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

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 PGC14 monoclonal antibodies and antigen binding portions. The antibodies are defined by specific complementarity determining region amino acid sequences and/or specific variable region amino acid sequences in light and heavy chains, using provided SEQ ID NOS for the light chain and heavy chain regions.

The document defines PGC14 light chain and heavy chain variable regions by specifying complementarity determining regions as amino-acid sequences associated with SEQ ID NO: 120, SEQ ID NO: 121, and SEQ ID NO: 44 for the light chain, and SEQ ID NO: 116, SEQ ID NO: 117, and SEQ ID NO: 118 for the heavy chain. It also describes encoded polynucleotides and amino-acid variable-region sequences with mapping of CDRs to specific SEQ ID Nos.

The document further describes related antibody formats and variant concepts, including bispecific and multivalent antibody formats, engineered heterodimer interface concepts, heteroconjugate antibodies, fragment-based formats, immunoconjugates and radioconjugates, and sequence modifications such as substitutions, insertions, deletions, alanine scanning mutagenesis, affinity maturation, glycosylation site engineering, and Fc effector modifications.

Claims Coverage

The provided excerpt contains three independent claims directed to non-naturally occurring anti-HIV-1 PGC14 monoclonal antibodies or antigen binding portions defined by specific sequence elements in light- and heavy-chain variable regions. The independent claim coverage is based on sequence-defined variable regions and CDR amino-acid sequences rather than process steps.

Across the independent claims shown, PGC14 antibody subject matter is defined by specific, non-naturally occurring light- and heavy-chain variable-region sequences, with one independent claim additionally specifying CDR amino-acid sequences. The coverage focuses on sequence-defined antibody specificity for anti-HIV-1 PGC14 monoclonal antibodies or antigen-binding portions.

Stated Advantages

Documented Applications