Anti-FLT3 antibodies
The present invention relates to anti-FLT3 antibodies with a modified Fc region comprising the amino acid substitutions 239D and 332E to enhance antibody-dependent cell cytotoxicity (ADCC) of these antibodies. The invention further relates to pharmaceutical compositions containing these antibodies, nucleic acids encoding these antibodies as well as methods of using such antibodies.
1. An antibody that binds human receptor tyrosine kinase FLT3, said antibody comprising a heavy chain and a light chain, the heavy chain comprising a V H CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:4, a V H CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:5, and a V H CDR3 region comprising or consisting of the amino acid sequence set forth in SEQ ID NO:6, and the light chain comprising a V L CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:1, a V L CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:2, and a V L CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:3, and the amino acid substitutions S239D and 1332E in the constant region relative to a parent anti-FLT3 antibody, wherein the positional numbering is according to the EU index.
2. The antibody of claim 1 , wherein the antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) effector function.
3. The antibody of claim 1 , wherein said antibody binds with enhanced affinity to the FcγRIIIa receptor or has enhanced ADCC effector function as compared to the parent antibody.
4. The antibody of claim 1 , wherein the heavy chain comprises a V H domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:14 and the light chain comprises a V L domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:13.
5. The antibody of claim 1 , wherein the antibody is a chimeric antibody and comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO:27 and a light chain having the amino acid sequence set forth in SEQ ID NO:23.
6. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
7. A nucleic acid molecule encoding a heavy and a light chain of the antibody of claim 1 .
8. The nucleic acid molecule of claim 7 , wherein the nucleic acid molecule comprises a nucleotide sequence encoding the variable domain of the light chain as set forth in SEQ ID NO: 17 and wherein the nucleic acid molecule comprises a nucleotide sequence encoding the variable domain of the heavy chain as set forth in SEQ ID NO: 18.
9. The nucleic acid molecule of claim 7 , wherein the nucleic acid molecule encoding the light chain of the antibody has a nucleotide sequence as set forth in SEQ ID NO: 24 and the nucleic acid molecule encoding the heavy chain of the antibody has a nucleotide sequence as set forth in SEQ ID NO:28.
10. A transfected cell line capable of producing an antibody according to claim 1 .
11. An antibody that binds human receptor tyrosine kinase FLT3, said antibody comprising a heavy chain and a light chain, the light chain comprising a V L CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:7; a V L CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:8; a V L CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:9; the heavy chain comprising a V H CDR1 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:10; a V H CDR2 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:11; and a V H CDR3 comprising or consisting of the amino acid sequence set forth in SEQ ID NO:12, and the amino acid substitutions S239D and 1332E in the constant region relative to a parent anti-FLT3 antibody, wherein the positional numbering is according to the EU index.
12. The antibody of claim 11 , wherein the antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) effector function.
13. The antibody of claim 11 , wherein said antibody binds with enhanced affinity to the FcγRIIIa receptor or has enhanced ADCC effector function as compared to the parent antibody.
14. The antibody of claim 11 , wherein the heavy chain comprises a V H domain comprising or consisting of the amino acid sequence set forth in SEQ ID NO:30 and the light chain comprises a V L domain comprising, consisting essentially of or consisting of the amino acid sequence set forth in SEQ ID NO:29.
15. The antibody of claim 11 , wherein the antibody is a chimeric antibody and comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO:43 and a light chain having the amino acid sequence set forth in SEQ ID NO:39.
16. A pharmaceutical composition comprising the antibody of claim 11 and a pharmaceutically acceptable carrier.
17. A nucleic acid molecule encoding a heavy and a light chain of the antibody of claim 11 .
18. The nucleic acid molecule of claim 17 , wherein the nucleic acid molecule comprises a nucleotide sequence encoding the variable domain of the light chain as set forth in SEQ ID NO: 33 and wherein the nucleic acid molecule comprises a nucleotide sequence encoding the variable domain of the heavy chain as set forth in SEQ ID NO: 34.
19. The nucleic acid molecule of claim 17 , wherein the nucleic acid molecule encoding the light chain of the antibody has a nucleotide sequence as set forth in SEQ ID NO: 40 and the nucleic acid molecule encoding the heavy chain of the antibody has a nucleotide sequence as set forth in SEQ ID NO:44.
20. A transfected cell line capable of producing an antibody according to claim 11 .