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-10239934-B2
Publication Date
2019-03-26
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 isolates broadly neutralizing HIV-1 monoclonal antibodies, including PG9 and PG16, by screening high-throughput neutralization activity from memory B-cell cultures derived from HIV-infected donors and rescuing monoclonal antibodies. The disclosed antibodies are non-naturally occurring and include antigen binding portions, with light chain and heavy chain variable regions defined by specific CDR amino acid sequences identified by SEQ ID NOS and by specific light chain and heavy chain sequences identified by SEQ ID NOS.
The disclosed monoclonal antibodies preferentially bind native trimeric HIV Env on infected/transfected cells and neutralize multiple HIV-1 clades with high breadth and potency. They can show weak or uncorrelated binding to soluble monomeric gp120/gp41, and epitope mapping identifies conserved V2/V3 variable loops with a requirement for an Asn-160 N-glycosylation site.
The disclosure further characterizes functional binding and neutralization, including neutralization of HIV-1 strains SF162 and/or JR-CSF and binding or non-binding to gp120/gp41 in quantitative ELISA. Epitopes, mimotopes, and antibodies are described for immunoassays, epitope mapping, vaccine monitoring, screening ligands that block epitopes, prophylaxis, diagnosis, treatment, and vaccination or immunogens targeting conserved Env variable-loop epitopes presented on trimeric spikes.
Claims Coverage
The provided independent claims comprise 6 inventive features, centered on inhibiting HIV in a host by administering non-naturally occurring monoclonal anti-HIV antibodies designated PG9 and PG16, and on expression vectors that encode and stably express in vivo specified PG9/PG16 antibody sequences and/or CDR-defined antibodies.
Sequence-defined PG9 antibody administration
Administering to the host a non-naturally occurring monoclonal anti-HIV antibody, designated 1496 C09 (PG9) or an antigen binding portion thereof comprising a light chain variable region with CDR amino acid sequences of SEQ ID NOS: 45, 126 and 127 and a heavy chain variable region with CDR amino acid sequences of SEQ ID NOS: 7, 123 and 124.
Sequence-defined PG16 antibody administration
Administering to the host a non-naturally occurring monoclonal anti-HIV antibody, designated 1443 C16 (PG16) or an antigen binding portion thereof comprising a light chain variable region with CDR amino acid sequences of SEQ ID NOS: 41, 95, and 97 and a heavy chain variable region with CDR amino acid sequences of SEQ ID NOS: 6, 88 and 89.
Sequence-defined PG9 antibody (light and heavy sequences) administration
Administering to the host a non-naturally occurring monoclonal anti-HIV PG9 antibody or antigen binding portion thereof comprising a light chain sequence of SEQ ID NO: 30 and a heavy chain sequence of SEQ ID NO: 28.
Sequence-defined PG16 antibody (light and heavy sequences) administration
Administering to the host a non-naturally occurring monoclonal anti-HIV PG16 antibody or antigen binding portion thereof comprising a light chain sequence of SEQ ID NO: 14 and a heavy chain sequence of SEQ ID NO: 12.
In vivo expression vector encoding PG9 light and heavy sequences
An expression vector that encodes and stably expresses in vivo an antibody comprising each of a light chain sequence of SEQ ID NO: 30 and a heavy chain sequence of SEQ ID NO: 28.
In vivo expression vector encoding PG16 light and heavy CDRs
An expression vector that encodes and stably expresses in vivo an antibody comprising (a) a light chain variable region comprising complementarity determining regions (CDRs) having the amino acid sequences of SEQ ID NOS: 45, 126 and 127 and (b) a heavy chain variable region comprising CDRs having the amino acid sequences of SEQ ID NOS: 7, 123 and 124.
The independent claims define methods of inhibiting HIV by administering non-naturally occurring PG9 or PG16 antibodies, or antigen binding portions, specified by sequence-defined light-chain and heavy-chain CDRs or full light/heavy sequences. Additional independent claims define expression vectors that encode and stably express in vivo antibodies with corresponding sequence-defined light- and heavy-chain features.
Stated Advantages
Neutralizes multiple HIV-1 clades with high breadth and potency.
Preferentially binds native trimeric HIV Env on infected/transfected cells.
Shows weak or uncorrelated binding to soluble monomeric gp120/gp41.
Neutralization activity against HIV-1 strains SF162 and/or JR-CSF.
Quantitative ELISA binding to gp120/gp41 (binding or non-binding is described).
Documented Applications
Prophylaxis.
Diagnosis.
Treatment.
Vaccination or immunogens targeting conserved Env variable-loop epitopes presented on trimeric spikes.
Immunoassays using epitopes/mimotopes and antibodies.
Epitope mapping using epitopes/mimotopes and antibodies.
Vaccine monitoring.
Screening ligands that block epitopes using epitopes/mimotopes and antibodies.
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