Monoclonal antibodies directed against trimeric forms of the HIV-1 envelope glycoprotein with broad and potent neutralizing activity
Inventors
Chan-Hui, Po-Ying • Frey, Steven • Olsen, Ole • Mitcham, Jennifer • Moyle, Matthew • Phogat, Sanjay K. • Burton, Dennis R. • Walker, Laura Marjorie • Poignard, Pascal Raymond Georges • Koff, Wayne • Simek-Lemos, Melissa Danielle De Jean De St. Marcel • Kaminsky, Stephen
Assignees
Scripps Research Institute • International AIDS Vaccine Initiative Inc • Theraclone Sciences Inc
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12312396-B2
Publication Date
2025-05-27
Expiration Date
Abstract
The invention provides a method for obtaining a broadly neutralizing antibody (bNab), including screening memory B cell cultures from a donor PBMC sample for neutralization activity against a plurality of HIV-1 species, cloning a memory B cell that exhibits broad neutralization activity; and rescuing a monoclonal antibody from that memory B cell culture. The resultant monoclonal antibodies are characterized by their ability to selectively bind epitopes from the Env proteins in native or monomeric form, as well as to inhibit infection of HIV-1 species from a plurality of clades. Compositions containing human monoclonal anti-HIV antibodies used for prophylaxis, diagnosis and treatment of HIV infection are provided. Methods for generating such antibodies by immunization using epitopes from conserved regions within the variable loops of gp120 are provided. Immunogens for generating anti-HIV1 bNAbs are also provided. Furthermore, methods for vaccination using suitable epitopes are provided.
Core Innovation
The invention relates to an antibody for HIV-1 that binds conformational epitopes and neutralizes HIV-1. The disclosed content specifies anti-HIV monoclonal antibodies including PG20, PGG14, PGC14, PG9, and multiple PG16 sister clones, and describes heavy-chain variable region and light-chain variable region sequences including Kabat-defined and Chothia-defined CDR amino-acid sequences. The document also describes antibody engineering and use of multivalent and bispecific antibody forms, antibody fragments, and Fv-based constructs.
The disclosed content provides sequence specifications for heavy-chain variable region CDRs and light-chain variable region CDRs, including corresponding nucleotide sequences and SEQ ID NOs, together with consensus and variation patterns for sister clones and sequence-identity guidance. It further links these sequence-defined regions to HIV-1 neutralization via binding to conformational epitopes, with assay context including binding to gp120 and gp41 and neutralization activity. The document also describes an antibody discovery pipeline using memory B cells, donor selection based on plasma neutralization, and high-throughput screening of B-cell supernatants.
In addition, the document describes immunoconjugate strategies using antibodies conjugated to maytansinoids, calicheamicin, toxins, and radioisotopes, with linker and coupling classes including disulfide, thioether, cleavable, and acid-labile linkers. It also describes delivery and formulation approaches including polymers, microcapsules, liposomes, and immunoliposomes, and discusses HIV-1 antibody applications including binding and neutralization screening concepts, diagnostic and prognostic contexts, and passive immunization.
The document highlights that some potent cross-clade antibodies, including PG9 and PG16, show poor or no correlation with ELISA binding to recombinant monomeric gp120/gp41 and instead bind preferentially to native trimeric Env. It also describes epitope mapping to conserved regions within gp120 variable loops V2/V3, including dependence on N-glycosylation such as Asn-160, and references neutralization breadth across clades A/B/C and CRF01_AE.
Claims Coverage
The claims center on an expression vector that encodes and stably expresses in vivo a sequence-defined antibody. Across the independent claims, the inventive features focus on specified antibody variable-region CDR or sequence assignments, the in vivo stable expression requirement, and related claim features including a pharmaceutically acceptable carrier, a viral based vector, specified host-cell categories, and gp120 as the antigen.
In vivo stable expression of sequence-defined light and heavy chain cdrs via an expression vector
The expression vector encodes and stably expresses in vivo an antibody comprising a light chain variable region with CDR amino acid sequences of SEQ ID NOS: 120, 121, and 44, and a heavy chain variable region with CDR amino acid sequences of SEQ ID NOS: 116, 117, and 118.
In vivo stable expression of sequence-defined light and heavy chain variable sequences via an expression vector
The expression vector encodes and stably expresses in vivo an antibody comprising each of a light chain variable sequence of SEQ ID NO: 38 and a heavy chain variable sequence of SEQ ID NO: 37.
In vivo stable expression of sequence-defined light and heavy chain variable sequences via an expression vector
The expression vector encodes and stably expresses in vivo an antibody comprising each of a light chain sequence of SEQ ID NO: 26 and a heavy chain sequence of SEQ ID NO: 24.
Pharmaceutical composition including the expression vector in a pharmaceutically acceptable carrier
A pharmaceutical composition that includes the expression vector together with a pharmaceutically acceptable carrier.
Expression vector including a viral based vector
The expression vector includes a viral based vector.
Specified host-cell categories for expressing the antibody
The host cell is a prokaryotic host cell or a eukaryotic host cell, including Escherichia coli, yeast cell, animal cell, or plant cell.
Antibody targeting gp120 as the antigen
The antibody encoded and expressed by the expression vector has an antigen of gp120.
The claims primarily cover expression vectors that stably encode and express in vivo antibodies specified by SEQ ID NO-defined light- and heavy-chain variable sequences or CDR sequences. Additional features include pharmaceutical composition support, a viral based vector, specified host-cell categories, and gp120 as the antigen.
Stated Advantages
Not explicitly described in patent.
Documented Applications
HIV-1 antibody applications including binding and neutralization screening concepts.
Diagnostic and prognostic use (within HIV-1 context).
Passive immunization (within HIV-1 context).
Neutralization assay measurement and breadth assessment across clades A/B/C and CRF01_AE using reported IC50/IC90/neutralization index concepts.
Interested in licensing this patent?