Epitope restriction for antibody selection
Inventors
Weidenbacher, Payton • Kim, Peter S.
Assignees
Leland Stanford Junior University • Chan Zuckerberg Biohub San Francisco
Publication Number
US-12304928-B2
Publication Date
2025-05-20
Expiration Date
2039-05-17
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Abstract
Provided are methods of producing antigenic proteins and antigenic protein complexes and compositions and vaccines produced from such methods. Also provided are methods of immunizing a subject using such compositions and vaccines. The antigenic proteins and protein complexes of this disclosure are useful as vaccine immunogens that can direct the immune system of a subject immunized with such vaccine immunogens to generate antibodies against a specific region, or epitope, of a protein that is known to be productive or neutralizing in the case of an infection. Also provided are methods of screening for B cells expressing antibodies that bind specifically to a particular, desired epitope (target region). Compositions and kits comprising one or more antigenic protein, protein complexes, binding partners, and polynucleotides encoding any thereof, are also described.
Core Innovation
The invention provides methods of producing modified hemagglutinin influenza virus proteins or variants thereof in which immune response can be focused toward a specific epitope of interest. This is achieved by employing a binding partner that specifically binds and protects a target region (the epitope of interest) on the hemagglutinin protein during chemical modification, while allowing modification of amino acid residues in non-target regions. The resulting modified protein is structured so that non-target regions contain covalently attached modifying components, and the target region remains unmodified and accessible for immune targeting.
The problem addressed by the invention is the difficulty in eliciting productive or broadly neutralizing antibody responses against conserved regions of variable viral proteins, such as those from influenza, due to immunodominance of non-protective and highly variable regions. Prior vaccines often fail to generate immunity effective against diverse strains because antibodies target non-conserved regions, and attempts to direct the immune response to a crucial, conserved epitope have been largely unsuccessful.
This approach enables the production of immunogens where the immune system's antibody response is directed primarily against the desired, conserved epitope by masking or altering the immunogenicity of other regions. The invention further encompasses compositions, vaccines, and kits based on such modified antigenic proteins, methods of immunizing subjects with these compositions, as well as methods for producing and isolating antibodies specific to the targeted epitope.
Claims Coverage
The independent claim defines a method of making a modified hemagglutinin influenza virus protein or a fragment or variant thereof, with several inventive features.
Specific protection of the target region during modification
A binding partner is provided that binds specifically to the target region (epitope of interest) of the hemagglutinin influenza virus protein (or fragment/variant), forming a protein complex. This binding specifically protects the target region from chemical modification, ensuring it remains unaltered during subsequent processing steps.
Selective chemical modification of non-target regions
A modifying reagent is used to react with amino acid residues in the non-target region of the hemagglutinin protein (or fragment/variant) within the formed complex, covalently attaching a modifying component to each of a plurality of these non-target amino acids, while leaving the protected target region unmodified.
Provision of modified antigen with reduced or ablated immunogenicity of non-target region
After modification, the modified hemagglutinin influenza virus protein (or fragment or variant thereof) is separated from the binding partner, resulting in a product where the non-target region has reduced or ablated immunogenicity due to the attached modifying component, and the target region is unaltered.
The inventive features cover a process that focuses immune response by protecting a specific epitope during modification, selectively altering only the non-target regions, and yielding a modified antigen with targeted immunogenic properties.
Stated Advantages
The methods direct the immune response toward a desired, productive, or broadly neutralizing epitope by masking immunodominant or variable regions.
Compositions produced with these methods reduce or ablate immune recognition of non-target regions, allowing focused antibody responses to conserved or functional regions.
Modified antigenic proteins retain proper conformation by protecting target regions during chemical modification.
Methods enable production of vaccine immunogens that can generate antibodies against conserved or protective regions despite high variability in other protein regions.
Documented Applications
Use in vaccines and immunizations to generate antibodies specifically targeting conserved or protective epitopes of influenza hemagglutinin.
Screening or sorting of B cells or antibody libraries to identify antibodies that bind specifically to target epitopes.
Preparation of pharmaceutical compositions or kits containing modified hemagglutinin proteins for therapeutic or prophylactic administration.
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