Epitope focusing by variable effective antigen surface concentration
Inventors
Assignees
Publication Number
US-9884893-B2
Publication Date
2018-02-06
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 immunogenic compositions and methods that focus an immune response toward a specific epitope by using a mixture of antigen variants, each sharing a conserved target epitope but with diverse non-epitope regions. The mixed antigens are combined so that the total concentration of the shared target epitope becomes immunogenic, though each antigen variant alone is below the threshold required to elicit an immune response. This results in effective epitope focusing, directing the immune system to generate responses, such as antibodies, specifically to the conserved target epitope.
The patent addresses the problem wherein pathogens evolve mechanisms like antigenic variation and antigenic drift that allow them to escape immune detection and neutralization. Traditional vaccine approaches are challenged by highly variable and immunodominant surface epitopes that mask more conserved, desirable vaccine targets, leading to ineffective immune protection. The disclosed method provides a way to overcome this by computational design and biochemical formulation of antigen libraries in which only the conserved target epitope is present at an immunogenic concentration, while other surface features are highly diversified.
Through a defined design process involving computational modeling, structural alignment, and in vitro testing, libraries of antigen variants are created and formulated into immunogenic compositions. The approach supports the generation and administration of such compositions as vaccines or antibody production tools, and further extends to diagnostic, therapeutic, and basic research uses where a focused immune response to a selected epitope is needed.
Claims Coverage
There are two independent claims in this patent, each providing distinct inventive features for the immunogenic composition and its method of generation.
Immunogenic composition with epitope focusing by variable effective antigen surface concentration
An immunogenic composition comprising at least six antigen proteins, each containing a common target epitope of surface exposed residues adjacent in tertiary space, where: - The common target epitope has an effective concentration in the composition that is higher than the individual concentrations of each antigen protein. - Each antigen protein is present at a concentration insufficient to be immunogenic alone. - The combined effective concentration of the common target epitope across the mixture is sufficient to elicit an immune response to that epitope in a subject.
Method for generating immunogenic compositions with focused epitope presentation
A method which includes: 1. Introducing into a cell at least one nucleic acid encoding at least six antigen proteins, each containing a common target epitope of surface exposed residues adjacent in tertiary space; 2. Optionally isolating the plurality of antigen proteins; 3. Generating an immunogenic composition including the at least six antigen proteins, with the common target epitope having an effective concentration greater than any individual antigen protein, and each antigen protein present at a concentration insufficient to be immunogenic alone, while the composition as a whole elicits an immune response to the common target epitope in a subject.
In summary, the inventive features focus on the formulation and method of producing immunogenic compositions with multiple antigen variants that enable selective immune targeting of a conserved epitope, while keeping each individual antigen variant below immunogenic levels to maximize epitope specificity.
Stated Advantages
The invention enables elicitation of an immune response selectively focused on a common target epitope, reducing or eliminating immune responses to variable, non-target antigen regions.
By maintaining each antigen variant at a sub-immunogenic concentration, undesired immune activation to non-target epitopes is minimized, allowing for precise targeting of immune response.
The compositions and methods are suitable for generating broadly effective vaccines and antibodies against conserved regions of antigens that may be resistant to escape by mutation or antigenic drift.
The approach allows the development of vaccines and antibody-based tools for pathogens, cancer, diagnostics, and research where specific epitope recognition is desirable.
Documented Applications
Development of vaccines for infectious diseases, autoimmune diseases, inflammatory diseases, neurological diseases, addiction, cardiovascular diseases, endocrine diseases, and cancer.
Generation of antibodies directed to a particular epitope of interest for research, diagnostic, or therapeutic use.
Use in diagnostic assays for detecting exposure to pathogens or immune threats by binding target-specific antibodies.
Formulation into therapeutic methods, including administration for treating or reducing the likelihood of disease in a human subject.
Incorporation into virus-like particles (VLPs) for vaccine delivery.
Production of antibody-based tools for applications such as immunoassays, protein purification, identification, quantification, and structural mapping.
Use with a recombinant expression vector for producing the antigen proteins of the immunogenic composition.
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