Monoclonal antibodies against Claudin-18 for treatment of cancer
The present invention provides antibodies useful as therapeutics for treating and/or preventing diseases associated with cells expressing CLD18, including tumor-related diseases such as gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, hepatic cancer, head-neck cancer, and cancer of the gallbladder.
1. An antibody that binds to CLD18A2 and mediates killing of cells expressing CLD18A2, wherein said antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), each of the VH and VL comprising a set of complementarity-determining regions CDR1, CDR2 and CDR3:
VH: CDR1: positions 45-52 of SEQ ID NO: 118, CDR2: positions 70-77 of SEQ ID NO: 118, CDR3: positions 116-126 of SEQ ID NO: 118, VL: CDR1: positions 47-58 of SEQ ID NO: 125, CDR2: positions 76-78 of SEQ ID NO: 125, CDR3: positions 115-123 of SEQ ID NO: 125,
wherein the VH and VL domains of the antibody are expressed on a single polypeptide chain.
2. The antibody of claim 1 , wherein said antibody binds to CLD18A2 but not to CLD18A1.
3. The antibody of claim 1 , wherein said antibody is capable of binding to an effector cell, preferably a T cell.
4. The antibody of claim 1 , wherein said antibody is selected from the group consisting of an IgG1, an IgG2, preferably IgG2a and IgG2b, an IgG3, an IgG4, an IgM, an IgA1, an IgA2, a secretory IgA, an IgD, an IgE antibody, a bispecific antibody, and a multispecific antibody.
5. The antibody of claim 4 , wherein said antibody is a bispecific or multispecific antibody comprising a first binding specificity for CLD18A2 and a second binding specificity for a second target epitope.
6. The antibody of claim 5 , wherein the second binding specificity is for CD64, CD89, or CD3.
7. The antibody of claim 1 , wherein CLD18A2 has the amino acid sequence according to SEQ ID NO: 2.
8. The antibody of claim 1 , wherein said antibody binds to native epitopes of CLD18A2 present on the surface of living cells.
9. The antibody of claim 1 , wherein said antibody comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 135 and a fragment thereof.
10. The antibody of claim 1 , wherein said antibody comprises a light chain variable region (VL) comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 142 and a fragment thereof.
11. The antibody of claim 1 , wherein said antibody comprises a combination of heavy chain variable region (VH) and light chain variable region (VL), wherein:
the VH comprises an amino acid sequence represented by SEQ ID NO: 135 or a fragment thereof and the VL comprises an amino acid sequence represented by SEQ ID NO: 142 or a fragment thereof.
12. The antibody of claim 1 , wherein said antibody comprises
(i) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 118 and a fragment thereof and/or
(ii) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 125 and a fragment thereof.
13. The antibody of claim 1 , wherein said antibody comprises a combination of a heavy chain and a light chain, wherein:
the heavy chain comprises an amino acid sequence represented by SEQ ID NO: 118 or a fragment thereof and the light chain comprises an amino acid sequence represented by SEQ ID NO: 125 or a fragment thereof.
14. A recombinant cell expressing the antibody of claim 1 .
15. A conjugate comprising an antibody of claim 1 coupled to a therapeutic agent, wherein the therapeutic agent preferably is a toxin, a radioisotope, a drug or a cytotoxic agent.
16. A pharmaceutical composition comprising an antibody of claim 1 , and a pharmaceutically acceptable carrier.
17. A method of treating or preventing a disease or disorder involving cells expressing CLD18A2, the method comprising administering to a subject an antibody of claim 1 .
18. The method of claim 17 , wherein the disease or disorder is a tumor-related disease, wherein the tumor-related disease preferably is selected from the group consisting of breast cancer, gastric cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, colorectal cancer, hepatic cancer, head-neck cancer, cancer of the gallbladder, and the metastases thereof.