NOVEL ANTI-CLAUDIN ANTIBODIES AND METHODS OF USE
Provided herein are novel anti-CLDN antibodies and antibody drug conjugates (ADC), including derivatives thereof, and methods of using the same to treat proliferative disorders.
1 .- 23 . (canceled)
24 . A method of treating ovarian cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent, wherein the monoclonal antibody binds to a human CLDN6 protein; and
wherein the monoclonal antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73, and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87.
25 .- 32 . (canceled)
33 . The method of claim 24 , wherein the monoclonal antibody is an internalizing antibody.
34 . The method of claim 24 , wherein the monoclonal antibody is selected from the group consisting of a chimeric antibody, humanized antibody, and CDR grafted antibody.
35 . The antibody of claim 24 , wherein the monoclonal antibody comprises:
(a) residues 24-34 of SEQ ID NO: 73 for CDR-L1, residues 50-56 of SEQ ID NO: 73 for CDR-L2, residues 89-97 of SEQ ID NO: 73 for CDR-L3, residues 31-35 of SEQ ID NO: 87 for CDR-H1, residues 50-65 of SEQ ID NO: 87 for CDR-H2 and residues 95-102 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to Kabat;
(b) residues 24-34 of SEQ ID NO: 73 for CDR-L1, residues 50-56 of SEQ ID NO: 73 for CDR-L2, residues 89-97 of SEQ ID NO: 73 for CDR-L3, residues 26-32 of SEQ ID NO: 87 for CDR-H1, residues 52-56 of SEQ ID NO: 87 for CDR-H2 and residues 95-102 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to Chothia; or
(c) residues 30-36 of SEQ ID NO: 73 for CDR-L1, residues 46-55 of SEQ ID NO: 73 for CDR-L2, residues 89-96 of SEQ ID NO: 73 for CDR-L3, residues 30-35 of SEQ ID NO: 87 for CDR-H1, residues 47-58 of SEQ ID NO: 87 for CDR-H2 and residues 93-101 of SEQ ID NO: 87 for CDR-H3, wherein the residues are numbered according to MacCallum.
36 . The method of claim 24 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87.
37 . The method of claim 36 , wherein the monoclonal antibody is an IgG1 antibody comprising:
(i) a cysteine residue at heavy chain position 220 and a deletion of a cysteine residue at light chain position 214, (ii) a cysteine residue at heavy chain position 220 and a substitution of a cysteine residue at light chain position 214, (iii) a cysteine residue at light chain position 214 and a deletion of a cysteine residue at heavy chain position 220, or (iv) a cysteine residue at light chain position 214 and a substitution of a cysteine residue at heavy chain position 220; and
wherein the engineered antibody comprises native cysteine residues at heavy chain positions 226 and 229.
38 . The method of claim 37 , wherein the monoclonal antibody comprises a cysteine residue at light chain position 214.
39 . The method of claim 24 , wherein the cytotoxic agent is a pyrrolobenzodiazepine, an auristatin, a maytansinoid, a calicheamicin, or a radioisotope.
40 . The method of claim 24 , wherein the cytotoxic agent is a pyrrolobenzodiazepine.
41 . The method of claim 24 , wherein the antibody drug conjugate comprises the formula M-[L-D]n wherein:
M comprises the monoclonal antibody;
L comprises an optional linker;
D comprises a drug, which is the cytotoxic agent; and
n is an integer from 1 to 20.
42 . The method of claim 24 , wherein the monoclonal antibody is conjugated to the cytotoxic agent via a linker.
43 . The method of claim 42 , wherein the linker comprises a cleavable linker.
44 . The method of claim 24 , wherein the antibody drug conjugate has a drug loading of 2.
45 . The method of claim 24 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87, and
wherein the cytotoxic agent is a pyrrolobenzodiazepine.
46 . The method of claim 24 , wherein the cancer is refractory, relapsed, or resistant to a platinum based agent.
47 . A method of treating ovarian cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
wherein the monoclonal antibody binds to a human CLDN6 protein and comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87;
wherein the cytotoxic agent is a pyrrolobenzodiazepine; and
wherein the antibody drug conjugate has a drug loading of 2.
48 . A method of treating cancer comprising administering to a subject in need thereof an antibody drug conjugate comprising a monoclonal antibody conjugated, linked, or otherwise associated with a cytotoxic agent,
wherein the monoclonal antibody comprises three complementarity determining regions of a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and three complementarity determining regions of a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87.
49 . The method of claim 48 , wherein the monoclonal antibody comprises a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 73 and a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 87, and
wherein the cytotoxic agent is a pyrrolobenzodiazepine.
50 . The method of claim 49 , wherein the cancer is lung adenocarcinoma.
51 . The method of claim 49 , wherein the cancer is endometrial cancer.