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CN-122003433-A - Broad spectrum neutralizing antibodies targeting V3 glycan sites on HIV ENV

CN122003433ACN 122003433 ACN122003433 ACN 122003433ACN-122003433-A

Abstract

The present invention relates to monoclonal human antibodies or binding fragments thereof directed against the V3 glycan site of human immunodeficiency virus HIV-1, pharmaceutical compositions comprising such monoclonal human antibodies or binding fragments thereof, kits comprising such antibodies or binding fragments thereof, as well as monoclonal antibodies or binding fragments thereof for use as a medicament and for the treatment or prevention of diseases caused by human immunodeficiency virus HIV-1, as well as pharmaceutical compositions and kits.

Inventors

  • F. Klein
  • L. Gizelman

Assignees

  • 科隆大学

Dates

Publication Date
20260508
Application Date
20241014
Priority Date
20231013

Claims (17)

  1. 1. An antibody or antigen-binding fragment thereof directed against the V3 glycan site of human immunodeficiency virus HIV-1, wherein the antibody or antigen-binding fragment thereof comprises a combination of a heavy chain comprising heavy chain CDRs 1-CDR 3 and a variable region light chain comprising light chain CDR 1-CDR 3 amino acid sequences of an antibody selected from the group consisting of: 007 (having the CDR-H1 amino acid sequence of SEQ ID No. 1, the CDR-H2 amino acid sequence of SEQ ID No. 2, the CDR-H3 amino acid sequence of SEQ ID No. 3, the CDR-L1 amino acid sequence of SEQ ID No. 4, the CDR-L2 amino acid sequence of SEQ ID No. 5 and the CDR-L3 amino acid sequence of SEQ ID No. 6), 03_A07 (having the CDR-H1 amino acid sequence of SEQ ID No. 7, the CDR-H2 amino acid sequence of SEQ ID No. 8, the CDR-H3 amino acid sequence of SEQ ID No. 9, the CDR-L1 amino acid sequence of SEQ ID No. 10, the CDR-L2 amino acid sequence of SEQ ID No. 11 and the CDR-L3 amino acid sequence of SEQ ID No. 12), 01_G04 (having the CDR-H1 amino acid sequence of SEQ ID No. 13, the CDR-H2 amino acid sequence of SEQ ID No. 14, the CDR-H3 amino acid sequence of SEQ ID No. 15, the CDR-L1 amino acid sequence of SEQ ID No. 16, the CDR-L2 amino acid sequence of SEQ ID No. 17 and the CDR-L3 amino acid sequence of SEQ ID No. 18), and 01_C10 (having the CDR-H1 amino acid sequence of SEQ ID No. 19, the CDR-H2 amino acid sequence of SEQ ID No. 20, the CDR-H3 amino acid sequence of SEQ ID No. 21, the CDR-L1 amino acid sequence of SEQ ID No. 22, the CDR-L2 amino acid sequence of SEQ ID No. 23 and the CDR-L3 amino acid sequence of SEQ ID No. 24).
  2. 2. The antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a combination of variable region heavy chain amino acid sequences and variable region light chain amino acid sequences of one antibody selected from the group consisting of: 007 (comprising or consisting of the amino acid sequence of SEQ ID No. 25 and the amino acid sequence of SEQ ID No. 26, respectively), 03_A07 (comprising or consisting of the amino acid sequence of SEQ ID No. 27 and the amino acid sequence of SEQ ID No. 28, respectively), 01_G04 (comprising or consisting of the amino acid sequence of SEQ ID No. 29 and the amino acid sequence of SEQ ID No.30, respectively), 01_C10 (comprising or consisting of the amino acid sequence of SEQ ID No. 31 and the amino acid sequence of SEQ ID No.32, respectively).
  3. 3. The antibody or antigen binding fragment thereof according to claim 1 or 2, wherein the amino acid sequence comprised is an antibody selected from the group comprising 007, 03_a07 and 01-G04, preferably an antibody selected from the group comprising 007 and 03_a07, more preferably antibody 007.
  4. 4. The antibody or antigen-binding fragment thereof of any one of claims 1-3, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain, a CH1 domain, a CL1 domain, a hinge domain, or any combination thereof, optionally wherein the antibody is of IgG1 isotype.
  5. 5. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 4 and at least one pharmaceutically acceptable excipient.
  6. 6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition is a vaccination composition for a human subject.
  7. 7. The pharmaceutical composition according to claim 5 or 6, further comprising at least one antibody directed against the CD4 binding site of HIV-1.
  8. 8. A kit comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 4 and a container.
  9. 9. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, the pharmaceutical composition according to any one of claims 5 to 7 or the kit according to claim 8 for use as a medicament.
  10. 10. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, the pharmaceutical composition according to any one of claims 5 to 7 or the kit according to claim 8 for use in the treatment or prevention of the human immunodeficiency virus HIV-1 infection in a mammalian subject.
  11. 11. The antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, the pharmaceutical composition according to any one of claims 5 to 7 or the kit according to claim 8 for use in the treatment or prevention of a disease caused by the human immunodeficiency virus HIV-1 in a mammalian subject.
  12. 12. The antibody or antigen-binding fragment thereof, pharmaceutical composition or kit for use according to any one of claims 9 to 11, wherein the use is in a human subject.
  13. 13. The antibody or antigen-binding fragment thereof, pharmaceutical composition or kit for use according to any one of claims 9 to 12, wherein the use is for the treatment or prevention of Acquired Immune Deficiency Syndrome (AIDS).
  14. 14. A nucleic acid encoding the antibody or antigen binding fragment thereof of any one of claims 1 to 4, optionally wherein the nucleic acid is codon optimized for expression in a host cell.
  15. 15. An expression vector comprising the nucleic acid of claim 14 functionally associated with an expression control sequence, optionally wherein the expression vector is a viral vector.
  16. 16. A host cell comprising the nucleic acid of claim 14 or the expression vector of claim 15.
  17. 17. A method of producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, the method comprising (A) Culturing the host cell of claim 16 under conditions permitting expression of the antibody or antigen-binding fragment thereof, and (B) Recovering the antibody or antigen binding fragment thereof.

Description

Broad spectrum neutralizing antibodies targeting V3 glycan sites on HIV ENV Technical Field The present invention relates to monoclonal human antibodies or binding fragments thereof directed against the V3 glycan site of human immunodeficiency virus HIV-1, pharmaceutical compositions comprising such monoclonal human antibodies or binding fragments thereof, kits comprising such antibodies or binding fragments thereof, as well as monoclonal antibodies or binding fragments thereof for use as a medicament and for the treatment or prevention of diseases caused by human immunodeficiency virus HIV-1, as well as pharmaceutical compositions and kits. Background Although effective antiretroviral therapy (ART) is widely used, fight against global HIV-1 epidemics remains a public health priority. The highly potent broad-spectrum neutralizing anti-HIV-1 antibodies (bNAb) represent a promising and powerful tool that opens up unprecedented opportunities for alternative therapeutic and prophylactic strategies. In recent years, potent bNAb has been isolated from HIV-1-infected donors that bind to different vulnerable epitopes on HIV-1 envelope (Env) trimers. These epitopes include the CD4 binding site (CD 4 bs), the V1/V2 loop, the V3 glycan site, the membrane proximal outer region, fusion peptides, silencing facets, and the interface between gp120 and gp41 Env subunits. Among these epitopes, the V3 glycan site is the primary site for viral vulnerability. This site serves as a binding site for CCR5 co-receptor and mediates viral entry. The V3 glycan site is located at the base of the env V3 loop region and spans between the two N-linked glycans at amino acid positions 301 and 332 in HIV-1. This region also includes the so-called "GDIR" amino acid motif (positions 324-327), which is the primary target of the V3 glycan site bNAb. Members of the anti-HIV-1 bNAb class are not limited to a particular heavy chain variable gene segment and typically exhibit a very long heavy chain complementarity determining region (CDRH 3) of 18 to 24 amino acids. The long CDRH3 enables the V3 glycan site bNAb to penetrate the glycan barrier of the env trimer and contact the underlying target amino acid residue. Importantly, the antiviral activity of all known V3 glycan sites bNAb isolated to date is highly dependent on the incorporation of the glycan at position 332 into the binding epitope. Thus, removal of glycans at position 332 would compromise the neutralization capacity and breadth of this previously described V3 glycan site bNAb. Representative members of this antibody class are 10-1074, BG18, BF520 PGT121, PGT128 and PGT135. In preclinical animal models, bNAb exhibits robust anti-infective protection even at low serum concentration levels, and has shown favorable safety and pharmacokinetic profiles. Furthermore, administration of bNAb in HIV-1 infected individuals results in prolonged inhibition of viremia and a delay in viral rebound following an interruption of Analytical Treatment (ATI). The most potent and broad neutralizing antibodies against HIV-1 are directed against the CD4 binding site (CD 4 bs). CD4bs are particularly relevant because CD4 acts as the primary receptor for viral entry. However, bNAb directed against other sites within the HIV-1 virus is also important because they can complement neutralization of certain viral strains by CD4bs bNAb by non-competitive inhibition and even cause improved neutralization of other viral strains due to their binding to different target sites. Thus, the identification and development of highly potent V3 glycan sites bNAb is highly relevant for anti-HIV-1 immunotherapy and prevention strategies. These bNAb are required to have enhanced neutralization potency and breadth. Thus, there remains an urgent need to isolate novel V3 glycan sites with antiviral activity that exceeds the known bNAb for this epitope. It is therefore an object of the present invention to provide novel human monoclonal antibodies targeting HIV-1 which exhibit a significant level of breadth and potency against various viral strains and subtypes, and which can be combined with known antibodies to further improve neutralization efficiency. Furthermore, it is another object of the present invention to provide novel human monoclonal antibodies directed against the V3 glycan site of HIV-1, which exhibit improved breadth and/or efficacy for neutralization of various viral strains and subtypes. Disclosure of Invention These objects have been solved by the aspects of the invention as specified below. According to a first aspect of the present invention there is provided an antibody or antigen binding fragment thereof directed against the V3 glycan site of human immunodeficiency virus HIV-1, wherein the antibody or antigen binding fragment thereof comprises a combination of a heavy chain CDR1 to CDR3 comprising variable region heavy chain and a light chain CDR1 to CDR3 comprising variable region light chain amino acid sequence