Methods of treating HIV-1 infection utilizing broadly neutralizing human immunodeficiency virus type 1 (HIV-1) GP120-specific monoclonal antibodies

Patent metadata

Field	Value
Publication number	US-11319362-B2
Application number	US-201916591175-A
Country	US
Kind code	B2
Filing date	Oct 2, 2019
Priority date	Aug 31, 2010
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

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.

First claim

The invention claimed is:

1. A method of passive immunization or treating an HIV-1 infection comprising the step of administering to a patient in need thereof, an effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion thereof comprising (a) a light chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 150, 151, and 152 and (b) a heavy chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 143, 144, and 145.

2. A method of passive immunization or treating an HIV-1 infection comprising the step of administering to a patient in need thereof, an effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion thereof comprising (a) a light chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 150, 151, and 152 and (b) a heavy chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 90, 265, and 143.

3. The method of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 79 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149.

4. The method of claim 2 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 79 and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149.

5. The method of claim 1 , wherein the antibody has a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 66 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 148.

6. The method of claim 2 , wherein the antibody has a heavy chain sequence comprising the amino acid sequence of SEQ ID NO: 66 and a light chain sequence comprising the amino acid sequence of SEQ ID NO: 148.

7. The method of claim 1 , wherein the passive immunization or treating an HIV-1 infection comprises inhibiting HIV-1 viral replication.

8. The method of claim 2 , wherein the passive immunization or treating an HIV-1 infection comprises inhibiting HIV-1 viral replication.

9. The method of claim 1 , wherein the PGT-121 monoclonal antibody or antigen binding portion thereof is encoded by an immortalized B cell clone.

10. The method of claim 2 , wherein the PGT-121 monoclonal antibody or antigen binding portion thereof is encoded by an immortalized B cell clone.

11. The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable carrier.

12. The method of claim 2 , wherein the composition further comprises a pharmaceutically acceptable carrier.

13. The method of claim 11 , wherein the pharmaceutically acceptable carrier is a buffer, antioxidant, a 10 residue or less polypeptide, a protein, a hydrophilic polymer, an amino acid, a sugar, carbohydrate; a chelating agent, a sugar alcohol, a salt-forming counterion, a nonionic surfactant.

14. The method of claim 13 , wherein the buffer is an acetate, Tris, phosphate, citrate or organic acid; the antioxidant is an ascorbic acid or methionine; the protein is a serum albumin, gelatin or immunoglobulin; the hydrophilic polymer is serum albumin, gelatin, immunoglobulin; the amino acid is glycine, glutamine, asparagine, arginine or lysine; the sugar is a monosaccharide, disaccharide, sucrose, mannitol, trehalose or sorbitol; the carbohydrate is glucose, mannose or dextrin, the chelating agent is EDTA, the sugar alcohol is mannitol or sorbitol; the salt-forming counterion is sodium or the non-ionic surfactant is TWEEN® (polysorbate), polyethylene glycol (PEG) or PLURONICS® (poloxamer).

15. The method of claim 12 , wherein the pharmaceutically acceptable carrier is a buffer, antioxidant, a 10 residue or less polypeptide, a protein, a hydrophilic polymer, an amino acid, a sugar, carbohydrate; a chelating agent, a sugar alcohol, a salt-forming counterion, a nonionic surfactant.

16. The method of claim 15 , wherein the buffer is an acetate, Tris, phosphate, citrate or organic acid; the antioxidant is an ascorbic acid or methionine; the protein is a serum albumin, gelatin or immunoglobulin; the hydrophilic polymer is serum albumin, gelatin, immunoglobulin; the amino acid is glycine, glutamine, asparagine, arginine or lysine; the sugar is a monosaccharide, disaccharide, sucrose, mannitol, trehalose or sorbitol; the carbohydrate is glucose, mannose or dextrin, the chelating agent is EDTA, the sugar alcohol is mannitol or sorbitol; the salt-forming counterion is sodium or the non-ionic surfactant is TWEEN® (polysorbate), polyethylene glycol (PEG) or PLURONICS® (poloxamer).

17. The method of claim 1 , wherein the therapeutically effective amount of a non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion thereof is in a sustained-release preparation.

18. The method of claim 17 , wherein the sustained-release preparation is a semi-permeable matrix of solid hydrophobic polymers containing the antibody.

19. The method of claim 18 , wherein the sustained-released matrix is a polyester, hydrogel, polylactide, copolymer of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate or degradable lactic acid-glycolic acid copolymer.

20. The method of claim 19 , wherein the hydrogel is a poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol) or the degradable lactic acid-glycolic acid copolymer is an injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate or and poly-D-(−)-3-hydroxyburyric acid.

21. The method of claim 2 , wherein the therapeutically effective amount of a non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion thereof is in a sustained-release preparation.

22. The method of claim 21 , wherein the sustained-release preparation is a semi-permeable matrix of solid hydrophobic polymers containing the antibody.

23. The method of claim 22 , wherein the sustained-released matrix is a polyester, hydrogel, polylactide, copolymer of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate or degradable lactic acid-glycolic acid copolymer.

24. The method of claim 23 , wherein the hydrogel is a poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol) or the degradable lactic acid-glycolic acid copolymer is an injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate or and poly-D-(−)-3-hydroxyburyric acid.

25. The method of claim 1 , wherein the patient has contacted a person infected with HIV-1 or who has been exposed to HIV-1.

26. The method of claim 2 , wherein the patient has contacted a person infected with HIV-1 or who has been exposed to HIV-1.

27. The method of claim 1 , wherein the administering is intravenous, intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intrathecal, oral, topical, inhalation or parenteral.

28. The method of claim 2 , wherein the administering is intravenous, intramuscular, intraperitoneal, intracerobrospinal, subcutaneous, intra-articular, intrasynovial, intratheca

Assignees

• Theraclone Sciences Inc
• Scripps Research Inst
• Int Aids Vaccine Initiative

Inventors

• Chan-Hui Po-Ying
• Doores Katherine
• Huber Michael
• Kaminsky Stephen
• Frey Steven
• Olsen Ole
• Mitcham Jennifer
• Moyle Matthew
• Phogat Sanjay K
• Burton Dennis R
• Walker Laura Marjorie
• Poignard Pascal Raymond Georges
• Koff Wayne
• Simek-Lemos Melissa Danielle De Jean De St Marcel

Classifications

• C07K16/114

  Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV] · CPC title

• C07K16/1145 Primary

  Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site · CPC title

• A61K39/21

  Retroviridae, e.g. equine infectious anemia virus · CPC title

• C07K2317/515

  Complete light chain, i.e. VL + CL · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title