Conformationally-specific viral immunogens
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Publication Number
US-11752191-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present invention provides methods of making engineered viral proteins and protein complexes that are useful as vaccine immunogens, engineered viral proteins and protein complexes made using such methods, and pharmaceutical compositions comprising such engineered viral proteins and protein complexes. Such engineered viral proteins and protein complexes may comprise one or more cross-links that stabilize the conformation of an antibody epitope, such as a quaternary neutralizing antibody, and may exhibit an enhanced ability to elicit a protective immune response when administered to a subject as a component of a vaccine.
Core Innovation
Conformationally-specific viral vaccine immunogens are engineered by introducing stabilizing cross-links into viral proteins or viral protein complexes so that the engineered proteins maintain a conformation that can bind to an antibody and can activate a B cell receptor. The disclosed approach uses one or more dityrosine cross-links, including dityrosine cross-links formed by introducing tyrosine point mutations at selected regions. Stabilization targets tertiary and/or quaternary structural regions to lock the intended epitope architecture.
Regions within recombinant viral envelope proteins or viral envelope protein complexes are selected using biochemical or structural analysis to identify one or more regions where introducing one or more dityrosine cross-links could stabilize the conformation that is capable of antibody binding and B cell receptor activation. The selected regions can be associated with quaternary neutralizing epitopes, including neutralizing and broadly neutralizing epitopes presented on envelope protein trimers and protein complexes. Engineered immunogens are described as showing enhanced binding to neutralizing antibodies, enhanced binding to broadly neutralizing antibodies, and enhanced binding to and activation of B cell receptors.
The disclosed examples focus on HIV Env gp140, including selecting V1/V2 loop residues for dityrosine cross-linking to form a dityrosine-locked trimeric HIV Env conformation. Dityrosine cross-links are characterized as stable under physiological conditions and associated with reduced aggregation, and engineered immunogens are analyzed for preserved antigenicity and epitope-relevant binding, including improved binding of broadly neutralizing antibodies such as PG16 relative to wild-type protomer. Further analysis includes determining cross-link positioning and supporting suitability for immunogenicity testing.
Claims Coverage
The independent claim set is centered on a method for producing a vaccine immunogen candidate using recombinant viral envelope proteins or envelope protein complexes engineered with one or more dityrosine cross-links to stabilize an antibody-binding, B cell receptor-activating conformation. The main inventive features correspond to selecting dityrosine cross-link regions by biochemical or structural analysis and then introducing tyrosine point mutations and dityrosine cross-links in the selected regions to yield engineered immunogens with specified enhanced properties.
Producing a recombinant viral envelope immunogen in an antibody-binding/BC receptor-activating conformation
Producing a recombinant viral envelope protein or viral envelope protein complex in a conformation that can bind to an antibody and can activate a B cell receptor.
Selecting cross-link regions by biochemical or structural analysis
Performing biochemical or structural analysis to identify and select one or more regions in the recombinant viral envelope protein or viral envelope protein complex where the introduction of one or more dityrosine cross-links could stabilize the conformation.
Introducing tyrosine point mutations at selected regions
Introducing into the viral envelope protein or viral envelope protein complex one or more point mutations to tyrosine at one or more of the regions selected in step (b).
Forming engineered dityrosine cross-links at selected regions
Introducing into the recombinant viral envelope protein or viral envelope protein complex one or more dityrosine cross-links at one or more of the regions selected in step (b) to form an engineered viral envelope protein or viral envelope protein complex.
Enhanced antibody binding, B cell receptor activation, and in-animal immune responses
Configuring the engineered viral envelope protein or viral envelope protein complex to have one or more properties selected from enhanced ability to bind to a neutralizing antibody, enhanced ability to bind to a broadly neutralizing antibody, enhanced ability to bind to and activate B cell receptors, enhanced ability to elicit an antibody response in an animal, enhanced ability to elicit a protective antibody response in an animal, enhanced ability to elicit production of neutralizing antibodies in an animal, enhanced ability to elicit production of broadly neutralizing antibodies in an animal, enhanced ability to elicit a protective immune response in an animal, and enhanced ability to bind to and elicit production of antibodies that recognize quaternary neutralizing epitopes in an animal.
Overall, the claim coverage focuses on engineering recombinant viral envelope proteins or complexes by selecting regions for dityrosine cross-linking through biochemical or structural analysis, introducing tyrosine point mutations, and forming dityrosine cross-links to stabilize an antibody-binding, B cell receptor-activating conformation, with enhanced neutralizing/broadly neutralizing antibody binding and specified antibody and immune response outcomes in animals.
Stated Advantages
Enhanced ability to bind to a neutralizing antibody as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to bind to a broadly neutralizing antibody as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to bind to and activate B cell receptors as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to elicit an antibody response in an animal as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to elicit a protective antibody response in an animal as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to elicit production of neutralizing antibodies in an animal as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to elicit production of broadly neutralizing antibodies in an animal as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to elicit a protective immune response in an animal as compared to the viral envelope protein or viral envelope protein complex.
Enhanced ability to bind to and elicit production of antibodies that recognize quaternary neutralizing epitopes in an animal as compared to the viral envelope protein or viral envelope protein complex.
Documented Applications
HIV Env gp140 engineered immunogens with dityrosine cross-links, including dityrosine-locked trimeric conformation, used to improve binding of broadly neutralizing antibodies such as PG16 and to support immunogenicity testing.
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