HIV-1 neutralizing antibodies and uses thereof
The invention is directed to HIV-1 neutralizing antibodies and methods for their uses.
1. A recombinant antibody or fragment thereof comprising: a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230, SEQ ID NO: 240 or SEQ ID NO: 241, respectively and wherein the amino acid sequence of the heavy chain variable region outside of HCDR1, HCDR2, and HCDR3 has an overall sequence identity of at least 90% to SEQ ID NO: 230, SEQ ID NO: 240, or SEQ ID NO: 241; and a light chain variable region comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253, SEQ ID NO: 255 or SEQ ID NO: 261 respectively, and wherein the amino acid sequence of the light chain variable region outside of LCDR1, LCDR2, and LCDR3 has an overall sequence identity of at least 90% to SEQ ID NO: 253, SEQ ID NO: 255, or SEQ ID NO: 261, and wherein the antibody or fragment thereof binds gp41 MPER of HIV-1 envelope.
2. A recombinant antibody or fragment thereof comprising: a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230, SEQ ID NO:240, or SEQ ID NO:241 and wherein the amino acid sequence of the heavy chain variable region outside of HCDR1, HCDR2, and HCDR3 has an overall sequence identity of at least 90% to SEQ ID NO: 230, SEQ ID NO: 240, or SEQ ID NO: 241; and a light chain variable region comprising light chain complementarity determining regions (LCDRs) that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253, SEQ ID NO: 255 or SEQ ID NO: 261 and wherein the amino acid sequence of the light chain variable region outside of LCDR1, LCDR2, and LCDR3 has an overall sequence identity of at least 90% to SEQ ID NO: 253, SEQ ID NO: 255, or SEQ ID NO: 261, and wherein the antibody or fragment thereof binds gp41 MPER of HIV-1 envelope.
3. A recombinant antibody or fragment thereof comprising: a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230, SEQ ID NO: 240 or SEQ ID NO: 241, respectively and wherein the V gene usage of the heavy chain variable region is IGHV3; and a light chain variable region comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253, SEQ ID NO: 255 or SEQ ID NO: 261 respectively, and wherein the V gene usage of the light chain variable region is a kappa light chain, and wherein the antibody or fragment thereof binds gp41 MPER of HIV-1 envelope.
4. A recombinant antibody or fragment thereof comprising: a heavy chain variable region comprising heavy chain complementarity determining regions (HCDRs) that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230, SEQ ID NO:240, or SEQ ID NO:241 and wherein the V gene usage of the heavy chain variable region is IGHV3; and a light chain variable region comprising light chain complementarity determining regions (LCDRs) that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253, SEQ ID NO: 255 or SEQ ID NO: 261, and wherein the V gene usage of the light chain variable region is a kappa light chain, and wherein the antibody or fragment thereof binds gp41 MPER of HIV-1 envelope.
5. The recombinant antibody or fragment thereof of claim 3 or 4 , wherein the V gene usage of the heavy chain variable region is IGHV3-15.
6. The recombinant antibody or fragment thereof of claim 3 or 4 , wherein the V gene usage of the light chain variable region is IGKV1-39.
7. The recombinant antibody or fragment thereof of claim 3 or 4 , wherein the V gene usage of the heavy chain variable region is IGHV3-15 and the V gene usage of the light chain variable region is IGKV1-39.
8. The recombinant antibody or fragment thereof of claim 5 , wherein the J gene usage of the heavy chain variable region is IGHJ6.
9. The recombinant antibody or fragment thereof of claim 5 , wherein the J gene usage of the light chain variable region is IGKJ2.
10. The recombinant antibody or fragment thereof of claim 1 or 3 , comprising: a heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230 and a LCDR1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253.
11. The recombinant antibody or fragment thereof of claim 1 or 3 , comprising: a heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230 and a LCDR1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 255.
12. The recombinant antibody or fragment thereof of claim 1 or 3 , comprising: a heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 240 and a LCDR1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 261.
13. The recombinant antibody or fragment thereof of claim 1 or 3 , comprising: a heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 241 and a LCDR1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 261.
14. The recombinant antibody or fragment thereof of claim 2 or 4 , comprising: a heavy chain variable region comprising HCDRs that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230; and a light chain variable region comprising LCDRs that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253.
15. The recombinant antibody or fragment thereof of claim 2 or 4 , comprising: a heavy chain variable region comprising HCDRs that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230; and a light chain variable region comprising LCDRs that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 255.
16. The recombinant antibody or fragment thereof of claim 2 or 4 , comprising: a heavy chain variable region comprising HCDRs that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 240; and a light chain variable region comprising LCDRs that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 261.
17. The recombinant antibody or fragment thereof of claim 2 or 4 , comprising: a heavy chain variable region comprising HCDRs that have an overall HCDR sequence identity of at least 90% to HCDR amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 241; and a light chain variable region comprising LCDRs that have an overall LCDR sequence identity of at least 90% to LCDR amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 261.
18. A bispecific antibody comprising the recombinant antibody or fragment thereof of any one of claims 1 - 4 .
19. The recombinant antibody or fragment thereof of any one of claims 1 - 4 wherein the antibody or fragment thereof comprises an Fc portion that is modified compared to a naturally occurring Fc domain.
20. A pharmaceutical composition comprising any one of the antibodies or fragments thereof of any one of claims 1 - 4 , or any combination thereof.
21. The pharmaceutical composition of claim 20 , further comprising another HIV-1 neutralizing antibody.
22. A pharmaceutical composition comprising a vector, the vector comprising a nucleic acid encoding an antibody or fragment thereof comprising a heavy chain variable region comprising a heavy chain variable region comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 comprising amino acids at positions 26-33, 51-60 and 99-121 of SEQ ID NO: 230, SEQ ID NO: 240 or SEQ ID NO: 241, respectively; and a light chain variable region comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3, comprising amino acids at positions 27-32, 50-52 and 89-99 of SEQ ID NO: 253, SEQ ID NO: 255 or SEQ ID NO: 261 respectively, wherein the antibody or fragment thereof binds gp41 MPER of HIV-1 envelope.
23. The pharmaceutical composition of claim 22 , wherein the vector is suitable for gene delivery and expression.
24. A pharmaceutical composition comprising a vector, the vector comprising a nucleic acid encoding an antibody or fragment thereof of any one of claims 1 - 4 .
25. The pharmaceutical composition of claim 24 , wherein the vector is suitable for gene delivery and expression.
26. A method to inhibit HIV-1 infection in a subject comprising administering to the subject the pharmaceutical composition of claim 20 in an effective amount.
27. The method of claim 26 , wherein the pharmaceutical composition is administered in an effective regimen.
28. The method of claim 26 further comprising administering an additional HIV-1 neutralizing antibody.