Antibodies that target HIV gp120 and methods of use
Inventors
Balakrishnan, Mini • Carr, Brian A. • Hung, Magdeleine S. • Kanwar, Manu • Pace, Craig S. • Rehder, Doug • Schenauer, Matthew R. • Serafini, Loredana • Stephenson, Heather T. • Thomsen, Nathan D. • Yu, Helen • Zhang, Xue
Assignees
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Publication Number
US-12338278-B2
Publication Date
2025-06-24
Expiration Date
Abstract
Antibodies that bind to HIV gp120 and neutralize HIV are disclosed. Also disclosed are methods of using such antibodies alone or in combination with other therapeutic agents to treat or prevent HIV infection.
Core Innovation
The invention relates to nucleic acid molecules encoding an antibody or an antigen-binding fragment thereof that binds to human immunodeficiency virus-1 (HIV-1) Envelope glycoprotein gp120. The antibody or antigen-binding fragment comprises a heavy chain variable region (VH) including VH complementary determining regions 1-3 (CDRs 1-3) and a light chain variable region (VL) including VL CDRs 1-3, with the CDRs defined by specified SEQ ID NO sets.
Framework region 3 (FR3) of the VH includes an amino acid sequence set forth in SEQ ID NO: 627 at Kabat numbering positions corresponding to 74a, 74b, 74c, and 74d. The document further describes antibody embodiments linked to immunoglobulin constant regions, including IgG1, IgG2, IgG3, and IgG4 constant region formats, and IgG1 allotype or isoallotype residues using EU numbering.
The disclosed constructs extend to antigen-binding fragments, minibodies, multispecific and bispecific constructs, and nucleic acids, vectors, and host cells encoding the antibodies. The disclosure also includes optional Fc constant-region mutations to alter effector function and pharmacokinetics/half-life, together with embodiments defining sialylation of N-linked glycosylation sites in the variable domains, including VL N72 sialylation.
The disclosed variants are characterized with respect to chemical liabilities and stability, including mass spectrometry identification of heavy-chain W74a oxidation and light-chain N26 deamidation as stress-associated modifications. The disclosure also evaluates HIV neutralization potency and breadth, Fc receptor interactions, C1q binding, ADCC reporter potency, off-target T-cell proliferation, polyspecificity, expression titer changes, and in vivo pharmacokinetics in cynomolgus monkeys as related to Fab sialylation.
Claims Coverage
The consolidated independent claim coverage includes 8 inventive features.
Gp120-binding antibody encoded by nucleic acids
A nucleic acid molecule or nucleic acid molecules encoding an antibody or an antigen-binding fragment thereof that binds to human immunodeficiency virus-1 (HIV-1) Envelope glycoprotein gp120.
Vh and Vl CDR sequence sets
The antibody or antigen-binding fragment comprises a heavy chain variable region (VH) comprising VH complementary determining regions 1-3 (CDRs 1-3) and a light chain variable region (VL) comprising VL CDRs 1-3, wherein the VH CDRs 1-3 and VL CDRs 1-3 have the sequences set forth in multiple alternative sets of SEQ ID NOs.
Vh fr3 sequence at Kabat positions 74a-74d
The antibody or antigen-binding fragment thereof includes in framework region 3 (FR3) of the VH at position corresponding to 74a, 74b, 74c, and 74d (Kabat numbering) the amino acid sequence set forth in SEQ ID NO: 627.
Nucleic acid type DNA, cDNA or mRNA
The nucleic acid molecules comprise DNA, cDNA or mRNA.
IgG1 Fc region EU-numbered amino-acid substitutions
A human IgG1 Fc region containing specified amino-acid substitutions at EU-numbered positions.
Sialylation of N-linked glycosylation sites in variable domains
At least a chosen fraction of N-linked glycosylation sites in the variable domains (Fv) of expressed antibodies or antigen-binding fragments are sialylated.
Vl N72 as sialylated asparagine
The cell or population of cells includes sialylation of the asparagine at VL amino acid position 72 according to Kabat numbering (N72).
Lipid nanoparticle comprising the nucleic acid
A lipid nanoparticle (LNP) comprising the nucleic acid molecule or nucleic acid molecules of the nucleic acid-encoding antibody or antigen-binding fragment.
The claim coverage centers on nucleic acids encoding gp120-binding antibodies or antigen-binding fragments defined by specific VH CDR1-3 and VL CDR1-3 sequence sets and a VH FR3 sequence at Kabat positions 74a-74d, with dependent refinements for nucleic-acid type, Fc substitutions, variable-domain sialylation including VL N72, and an LNP embodiment.
Stated Advantages
Enhanced serum half-life, including human half-life thresholds described in the partial content.
Alter effector function and pharmacokinetics/half-life.
Increased ADCC killing potency against HIV-infected cells.
Differences in N72-linked Fab glycan composition, including sialylation, are linked to differences in off-target T-cell proliferation.
Removal of the N72 glycan increases polyspecificity.
The disclosure correlates in vivo pharmacokinetics in cynomolgus monkeys with the percentage of Fab sialylation.
Documented Applications
Treating or preventing HIV, including method-of-use for HIV treatment/prevention [procedural detail omitted for safety].
Combination regimens with latency reversing agents (LRAs) and TLR agonists, including TLR7 agonists, for HIV [procedural detail omitted for safety].
Pharmaceutical compositions comprising the antibodies or antigen-binding fragments [procedural detail omitted for safety].
Use of bispecific antibodies in the context of HIV [procedural detail omitted for safety].
Use of encoding nucleic acids, expression vectors, and host cells with enhanced sialylation in connection with HIV [procedural detail omitted for safety].
CAR constructs associated with the described HIV antibody concepts [procedural detail omitted for safety].
HIV-1 Envelope glycoprotein gp120-binding antibodies and antigen-binding fragments.
Multispecific/bispecific constructs.
Antigen-binding fragments and minibodies.
Vectors and host cells encoding the antibodies.
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