Broadly neutralizing human immunodeficiency virus type 1 (HIV-1) GP120-specific monoclonal antibody
Inventors
Chan-Hui, Po-Ying • Doores, Katherine • Huber, Michael • Kaminsky, Stephen • Frey, Steven • Olsen, Ole • Mitcham, Jennifer • Moyle, Matthew • Phogat, Sanjay K. • Burton, Dennis R. • Walker, Laura Majorie • Poignard, Pascal Raymond Georges • Koff, Wayne • Simek-Lemos, Melissa Danielle De Jean De St. Marcel
Assignees
Scripps Research Institute • International AIDS Vaccine Initiative Inc • Theraclone Sciences Inc
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Publication Number
US-10836811-B2
Publication Date
2020-11-17
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 may be 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 document provides a non-naturally occurring PGT-121 monoclonal antibody, or an antigen binding portion thereof, defined by specified variable-region complementarity determining regions. The antibody includes a light chain variable region comprising three complementarity determining regions with amino acid sequences given by SEQ ID NOS: 150, 151 and 152, and a heavy chain variable region comprising three complementarity determining regions with amino acid sequences given by SEQ ID NOS: 143, 144 and 145 or SEQ ID NOS: 90, 265 and 143.
The disclosure also provides detailed sequence listings for multiple human monoclonal antibodies, including heavy-chain and light-chain variable-region nucleotide and amino-acid sequences and corresponding Kabat and Chothia CDR sequences. Antibodies identified include PGT-121, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-127, PGT-128, PGT-130, PGT-131, PGT-132, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, PGT-141, PGT-142, PGT-143, PGT-144, PGT-145, PGT-151, PGT-152, PGT-153, PGT-154, PGT-155, PGT-156, PGT-157, and PGT-158, with some cases including constant regions, signal peptides, leader regions, and variable-region context.
The document describes selection and characterization of HIV broadly neutralizing antibodies including PGT-121 and related antibodies from B-cell culture hits and memory B-cell culture supernatants. It includes screening and neutralization profiling across diverse HIV pseudovirus panels, together with binding specificity testing by ELISA, soluble CD4 inhibition, transfectant screening, and FACS/flow cytometry binding assays.
The disclosed antibodies are presented with neutralization breadth and potency across a 162-pseudovirus cross-clade panel, and the content notes that potent breadth and potency can occur without strong binding to soluble recombinant gp120/gp41 in ELISA. The material further describes preference for native trimeric Env on infected or transfected cells and dependence on gp120 variable-loop epitopes, including conserved regions of V2/V3 and N-glycosylation at Asn-160.
Claims Coverage
Across the independent claims, there are two inventive sequence-constraint sets for a non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion thereof, each defined by three light-chain CDRs and three heavy-chain CDRs.
Sequence-defined light-chain CDR set for PGT-121 antibodies
A non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion comprising a light chain variable region with three complementarity determining regions having the amino acid sequences of SEQ ID NOS: 150, 151 and 152.
Sequence-defined heavy-chain CDR set for PGT-121 antibodies
A non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion comprising a heavy chain variable region with three complementarity determining regions having the amino acid sequences of SEQ ID NOS: 143, 144 and 145.
Alternative sequence-defined heavy-chain CDR set for PGT-121 antibodies
A non-naturally occurring PGT-121 monoclonal antibody or antigen binding portion comprising a heavy chain variable region with three complementarity determining regions having the amino acid sequences of SEQ ID NOS: 90, 265 and 143.
Immortalized B cell clone expressing the PGT-121 antibody
An immortalized B cell clone expressing the antibody or antigen binding portion thereof.
Pharmaceutical composition including the PGT-121 antibody with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising the antibody or antigen binding portion thereof and a pharmaceutically acceptable carrier.
The claim set defines non-naturally occurring PGT-121 monoclonal antibodies, or antigen binding portions, by specified amino acid sequences for three complementarity determining regions in the light chain and three complementarity determining regions in the heavy chain, with the independent claims differing in the heavy-chain CDR set. Dependent coverage further includes an immortalized B cell clone expressing the antibody and a pharmaceutical composition including a pharmaceutically acceptable carrier.
Stated Advantages
Provides PGT broadly neutralizing HIV-1 monoclonal antibodies with neutralization potency and breadth across a 162-pseudovirus cross-clade panel.
Potent breadth and potency can occur without strong binding to soluble recombinant gp120/gp41 in ELISA.
Preference for native trimeric Env on infected or transfected cells is described.
Identifies glycan-dependency and epitope behavior, including glycan contacts near the V3 loop and loss of binding after Endo H treatment.
Supports comparison of neutralization potency across many isolates or variants versus multiple control bnAbs across clade panels.
Documented Applications
Neutralization testing and breadth evaluation on a 162-pseudovirus cross-clade panel.
Binding studies to monomeric gp120 and membrane-bound trimeric Env.
Epitope characterization through competition and glycan-dependency analyses, including Endo H treatment and alanine mutant analyses.
Comparative potency assessment across isolates or variants versus control bnAbs across clade panels.
Prophylaxis/therapy/diagnosis using the described antibodies is mentioned.
Vaccination immunogens/epitopes using the described epitopes are mentioned.
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