Broadly neutralizing monoclonal antibodies against HIV-1 V1V2 Env region
Inventors
Schramm, Chaim Aryeh • Gorman, Jason • Mascola, John • Shapiro, Lawrence Stewart • Morris, Lynn • Doria-Rose, Nicole Amy • Moore, Penelope Linda • Kwong, Peter Dak Pin • Karim, Salim Safurdeen Abdool
Assignees
Columbia University in the City of New York • US Department of Health and Human Services • CENTRE FOR AIDS PROGRAMME OF RESEARCH IN SOUTH AFRICA • National Health Laboratory Service
Publication Number
US-10519222-B2
Publication Date
2019-12-31
Expiration Date
2035-02-27
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Abstract
The present invention relates anti-HIV therapies and prophylaxis. Specifically, the invention relates to broadly neutralizing antibodies against HIV-1, nucleic acids encoding these antibodies, vectors comprising the nucleic acids and cells and pharmaceutical compositions Comprising said vectors and/or antibodies. The present invention also relates to use of the antibodies and/or vectors for the treatment and/or prevention of HIV-1 infection in a subject. Furthermore, the invention also relates to a kit containing the antibodies of the invention.
Core Innovation
The invention relates to broadly neutralizing anti-HIV antibodies that bind to the V1V2 epitope of HIV-1 Env, as well as nucleic acids encoding these antibodies, vectors containing such nucleic acids, cells harboring these vectors, and pharmaceutical compositions comprising these components. The antibodies are isolated and characterized by specific heavy and light chain variable regions and demonstrate neutralization of both autologous and heterologous HIV-1 strains. The invention further relates to the use of these antibodies and vectors for treatment and prevention of HIV-1 infection, as well as kits containing the antibodies.
The problem being addressed is the challenge of eliciting and studying broadly neutralizing antibodies against HIV-1, which typically arise as subdominant immune responses and are vastly outnumbered by strain-specific antibodies. Understanding the molecular events and genetic determinants that lead to the development of potent neutralizing antibodies targeting conserved and vulnerable regions such as the V1V2 region of the HIV-1 envelope is critical. Prior antibodies targeting V1V2, such as PG9 and PG16, have demonstrated broad neutralization but the mechanisms and ontogeny of such antibodies require further elucidation. The invention isolates a family of potent V1V2-directed broadly neutralizing antibodies from donor CAP256 and characterizes their evolution, binding characteristics, and viral interplay to delineate the molecular pathway that yields effective HIV-1 neutralization.
Claims Coverage
The claims encompass a single independent antibody claim with associated dependent claims covering compositions, methods of treatment, and kits. The main inventive features include structural and sequence characteristics of anti-HIV-1 antibodies binding specifically to the V1V2 region.
Anti-HIV-1 antibody with defined CDR regions from specific sequences
An isolated anti-HIV-1 antibody which binds the V1V2 epitope, comprising a heavy chain with CDR1, CDR2, and CDR3 regions consisting of amino acids at positions 31-35, 50-66, and 99-134 of SEQ ID NO:172, respectively, and a light chain with CDR1, CDR2, and CDR3 comprising amino acids at positions 23-35, 51-57, and 90-101 of SEQ ID NO:173, respectively.
Anti-HIV-1 antibody comprising defined variable heavy and light chain sequences
An isolated anti-HIV-1 antibody comprising a variable heavy chain sequence having the amino acid sequence of SEQ ID NO:172 and a variable light chain sequence having the amino acid sequence of SEQ ID NO:173.
Neutralization potency against specific HIV-1 strains
The antibody neutralizes autologous HIV-1 virus CAP256.SU at IC50 concentrations below 0.5 μg/ml, and neutralizes heterologous HIV-1 virus ZM53.12 at IC50 below 0.5 μg/ml.
Antibody fragments encompassed by the invention
The antibody includes embodiments as Fab, Fab′, F(ab′)2, single-chain Fv (scFv), Fv fragment, or linear antibody, covering antigen-binding portions.
Pharmaceutical and composition embodiments
Compositions and pharmaceutical compositions comprising the isolated antibody or fragments thereof in a pharmaceutically acceptable carrier.
Methods of treatment employing the antibody
Methods of inhibiting HIV-1 replication or reducing viral load in a subject by administering the isolated antibody or fragments thereof.
Combination therapy possibilities
Treatment methods may include administration of a second therapeutic agent, such as an antiviral agent, alongside the antibody.
Kit comprising the antibody
A kit comprising a container holding the isolated anti-HIV-1 antibody or fragment thereof for therapeutic or diagnostic use.
The patent claims cover isolated anti-HIV-1 antibodies with defined variable region sequences and complementarity-determining regions that bind the V1V2 region of HIV-1 Env, including their fragments, compositions, uses in treatment methods possibly combined with other agents, and kits containing these antibodies.
Stated Advantages
The antibodies have broad and potent neutralizing activity against diverse HIV-1 strains, including autologous and heterologous viruses.
The antibodies exhibit quaternary specificity to the native Env trimer and recognize the V1V2 apex, which is relevant to viral vulnerability.
The lineage of antibodies can develop neutralization breadth relatively rapidly without requiring extraordinary somatic mutation levels.
The antibodies are minimally autoreactive, reducing concerns related to tolerance and clonal deletion.
Documented Applications
Use of the antibodies and vectors encoding them for treatment and prevention (prophylaxis) of HIV-1 infection in subjects.
Pharmaceutical compositions for administration to subjects to inhibit HIV-1 replication or reduce viral load.
Diagnostic compositions and kits for detecting anti-HIV-1 antibodies or antigens.
Potential use in vaccine design to elicit broadly neutralizing antibodies targeting the V1V2 region of HIV-1 Env.
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