Epitope focusing by variable effective antigen surface concentration
Inventors
Assignees
Publication Number
US-10836797-B2
Publication Date
2020-11-17
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 immunogenic compositions, such as vaccines, through a strategy called epitope focusing by variable effective antigen surface concentration. This process involves three main stages: a design process utilizing in silico bioinformatics to select and produce a library of potential antigen variants; a formulation process where those antigens are tested and assembled in combinations with precise concentrations; and an administering step where the resulting immunogenic composition is delivered to a host, immune cell, or subject. Additional steps may include the isolation and production of antibodies generated by the immunogenic composition.
The problem addressed is that many pathogens evade immune detection and neutralization through mechanisms such as antigenic variation or drift, conformational masking, and glycosylation changes, thereby undermining vaccine effectiveness. Immunodominant epitopes often undergo structural variation and can mask immune responses to more conserved epitopes, leading to antibodies that quickly become ineffective. There is a need for innovative approaches to generate vaccines that elicit antibodies against conserved and desirable epitopes, circumventing immune evasion strategies of pathogens.
The core of the innovation is the design of immunogenic compositions containing at least six antigen variants, each sharing a common target epitope but diversified in their non-target surface-exposed regions. These variants are selected and optimized computationally so that their non-target epitopes are sufficiently diverse (sharing at most 90% sequence identity) while their internal or non-surface residues remain more conserved (at least 30% identity). Each variant is present at an individual concentration not sufficient to be immunogenic on its own, but the combined effective concentration of the conserved epitope across all variants is sufficient to elicit a focused immune response. This strategy amplifies immune recognition of the selected epitope while minimizing responses to undesired, variable regions.
Claims Coverage
There is one independent claim, which defines the fundamental inventive features incorporated in the computing device for designing antigen variant libraries.
Computing device for generating antigen variant libraries with controlled epitope conservation and diversity
A computing device comprises a processor and data storage storing instructions that, when executed, enable the acquisition of a target antigen protein sequence and one or more antigen homolog sequences. The device obtains structural models of the antigen and its homologs, identifying a plurality of surface-exposed amino acid residues. Using these models, the device generates, in silico, a library of antigen variants by: - Diversifying non-target epitope surface-exposed amino acid residues for each antigen variant based on the structural models. - Performing comparisons between each of a plurality of non-target epitope surface-exposed regions (of a commonly defined area) among antigen variants. Antigen variants in the library must share at least 30% sequence identity in non-surface exposed amino acid residues and at most 90% sequence identity in the non-target epitope surface-exposed residues. The device is capable of selecting six or more antigen variants generated through this procedure. This coverage extends to computing devices where the target antigen may include a pneumococcal antigen, tuberculosis antigen, anthrax antigen, HIV antigen, flu antigen, meningococcal antigen, Haemophilus antigen, or HPV antigen, with libraries potentially comprising at least 1×10^5, 1×10^6, or 1×10^7 antigen variants.
In summary, the claim coverage centers on a computing device that generates immunogenic antigen variant libraries, optimizing targeted epitope conservation and non-target surface diversity to enable focused immune responses, with precise sequence identity constraints and selection of variant ensembles.
Stated Advantages
The methods and compositions enable epitope-focused immune responses by increasing effective concentration of conserved epitopes and minimizing immune recognition of variable, non-target epitopes.
Immunogenic compositions designed according to this invention can circumvent immune evasion strategies such as antigenic drift or variation, leading to more robust and durable vaccines.
The process allows generation of antibodies specific to defined, conserved epitopes, which can be used not only for vaccines but also for diagnostics, therapeutic antibodies, and research tools.
The computational approach systematically diversifies non-target surfaces while maintaining the native fold and high stability of antigen variants in the library.
By assigning each antigen variant an individually non-immunogenic concentration, off-target immune response is reduced while enabling strong responses to desired epitopes.
The approach is applicable to a wide range of antigens, including those from viruses, bacteria, parasites, cancers, and biowarfare agents.
Documented Applications
Development of vaccines for the prevention and/or treatment of infectious diseases caused by viruses, bacteria, fungi, parasites, and cancer.
Generation of antibodies specific to single epitopes for use in therapeutic applications, including monoclonal and humanized antibodies.
Use in diagnostic applications to detect exposure to pathogens or immune threats using the designed immunogenic compositions.
Generation of research tools such as immunoassays, protein purification reagents, quantification, identification, and structural mapping tools.
Production of immune cell therapeutics by training immune cells with the immunogenic composition and administering them for disease treatment.
Design of DNA-based vaccines where nucleic acids encoding antigen variants are delivered for in situ antigen expression and immune response.
Development and evaluation of bi-specific T-cell engagers or targeted immunotherapies by generating antibodies with desired epitope specificity.
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