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US-12617843-B2 - Human broadly neutralizing antibodies against the membrane-proximal external region of HIV Env for vaccine design and intervention

US12617843B2US 12617843 B2US12617843 B2US 12617843B2US-12617843-B2

Abstract

The present disclosure relates to anti-HIV antibodies and their use in the treatment or prevention of HIV/AIDS and in the development of HIV vaccines.

Inventors

  • Michael Zwick
  • Lei Zhang
  • Adriana IRIMIA
  • Jiang Zhu
  • Ian Wilson

Assignees

  • THE SCRIPPS RESEARCH INSTITUTE

Dates

Publication Date
20260505
Application Date
20201014

Claims (17)

  1. 1 . An isolated monoclonal antibody or antigen-binding fragment thereof that binds Human Immunodeficiency Virus (HIV) envelope glycoprotein (Env) membrane-proximal external region (MPER) and comprises a heavy chain variable region (VH) comprising a VH CDR1, VH CDR2, and VH CDR3 and a light chain variable region (VL) comprising a VL CDR1, VL CDR2, and VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and VL CDR3 comprise the amino acid sequence of (a) SEQ ID NO: 61, 62, 63, 70, 71, and 72, respectively, or (b) SEQ ID NO: 64, 65, 66, 73, 74, and 75, respectively, wherein the HIV Env MPER comprises the amino acid sequence of DLLALDRWQNLWNWFDITNWLWYIK (SEQ ID NO: 2).
  2. 2 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the VH and VL comprise the amino acid sequence of SEQ ID NO: 5 and 8, respectively, or SEQ ID NO: 6 and 9, respectively.
  3. 3 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is not PGZL1, or PGZL1.H4K3.
  4. 4 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 characterized by one or more of: (a) the isolated monoclonal antibody or antigen-binding fragment thereof is a recombinant antibody, a chimeric antibody, a bispecific antibody, or a trispecific antibody; and (b) the isolated monoclonal antibody or antigen-binding fragment thereof comprises a single-chain Fv (scFv), Fab fragment, or F(ab′)2 fragment.
  5. 5 . A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient.
  6. 6 . An isolated polynucleotide encoding the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 .
  7. 7 . The isolated polynucleotide of claim 6 , wherein the polynucleotide comprises an mRNA.
  8. 8 . A host cell comprising the polynucleotide of claim 6 .
  9. 9 . A method of producing the isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 comprising culturing a host cell comprising an expression vector comprising a polynucleotide encoding the isolated monoclonal antibody or antigen-binding fragment thereof so that the isolated monoclonal antibody or antigen-binding fragment thereof is expressed and the isolated monoclonal antibody or antigen-binding fragment thereof is produced.
  10. 10 . A method of neutralizing an HIV virus comprising contacting the virus with a sufficient amount of the isolated monoclonal antibody or antigen-binding fragment thereof of claim 2 , wherein the VH and VL comprise the amino acid sequence of SEQ ID NO: 6 and 9, respectively.
  11. 11 . A method of reducing the likelihood of becoming infected by a subject exposed to HIV comprising administering to the subject a therapeutically sufficient amount of the isolated monoclonal antibody or antigen-binding fragment thereof of claim 2 , wherein the VH and VL comprise the amino acid sequence of SEQ ID NO: 6 and 9, respectively.
  12. 12 . A method of treating HIV/AIDS comprising administering to a subject in need thereof a therapeutically sufficient amount of the isolated monoclonal antibody or antigen-binding fragment thereof of claim 2 , wherein the VH and VL comprise the amino acid sequence of SEQ ID NO: 6 and 9, respectively.
  13. 13 . The method of claim 12 , further comprising administering at least one additional therapeutic agent.
  14. 14 . The method of claim 11 characterized by one or more of: (a) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy and/or light chain constant region; (b) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a human heavy and/or light chain constant region; (c) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region selected from the group consisting of a human immunoglobulin IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 constant region; (d) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising a native amino acid sequence; (e) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising a non-native variant amino acid sequence; (f) wherein the isolated monoclonal antibody or antigen-binding fragment thereof is a recombinant antibody, a chimeric antibody, a bispecific antibody, or a trispecific antibody; and (g) wherein the isolated monoclonal antibody or antigen-binding fragment thereof comprises a single-chain Fv (scFv), Fab fragment, or F(ab′)2 fragment.
  15. 15 . The method of claim 12 characterized by one or more of: (a) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy and/or light chain constant region; (b) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a human heavy and/or light chain constant region; (c) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region selected from the group consisting of a human immunoglobulin IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 constant region; (d) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising a native amino acid sequence; (e) wherein the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region comprising a non-native variant amino acid sequence; (f) wherein the isolated monoclonal antibody or antigen-binding fragment thereof is a recombinant antibody, a chimeric antibody, a bispecific antibody, or a trispecific antibody; and (g) wherein the isolated monoclonal antibody or antigen-binding fragment thereof comprises a single-chain Fv (scFv), Fab fragment, or F(ab′)2 fragment.
  16. 16 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 characterized by one or more of: (a) the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy and/or light chain constant region; (b) the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a human heavy and/or light chain constant region; and (c) the isolated monoclonal antibody or antigen-binding fragment thereof further comprises a heavy chain constant region selected from the group consisting of a human immunoglobulin IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 constant region.
  17. 17 . The isolated monoclonal antibody or antigen-binding fragment thereof of claim 1 further comprising a heavy chain constant region comprising a non-native variant amino acid sequence.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is the U.S. national phase of International Application No. PCT/US2020/055486, filed Oct. 14, 2020, which designated the U.S. and claims the benefit of U.S. Provisional Application No. 62/914,640, filed Oct. 14, 2019, each of which is incorporated herein by reference in its entirety. GOVERNMENT INTEREST This invention was made with government support under Grant Nos. AI011244, AI114401, AI143563, AI100663 and AI144462 awarded by the NIH. The government has certain rights in the invention. FIELD OF THE INVENTION The field of the invention generally relates to anti-HIV antibodies and their use in the treatment or prevention of HIV/AIDS, and in the development of HIV vaccines. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY The content of the electronically submitted sequence listing (Name: 6761_0310_Sequence_Listing.txt; Size: 129 kilobytes; and Date of Creation: Apr. 12, 2022) filed with the application is incorporated herein by reference in its entirety. BACKGROUND A key goal in HIV vaccine design is to elicit broadly neutralizing antibodies (bnAbs). Burton & Hangartner, Annu Rev Immunol 34, 635-659 (2016). Most bnAbs to HIV-1 have been cloned from elite donors whose plasma shows broad neutralizing activity. These bnAbs target six distinct sites on the HIV-1 envelope glycoprotein (Env) spike, including the CD4-binding site (CD4bs), V2 apex, N332/V3 base supersite, silent face, gp120-gp41 interface including the fusion peptide, and membrane-proximal external region (MPER). As bnAbs arise from complex affinity maturation pathways, efforts are underway to dissect the structural and genetic bases of bnAb function to uncover common elements that can simplify vaccine design. Kwong & Mascola, Immunity 48, 855-871 (2018). MPER bnAbs show outstanding breadth, neutralizing up to >98% primary isolates, but have uncommon features. Molinos-Albert et al., Front. Immunol. 8, 1154 (2017). MPER bnAbs are often from the IgG3 subtype, which has caused speculation that eliciting these bnAbs involves certain B cell subsets, class-switching, or a specific hinge region. Haynes B F et al., Hum. Antibodies 14, 59-67 (2005); Krebs S J, et al., Immunity 50, 677-691 e613 (2019). While 2F5, 4E10, 10E8, DH511, DH517, VRC46 and VRC43.01 are IgG3s, the MPER bnAb VRC42 was isolated as an IgG1 from the same subject as the latter two bnAbs. Krebs S J, et al., Immunity 50, 677-691 e613 (2019). Notably, long heavy complementarity-determining region (CDR) H3 loops with aromatic residues at the tip facilitate bnAb binding to the hydrophobic MPER and nearby membrane. Irimia A, et al., Immunity 44, 21-31 (2016). However, B cell receptors (BCRs) with long and hydrophobic CDRH3s tend to be down-regulated during B cell ontogeny, and some MPER bnAbs, e.g. 4E10, are mildly polyreactive. Ivanov I I, et al., J Immunol 174, 7773-7780 (2005); Haynes B F, et al., Science 308, 1906-1908 (2005). Further, 4E10 knock-in mice exhibit B cell tolerance via clonal deletion and anergy. Doyle-Cooper C, et al., J Immunol 191, 3186-3191(2013). BnAbs 10E8 and DH511 were recently shown to recognize a similar epitope as 4E10 with less polyreactivity and higher potency, but key information is missing on the precise antigens and mechanisms that drove their evolution. Huang J, et al., Nature 491, 406-412 (2012); Williams L D, et al., Sci Immunol 2, eaa12200 (2017). The hydrophobic MPER is often truncated from Env constructs to render soluble gp140 trimers; thus, the MPER has been commonly studied in isolation. Sanders R W, et al., PLoS Pathog 9, e1003618 (2013). MPER peptide, N671WFDITNWLWYIK683 (residues 1-13 of SEQ ID NO: 146), adopts a mainly α-helical conformation with W672-D674 in a 310 helix when bound to 4E10 and is fully helical when bound to 10E8 and DH511. Williams L D, et al., Sci Immunol 2, eaa12200 (2017); Cardoso R M, et al., Immunity 22, 163-173 (2005). However, MPER peptides constrained as an α-helix have not elicited nAbs. Molinos-Albert L M, et al., Front. Immunol. 8, 1154 (2017). One issue is that the membrane can hinder antibody access to the MPER on the virus. Irimia A, et al., Immunity 44, 21-31 (2016). Further, cryo-EM reconstructions have revealed interaction of 10E8 with N-linked glycans on membrane extracted Env at positions 88 and 625. Lee J H, et al., Science 351, 1043-1048 (2016). Thus, elicited antibodies should accommodate membrane and adjacent glycans on the Env trimer. MPER accessibility increases transiently when Env binds to CD4 receptor, just prior to co-receptor binding and virus entry into host cells, but structural details of this transient state are lacking. Recently, vaccine design has focused on targeting common elements among certain bnAb precursors. For example, VRC01-class CD4bs antibodies typically use germline gene VH1-2, for which specific immunogens have been designed. Jardine J G, et al., Science 351, 1458-1463 (2016). Germline-encoded residues important for Env