Antibodies specific for claudin 6 (CLDN6)
The present invention provides antibodies useful as therapeutics for treating and/or preventing diseases associated with cells expressing Claudin-6 (CLDN6), including tumor-related diseases such as ovarian cancer, lung cancer, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, malignant melanoma, head and neck cancer, sarcoma, bile duct cancer, cancer of the urinary bladder, kidney cancer, colon cancer, placental choriocarcinoma, cervical cancer, testicular cancer, and uterine cancer.
1. A monoclonal antibody which is capable of binding to CLDN6, wherein the antibody comprises a set of heavy chain CDR (HCDR) and light chain CDR (LCDR) selected from the group consisting of
(a) a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47) identified within SEQ ID NO: 34,
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54) identified within SEQ ID NO: 34,
a HCDR3 of amino acid sequence ARDYGYVLDY (SEQ ID NO: 55) identified within SEQ ID NO: 34,
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56) identified within SEQ ID NO: 35,
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53) identified within SEQ ID NO: 35, and
a LCDR3 of amino acid sequence QQRSIYPPWT (SEQ ID NO: 57) identified within SEQ ID NO: 35;
(b) a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47) identified within SEQ ID NO: 36,
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54) identified within SEQ ID NO: 36,
a HCDR3 of amino acid sequence ARDYGFVLDY (SEQ ID NO: 58) identified within SEQ ID NO: 36,
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56) identified within SEQ ID NO: 37,
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53) identified within SEQ ID NO: 37, and
a LCDR3 of amino acid sequence QQRSNYPPWT (SEQ ID NO: 59) identified within SEQ ID NO: 37;
(c) a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47) identified within SEQ ID NO: 38,
a HCDR2 of amino acid sequence INPYNGGI (SEQ ID NO: 60) identified within SEQ ID NO: 38,
a HCDR3 of amino acid sequence ARDFGYVLDY (SEQ ID NO: 61) identified within SEQ ID NO: 38,
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56) identified within SEQ ID NO: 39,
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53) identified within SEQ ID NO: 39, and
a LCDR3 of amino acid sequence QQRSTYPPWT (SEQ ID NO: 62) identified within SEQ ID NO: 39; and
(d) a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47) identified within SEQ ID NO: 40,
a HCDR2 of amino acid sequence INPYNGGS (SEQ ID NO: 63) identified within SEQ ID NO: 40,
a HCDR3 of amino acid sequence ARDYGYVFDY (SEQ ID NO: 64) identified within SEQ ID NO: 40,
a LCDR1 of amino acid sequence SSVNY (SEQ ID NO: 65) identified within SEQ ID NO: 41,
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53) identified within SEQ ID NO: 41, and
a LCDR3 of amino acid sequence QQRNNYPPWT (SEQ ID NO: 66) identified within SEQ ID NO: 41.
2. The antibody of claim 1 , which is not capable of detectably binding to (i) CLDN9 associated with the surface of a cell that expresses CLDN9 and (ii) CLDN4 associated with the surface of a cell that expresses CLDN4.
3. The antibody of claim 1 , which is not capable of detectably binding to CLDN3 associated with the surface of a cell that expresses CLDN3.
4. The antibody of or claim 1 , which is specific for CLDN6.
5. The antibody of or claim 1 , wherein CLDN6 has the amino acid sequence of SEQ ID NO: 2 or the amino acid sequence of SEQ ID NO: 8.
6. The antibody of claim 1 , which
(a) has one or more of the following activities selected from the group consisting of:
(i) killing of a cell expressing CLDN6,
(ii) inhibition of proliferation of a cell expressing CLDN6,
(iii) inhibition of colony formation of a cell expressing CLDN6,
(iv) mediating remission of established tumors,
(v) preventing formation or re-formation of tumors, and
(vi) inhibition of metastasis of a cell expressing CLDN6;
(b) exhibits one or more immune effector functions against a cell carrying CLDN6 in its native conformation, wherein the one or more immune effector functions are optionally selected from the group consisting of complement dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), induction of apoptosis, and inhibition of proliferation; or
(c) has one or more of the activities of (a) and exhibits (b).
7. The antibody of claim 1 , which is a chimeric or humanized antibody, or a fragment of an antibody.
8. An antibody selected from the group consisting of (i) an antibody produced by or obtainable from a clone deposited under the accession no. DSM ACC3067 (GT512muMAB 59A), DSM ACC3068 (GT512muMAB 60A), DSM ACC3069 (GT512muMAB 61D), DSM ACC3070 (GT512muMAB 64A), DSM ACC3071 (GT512muMAB 65A), DSM ACC3072 (GT512muMAB 66B), DSM ACC3073 (GT512muMAB 67A), DSM ACC3089 (GT512muMAB 55A), or DSM ACC3090 (GT512muMAB 89A), (ii) an antibody which is a chimerized or humanized form of the antibody under (i), and (iii) an antibody comprising the antigen binding portion or antigen binding site of the antibody under (i).
9. A hybridoma capable of producing the antibody of claim 1 or claim 8 .
10. A hybridoma deposited under the accession no. DSM ACC3067 (GT512muMAB 59A), DSM ACC3068 (GT512muMAB 60A), DSM ACC3069 (GT512muMAB 61D), DSM ACC3070 (GT512muMAB 64A), DSM ACC3071 (GT512muMAB 65A), DSM ACC3072 (GT512muMAB 66B), DSM ACC3073 (GT512muMAB 67A), DSM ACC3089 (GT512muMAB 55A), or DSM ACC3090 (GT512muMAB 89A).
11. A conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent.
12. A pharmaceutical composition comprising (i) the antibody of claim 1 ; (ii) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent, and a pharmaceutically acceptable carrier; or (i) and (ii).
13. A method of inhibiting growth of a cell expressing CLDN6 and being characterized by association of CLDN6 with its cell surface, comprising contacting the cell with (i) an antibody of claim 1 ; (ii) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent; or (i) and (ii).
14. A method of killing a cell expressing CLDN6 and being characterized by association of CLDN6 with its cell surface, comprising contacting the cell with (i) an antibody of claim 1 ; (ii) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent; or (i) and (ii).
15. A method of treating or preventing a disease or disorder involving a cell expressing CLDN6 and being characterized by association of CLDN6 with its cell surface in a subject, comprising administering to said subject
(a) an antibody of claim 1 ;
(b) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent; or
(c) a pharmaceutical composition comprising (i) the antibody of claim 1 ; (ii) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent, and a pharmaceutically acceptable carrier; or (i) and (ii).
16. The method of claim 15 , wherein the disease or disorder is a tumor-related disease, wherein the tumor-related disease is optionally a cancer selected from the group consisting of ovarian cancer, in particular ovarian adenocarcinoma and ovarian teratocarcinoma, lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), in particular squamous cell lung carcinoma and adenocarcinoma, gastric cancer, breast cancer, hepatic cancer, pancreatic cancer, skin cancer, in particular basal cell carcinoma and squamous cell carcinoma, malignant melanoma, head and neck cancer, in particular malignant pleomorphic adenoma, sarcoma, in particular synovial sarcoma and carcinosarcoma, bile duct cancer, cancer of the urinary bladder, in particular transitional cell carcinoma and papillary carcinoma, kidney cancer, in particular renal cell carcinoma including clear cell renal cell carcinoma and papillary renal cell carcinoma, colon cancer, small bowel cancer, including cancer of the ileum, in particular small bowel adenocarcinoma and adenocarcinoma of the ileum, testicular embryonal carcinoma, placental choriocarcinoma, cervical cancer, testicular cancer, in particular testicular seminoma, testicular teratoma and embryonic testicular cancer, uterine cancer, a germ cell tumor such as a teratocarcinoma or an embryonal carcinoma, in particular a germ cell tumor of the testis, and the metastatic forms thereof.
17. A method of inhibiting metastatic spread of a cell expressing CLDN6 and being characterized by association of CLDN6 with its cell surface, comprising contacting the cell with (i) an antibody of claim 1 ; (ii) a conjugate comprising an antibody of claim 1 , coupled to a therapeutic agent, wherein the therapeutic agent is optionally a toxin, a radioisotope, a drug or a cytotoxic agent; or (i) and (ii).
18. The antibody of claim 1 , wherein said antibody induces CDC- or ADCC-mediated killing of cells expressing CLDN6.
19. The antibody of claim 18 , wherein said antibody does not detectably bind to CLDN9.
20. The monoclonal antibody of claim 1 , wherein the antibody comprises a set of antibody heavy chain sequence and an antibody light chain sequence selected from the group consisting of
(a) an antibody heavy chain sequence comprising SEQ ID NO: 34, and
an antibody light chain sequence comprising SEQ ID NO: 35;
(b) an antibody heavy chain sequence comprising SEQ ID NOs: 36, and
an antibody light chain sequence comprising SEQ ID NO: 37;
(c) an antibody heavy chain sequence comprising SEQ ID NOs: 38, and
an antibody light chain sequence comprising SEQ ID NO: 39; and
(d) an antibody heavy chain sequence comprising SEQ ID NO: 40 and
an antibody light chain sequence comprising SEQ ID NO: 41.