Multispecific antibodies targeting multiple epitopes on the HIV-1 envelope
Inventors
Li, Yuxing • Steinhardt, James • Guenaga, Javier • Mascola, John R. • Chun, Tae-Wook • Moir, Susan • Chiang, Chi-I
Assignees
United States, REPRESENTED BY SECRETARY Department Of Health And Human Servives AS • University of Maryland Baltimore • International AIDS Vaccine Initiative Inc • University of Maryland College Park
Publication Number
US-12365722-B2
Publication Date
2025-07-22
Expiration Date
2039-10-18
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Abstract
The present invention provides a multispecific anti-HIV antibody that binds to multiple epitopes on HIV envelope protein, wherein the antibody comprises: i. an amino acid sequence that binds to a V1/V2 apex glycan epitope; ii. an amino acid sequence that binds to a V3-base glycan region epitope; iii. an amino acid sequence that binds to a CD4 binding site (CD4bs) epitope; iv. an amino acid sequence that binds to a gp120/gp41 interface epitope; and v. an amino acid sequence that binds to a membrane proximal external region (MPER) epitope.
Core Innovation
The invention provides multispecific anti-HIV antibodies capable of binding multiple epitopes on the HIV-1 envelope protein. These antibodies comprise amino acid sequences specifically targeting the V1/V2 apex glycan epitope, the V3-base glycan region epitope, the CD4 binding site (CD4bs) epitope, the gp120/gp41 interface epitope, and the membrane proximal external region (MPER) epitope. The antibodies can be constructed using single chain fragment variable (ScFv) moieties from known broadly neutralizing antibodies (bNAbs) such as VRC26.25, PGDM1400, PGT121, N6, 35O22, and 10E8 variants, linked via flexible linkers and optionally fused to Fc regions for effector functions. These multispecific antibodies demonstrate the capacity for simultaneous engagement of five separate epitopes, achieving superior binding avidity and profoundly enhanced neutralization breadth and potency.
The problem addressed by the invention arises from the limitations of current HIV therapies and single bNAb treatments. While antiretroviral therapy (ART) effectively suppresses viral replication, it requires lifelong adherence and has associated toxicities and costs. Single broadly neutralizing antibodies have shown transient viremia suppression but often lead to rapid viral resistance due to selective pressure. Therefore, there is a need for novel therapeutic agents capable of sustainably suppressing HIV by targeting multiple conserved epitopes on the viral envelope, thereby preventing viral escape and enhancing neutralization breadth and potency. The invention aims to fulfill this need by creating single multispecific antibodies combining functional moieties of multiple bNAbs.
Claims Coverage
The patent discloses multiple independent claims describing multispecific anti-HIV antibodies composed of amino acid sequences recognizing five distinct HIV-1 envelope epitopes.
Multispecific antibody binding five distinct HIV epitopes
An antibody comprising amino acid sequences that bind to (i) V1/V2 apex glycan epitope derived from antibodies VRC26.25 or PGDM1400, (ii) V3-base glycan region epitope derived from antibody PGT121, (iii) CD4 binding site (CD4bs) epitope derived from antibody N6, (iv) gp120/gp41 interface epitope derived from antibody 35O22, and (v) MPER epitope derived from 10E8 variants.
Simultaneous multisite binding and specific polypeptide organization
The antibody simultaneously binds multiple epitopes, with the amino acid sequences organized either on a single polypeptide chain or two polypeptide chains, each comprising five ScFv moieties, optionally linked by flexible linkers including (G4S)n sequences, and optionally fused to an immunoglobulin Fc region or variant thereof.
Specific organization and linking of variable regions
Each ScFv moiety comprises variable light (VL) and heavy (VH) chain regions arranged either VL-to-VH, VH-to-VL, or exclusively VL-to-VH, separated by linking amino acids, and the entire multispecific antibody can include an Fc region modified for enhanced half-life and heterodimerization.
Pharmaceutical composition and therapeutic methods
Compositions comprising the multispecific antibodies with pharmaceutically acceptable carriers, and methods of treating or preventing HIV infection by administering effective amounts of these antibodies, alone or in combination with other therapies including antiretroviral therapy.
Inclusion of anti-CD4 specificity in hexa-specific antibody
An embodiment encompassing a hexa-specific antibody including anti-CD4 antibody dB4C7/UB-421 variable domains combined with five HIV epitope-binding sequences to enhance antiviral breadth and resistance prevention.
The claims collectively cover multispecific anti-HIV antibodies constructed from known broadly neutralizing antibody sequences that target five major HIV-1 envelope epitopes, organized as ScFv moieties linked into single or dual polypeptides optionally fused to Fc regions, their pharmaceutical compositions, and methods of use for HIV treatment and prevention.
Stated Advantages
The multispecific antibodies exhibit near pan-isolate neutralization breadth (99.6% coverage) against diverse HIV-1 viral strains and extremely high potency (geometric mean IC50 as low as 0.006 μg/mL).
They effectively neutralize viral quasi-species resistant to individual bNAbs such as in VRC01 clinical trials, overcoming viral escape mutations.
The antibodies possess substantially higher antibody-dependent cell-mediated cytotoxicity (ADCC) capacity than their parental bNAbs.
Multispecific single agents are preferable for manufacturing compared to antibody cocktails and benefit from improved avidity resulting in enhanced neutralization breadth and potency.
Documented Applications
Therapeutic treatment and management of persistent HIV-1 infection in infected individuals focusing on HIV suppression and prevention of plasma viral rebound upon ART withdrawal.
Prevention of HIV infection through administration of broadly neutralizing multispecific antibodies.
Use in diagnostic assays to detect HIV or HIV envelope proteins by binding specific epitopes.
Engineering of immune cells, such as B cells, to express these multispecific antibodies for potential adoptive transfer therapies.
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