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-10865234-B2
Publication Date
2020-12-15
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 broadly neutralizing anti-HIV monoclonal antibodies directed to native trimeric Env, including anti-HIV-1 PG9 and anti-HIV-1 PG16 monoclonal antibodies and antigen binding portions thereof. The disclosure provides pharmaceutical compositions comprising non-naturally occurring anti-HIV-1 PG9 and PG16 monoclonal antibodies defined by specified light chain variable regions and heavy chain variable regions with complementarity determining regions identified by SEQ ID number combinations, together with a pharmaceutically acceptable carrier selected from a listed group of excipients.
A key aspect is that neutralization-identifying antibodies may show weak or no binding to recombinant monomeric gp120/gp41 while still binding at high affinity to trimeric Env. The document describes epitopes associated with conserved V2/V3 variable loops presented on trimeric gp120 spikes with dependence on N-glycosylation, including an N-glycosylation site such as Asn-160.
The document further describes antibody sequence embodiments for multiple anti-HIV antibodies, including heavy-chain CDR amino acid sequences using Kabat and Chothia numbering with associated SEQ ID numbers, lambda light-chain nucleotide and amino-acid variable region sequences, and additional gamma heavy-chain variable region sequence variants. The specifications include sister clones and related sequence embodiments for anti-HIV monoclonal antibodies including PG16, PG20, PGG14, PGC14, and sister clones to human monoclonal antibody 1443_C16.
Claims Coverage
The consolidated claim coverage includes two independent pharmaceutical composition claims for non-naturally occurring anti-HIV-1 PG9 or PG16 monoclonal antibodies, or antigen binding portions thereof, defined by specific CDR-based light-chain and heavy-chain variable regions and a pharmaceutically acceptable carrier selected from an enumerated group. No other independent claims are provided in the input items.
Cdr-defined anti-HIV-1 PG9 monoclonal antibody composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a non-naturally occurring anti-HIV-1 PG9 monoclonal antibody or antigen binding portion thereof comprising a light chain variable region with three complementarity determining regions comprising amino acid sequences of SEQ ID NOS: 126, 127, and 45, and a heavy chain variable region with three complementarity determining regions comprising amino acid sequences of SEQ ID NOS: 123, 124, and 7, and a pharmaceutically acceptable carrier selected from the group consisting of a buffer, organic acid, antioxidant, preservative, alkyl paraben, oligopeptide, protein, amino acid, hydrophilic polymer, carbohydrate, chelating agent, tonicifier, sugar, and surfactant.
Cdr-defined anti-HIV-1 PG16 monoclonal antibody composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a non-naturally occurring anti-HIV-1 PG16 monoclonal antibody or antigen binding portion thereof comprising a light chain variable region with three complementarity determining regions comprising amino acid sequences of SEQ ID NOS: 92, 95, and 41 or SEQ ID NOS: 93, 95, and 41 or SEQ ID NOS: 97, 95, and 41, and a heavy chain variable region with three complementarity determining regions comprising amino acid sequences of SEQ ID NOS: 88, 89, and 6 or SEQ ID NOS: 88, 98, and 6, and a pharmaceutically acceptable carrier selected from the group consisting of a buffer, organic acid, antioxidant, preservative, alkyl paraben, oligopeptide, protein, amino acid, hydrophilic polymer, carbohydrate, chelating agent, tonicifier, sugar, and surfactant.
Overall, the claims cover pharmaceutical compositions of non-naturally occurring anti-HIV monoclonal antibodies, specifically PG9 and PG16, where the antibody is defined by CDR-based light-chain and heavy-chain variable region amino acid sequences together with a pharmaceutically acceptable carrier chosen from a listed group.
Stated Advantages
The antibodies are reported in connection with neutralization activity against HIV-1 strains SF162 and JR-CSF.
Documented Applications
Immunoassays [procedural detail omitted for safety].
Epitope mapping [procedural detail omitted for safety].
Neutralization activity against HIV-1 strains SF162 and JR-CSF.
Detection of infected cells and/or strain presence.
Diagnostic and prognostic use.
Therapeutic, diagnostic, and vaccine use concepts for the described antibodies, including pharmaceutical compositions.
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