Antibody therapies for human immunodeficiency virus (HIV)

Patent metadata

Field	Value
Publication number	US-12459989-B2
Application number	US-201917295798-A
Country	US
Kind code	B2
Filing date	Nov 19, 2019
Priority date	Nov 21, 2018
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

Featured are PGDM1400 variant antibodies or fragments thereof, which can be administered, e.g., as antibody therapies for treating human immunodeficiency virus (HIV) infection. In particular, featured are methods of treating or curing subjects infected with HIV and/or preventing HIV infections in subjects at risk of HIV transmission using the PGDM1400 variant antibodies or fragments thereof.

First claim

The invention claimed is:

1 . An antibody or antigen-binding fragment thereof comprising:
(a) a heavy chain variable domain comprising a sequence with at least 98% sequence identity to SEQ ID NO: 136; and (b) a light chain variable domain comprising a sequence with at least 97% sequence identity to SEQ ID NO: 135 and an F2I mutation, wherein the antibody is a V2-specific antibody and the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) complementarity determining region (CDR) HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 12, a HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 14, a HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 16, a light chain (LC)-CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 8.

2 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody comprises:
(a) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 144; (b) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 164; (c) a heavy chain variable domain comprising the sequence of SEQ ID NO: 175 and a light chain variable domain comprising the sequence of SEQ ID NO: 174; (d) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 176; (e) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 177; (f) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 178; (g) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 179; (h) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 187; (i) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 188; (j) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 189; (k) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 190; (l) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 191; (m) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 196; (n) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 197; (o) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 198; (p) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 199; or (q) a heavy chain variable domain comprising the sequence of SEQ ID NO: 136 and a light chain variable domain comprising the sequence of SEQ ID NO: 201.

3 . The antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof is (d).

4 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof exhibits one or more of the following properties:
(a) increased solubility in a PEG 10,000 concentration of 6-10%; (b) increased stability at a pH less than pH 5.0; (c) increased thermal stability at a temperature in the range of 20-95° C.; and/or (d) increased chemical stability, wherein the antibody or antigen-binding fragment thereof is resistant to chemical denaturation by at least 2M guanidine hydrochloride (GuHCl) or greater, as compared to an antibody or antigen-binding fragment thereof lacking the F2I mutation in the heavy chain variable domain and/or the light chain variable domain.

5 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof exhibits one or more of the following properties:
(a) increased storage stability, wherein the antibody or antigen-binding fragment thereof:
(i) does not aggregate during storage over a period of time, wherein optionally the period of time is about 2 days;
(ii) exhibits more than about 60% high monomer content and/or less than about 10% low oligomer content; and
(b) increased manufacturability, wherein the antibody or antigen-binding fragment thereof does not aggregate during manufacture.

6 . The antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of a monoclonal antibody or antigen-binding fragment thereof, a polyclonal antibody or antigen-binding fragment thereof, a human antibody or antigen-binding fragment thereof, a humanized antibody or antigen-binding fragment thereof, a primatized antibody or antigen-binding fragment thereof, a bispecific antibody or antigen-binding fragment thereof, a multi-specific antibody or antigen-binding fragment thereof, a dual-variable immunoglobulin domain, a monovalent antibody or antigen-binding fragment thereof, a chimeric antibody or antigen-binding fragment thereof, a single-chain Fv molecule (scFv), a diabody, a triabody, a single-domain antibody, an antibody-like protein scaffold, a domain antibody, a Fv fragment, a Fab fragment, a F(ab′) 2 molecule, and a tandem scFv (taFv).

7 . A polynucleotide encoding the antibody or antigen-binding fragment thereof of claim 1 .

8 . A vector comprising the polynucleotide of claim 7 .

9 . The vector of claim 8 , wherein the vector is an expression vector or a viral vector.

10 . The vector of claim 9 , wherein:
(a) the expression vector is a prokaryotic or eukaryotic expression vector; or (b) the viral vector is selected from the group consisting of an adenovirus (Ad), a retrovirus, a poxvirus, an adeno-associated virus, a baculovirus, a herpes simplex virus, and a vaccinia virus.

11 . The viral vector of claim 10 , wherein:
(a) the adenovirus is a serotype 2, 5, 11, 12, 24, 26, 34, 35, 40, 48, 49, 50, 52, or Pan9 adenovirus, or a human, chimpanzee, or rhesus adenovirus; (b) the retrovirus is a γ-retrovirus or a lentivirus; or (c) the vaccinia virus is a modified vaccinia Ankara (MVA).

12 . An isolated host cell comprising the polynucleotide of claim 7 or a vector comprising the polynucleotide.

13 . A composition comprising the antibody or antigen-binding fragment thereof of claim 1 , a polynucleotide encoding the antibody or antigen-binding fragment thereof, a vector comprising the polynucleotide, or a host cell comprising the polynucleotide or the vector.

14 . The composition of claim 13 , wherein the composition further comprises:
(a) a pharmaceutically acceptable carrier, excipient, or diluent; (b) an immunomodulator; (c) at least one reservoir activator; (d) an antiretroviral agent (ARV); or (e) one, two, three, or more different HIV-specific broadly neutralizing antibodies (bnAb).

Assignees

• Beth Israel Deaconess Medical Ct Inc

Inventors

• Barouch Dan H
• Kerwin Bruce A
• Ketchem Randal R
• Gillespie Alison J
• Siska Christine C
• Clark Rutilio H
• Floyd Julee A
• Shaver Jeremy M

Classifications

• C07K16/114 Primary

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

• C07K16/1145

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

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title