Epitope focusing by variable effective antigen surface concentration
Inventors
Assignees
Publication Number
US-11560409-B2
Publication Date
2023-01-24
Expiration Date
2033-05-21
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Abstract
The present disclosure provides compositions and methods for the generation of an antibody or immunogenic composition, such as a vaccine, through epitope focusing by variable effective antigen surface concentration. Generally, the composition and methods of the disclosure comprise three steps: a “design process” comprising one or more in silico bioinformatics steps to select and generate a library of potential antigens for use in the immunogenic composition; a “formulation process”, comprising in vitro testing of potential antigens, using various biochemical assays, and further combining two or more antigens to generate one or more immunogenic compositions; and an “administering” step, whereby the immunogenic composition is administered to a host animal, immune cell, subject or patient. Further steps may also be included, such as the isolation and production of antibodies raised by host immune response to the immunogenic composition.
Core Innovation
The invention provides compositions and methods for generating antibodies or immunogenic compositions, such as vaccines, through epitope focusing by variable effective antigen surface concentration. The compositions and methods involve three main steps: an in silico bioinformatics-based design process to select and generate a library of potential antigens to be used in the immunogenic composition, a formulation process involving in vitro testing and combination of selected antigens, and finally the administering of the formed immunogenic composition to a host animal, immune cell, or subject.
A central feature of this invention is the design of immunogenic compositions that contain at least six different antigen variants, each presenting a common target epitope but differing substantially in non-target surface regions. Each antigen, when present individually, is at a concentration insufficient to stimulate an immune response, but when administered collectively, the sum concentration of the conserved epitope is sufficient to elicit immune activation. This approach allows the immune system to focus its response on a specific, conserved epitope, rather than variable or immunodominant but less desirable regions.
The problem being solved arises from the fact that pathogens have evolved mechanisms such as antigenic variation and drift to evade immune recognition, often rendering conventional vaccines ineffective as antibodies are directed toward variable regions. Current methods struggle to induce strong, epitope-specific responses, particularly for conserved epitopes critical for pathogen neutralization. The disclosed compositions and methods provide a solution by computationally guiding the design, selection, and formulation of antigenic ensembles that retain high identity in the target epitope and maximize diversity elsewhere, enabling the effective generation of antibodies or immune responses selectively targeting these conserved sites.
Claims Coverage
The patent contains two independent claims, each focusing on a distinct inventive aspect related to immunogenic compositions leveraging epitope focusing by variable effective antigen surface concentration.
Immunogenic composition comprising multiple antigens sharing a target epitope at individually sub-immunogenic concentrations
An immunogenic composition is described that includes at least six antigens. Each antigen comprises a common target epitope. Importantly, each antigen in the immunogenic composition is present at an individual concentration that is insufficient to be immunogenic in the subject when administered alone. The inventive feature lies in the deliberate formulation wherein the ensemble of antigens collectively achieves an effective concentration capable of eliciting an immune response, focusing the response on the conserved epitope shared among antigens, while the distinct non-target surface regions reduce immune dominance for other epitopes.
Method for detecting antibody binding using an epitope-focused antigen variant composition
A method is provided for detecting the presence or absence of an antibody by contacting the immunogenic composition or one or more antigen variants, each comprising one or more epitopes, with a composition containing an antibody, under conditions suitable for antibody-epitope binding. The method involves detecting one or more epitopes complexed with the antibody, leveraging the unique presentation of conserved epitopes within the antigen variants. This enables specific interrogation of antibody binding to targeted epitopes using the diversified antigen composition.
In summary, the claims cover the creation and use of immunogenic compositions containing multiple antigen variants that share a conserved target epitope and are individually sub-immunogenic, as well as methods for specifically detecting antibody responses using these compositions. The inventive features enforce both rigorous epitope conservation and diversification of non-target antigen regions to direct and interrogate immune responses.
Stated Advantages
Allows precise focusing of the immune response to a specific, conserved epitope, reducing unwanted responses to variable or immunodominant regions.
Overcomes pathogen mechanisms of immune evasion such as antigenic drift and variation, providing improved effectiveness for diseases where conventional vaccines fail.
Enables generation of antibodies highly specific to desired epitopes, useful for antibody-based diagnostics, therapeutics, and basic research assays.
Permits creation of vaccines and immunogenic compositions for difficult targets, including viruses with high antigenic variability (such as HIV and influenza), by using computational and experimental design to ensure desired epitope targeting.
Supports high-throughput screening and validation of antigen variants for stability, target epitope specificity, and manufacturability.
Documented Applications
Development of vaccines for infectious diseases, autoimmune diseases, inflammatory diseases, neurological diseases, addiction, cardiovascular diseases, endocrine diseases, and cancer.
Production of antibody drugs targeting specific epitopes for therapeutic use, including monoclonal antibodies and bispecific T-cell engagers (BiTEs).
Generation of diagnostic tools for detecting the presence or absence of antibodies, antigen exposure, or immune responses, using specially designed antigen variants.
Creation of research tools such as antibodies for protein detection, purification, characterization, or quantification in basic scientific research.
Use in generating cell-based therapeutics, including immune cell training and adoption, via administration of immunogenic compositions targeting disease-relevant epitopes.
Application in vaccine research and production for pathogens including HIV, influenza, pneumococcus, tuberculosis, anthrax, pertussis, Staphylococcus aureus, Meningococcus, Haemophilus, and HPV.
Use of formulated compositions and methods in phage display, yeast display, and mammalian display platforms for antibody discovery and screening.
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