Anti-GD2 antibodies
In this application are described chimeric, humanized, affinity matured, stability enhanced, and bispecific Anti-GD2 antibodies and fragments thereof. Also provided are methods of using individual antibodies or compositions thereof for the detection, prevention, and/or therapeutical treatment of GD2-related diseases, in particular, neuroblastoma.
1. A humanized or chimeric antibody or fragment thereof capable of binding to GD2, wherein the antibody or fragment thereof comprises any of the following:
(i) a variable heavy chain domain of SEQ ID NO: 1 and a variable light chain domain of SEQ ID NO:2;
(ii) a variable heavy chain domain of SEQ ID NO:3 and a variable light chain domain of SEQ ID NO:2;
(iii) a variable heavy chain domain of SEQ ID NO:4 and a variable light chain domain of SEQ ID NO:5;
(iv) a variable heavy chain domain of SEQ ID NO:6 and a variable light chain domain of SEQ ID NO:7;
(v) a variable heavy chain domain of SEQ ID NO:8 and a variable light chain domain of SEQ ID NO:5;
(vi) a variable heavy chain domain of SEQ ID NO:9 and a variable light chain domain of SEQ ID NO: 10; and
(vii) a variable heavy chain domain of SEQ ID NO:6 and a variable light chain domain of SEQ ID NO: 5.
2. The humanized or chimeric antibody or fragment of claim 1 , wherein the antibody or fragment is glycosylated with terminal mannose, N-acetylglucose or glucose, but no fucose.
3. A pharmaceutical composition comprising the humanized or chimeric antibody or fragment thereof of claim 1 , and further comprising a pharmaceutically acceptable carrier or diluent.
4. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment is conjugated to a cytotoxic agent.
5. A bispecific antibody having first and second antigen binding sites, one of which comprises antigen binding sequences of a light chain and a heavy chain of a humanized 3F8 antibody.
6. The bispecific antibody of claim 5 wherein the second antigen binding site is selected from the group consisting of scFv, scFab, Fab, and Fv.
7. The bispecific antibody of claim 5 wherein the second antigen binding site is associated with an immunological cell chosen from the group consisting of T-lymphocytes, NK cell, B-lymphocytes, dendritic cells, monocytes, macrophages, neutrophils, mesenchymal stem cells, and neural stem cells.
8. The bispecific antibody of claim 5 wherein the second antigen binding site is specific for CD3 or for a DOTA (metal).
9. The bispecific antibody of claim 6 , further comprising a peptide of SEQ ID NO:23 that includes the second antigen binding site.
10. The bispecific antibody of claim 6 , further comprising a peptide of SEQ ID NO:24 that includes the second antigen binding site.
11. A pharmaceutical composition comprising the bispecific antibody of claim 5 , and further comprising a pharmaceutically acceptable carrier or diluent.
12. A chimeric antigen receptor comprising an antigen binding domain of a humanized or chimeric antibody or fragment of claim 1 .
13. The chimeric antigen receptor of claim 12 , wherein the antigen binding domain is a scFv.
14. The chimeric antigen receptor of claim 13 , expressed by an immune effector cell.
15. A bispecific T-cell engaging monoclonal antibody comprising a first binding site comprising scFv from hu3F8 monoclonal antibody, and a second binding site binding to a T-cell.
16. A pharmaceutical composition comprising the antibody or fragment thereof of claim 2 , and further comprising a pharmaceutically acceptable carrier or diluent.
17. A pharmaceutical composition comprising the bispecific antibody of claim 6 , and further comprising a pharmaceutically acceptable carrier or diluent.
18. A pharmaceutical composition comprising the bispecific antibody of claim 7 , and further comprising a pharmaceutically acceptable carrier or diluent.
19. A pharmaceutical composition comprising the bispecific antibody of claim 8 , and further comprising a pharmaceutically acceptable carrier or diluent.
20. A pharmaceutical composition comprising the bispecific antibody of claim 9 , and further comprising a pharmaceutically acceptable carrier or diluent.
21. A pharmaceutical composition comprising the bispecific antibody of claim 10 , and further comprising a pharmaceutically acceptable carrier or diluent.
22. A pharmaceutical composition comprising the antibody or fragment thereof of claim 4 , and further comprising a pharmaceutically acceptable carrier or diluent.
23. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO: 1 and a variable light chain domain of SEQ ID NO:2.
24. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:3 and a variable light chain domain of SEQ ID NO:2.
25. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:4 and a variable light chain domain of SEQ ID NO:5.
26. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:6 and a variable light chain domain of SEQ ID NO:7.
27. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:8 and a variable light chain domain of SEQ ID NO:5.
28. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:9 and a variable light chain domain of SEQ ID NO: 10.
29. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the antibody or fragment comprises a variable heavy chain domain of SEQ ID NO:6 and a variable light chain domain of SEQ ID NO: 5.
30. The humanized or chimeric antibody or fragment thereof of claim 1 , wherein the humanized or chimeric antibody comprises a variant Fc region.
31. The humanized or chimeric antibody or fragment thereof of claim 30 , wherein the variant Fc region comprises a substitution of S239D, A330L and 1332E.
32. The humanized or chimeric antibody or fragment thereof of claim 30 , wherein the variant Fc region comprises a N297A substitution.
33. The humanized or chimeric antibody or fragment thereof of claim 2 , wherein the humanized or chimeric antibody comprises a variant Fc region.
34. The humanized or chimeric antibody or fragment thereof of claim 33 , wherein the variant Fc region comprises a substitution of S239D, A330L and 1332E.
35. The humanized or chimeric antibody or fragment thereof of claim 33 , wherein the variant Fc region comprises a N297A substitution.