Anti-CD123 antibodies and conjugates and derivatives thereof
The present invention generally relates to antibodies, antigen-binding fragments thereof, polypeptides, and immunoconjugates that bind to CD123 antigen (the α chain of the interleukine 3 receptor, or IL-3Rα). The present invention also relates to methods of using such CD123-binding molecules for diagnosing and treating diseases, such as B-cell malignancies.
1. An antibody or antigen-binding fragment thereof that binds to human CD123 or human IL-3Rα, said antibody or antibody fragment thereof, comprising:
a) a heavy chain variable region CDR1 having the amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 5, and 12; a heavy chain variable region CDR2 having the amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 3, 6-10, 13, and 14; and a heavy chain variable region CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 4, 11, and 15; and
b) a light chain variable region CDR1 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 16, 19, 20, 23 and 72; a light chain variable region CDR2 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 17, 21, 24 and 71; and a light chain variable region CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NOs: 18, 22, and 25;
wherein the antibody or antigen-binding fragment thereof binds an epitope within amino acids 101 to 346 of human CD123 or IL3-Rα antigen and inhibits IL3-dependent proliferation in antigen-positive TF-1 cells.
2. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) an immunoglobulin heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 34; and
b) an immunoglobulin light chain variable region having the amino acid sequence set forth in SEQ ID NO: 35.
3. The antibody or antigen-binding fragment thereof of claim 2 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 34, is Phe.
4. The antibody or antigen-binding fragment thereof of claim 2 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 34, is Val.
5. A polypeptide comprising the heavy chain variable region and the light chain variable region sequences of claim 2 .
6. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) an immunoglobulin heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 34; and
b) an immunoglobulin light chain variable region having the amino acid sequence set forth in SEQ ID NO: 37.
7. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) an immunoglobulin heavy chain region having the amino acid sequence set forth in SEQ ID NO: 54; and
b) an immunoglobulin light chain variable region having the amino acid sequence set forth in SEQ ID NO: 35.
8. The antibody or antigen-binding fragment thereof of claim 7 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 54, is Phe.
9. The antibody or antigen-binding fragment thereof of claim 7 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 54, is Val.
10. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) a heavy chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 5; a heavy chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 6, 7, 8, 9, or 10; and a heavy chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 11; and
b) a light chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 19 20 or 72; a light chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 21 or 71; and a light chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 22.
11. A cell producing the antibody or antigen-binding fragment thereof of claim 1 .
12. A method of producing the antibody or antigen-binding fragment thereof of claim 1 , comprising:
(a) culturing a cell producing said antibody or antigen-binding fragment thereof; and,
(b) isolating said antibody, antigen-binding fragment thereof, or polypeptide from said cultured cell.
13. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 , and a pharmaceutically acceptable carrier.
14. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) a heavy chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 1; a heavy chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 2 or 3; and a heavy chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 4; and
b) a light chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 16; a light chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 17; and a light chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 18.
15. The antibody or antigen-binding fragment thereof of claim 1 , comprising:
a) a heavy chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 12; a heavy chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 13 or 14; and a heavy chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 15 or 70; and
b) a light chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 23; a light chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 24; and a light chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 25.
16. An antibody or antigen-binding fragment thereof, comprising:
a) a heavy chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 5; a heavy chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 8; and a heavy chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 11; and
b) a light chain variable region CDR1 having the amino acid sequence set forth in SEQ ID NO: 20; a light chain variable region CDR2 having the amino acid sequence set forth in SEQ ID NO: 21; and a light chain variable region CDR3 having the amino acid sequence set forth in SEQ ID NO: 22.
17. The antibody or antigen-binding fragment thereof of claim 16 , comprising:
a) an immunoglobulin heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 34; and
b) an immunoglobulin light chain variable region having the amino acid sequence set forth in SEQ ID NO: 35.
18. The antibody or antigen-binding fragment thereof of claim 17 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 34, is Val.
19. A polypeptide comprising the heavy chain variable region and the light chain variable region sequences of claim 17 .
20. The antibody or antigen-binding fragment thereof of claim 16 , comprising:
a) an immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO: 54; and
b) an immunoglobulin light chain variable region having the amino acid sequence set forth in SEQ ID NO: 35.
21. The antibody or antigen-binding fragment thereof of claim 20 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 54, is Val.
22. The antibody or antigen-binding fragment thereof of claim 16 , comprising:
a) an immunoglobulin heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 34; and
b) an immunoglobulin light chain having the amino acid sequence set forth in SEQ ID NO: 51.
23. The antibody or antigen-binding fragment thereof of claim 22 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 34, is Val.
24. The antibody or antigen-binding fragment thereof of claim 16 , wherein the antibody comprises:
a) an immunoglobulin heavy chain having the amino acid sequence set forth in SEQ ID NO: 54; and
b) an immunoglobulin light chain having the amino acid sequence set forth in SEQ ID NO: 51.
25. The antibody or antigen-binding fragment thereof of claim 24 , wherein Xaa, the second residue from the N-terminus of SEQ ID NO: 54, is Val.
26. A cell producing the antibody or antigen-binding fragment thereof of claim 16 .
27. A method of producing the antibody or antigen-binding fragment thereof of claim 16 , comprising:
(a) culturing a cell producing said antibody or antigen-binding fragment thereof; and,
(b) isolating said antibody, antigen-binding fragment thereof, or polypeptide from said cultured cell.
28. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 16 , and a pharmaceutically acceptable carrier.