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
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Publication Number
US-12018067-B2
Publication Date
2024-06-25
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 non-naturally occurring anti-HIV-1 PGG14 monoclonal antibodies, or antigen binding portions thereof, with defined complementarity determining regions. The antibody comprises a light chain variable region with complementarity determining regions having the amino acid sequences of SEQ ID NOS: 113, 114, and 43, and a heavy chain variable region with complementarity determining regions having the amino acid sequences of SEQ ID NOS: 110, 111, 102, and 103.
The content provides sequence definitions for anti-HIV-1 monoclonal antibodies, including PGG14, and includes heavy and light chain variable region amino acid sequences. It specifies Kabat and Chothia CDR sequences and consensus and variation tables for sister-clone CDRs, supporting defined CDR sequence relationships across related antibody clones.
The content also includes reported neutralization behavior and binding observations for antibodies against HIV-1 strains SF162 and JR-CSF (clade B). It references anti-gp120 and anti-gp41 binding observations and assay-based measurements such as total IgG ELISA, associating particular antibody sequence definitions with observed binding and neutralization behavior against the specified HIV-1 strains.
Claims Coverage
The claim coverage includes one independent claim directed to a non-naturally occurring anti-HIV-1 PGG14 monoclonal antibody defined by specific light-chain and heavy-chain CDR amino acid sequences. Dependent claims further specify pharmaceutical composition characteristics and selected excipient or carrier components.
Non-naturally occurring anti-HIV-1 PGG14 CDR-defined antibody
A non-naturally occurring anti-HIV-1 PGG14 monoclonal antibody or antigen binding portion thereof comprising a light chain variable region comprising complementarity determining regions having the amino acid sequences of SEQ ID NOS: 113, 114, and 43 and a heavy chain variable region comprising complementarity determining regions having the amino acid sequences of SEQ ID NOS: 110, 111, 102, and 103.
Pharmaceutical composition with pharmaceutically acceptable carrier excipient selection
A pharmaceutical composition including the antibody and a pharmaceutically acceptable carrier selected from specified excipient types.
Selected named buffer for the carrier
The pharmaceutical composition further specifies that the buffer is one of acetate, Tris, phosphate, or citrate.
Chelating agent specified as EDTA
The pharmaceutical composition is defined such that its chelating agent is EDTA.
Antibody concentration range constraint
A composition is defined in which the antibody concentration is between 10 and 100 mg/mL.
Antibody encapsulated in microcapsules
The composition includes an antibody that is encapsulated in microcapsules.
Overall, the inventive claim scope is anchored by a PGG14 monoclonal antibody defined by specific light-chain and heavy-chain complementarity determining region amino acid sequences. Dependent claim coverage further specifies pharmaceutical composition formulation elements, including selected carrier or excipient types, named buffer options, EDTA as a chelating agent, an antibody concentration range, and encapsulation of the antibody in microcapsules.
Stated Advantages
Preferential binding to native trimeric Env rather than strongly binding to monomeric gp120 or gp41.
Epitope recognition is linked to conserved V2/V3 variable loop regions including an N-glycosylation site at Asn-160 in V2.
Cross-clade neutralization activity with functional breadth across multiple clades.
Potent neutralization is characterized using IC50/IC90 potency ranges.
Documented Applications
General uses for prophylaxis, diagnosis, and treatment, including vaccine immunogens and antibody-linked labels.
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