Cadherin-17 specific antibodies and cytotoxic cells for cancer treatment
Embodiments of the present disclosure relate to cadherin-17 specific antibodies and cytotoxic cells for cancer treatment. For example, an antibody may have specificity for cadherin-17 and include an amino acid sequence having at least 70% similarity with an amino acid sequence selected from SEQ ID NO: 1-21.
1. An antibody having specificity for cadherin-17, comprising an amino acid sequence selected from the group consisting of SEQ ID NO(s): 1, 2, 17, and 19.
2. The antibody of claim 1 , comprising a variable region of light chain (VL), a variable region of heavy chain (VH), wherein the VL comprises an amino acid sequence of SEQ ID NO: 1.
3. The antibody of claim 2 , wherein the VH comprises an amino acid sequence of SEQ ID NO: 2.
4. The antibody of claim 1 , further comprising a conjugated cytotoxic moiety, wherein the conjugated cytotoxic moiety comprises irinotecan, auristatins, PBDs, maytansines, amantins, spliceosome inhibitors, a chemotherapeutic agent, or a combination thereof.
5. The antibody of claim 1 , wherein the antibody is a bispecific monoclonal antibody.
6. The antibody of claim 5 , having specificity for a cell receptor from a cytotoxic T or NK cell, wherein the cell receptor comprises 4-1BB, OX40, CD27, CD40, TIM-1, CD28, HVEM, GITR, ICOS, IL12receptor, IL14 receptor, or a combination thereof.
7. The antibody of claim 5 , comprising a first single-chain variable fragment (ScFv) having specificity for cadherin-17 and a second sing-chain variable fragment (ScFv) having specificity for CD3, wherein the first ScFv comprises a first VH and a first VL, the second ScFv comprises a second VH and a second VL.
8. The antibody of claim 7 , wherein the first VH comprises an amino acid sequence of SEQ ID NO: 2.
9. The antibody of claim 7 , wherein the first VL comprises an amino acid sequence of SEQ ID NO: 1.
10. The antibody of claim 7 , wherein the second VH and the second VL comprises the VH and the VL, respectively, of the amino acid sequence of SEQ ID NO: 18.
11. The antibody of claim 1 , having specificity for an immune checkpoint inhibitor, wherein the checkpoint inhibitor comprises PD-1, TIM-3, LAG-3, TIGIT, CTLA-4, PD-L1, BTLA, VISTA, or a combination thereof.
12. The antibody of claim 1 , having specificity for an angiogenic factor, wherein the angiogenic factor comprises VEGF.
13. The antibody of claim 1 , wherein the antibody is configured to antagonize the binding of the RGD site in cadherin-17 domain 6 to integrin, wherein the integrin comprises alpha2beta1.
14. An IgG heavy chain for an antibody, comprising an amino acid sequence having a sequence selected from SEQ ID NO: 2.
15. A light chain for an antibody, comprising an amino acid sequence having a sequence selected from SEQ ID NO: 1.
16. A variable region for an antibody, comprising a light chain variable region comprising SEQ ID NO: 1, and a heavy chain variable region comprising SEQ ID NO:2.
17. A scFv or Fab having specificity for cadherin-17, comprising an amino acid sequence selected from SEQ ID NO(s): 1, 2, 17, and 19, wherein the scFv or Fab has specificity for a cell receptor from a cytotoxic T or NK cell, an immune checkpoint inhibitor, or an angiogenic factor.
18. A pharmaceutical composition, comprising the antibody of claim 1 and a cytotoxic agent, wherein the cytotoxic agent comprises cisplatin, gemcitabine, irinotecan, or an anti-tumor antibody.
19. A method for treating a subject having a cadherin-1.7-expressing cancer, comprising administering to the subject an effective amount of the antibody of claim 1 .