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-10087239-B2
Publication Date
2018-10-02
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 disclosure provides extensive immunoglobulin variable-region sequence information for multiple PGT antibodies and related variants, including gamma/heavy and light chain variable region nucleic acid and amino acid sequences. It specifies Kabat and Chothia CDRs, mapped CDR sets, consensus and alignment presentations, and associated sequence identifiers across multiple variants and sister clones.
The document includes sequence alignment data for heavy-chain variable regions and light-chain coding sequences, with numbered positions, consensus or representative alignments, and highlighted CDR regions. It also presents VH sequence segments and CDR3-labeled alignment rows for PGT-121 and related clones, together with annotation graphics and clone identifiers.
The patent portion further reports neutralization and epitope mapping results for PGT bnAbs, including comparisons among PGT-121 to PGT-145 subsets and comparator antibodies. It describes differences in potency and breadth, binding to gp120 monomer versus membrane-bound trimeric Env, V3-loop proximity, glycan dependence, and mutant analyses implicating specific N-linked glycan positions.
Claims Coverage
The independent claims present three core inventive features. They define a sequence-identified PGT-121 monoclonal antibody in an immortalized B cell clone, and vectors or nucleic-acid vectors containing and expressing the corresponding PGT-121 light and/or heavy chain sequences.
Immortalized B cell clone expressing a PGT-121 monoclonal antibody
An immortalized B cell clone expressing a PGT-121 monoclonal antibody comprising a light chain sequence of SEQ ID NO: 148 and a heavy sequence of SEQ ID NO: 66.
Vectors containing and expressing PGT-121 light and/or heavy chain sequences
One or more vectors containing and expressing a PGT-121 light chain sequence of SEQ ID NO: 148 and/or a PGT-121 heavy chain sequence of SEQ ID NO: 66.
Nucleic-acid vectors containing PGT-121 light and/or heavy chain sequences
One or more vectors containing a nucleic acid comprising a PGT-121 light chain sequence of SEQ ID NO.: 146 and/or a PGT-121 heavy chain sequence of SEQ ID NO.: 62.
The claims center on exact PGT-121 light-chain and heavy-chain sequence identities, covering an immortalized B cell clone and vector-based embodiments that contain and express the specified sequences.
Stated Advantages
Differences in neutralization potency and breadth are described among clonal and somatically related PGT monoclonal antibodies.
Some variants are described as maintaining potency while showing broader neutralization than somatic relatives.
The results link neutralization breadth and potency to vaccine and combination coverage concepts.
Documented Applications
Vaccine and combination coverage concepts are discussed in connection with the neutralization breadth and potency profiles.
Neutralization testing against HIV-1 strains and diverse HIV isolates and subtypes is described.
Epitope mapping, glycan dependence analysis, and immunoassay characterization are documented.
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