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 bispecific antibody comprising a first antigen binding site having a binding specificity for CLDN6 and a second antigen binding site having a binding specificity for a second target epitope,
wherein the first antigen binding site 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),
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54),
a HCDR3 of amino acid sequence ARDYGYVLDY (SEQ ID NO: 55),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSIYPPWT (SEQ ID NO: 57);
b. a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54),
a HCDR3 of amino acid sequence ARDYGFVLDY (SEQ ID NO: 58),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSNYPPWT (SEQ ID NO: 59);
c. a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGI (SEQ ID NO: 60),
a HCDR3 of amino acid sequence ARDFGYVLDY (SEQ ID NO: 61),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSTYPPWT (SEQ ID NO: 62); and
d. a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGS (SEQ ID NO: 63),
a HCDR3 of amino acid sequence ARDYGYVFDY (SEQ ID NO: 64),
a LCDR1 of amino acid sequence SSVNY (SEQ ID NO: 65),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRNNYPPWT (SEQ ID NO: 66); and
wherein the second target epitope is selected from the group consisting of human Fc-gammaRI (CD64), human Fc-alpha receptor (CD89), and CD3.
2. The bispecific antibody of claim 1 , wherein the first antigen binding site is not capable of detectably binding to at least one of (i) CLDN3 associated with the surface of a cell that expresses CLDN3, (ii) CLDN4 associated with the surface of a cell that expresses CLDN4, or (iii) CLDN9 associated with the surface of a cell that expresses CLDN9.
3. The bispecific antibody of claim 1 , wherein CLDN6 has the amino acid sequence of SEQ ID NO: 2 or the amino acid sequence of SEQ ID NO: 8.
4. The bispecific antibody of claim 1 , wherein the second target epitope is selected from the group consisting of an Fc receptor and a T cell receptor.
5. The bispecific antibody of claim 1 , wherein the second target epitope is CD3.
6. The bispecific antibody of claim 1 , wherein the first antigen binding site comprises:
a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54),
a HCDR3 of amino acid sequence ARDYGYVLDY (SEQ ID NO: 55),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSIYPPWT (SEQ ID NO: 57).
7. The bispecific antibody of claim 6 , wherein the first antigen binding site comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 34 and a light chain variable region having an amino acid sequence of SEQ ID NO: 35.
8. The bispecific antibody of claim 7 , wherein the second target epitope is CD3.
9. The bispecific antibody of claim 1 , wherein the first antigen binding site comprises:
a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGT (SEQ ID NO: 54),
a HCDR3 of amino acid sequence ARDYGFVLDY (SEQ ID NO: 58),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSNYPPWT (SEQ ID NO: 59).
10. The bispecific antibody of claim 9 , wherein the first antigen binding site comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 36 and a light chain variable region having an amino acid sequence of SEQ ID NO: 37.
11. The bispecific antibody of claim 10 , wherein the second target epitope is CD3.
12. The bispecific antibody of claim 1 , wherein the first antigen binding site comprises:
a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGI (SEQ ID NO: 60),
a HCDR3 of amino acid sequence ARDFGYVLDY (SEQ ID NO: 61),
a LCDR1 of amino acid sequence SSVSY (SEQ ID NO: 56),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRSTYPPWT (SEQ ID NO: 62).
13. The bispecific antibody of claim 12 , wherein the first antigen binding site comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 38 and a light chain variable region having an amino acid sequence of SEQ ID NO: 39.
14. The bispecific antibody of claim 13 , wherein the second target epitope is CD3.
15. The bispecific antibody of claim 1 , wherein the first antigen binding site comprises:
a HCDR1 of amino acid sequence GYSFTGYT (SEQ ID NO: 47),
a HCDR2 of amino acid sequence INPYNGGS (SEQ ID NO: 63),
a HCDR3 of amino acid sequence ARDYGYVFDY (SEQ ID NO: 64),
a LCDR1 of amino acid sequence SSVNY (SEQ ID NO: 65),
a LCDR2 of amino acid sequence STS (SEQ ID NO: 53), and
a LCDR3 of amino acid sequence QQRNNYPPWT (SEQ ID NO: 66).
16. The bispecific antibody of claim 15 , wherein the first antigen binding site comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 40 and a light chain variable region having an amino acid sequence of SEQ ID NO: 41.
17. The bispecific antibody of claim 16 , wherein the second target epitope is CD3.
18. The bispecific antibody of claim 1 , wherein the bispecific antibody is a diabody.
19. A pharmaceutical composition comprising the bispecific antibody of claim 1 .