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AssigneesUniversity of Washington Center for Commercialization, The Scripps Research Institute, International AIDS Vaccine Initiative
InventorsPo-Ssu Huang, Joseph Graham Jardine, Sergey V. Menis, William Ray Schief, Neil P. King
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The invention relates to an engineered outer domain (eOD) of HIV gp120 and mutants thereof and methods of making and using the same. The mutant eODs may be advantageous for the elicitation of CD4-binding site (CD4bs)-directed broadly-neutralizing antibodies (bnAbs) and/or improve binding to mature VRC01 and/or improve binding to germline VRC01 and the germlines of other VH1-2 derived broadly-neutralizing antibodies. The mutant eODs may also include glycan-masking mutations on eOD. The present invention also includes fusions of eOD to various protein multimers to enhance immunogenicity as well as the design of cocktails of different eODs that represent the full diversity of HIV sequences within the VRC01 epitope and surroundings.
A non-naturally occurring protein comprising an engineered outer domain (eOD) mutation advantageous for the elicitation of CD4-binding site (CD4bs)-directed broadly-neutralizing antibodies (bnAbs), wherein the protein comprises any one of:
A non-naturally occurring protein comprising an eOD mutation to improve binding of mature VRC01, wherein the protein comprises any one of:
A non-naturally occurring protein comprising an eOD variant engineered to improve binding to germline VRC01 and/or other VH1-2 antibodies comprising any one of:
A non-naturally occurring protein comprising an eOD variant engineered to improve binding to germline VRC01 to eOD comprising at least one mutation relative to eOD (=c1d1) in the eOD variants in this section listed below, in both eOD numbering (left column) and HxB2 numbering (right column), wherein the HxB2 numbering uniquely defines a position in any HIV Env sequence once it has been aligned to the HxB2 sequence, wherein the mutation is selected from the table consisting of:
A non-naturally occurring protein comprising a mutation and/or modification in core_gp120_VH1-2_v2.0 and core_gp120_VH1-2_v2.1 relative to core_gp120_VH1-2_v1.0, wherein the mutation and/or modification improves binding of core gp120 to germline VH1-2 antibodies, wherein the mutation and/or modification is selected from the group consisting of:
A non-naturally occurring protein comprising an eOD variant, wherein the eOD variant is involved in glycan masking, wherein the eOD variant is selected from the group consisting of:
A non-naturally occurring protein comprising an eOD variant fused with one or more multimerization domains, wherein the eOD variant is selected from the group consisting of:
A non-naturally occurring protein comprising a HIV Env-based construct having improved binding to a germline VH1-2 antibody comprising one or more of the mutations or modifications selected from the group consisting of:
A non-naturally occurring protein comprising any HIV Env-based construct or sequence having improved binding to a germline VH1-2 antibody comprising one or more of the mutations or modifications selected from the group consisting of:
A non-naturally occurring protein comprising any HIV Env-based construct or sequence having improved binding to a germline VH1-2 antibody comprising a deletion of the glycosylation site at position 276 and/or deletion of glycosylation sites on a V5 loop at positions 460, 461, 462, or 463.
Dependencies are inferred from the claim text.