Broadly neutralizing anti-HIV-1 antibodies that bind to an N-glycan epitope on the envelope
This invention relates to novel anti-HIV antibodies that can be used in the treatment and detection of human immunodeficiency virus (HIV). These antibodies exhibit a high degree of sensitivity and can provide a broad range of specificity.
1. An antibody or antigen-binding fragment thereof that specifically binds to an N-glycan epitope of HIV-1 Env, comprising:
(a) a heavy chain variable domain (V H ) comprising: a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 23, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 24, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 25; and
(b) a light chain variable domain (V L ) comprising: a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 26, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 28.
2. The antibody or antigen-binding fragment of claim 1 , comprising:
(a) a V H sequence having the amino acid sequence of SEQ ID NO: 3 or up to 5% variation thereof, wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO: 23, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 24, and CDR-H3 comprises the amino acid sequence of SEQ ID NO: 25, and wherein CDR-H1, CDR-H2, and CDR-H3 are invariant; and
(b) a V L sequence having the amino acid sequence of SEQ ID NO: 4 or up to 5% variation thereof, wherein CDR-L1 comprises the amino acid sequence of SEQ ID NO: 26, CDR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 28, and wherein CDR-L1, CDR-L2, and CDR-L3 are invariant;
wherein the antibody or antigen-binding fragment retains the ability to bind to HIV-1.
3. The antibody or antigen-binding fragment of claim 1 , comprising a V H sequence having the amino acid sequence of SEQ ID NO: 3 and a V L sequence having the amino acid sequence of SEQ ID NO: 4.
4. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment binds to or is capable of binding to an N-glycan epitope of HIV-1 Env with an affinity of 1 nM or less.
5. The antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment inhibits the infectivity of two or more strains or subtypes of HIV-1.
6. The antibody or antigen-binding fragment of claim 1 , wherein the HIV-1 is group M HIV-1.
7. The antibody of claim 1 , wherein the antibody is glycoengineered to modify the oligosaccharides in the Fc region, and wherein the antibody has increased ADCC effector function as compared to a non-glycoengineered antibody.
8. The antibody of claim 1 , wherein the antibody is a monoclonal antibody.
9. The antibody of claim 1 , wherein the antibody is a human antibody, a humanized antibody, or a chimeric antibody.
10. The antibody of claim 9 , wherein the antibody is a full-length IgG class antibody.
11. The antigen-binding fragment of claim 1 , wherein the antigen-binding fragment is a single chain variable fragment (scFv).
12. An isolated nucleic acid encoding the antibody or antigen-binding fragment of claim 1 .
13. A vector comprising the nucleic acid of claim 12 .
14. An isolated host cell comprising the vector of claim 13 .
15. A method for making an antibody or antigen-binding fragment that specifically binds to an N-glycan epitope of HIV-1 Env, the method comprising:
(a) culturing the cell of claim 14 in a medium under conditions permitting expression of a polypeptide encoded by the vector and assembling of an antibody or antigen-binding fragment thereof; and
(b) purifying the antibody or antigen-binding fragment from the cultured cell or the medium of the cell.
16. An immunoconjugate comprising the antibody or antigen-binding fragment of claim 1 and a therapeutic agent.
17. A fusion protein or conjugate comprising the antibody or antigen-binding fragment of claim 1 .
18. A pharmaceutical formulation comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier.
19. A method of neutralizing HIV-1, comprising administering to the individual an effective amount of the antibody or antigen-binding fragment of claim 1 .
20. A method of neutralizing HIV-1, comprising administering to the individual an effective amount of the immunoconjugate of claim 16 .
21. A method of detecting HIV-1, comprising
(a) contacting a sample with the antibody or antigen-binding fragment of claim 1 under conditions permissive for formation of a complex between the antibody or antigen-binding fragment and HIV-1 present in the sample, and
(b) detecting the presence or absence of the complex, optionally by an immunodetection method.
22. A kit comprising a pharmaceutically acceptable dosage unit of a pharmaceutically effective amount of at least one isolated antibody or antigen-binding fragment according to claim 1 .
23. A kit comprising at least one isolated antibody or antigen-binding fragment according to claim 1 , and one or more detection reagents that specifically bind to the antibody or antigen-binding fragment.