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-10407493-B2
Publication Date
2019-09-10
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 isolated and non-naturally occurring polynucleotides that encode antibody light chain variable regions and heavy chain variable regions. The encoded variable regions are defined by complementarity determining region (CDR) amino acid sequences using specified SEQ ID NOS, including light chain variable regions comprising three CDRs and heavy chain variable regions comprising three CDRs. The polynucleotides are used to produce antibody structures whose variable region sequences are constrained by these SEQ ID NO definitions.
The disclosure further includes extensive sequence characterization for HIV-neutralizing monoclonal antibodies in the PG16 class and related variants, together with heavy-chain and light-chain CDR definitions using Kabat and Chothia frameworks. It specifies nucleotide and amino-acid sequences for lambda light chains and gamma heavy chains, including defined CDR amino-acid sequences referenced in the claim set. The sequence disclosure is presented for antibodies with neutralizing activity against HIV-1 and for characterization via binding and epitope mapping workflows.
The document also provides acceptable homology and identity thresholds and silent or degenerate nucleotide variants for the defined sequences, while keeping the defined CDR content tied to the enumerated SEQ ID NOS. It includes general usage context for antibodies in immunoassays and epitope mapping, including ELISA and related binding and neutralization assay context, together with compositions and uses for prophylaxis, diagnosis, treatment, and vaccine immunogen design.
Claims Coverage
The provided claim set includes seven independent claims, all directed to isolated, non-naturally occurring polynucleotides encoding antibody light and heavy chain variable regions defined by SEQ ID NO sequence identifiers. The inventive features span CDR-defined amino-acid compositions, full variable-region amino-acid sequences, and nucleotide sequences, with dependent refinements covering vectors, host cells, pharmaceutical composition, and HIV inhibition.
CDR-defined light and heavy variable regions by specified SEQ ID NOS
An isolated and non-naturally occurring polynucleotide encoding a light chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 126, 127 and 45 and a heavy chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 123, 124 and 7.
CDR-defined light and heavy variable regions by alternative specified SEQ ID NOS
An isolated and non-naturally occurring polynucleotide encoding a light chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 97, 95 and 41 and a heavy chain variable region comprising three complementarity determining regions comprising the amino acid sequences of SEQ ID NOS: 88, 89 and 6.
Light and heavy variable regions defined by specified amino-acid sequences
An isolated and non-naturally occurring polynucleotide encoding a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28.
Polynucleotide comprising nucleotide sequences for light and heavy variable regions
An isolated and non-naturally occurring polynucleotide comprising a light chain variable region comprising the nucleotide sequence of SEQ ID NO: 125 and a heavy chain variable region comprising the nucleotide sequence of SEQ ID NO: 122.
Polynucleotide comprising nucleotide-encoded light and heavy variable regions by specified SEQ ID NOS
An isolated and non-naturally occurring polynucleotide encoding a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12.
Polynucleotide comprising nucleotide sequences for alternative light and heavy variable regions
An isolated and non-naturally occurring polynucleotide comprising a light chain variable region comprising the nucleotide sequence of SEQ ID NO: 100 and a heavy chain variable region comprising the nucleotide sequence of SEQ ID NO: 99.
Vector and host cell delivery for defined polynucleotide
One or more vectors selected from viral vectors, plasmid vectors, plant expression vectors, or yeast expression vectors, where the vectors encode the light chain and heavy chain variable regions; a prokaryotic host cell is Escherichia coli and a eukaryotic host cell is a yeast cell, an animal cell, or a plant cell; the viral vector is an adeno-associated virus vector.
Pharmaceutical composition and HIV inhibition method
A pharmaceutical composition comprising the polynucleotide together with a pharmaceutically acceptable excipient, and a method of inhibiting HIV in a host by administering the pharmaceutical composition so that the polynucleotide or vector expresses an antibody.
Across the independent claims, the inventive subject matter is the encoding of specific antibody light chain variable regions and heavy chain variable regions by isolated, non-naturally occurring polynucleotides. The claims are centered on specified SEQ ID NO amino-acid or nucleotide sequences, with dependent limitations directed to vectors, host cells, pharmaceutical composition, and a method of inhibiting HIV through antibody expression.
Stated Advantages
Neutralization of multiple HIV-1 clades at sub-microgram/mL levels.
Preferential binding to native trimeric Env rather than correlated or strong binding to recombinant monomeric gp120/gp41.
Targeting in conserved V2/V3 variable loop regions with dependence on Env trimer presentation and glycosylation features.
Documented Applications
Prophylaxis using antibody-containing compositions.
Diagnosis using antibody-containing compositions and/or diagnostic kits.
Treatment by inhibiting HIV in a host through administering a pharmaceutical composition such that the polynucleotide or vector expresses an antibody.
Vaccine immunogen design using vaccine epitopes informed by the described antibody targeting and characterization.
Immunoassays and epitope mapping, including ELISA and related binding and neutralization assay context for assessing neutralization and binding.
Inhibiting HIV in a host by administering a pharmaceutical composition so that the polynucleotide or vector expresses an antibody.
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