Fully human therapeutic antibodies specific for human CD38
The present invention nucleic acids encoding novel antibodies and functional fragments thereof specific for CD38. Such antibodies are useful for the treatment of diseases associated with CD38 expression, including hematological malignancies such as multiple myeloma.
1. An isolated nucleic acid encoding an antibody or antigen-binding fragment thereof that binds to CD38, comprising the nucleic acid sequences encoding the three variable heavy chain complementarity determining regions (H-CDRs) and the nucleic acid sequences encoding the three variable light-chain complementarity determining regions (L-CDRs) in the nucleic acid sequences encoding a variable heavy chain and a variable light chain pair selected from:
(i) SEQ ID NO: 3 and 33;
(ii) SEQ ID NO: 5 and 35;
(iii) SEQ ID NO: 6 and 36;
(iv) SEQ ID NO: 7 and 37; and
(v) SEQ ID NO: 10 and 40.
2. The isolated nucleic acid of claim 1 , comprising the nucleic acid sequences encoding the three H-CDRs in SEQ ID NO: 3, and the nucleic acid sequences encoding the three L-CDRs in SEQ ID NO: 33.
3. The isolated nucleic acid of claim 1 , comprising the nucleic acid sequences encoding the three H-CDRs in SEQ ID NO: 5, and the nucleic acid sequences encoding the three L-CDRs in SEQ ID NO: 35.
4. The isolated nucleic acid of claim 1 , comprising the nucleic acid sequences encoding the three H-CDRs in SEQ ID NO: 6, and the nucleic acid sequences encoding the three L-CDRs in SEQ ID NO: 36.
5. The isolated nucleic acid of claim 1 , comprising the nucleic acid sequences encoding the three H-CDRs in SEQ ID NO: 7, and the nucleic acid sequences encoding the three L-CDRs in SEQ ID NO: 37.
6. The isolated nucleic acid of claim 1 , comprising the nucleic acid sequences encoding the three H-CDRs in SEQ ID NO: 10, and the nucleic acid sequences encoding the three L-CDRs in SEQ ID NO: 40.
7. The isolated nucleic acid of claim 1 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 80% identical to SEQ ID NO: 3, 5, 6, 7, or 10.
8. The isolated nucleic acid of claim 7 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 90% identical to SEQ ID NO: 3, 5, 6, 7, or 10.
9. The isolated nucleic acid of claim 8 , comprising SEQ ID NO: 3, 5, 6, 7, or 10.
10. The isolated nucleic acid of claim 1 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 80% identical to SEQ ID NO: 33, 35, 36, 37, or 40.
11. The isolated nucleic acid of claim 10 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 90% identical to SEQ ID NO: 33, 35, 36, 37, or 40.
12. The isolated nucleic acid of claim 11 , comprising SEQ ID NO: 33, 35, 36, 37,or 40.
13. The isolated nucleic acid of claim 4 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 80% identical to SEQ ID NO: 6.
14. The isolated nucleic acid of claim 13 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 90% identical to SEQ ID NO: 6.
15. The isolated nucleic acid of claim 14 , comprising SEQ ID NO: 6.
16. The isolated nucleic acid of claim 5 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 80% identical to SEQ ID NO: 7.
17. The isolated nucleic acid of claim 16 , comprising a nucleic acid sequence encoding a variable heavy chain, said nucleic acid sequence encoding the framework regions of the variable heavy chain being at least 90% identical to SEQ ID NO: 7
18. The isolated nucleic acid of claim 17 , comprising SEQ ID NO: 7.
19. The isolated nucleic acid of claim 4 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 80% identical to SEQ ID NO: 36.
20. The isolated nucleic acid of claim 19 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 90% identical to SEQ ID NO: 36.
21. The isolated nucleic acid of claim 20 , comprising SEQ ID NO: 36.
22. The isolated nucleic acid of claim 5 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 80% identical to SEQ ID NO: 37.
23. The isolated nucleic acid of claim 22 , comprising a nucleic acid sequence encoding a variable light chain, said nucleic acid sequence encoding the framework regions of the variable light chain being at least 90% identical to SEQ ID NO: 37.
24. The isolated nucleic acid of claim 23 , comprising SEQ ID NO: 37.
25. The isolated nucleic acid of claim 1 , comprising a nucleic acid sequence pair encoding a heavy and light chain pair, said nucleic acid sequence pair encoding the framework regions of the heavy and light chain pair having at least 80% identity to the pairs selected from: (i) SEQ ID NO: 3 and 33; (ii) SEQ ID NO: 5 and 35; (iii) SEQ ID NO: 6 and 36; (iv) SEQ ID NO: 7 and 37; and (v) SEQ ID NO: 10 and 40.
26. The isolated nucleic acid of claim 1 , comprising a nucleic acid sequence pair encoding a heavy and light chain pair, said nucleic acid sequence pair encoding the framework regions of the heavy and light chain pair having at least 90% identity to the pairs selected from: (i) SEQ ID NO: 3 and 33; (ii) SEQ ID NO: 5 and 35; (iii) SEQ ID NO: 6 and 36; (iv) SEQ ID NO: 7 and 37; and (v) SEQ ID NO: 10 and 40.
27. The isolated nucleic acid of claim 1 , comprising SEQ ID NO: 3 and SEQ ID NO: 33.
28. The isolated nucleic acid of claim 1 , comprising SEQ ID NO: 5 and SEQ ID NO: 35.
29. The isolated nucleic acid of claim 25 , comprising a nucleic acid sequence encoding a heavy chain, said nucleic acid sequence encoding the framework regions of the heavy chain being at least 80% identical to SEQ ID NO: 6, and a nucleic acid sequence encoding a light chain, said nucleic acid sequence encoding the framework regions of the light chain being at least 80% identical to SEQ ID NO: 36.
30. The isolated nucleic acid of claim 26 , comprising a nucleic acid sequence encoding the heavy chain, said nucleic acid sequence encoding the framework regions of the heavy chain being at least 90% identical to SEQ ID NO: 6, and a nucleic acid sequence encoding the light chain, said nucleic acid sequence encoding the framework regions of the light chain being at least 90% identical to SEQ ID NO: 36.
31. The isolated nucleic acid of claim 1 , comprising SEQ ID NO: 6 and SEQ ID NO: 36.
32. The isolated nucleic acid of claim 25 , comprising a nucleic acid sequence encoding the heavy chain, said nucleic acid sequence encoding the framework regions of the heavy chain being at least 80% identical to SEQ ID NO: 7, and a nucleic acid sequence encoding the light chain, said nucleic acid sequence encoding the framework regions of the light chain being at least 80% identical to SEQ ID NO: 37.
33. The isolated nucleic acid of claim 26 , comprising a nucleic acid sequence encoding a heavy chain, said nucleic acid sequence encoding the framework regions of the heavy chain being at least 90% identical to SEQ ID NO:7, and a nucleic acid sequence encoding a light chain, said nucleic acid sequence encoding the framework regions of the light chain being at least 90% identical to SEQ ID NO: 37.
34. The isolated nucleic acid of claim 1 , comprising SEQ ID NO: 7 and SEQ ID NO: 37.
35. The isolated nucleic acid of claim 1 , comprising SEQ ID NO: 10 and SEQ ID NO: 40.
36. The isolated nucleic acid of claim 1 , encoding an scFv, Fab or F(ab) 2 fragment.
37. The isolated nucleic acid of claim 1 , encoding an IgG.
38. The isolated nucleic acid of claim 37 , encoding IgGl.
39. A vector comprising the isolated nucleic acid of claim 1 .
40. A cultured cell, comprising the vector of claim 39 .