Methods of treating HIV-1 infection utilizing broadly neutralizing human immunodeficiency virus type 1 (HIV-1) GP120-specific monoclonal antibodies
The invention provides a method for obtaining a broadly neutralizing antibody (bNab), including screening memory B cell cultures from a donor PBMC sample for neutralization activity against a plurality of HIV-1 species, cloning a memory B cell that exhibits broad neutralization activity; and rescuing a monoclonal antibody from that memory B cell culture. The resultant monoclonal antibodies may be characterized by their ability to selectively bind epitopes from the Env proteins in native or monomeric form, as well as to inhibit infection of HIV-1 species from a plurality of clades. Compositions containing human monoclonal anti-HIV antibodies used for prophylaxis, diagnosis and treatment of HIV infection are provided. Methods for generating such antibodies by immunization using epitopes from conserved regions within the variable loops of gp120 are provided. Immunogens for generating anti-HIV1 bNAbs are also provided. Furthermore, methods for vaccination using suitable epitopes are provided.
1. A non-naturally occurring PGT-124 monoclonal antibody comprising (a) a light chain variable region comprising three complementarity determining regions having the amino acid sequences of SEQ ID NOs: 415, 151, and 416 and (b) a heavy chain variable region comprising three complementarity determining regions having the amino acid sequences of SEQ ID NOs: 406, 407, and 408, wherein the CDRs are per Kabat definition, wherein the antibody comprises an engineered Fc region incorporating a salvage receptor binding epitope, thereby exhibiting increased serum half-life through enhanced interaction with the neonatal Fc receptor (FcRn).
2. The antibody of claim 1 , comprising a light chain variable region having the amino acid sequence of SEQ ID NO: 414 and a heavy chain variable region having the amino acid sequence of SEQ ID NO: 405.
3. The antibody of claim 1 , comprising a light chain having the amino acid sequence of SEQ ID NO: 413 and a heavy chain having the amino acid sequence of SEQ ID NO: 404.
4. An antigen-binding fragment of the antibody according to claim 1 .
5. The antigen-binding fragment of the antibody according to claim 4 , which is selected from the group consisting of the Fab, Fab′, F(ab′)2, Fv, single chain Fv, diabody, and domain antibody (dAb) fragments.
6. A nucleic acid molecule encoding the antibody according to claim 1 , wherein the nucleic acid molecule encodes a light chain variable region comprising the nucleic acid sequence of SEQ ID NO: 412 and a heavy chain variable region comprising the nucleic acid sequence of SEQ ID NO: 403.
7. A nucleic acid molecule encoding the antibody according to claim 1 , wherein the nucleic acid molecule encodes a light chain sequence comprising the nucleic acid sequence of SEQ ID NO: 411 and a heavy chain sequence comprising the nucleic acid sequence of SEQ ID NO: 402.
8. The nucleic acid molecule according to claim 6 , which is selected from the group consisting of cDNA, hnRNA, and mRNA.
9. A vector comprising the nucleic acid molecule according to claim 6 .
10. A cell comprising the vector according to claim 8 .
11. An immortalized B cell clone expressing the antibody according to claim 1 .
12. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising the nucleic acid molecule of claim 6 and a pharmaceutically acceptable carrier.
14. A method of treating an HIV-1 infection, or for post-exposure prophylaxis comprising administering a pharmaceutical composition, in an effective amount, comprising the antibody of claim 1 to a patient in need thereof.
15. A method of treating an HIV-1 infection, or for post-exposure prophylaxis comprising administering a pharmaceutical composition, in an effective amount comprising the nucleic acid molecule of claim 6 to a patient in need thereof;
wherein the nucleic acid molecule comprises a DNA expression system comprising a promoter and leader sequence operably linked to the variable region sequence, and/or operably linked to an origin of replication, and/or operably linked to one or more selectable markers, and/or operably linked to one or more control elements/regulatory sequences.
16. A method for producing the antibody of claim 1 , comprising the steps of (i) culturing a host cell that expresses the antibody of claim 1 and (ii) isolating the antibody.