: 521); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0271] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2 comprising the amino acid sequence of VLSTRAS (SEQ ID NO: 521); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTANYNQKFKG (SEQ ID NO: 509); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RSSQSLLYKDGKTYLN (SEQ ID NO: 520); (ii) LCDR2 comprising the amino acid sequence of VLSTRAS (SEQ ID NO: 521); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0272] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 480. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 466 and VL comprises the amino acid sequence of SEQ ID NO: 480.

[0273] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of GYTFTSY (SEQ ID NO: 322); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of GYTFTSY (SEQ ID NO: 322); (ii) HCDR2 comprising the amino acid sequence of HPSDST (SEQ ID NO: 351); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0274] In one embodiment, VH comprises one, two, or all of: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); or (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises one, two, or all of: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); or (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354). In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of SYYMH (SEQ ID NO: 380); (ii) HCDR2 comprising the amino acid sequence of TIHPSDSTTNYNQKFKG (SEQ ID NO: 382); and (iii) HCDR3 comprising the amino acid sequence of FVY (SEQ ID NO: 508); and VL comprises: (i) LCDR1 comprising the amino acid sequence of RASKSLLYKDGKTYLN (SEQ ID NO: 515); (ii) LCDR2 comprising the amino acid sequence of VVSSLQS (SEQ ID NO: 516); and (iii) LCDR3 comprising the amino acid sequence of QQLVEYPYT (SEQ ID NO: 354).

[0275] In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 472. In one embodiment, VL comprises the amino acid sequence of SEQ ID NO: 477. In one embodiment, VH comprises the amino acid sequence of SEQ ID NO: 472 and VL comprises the amino acid sequence of SEQ ID NO: 477.

[0276] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH38, VH43, or VH45, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 having an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 having an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a heavy chain variable region (VH); or (b) comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL20 by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 having an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 having an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a light chain variable region (VL) characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0277] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0278] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0279] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0280] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0281] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto comprising.

[0282] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0283] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH43, or VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH38, VH43, or VH45.

[0284] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL20 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, VL comprises the amino acid sequence of VL20.

[0285] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH43, or VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL20 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0286] In one embodiment, VH comprises the amino acid sequence of VH38, VH43, or VH45, and VL comprises the amino acid sequence of VL20.

[0287] In one embodiment, the antibody molecule comprises an Fc region.

[0288] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH38, VH42, VH43, VH44, VH45, or VH36, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 having an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 having an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a heavy chain variable region (VH); or (b) comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL21 by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 having an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 having an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a light chain variable region (VL) characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0289] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto.

[0290] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0291] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto.

[0292] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0293] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto comprising.

[0294] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0295] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36.

[0296] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL21 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, VL comprises the amino acid sequence of VL21.

[0297] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL21 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith.

[0298] In one embodiment, VH comprises the amino acid sequence of VH38, VH42, VH43, VH44, VH45, or VH36, and VL comprises the amino acid sequence of VL21.

[0299] In one embodiment, the antibody molecule comprises an Fc region.

[0300] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) Comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH38, VH42, VH43, or VH45, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 having an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 having an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a heavy chain variable region (VH); or (b) Comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL26 by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 having an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 having an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a light chain variable region (VL) Characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0301] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0302] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0303] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0304] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0305] In one embodiment, the antibody molecule is (a)(i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto, and (b)(i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2 or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99 or 100% homology thereto thereof.

[0306] In one embodiment, the antibody molecule comprises (a)(i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH, and (b)(i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0307] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH42, VH43, or VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH38, VH42, VH43, or VH45.

[0308] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, VL comprises the amino acid sequence of VL26.

[0309] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH38, VH42, VH43, or VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith.

[0310] In one embodiment, VH comprises the amino acid sequence of VH38, VH42, VH43, or VH45, and VL comprises the amino acid sequence of VL26.

[0311] In one embodiment, the antibody molecule comprises an Fc region.

[0312] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) Comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 having an amino acid sequence that is different from the amino acid sequence of HCDR1 of VH43, VH35, VH38, or VH44, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 having an amino acid sequence that is different from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 having an amino acid sequence that is different from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a heavy chain variable region (VH); or (b) Comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 having an amino acid sequence that is different from the amino acid sequence of LCDR1 of VL22 by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 having an amino acid sequence that is different from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 having an amino acid sequence that is different from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a light chain variable region (VL) Characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0313] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0314] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0315] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0316] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0317] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto and contains.

[0318] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0319] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH43, VH35, VH38, or VH44 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH43, VH35, VH38, or VH44.

[0320] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL22 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, VL comprises the amino acid sequence of VL22.

[0321] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH43, VH35, VH38, or VH44 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL22 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0322] In one embodiment, VH comprises the amino acid sequence of VH43, VH35, VH38, or VH44, and VL comprises the amino acid sequence of VL22.

[0323] In one embodiment, the antibody molecule comprises an Fc region.

[0324] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) Comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH38, for example those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a heavy-chain variable region (VH); or (b) Comprising three light-chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL20, VL21, or VL26 by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a light-chain variable region (VL) Characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0325] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0326] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0327] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0328] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0329] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, comprising.

[0330] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0331] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH38 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH38.

[0332] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0333] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH38 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0334] In one embodiment, VH comprises the amino acid sequence of VH38 and VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0335] In one embodiment, the antibody molecule comprises an Fc region.

[0336] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 having an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH42, for example, those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 having an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 having an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a heavy chain variable region (VH); or (b) comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 having an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL21 or VL26 by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 having an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 having an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having an amino acid sequence with at least 85, 90, 95, 99 or 100% homology thereto, a light chain variable region (VL) characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0337] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0338] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0339] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0340] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0341] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology therewith, and includes.

[0342] In one embodiment, the antibody molecule includes (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0343] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH42 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH42.

[0344] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL21 or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, VL comprises the amino acid sequence of VL21 or VL26.

[0345] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH42 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL21 or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith.

[0346] In one embodiment, VH comprises the amino acid sequence of VH42 and VL comprises the amino acid sequence of VL21 or VL26.

[0347] In one embodiment, the antibody molecule comprises an Fc region.

[0348] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) Comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH43, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a heavy-chain variable region (VH); or (b) Comprising three light-chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL20, VL21, VL26, or VL22 by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a light-chain variable region (VL) Characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0349] In one embodiment, VH comprises: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0350] In one embodiment, VH comprises: (i) HCDR1 comprising the amino acid sequence of HCDR1 of said VH; (ii) HCDR2 comprising the amino acid sequence of HCDR2 of said VH; and (iii) HCDR3 comprising the amino acid sequence of HCDR3 of said VH.

[0351] In one embodiment, VL comprises: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0352] In one embodiment, VL comprises: (i) LCDR1 comprising the amino acid sequence of LCDR1 of said VL; (ii) LCDR2 comprising the amino acid sequence of LCDR2 of said VL; and (iii) LCDR3 comprising the amino acid sequence of LCDR3 of said VL.

[0353] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto is included.

[0354] In one embodiment, the antibody molecule includes (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0355] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH43 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH43.

[0356] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, VL26, or VL22 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, VL26, or VL22.

[0357] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH43 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, VL26, or VL22 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology therewith.

[0358] In one embodiment, VH comprises the amino acid sequence of VH43 and VL comprises the amino acid sequence of VL20, VL21, VL26, or VL22.

[0359] In one embodiment, the antibody molecule comprises an Fc region.

[0360] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2 and HCDR3), as follows: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH45, such as those listed in Table 1 or 2, by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a heavy-chain variable region (VH); or (b) comprising three light-chain complementarity-determining regions (LCDR1, LCDR2 and LCDR3), as follows: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL20, VL21, or VL26 by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto; or (iii) one, two or all of LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2 or 3 or fewer amino acid residues, or having at least 85, 90, 95, 99 or 100% homology thereto, a light-chain variable region (VL) characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above.

[0361] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0362] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0363] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0364] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0365] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto thereof.

[0366] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0367] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH45.

[0368] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0369] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH45 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL20, VL21, or VL26 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0370] In one embodiment, VH comprises the amino acid sequence of VH45 and VL comprises the amino acid sequence of VL20, VL21, or VL26.

[0371] In one embodiment, the antibody molecule comprises an Fc region.

[0372] In one aspect, the present disclosure provides a humanized anti-CD138 antibody molecule, (a) comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), as follows: (i) HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of HCDR1 of VH38, such as those listed in Table 1 or 2, by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto; or (iii) a heavy-chain variable region (VH) comprising one, two, or all three of HCDR3s comprising an amino acid sequence that differs from the amino acid sequence of HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto; or (b) comprising three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), as follows: (i) LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of LCDR1 of VL22 or VL25 by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto; or (iii) a light-chain variable region (VL) comprising one, two, or all three of LCDR3s comprising an amino acid sequence that differs from the amino acid sequence of said VL by 1, 2, or 3 or fewer amino acid residues, or having at least 85%, 90%, 95%, 99%, or 100% homology thereto characterized by a humanized anti-CD138 antibody molecule comprising one or both of the above

[0373] In one embodiment, VH comprises: (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of said VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0374] In one embodiment, VH comprises: (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of said VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of said VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of said VH.

[0375] In one embodiment, VL comprises: (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of said VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0376] In one embodiment, VL comprises: (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of said VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of said VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of said VL.

[0377] In one embodiment, the antibody molecule is (a) (i) an HCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR1 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an HCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR2 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an HCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the HCDR3 of the VH by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto, and (b) (i) an LCDR1 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR1 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; (ii) an LCDR2 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR2 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto; and (iii) an LCDR3 comprising an amino acid sequence that differs from the amino acid sequence of the LCDR3 of the VL by 1, 2, or 3 or fewer amino acid residues, or has at least 85, 90, 95, 99, or 100% homology thereto thereof.

[0378] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of the VH; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the VH; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the VH, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the VL; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the VL; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the VL.

[0379] In one embodiment, VH comprises an amino acid sequence that differs from the amino acid sequence of VH38 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, the antibody molecule of VH comprises the amino acid sequence of VH38.

[0380] In one embodiment, VL comprises an amino acid sequence that differs from the amino acid sequence of VL22 or VL25 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto. In one embodiment, VL comprises the amino acid sequence of VL22 or VL25.

[0381] In one embodiment, (a) VH comprises an amino acid sequence that differs from the amino acid sequence of VH38 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto; and (b) VL comprises an amino acid sequence that differs from the amino acid sequence of VL22 or VL25 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, 99%, or 100% homology thereto.

[0382] In one embodiment, VH comprises the amino acid sequence of VH38 and VL comprises the amino acid sequence of VL22 or VL25.

[0383] In one embodiment, the antibody molecule comprises an Fc region.

[0384] In one embodiment, the anti-CD138 antibody molecule is (a) Comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), (i) an HCDR1 comprising the amino acid sequence of G-Y-N / S / T-F-A / S / T-S-Y (SEQ ID NO: 438); (ii) an HCDR2 comprising the amino acid sequence of H-P-S-D-S-T (SEQ ID NO: 351); or (iii) a heavy-chain variable region (VH) comprising one, two, or all of the HCDR3s comprising the amino acid sequence of F-V-Y (SEQ ID NO: 508); and (b) Comprising three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), (i) an LCDR1 comprising the amino acid sequence of K / R-A / S-S-K / Q-S-L-L-Y-K-D-G-K-T-Y-L-N (SEQ ID NO: 522); (ii) an LCDR2 comprising the amino acid sequence of V-L / V-S-S / T-L / R-A / Q-S (SEQ ID NO: 523); or (iii) a light-chain variable region (VL) comprising one, two, or all of the LCDR3s comprising the amino acid sequence of Q-Q-L-V-E / Q-Y-P-Y-T (SEQ ID NO: 524) Comprising.

[0385] In one embodiment, the anti-CD138 antibody molecule is (a) Comprising three heavy-chain complementarity-determining regions (HCDR1, HCDR2, and HCDR3), (i) an HCDR1 comprising the amino acid sequence of S-Y-Y-I / M-H (SEQ ID NO: 525); (ii) an HCDR2 comprising the amino acid sequence of T-I-H-P-S-D-S-T-A / T-N-Y-A / N-Q-K-F-K / Q-G (SEQ ID NO: 526); or (iii) a heavy-chain variable region (VH) comprising one, two, or all of the HCDR3s comprising the amino acid sequence of F-V-Y (SEQ ID NO: 508); and (b) Comprising three light-chain complementarity-determining regions (LCDR1, LCDR2, and LCDR3), (i) an LCDR1 comprising the amino acid sequence of K / R-A / S-S-K / Q-S-L-L-Y-K-D-G-K-T-Y-L-N (SEQ ID NO: 522); (ii) an LCDR2 comprising the amino acid sequence of V-L / V-S-S / T-L / R-A / Q-S (SEQ ID NO: 523); or (iii) a light-chain variable region (VL) comprising one, two, or all of the LCDR3s comprising the amino acid sequence of Q-Q-L-V-E / Q-Y-P-Y-T (SEQ ID NO: 524) comprises.

[0386] In one embodiment, the antibody molecule comprises a VH comprising (a)(i) an HCDR1 comprising the consensus amino acid sequence of the HCDR1 sequences of, for example, antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, and 4422 described herein, or a subset thereof; (ii) an HCDR2 comprising the consensus amino acid sequence of the HCDR2 sequence of the same antibody; and (iii) an HCDR3 comprising the consensus amino acid sequence of the HCDR3 sequence of the same antibody, and a VL comprising (b)(i) an LCDR1 comprising the consensus amino acid sequence of the LCDR1 sequence of the same antibody; (ii) an LCDR2 comprising the consensus amino acid sequence of the HCDR2 sequence of the same antibody; and (iii) an LCDR3 comprising the consensus amino acid sequence of the HCDR3 sequence of the same antibody.

[0387] In one embodiment, the antibody molecule comprises a VH comprising (a)(i) an HCDR1 comprising the consensus amino acid sequence of the HCDR1 sequences of, for example, antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, and 4422 described herein, or a subset thereof; (ii) an HCDR2 comprising the consensus amino acid sequence of the HCDR2 sequence of the same antibody; and (iii) an HCDR3 comprising the consensus amino acid sequence of the HCDR3 sequence of the same antibody, and a VL comprising (b)(i) an LCDR1 comprising the consensus amino acid sequence of the LCDR1 sequence of the same antibody; (ii) an LCDR2 comprising the consensus amino acid sequence of the HCDR2 sequence of the same antibody; and (iii) an LCDR3 comprising the consensus amino acid sequence of the HCDR3 sequence of the same antibody.

[0388] In one embodiment, the antibody molecule comprises (a) a VH comprising (i) an HCDR1 comprising the amino acid sequence of an anti-CD138 antibody HCDR1 selected from those described herein, such as antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422, or those listed in Table 1; (ii) an HCDR2 comprising the amino acid sequence of an anti-CD138 antibody HCDR2; and (iii) an HCDR3 comprising the amino acid sequence of an anti-CD138 antibody HCDR3, and (b) a VL comprising (i) an LCDR1 comprising the amino acid sequence of an anti-CD138 antibody LCDR1; (ii) an LCDR2 comprising the amino acid sequence of an anti-CD138 antibody LCDR2; and (iii) an LCDR3 comprising the amino acid sequence of an anti-CD138 antibody LCDR3.

[0389] In one embodiment, the anti-CD138 antibody molecule comprises (a) three heavy chain complementarity determining regions (HCDR1, HCDR2, and HCDR3), a heavy chain variable region (VH) comprising one, two, or all of (i) an HCDR1 comprising the amino acid sequence G-Y-N / S / T-F-A / S / T-S-Y (SEQ ID NO: 438); (ii) an HCDR2 comprising the amino acid sequence H-P-S-D-S-T (SEQ ID NO: 351); or (iii) an HCDR3 comprising the amino acid sequence F-V-Y (SEQ ID NO: 508); and (b) three light chain complementarity determining regions (LCDR1, LCDR2, and LCDR3), a light chain variable region (VL) comprising one, two, or all of (i) an LCDR1 comprising the amino acid sequence K / R-A / S-S-K / Q-S-L-L-Y-K-D-G-K-T-Y-L-N (SEQ ID NO: 522); (ii) an LCDR2 comprising the amino acid sequence V-L / V-S-S / T-L / R-A / Q-S (SEQ ID NO: 523); or (iii) an LCDR3 comprising the amino acid sequence Q-Q-L-V-E / Q-Y-P-Y-T (SEQ ID NO: 524). comprises.

[0390] In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 355, 322, 517 or 356, HCDR2 comprises the amino acid sequence of SEQ ID NO: 351, and HCDR3 comprises the amino acid sequence of F-V-Y (SEQ ID NO: 508). In one embodiment, LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511. In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 355, 322, 517 or 356, HCDR2 comprises the amino acid sequence of SEQ ID NO: 351, HCDR3 comprises the amino acid sequence of F-V-Y (SEQ ID NO: 508), LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511.

[0391] In one embodiment, the anti-CD138 antibody molecule is (a) comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), and comprising three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), (i) HCDR1 comprising the amino acid sequence of S-Y-Y-I / M-H (SEQ ID NO: 525); (ii) HCDR2 comprising the amino acid sequence of T-I-H-P-S-D-S-T-A / T-N-Y-A / N-Q-K-F-K / Q-G (SEQ ID NO: 526); or (iii) a heavy chain variable region (VH) comprising one, two or all of HCDR3 comprising the amino acid sequence of F-V-Y (SEQ ID NO: 508); and (b) comprising three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), (i) LCDR1 comprising the amino acid sequence of K / R-A / S-S-K / Q-S-L-L-Y-K-D-G-K-T-Y-L-N (SEQ ID NO: 522); (ii) LCDR2 comprising the amino acid sequence of V-L / V-S-S / T-L / R-A / Q-S (SEQ ID NO: 523); or (iii) a light chain variable region (VL) comprising one, two or all of LCDR3 comprising the amino acid sequence of Q-Q-L-V-E / Q-Y-P-Y-T (SEQ ID NO: 524) comprises

[0392] In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 380 or 518, HCDR2 comprises the amino acid sequence of SEQ ID NO: 382, 509, 513, 514 or 519, and HCDR3 comprises the amino acid sequence of F-V-Y (SEQ ID NO: 508). In one embodiment, LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511. In one embodiment, HCDR1 comprises the amino acid sequence of SEQ ID NO: 380 or 518, HCDR2 comprises the amino acid sequence of SEQ ID NO: 382, 509, 513, 514 or 519, HCDR3 comprises the amino acid sequence of F-V-Y (SEQ ID NO: 508), LCDR1 comprises the amino acid sequence of SEQ ID NO: 352, 510, 512, 515 or 520, LCDR2 comprises the amino acid sequence of SEQ ID NO: 353, 516 or 521, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 354 or 511.

[0393] In one embodiment, the antibody molecule comprises (a) (i) an HCDR1 comprising the amino acid sequence of the HCDR1 of an anti-CD138 antibody selected from, for example, anti-CD138 antibodies 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422 described herein; (ii) an HCDR2 comprising the amino acid sequence of the HCDR2 of the anti-CD138 antibody; and (iii) an HCDR3 comprising the amino acid sequence of the HCDR3 of the anti-CD138 antibody, and (b) (i) an LCDR1 comprising the amino acid sequence of the LCDR1 of the anti-CD138 antibody; (ii) an LCDR2 comprising the amino acid sequence of the LCDR2 of the anti-CD138 antibody; and (iii) an LCDR3 comprising the amino acid sequence of the LCDR3 of the anti-CD138 antibody.

[0394] In one embodiment, VH comprises the amino acid sequence of the VH of an anti-CD138 antibody, and VL comprises the amino acid sequence of the VL of an anti-CD138 antibody.

[0395] In one embodiment, the antibody molecule comprises two VHs and two Vls.

[0396] 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.

[0397] In one embodiment, the antibody molecule comprises a VH region that contains one or more mutations compared to the anti-CD138 antibodies described herein (e.g., antibody 2810, 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825, or 4422).

[0398] In one embodiment, the antibody molecule binds to the extracellular domain of CD138. In one embodiment, the antibody molecule binds to the extracellular region of CD138 adjacent to the transmembrane domain. In one embodiment, the antibody molecule can bind to one or more (e.g., two, three, or all) of the following peptides: a peptide comprising the amino acid sequence of ENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 440), a peptide comprising the amino acid sequence of TAVVAVEPDRRNQSPVDQGATGASQ (SEQ ID NO: 441), a peptide comprising the amino acid sequence of ENTAVVAVEPDRRNQSPVDQGATG (SEQ ID NO: 442), or a peptide comprising the amino acid sequence of ENTAVVAVEPDRRNQ (SEQ ID NO: 443). In one embodiment, the antibody molecule can bind to one or more (e.g., two or all) of the following peptides: a peptide comprising the amino acid sequence of ENTAVVAVEPDRRNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 440), a peptide comprising the amino acid sequence of RNQSPVDQGATGASQGLLDRKEVLG (SEQ ID NO: 444), or a peptide comprising the amino acid sequence of ENTAVVAVEPDRRNQ (SEQ ID NO: 443).

[0399] In one embodiment, the antibody molecule further binds to the extracellular region of CD138 distal to the transmembrane domain, e.g., a region corresponding to or adjacent to the integrin binding domain (IBD) of CD138. In one embodiment, the antibody molecule can bind to one or both of the following peptides: a peptide comprising the amino acid sequence of ASTSTLPAGEGPKEGEAVVLPEVEPGLTAREQEA (SEQ ID NO: 10), or a peptide comprising the amino acid sequence of GEAVVLPEVEPGLTA (SEQ ID NO: 445).

[0400] 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.

[0401] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule comprises a heavy chain constant region of IgG selected from IgG1, IgG2, IgG3 or IgG4. In one embodiment, the antibody molecule comprises a light chain constant region of kappa or lambda light chain.

[0402] In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations for increasing the 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 for increasing one or more of, for example, half-life, ADCC, CDC or ADCP.

[0403] In one embodiment, the antibody molecule is an IgG antibody. In one embodiment, the antibody molecule comprises a heavy chain constant region of IgG selected from IgG1, IgG2, IgG3 or IgG4. In one embodiment, the antibody molecule comprises a light chain constant region of kappa or lambda light chain.

[0404] In one embodiment, the antibody molecule comprises an Fc region comprising one or more mutations for increasing the 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 for increasing one or more of, for example, half-life, ADCC, CDC or ADCP. In one embodiment, the antibody molecule induces at least 10% (e.g., at least 15%, 20%, 25%, 30%, 35% or 40%) greater ADCC activity compared to a reference anti-CD138 antibody (e.g., antibody BB4) when determined, for example, by the methods described herein.

[0405] 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 variable region and a light chain variable region of the antibody molecules described in Table 1 or 2. In certain embodiments, the antibody molecule comprises a heavy chain constant region, a light chain constant region, and a variable region comprising 1, 2, 3, 4, 5, or 6 CDRs of the antibody molecules described in Table 1 or 2.

[0406] Exemplary heavy chain constant regions are described below.

Chemical formula

[0407] In one embodiment, the antibody molecule comprises a heavy chain sequence listed in Table 6 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2, 3, 4 or 5) of the sequences listed in Table B, or one or more amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto, and a heavy chain. In one embodiment, the antibody molecule comprises a light chain sequence listed in Table 6 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises one or more (e.g., 1, 2 or 3) of the sequences listed in Table 8, or one or more amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto, and a light chain.

[0408] In one embodiment, the antibody molecule comprises one, two or all of the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises all of the CH1, CH2 and CH3 sequences listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises a heavy chain constant hinge region sequence listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0409] In one embodiment, the antibody molecule comprises a light chain constant region sequence (e.g., CL) listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises a light chain constant hinge region sequence listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0410] In one embodiment, the antibody molecule comprises one, two or all of the heavy chain constant region sequences (e.g., CH1, CH2, or CH3) listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and a light chain constant region sequence (e.g., CL) listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises all of the CH1, CH2 and CH3 sequences listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and a light chain constant hinge region sequence (e.g., CL) listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises a heavy chain constant hinge region sequence listed in Table 7 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and a light chain constant hinge region sequence (e.g., CL) listed in Table 8 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0411] In one embodiment, the antibody molecule comprises one, two or all of the amino acid sequences of SEQ ID NO: 529, 531, or 532 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises all of the amino acid sequences of SEQ ID NO: 529, 531 and 532 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 530 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0412] In one embodiment, the antibody molecule comprises the amino acid sequence of SEQ ID NO: 534 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 533 (or an amino acid sequence having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0413] In one embodiment, the antibody molecule comprises one, two or all of the amino acid sequences of SEQ ID NO: 529, 531, or 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and the amino acid sequence of SEQ ID NO: 534 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule comprises all of the amino acid sequences of SEQ ID NO: 529, 531 and 532 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and the amino acid sequence of SEQ ID NO: 534 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto). In one embodiment, the antibody molecule further comprises the amino acid sequence of SEQ ID NO: 530 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto) and / or the amino acid sequence of SEQ ID NO: 533 (or amino acid sequences having at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity thereto).

[0414] In one embodiment, the antibody molecule comprises 1, 2, 3, 4, 5 or all of the amino acid sequences of SEQ ID NOs: 529-534. In one embodiment, the antibody molecule comprises the amino acid sequences of SEQ ID NOs: 529-534. [Table 6] [Table 7]

[0415] The CDRs defined by Chothia in the variable region (VH) are underlined. The heavy chain constant region is Homo sapiens immunoglobulin heavy chain constant gamma 1 (m3 allotype). Any of the humanized anti-CD138 antibody molecules described herein (e.g., antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825 or 4422) can include the constant CH1, hinge, CH2 and / or CH3 sequences described in Table 7.

Table 8

[0416] The CDRs defined by Chothia in the variable region (VL) are underlined. The light chain is Homo sapiens kappa constant * 01. Any of the humanized anti-CD138 antibody molecules described herein (e.g., antibody 3820, 3821, 3826, 4221, 4226, 4320, 4321, 4322, 4326, 4421, 4520, 4521, 4526, 3522, 3621, 3822, 3825 or 4422) can include the constant CL and / or hinge sequences described in Table 8.

[0417] 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 can include two or more sets of identical or substantially identical VH-VL pairs, and each VH-VL pair binds to two or more different regions in CD138. As another example, the antibody molecule can include two or more sets of different VH-VL pairs, and each VH-VL pair binds to a different region in CD138.

[0418] In one embodiment, the antibody molecule is a multispecific (e.g., bispecific, trispecific or tetra-specific) antibody molecule. In one embodiment, the antibody molecule has a first binding specificity for CD138 and a second binding specificity other than CD138. For example, the antibody molecule may comprise two or more sets of identical or substantially identical VH-VL pairs, each VH-VL pair having both the first binding specificity and the second binding specificity. As another example, the antibody molecule may comprise two or more sets of different VH-VL pairs, each VH-VL pair having a different binding specificity.

[0419] In one embodiment, the humanized antibody molecule is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% or at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times more stable in vitro than a reference antibody molecule, e.g., a related non-humanized antibody molecule, as determined by the methods described herein. In one embodiment, the humanized antibody molecule has a first thermal transition temperature of at least about 62°C, e.g., about 65°C to about 70°C (e.g., at about 65°C, 66°C, 67°C, 68°C, 69°C or 70°C), as determined by, for example, differential scanning fluorimetry (DSF). In one embodiment, the humanized antibody molecule has a second thermal transition temperature of at least about 70°C, e.g., about 75°C to about 80°C (e.g., at about 75°C, 76°C, 77°C, 78°C, 79°C or 80°C), as determined by, for example, DSF.

[0420] In one embodiment, when determined by the methods described herein, the humanized antibody molecule is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% more stable in vivo, or at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times more stable than a reference antibody molecule, such as a related non-humanized antibody molecule. In one embodiment, the antibody molecule has a serum half-life that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or ...

Claims

**Claim 1** A humanized anti-CD138 antibody molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein said VH comprises three heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3), and said VL comprises three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3), (i) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Chothia system, and said VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 355, HCDR2 comprising the amino acid sequence of SEQ ID NO: 351, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 508, and said VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 510, LCDR2 comprising the amino acid sequence of SEQ ID NO: 353, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 354; or (ii) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are defined according to the Kabat system, and said VH comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 380, HCDR2 comprising the amino acid sequence of SEQ ID NO: 514, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 508, and said VL comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 510, LCDR2 comprising the amino acid sequence of SEQ ID NO: 353, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 354, a humanized anti-CD138 antibody molecule. **Claim 2** (i) said VH comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 471 or 466 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, or 99% homology thereto; and / or (ii) said VL comprises an amino acid sequence that differs from the amino acid sequence of SEQ ID NO: 475 by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues, or has at least 85%, 90%, 95%, or 99% homology thereto, the antibody molecule according to claim 1. **Claim 3** The antibody molecule according to claim 1 or 2, wherein said VH comprises the amino acid sequence of SEQ ID NO: 471 or 466, and / or said VL comprises the amino acid sequence of SEQ ID NO:

475. **Claim 4** The antibody molecule according to any one of claims 1 to 3, wherein the antibody molecule comprises an Fc region.

5. (a) a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO: 527 and having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues different therefrom, or having at least 85%, 90%, 95%, or 99% homology thereto; and / or (b) a light chain (LC) comprising an amino acid sequence of SEQ ID NO: 528 and having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 or fewer amino acid residues different therefrom, or having at least 85%, 90%, 95%, or 99% homology thereto The antibody molecule according to any one of claims 1 to 4, comprising the same.

6. The antibody molecule according to claim 5, wherein the HC comprises the amino acid sequence of SEQ ID NO: 527 and / or the LC comprises the amino acid sequence of SEQ ID NO:

528.

7. The antibody molecule is (i) comprising two VH and two VL, (ii) a synthetic antibody molecule or an isolated antibody molecule, (iii) 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 tetravalent) antibody molecule, (iv) comprising one or more framework regions derived from human framework germline sequences, (v) an IgG antibody, (vi) comprising a heavy chain constant region of IgG selected from IgG1, IgG2, IgG3 or IgG4, (vii) comprising a light chain constant region of a kappa or lambda light chain, (viii) comprising an Fc region comprising one or more mutations for increasing the binding affinity to the neonatal receptor FcRn and / or the half-life of the antibody molecule, and / or (ix) comprising an Fc region comprising one or more mutations for increasing one or more of half-life, ADCC, CDC or ADCP, The antibody molecule according to any one of claims 1 to 6.

8. The antibody molecule according to any one of claims 1 to 7, comprising a heavy chain constant region of IgG1 and a light chain constant region of a kappa light chain.

9. An anti-CD138 antibody molecule comprising a VH comprising the amino acid sequence of SEQ ID NO: 471 and a VL comprising the amino acid sequence of SEQ ID NO:

475.

10. An anti-CD138 antibody molecule comprising an HC containing the amino acid sequence of SEQ ID NO: 527 and an LC containing the amino acid sequence of SEQ ID NO:

528.

11. An antibody-drug conjugate (ADC) comprising the antibody molecule according to any one of Claims 1 to 10, optionally containing a cytotoxic agent, and further optionally containing a linker.

12. A composition comprising the antibody molecule according to any one of Claims 1 to 10 or the ADC according to Claim 11, which is optionally a pharmaceutical composition and further optionally contains a pharmaceutically acceptable carrier.

13. A nucleic acid molecule encoding the heavy chain variable region (VH) and the light chain variable region (VL) of the antibody molecule according to any one of Claims 1 to 10.

14. A vector containing the nucleic acid molecule according to Claim 13.

15. A cell containing the nucleic acid molecule according to Claim 13 or the vector according to Claim 14, which is optionally an isolated cell.

16. A kit comprising the antibody molecule according to any one of Claims 1 to 10, the ADC according to Claim 11 or the composition according to Claim 12, and an instruction manual for the use of the antibody molecule or the composition.

17. A container containing the antibody molecule according to any one of Claims 1 to 10, the ADC according to Claim 11 or the composition according to Claim 12.

18. A method for producing an anti-CD138 antibody molecule, which comprises culturing the cell according to Claim 15 under conditions enabling the production of the antibody molecule, thereby producing the antibody molecule, and further optionally isolating or purifying the antibody molecule.

19. A pharmaceutical composition for use in a method for treating cancer in a subject, comprising the antibody molecule according to any one of Claims 1 to 10, the ADC according to Claim 11 or the composition according to Claim 12.

20. (i) the cancer is a blood cancer, (ii) the cancer is multiple myeloma, (iii) the cancer is a solid tumor, (iv) the pharmaceutical composition for the use is characterized in that it is intravenously administered to the subject (v) the antibody molecule, ADC or composition is administered to the subject at a dose of 0.1 mg / kg to 50 mg / kg, 0.2 mg / kg to 25 mg / kg, 0.5 mg / kg to 10 mg / kg, 0.5 mg / kg to 5 mg / kg, 0.5 mg / kg to 3 mg / kg, 0.5 mg / kg to 2.5 mg / kg, 0.5 mg / kg to 2 mg / kg, 0.5 mg / kg to 1.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 1.5 mg / kg, 1 mg / kg to 2 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 3 mg / kg, or 1 mg / kg to 5 mg / kg, (vi) the antibody molecule, ADC or composition is administered to the subject at a fixed dose of 10 mg to 1000 mg, 10 mg to 500 mg, 10 mg to 250 mg, 10 mg to 150 mg, 10 mg to 100 mg, 10 mg to 50 mg, 250 mg to 500 mg, 150 mg to 500 mg, 100 mg to 500 mg, 50 mg to 500 mg, 25 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 150 mg, 100 mg to 200 mg or 150 mg to 250 mg, (vii) the pharmaceutical composition for use is administered once a week, twice a week, once every two weeks, once every three weeks or once every four weeks, (viii) the use further comprises determining the level of CD138 in a sample from the subject, and / or (ix) the use further comprises administering a second cancer therapeutic agent to the subject, A pharmaceutical composition for use according to claim 19.

21. A pharmaceutical composition comprising an antibody molecule according to any one of claims 1 to 10, an ADC according to claim 11 or a composition according to claim 12 for use in a method of treating pre-cancerous conditions or preventing cancer.

22. (i) the pre-cancerous condition is smoldering myeloma or monoclonal gammopathy of undetermined significance (MGUS), or (ii) the cancer is multiple myeloma, A pharmaceutical composition for use according to claim 21.

23. A pharmaceutical composition comprising the antibody molecule according to any one of claims 1 to 10, the ADC according to claim 11 or the composition according to claim 12 for use in a method of inducing ADCC activity, wherein the method comprises contacting a cell or a subject with the antibody molecule, the ADC or the composition, thereby inducing the ADCC activity.

24. A pharmaceutical composition comprising the antibody molecule according to any one of claims 1 to 10 for use in a method of detecting a CD138 molecule, wherein the method comprises contacting a cell or a subject with the antibody molecule, thereby detecting the CD138 molecule, optionally, (i) the antibody molecule is coupled to a detectable label and / or (ii) the CD138 molecule is detected in vitro, ex vivo or in vivo.

25. The pharmaceutical composition is characterized by being used or administered in combination with a second therapeutic agent or modality, optionally, the second therapeutic agent or modality comprises a proteasome inhibitor, and further optionally, the proteasome inhibitor comprises bortezomib. A pharmaceutical composition for use according to any one of claims 19 to 22.

26. A pharmaceutical composition comprising an anti-CD138 antibody molecule comprising a VH comprising the amino acid sequence of SEQ ID NO: 471 and a VL comprising the amino acid sequence of SEQ ID NO:

475.

27. A pharmaceutical composition comprising an anti-CD138 antibody molecule comprising an HC comprising the amino acid sequence of SEQ ID NO: 527 and an LC comprising the amino acid sequence of SEQ ID NO:

528.

28. A pharmaceutical composition comprising an anti-CD138 antibody molecule comprising a VH comprising the amino acid sequence of SEQ ID NO: 471 and a VL comprising the amino acid sequence of SEQ ID NO: 475 for use in the treatment of cancer or pre-cancerous conditions in a subject.

29. A pharmaceutical composition comprising an anti-CD138 antibody molecule comprising an HC comprising the amino acid sequence of SEQ ID NO: 527 and an LC comprising the amino acid sequence of SEQ ID NO: 528 for use in the treatment of cancer or pre-cancerous conditions in a subject.

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