Epitope focusing by variable effective antigen surface concentration
Inventors
Assignees
Publication Number
US-10196427-B2
Publication Date
2019-02-05
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, by epitope focusing through variable effective antigen surface concentration. The approach involves designing an immunogenic composition using a library of antigen variants, each containing a highly conserved target epitope but with diversified non-target surface regions. The process includes in silico bioinformatics steps to select and generate the antigen library, in vitro formulation to screen and assemble the antigen variants, and administration of the resulting immunogenic composition so that individual variants are present at concentrations insufficient to be immunogenic alone, but together induce an immune response specific to the target epitope.
The problem addressed by the invention is the development of vaccines against pathogens that evade detection by antigenic variation, epitope masking, and antigenic drift, leading to ineffective immune responses. Existing vaccine strategies are undermined by pathogens altering their immunodominant epitopes, masking conserved regions, and rendering raised antibodies obsolete. There is a need for methods that redirect the immune response toward conserved epitopes that are less prone to variation, to produce effective antibodies or vaccines against pathogens and diseases such as viruses, bacteria, and cancers.
The core innovation centers on delivering a mixture of at least six antigen variants, each sharing a conserved target epitope but differing in other surface features, at doses where no individual antigen is immunogenic but the total composition elicits an immune response to the conserved target epitope. The design ensures the focused elicitation of antibodies against the target epitope while reducing responses to variable non-target regions, thereby overcoming the limitations of immune evasion by antigenic drift or masking. This method can be applied broadly to generate antibodies or vaccines for a wide range of antigens.
Claims Coverage
The independent claims cover two main inventive features related to methods for eliciting an immune response using multiple antigens with a focused approach on a common conserved epitope.
Delivering multiple antigen variants sharing a conserved epitope at sub-immunogenic individual doses
A method for eliciting an immune response in a human subject by delivering at least six antigens, where each antigen contains a target epitope that is common to all antigens and also includes one or more non-conserved regions outside the target epitope. Importantly, each antigen is administered at a concentration insufficient to be immunogenic alone, but the combined amount is sufficient to generate an immune response focused on the target epitope. The antigens may have the following properties: - Delivered as a single composition - Each may have a peptide backbone - The target epitope is a contiguous surface-exposed patch in tertiary structure - Surface-exposed patch area: at least 25 Å2 up to 2000 Å2 (preferably 100-1500 Å2) - Each antigen is at least 100 amino acids, 5–1000 kDa in size - Antigens share a common protein fold - The conserved target epitope is at least 90% identical among antigens - Non-target surfaces are less than 90% identical between any two antigens - The immune response can involve CD4+ T-cell interactions - Application to diseases including infectious, autoimmune, inflammatory, neurological, addiction, cardiovascular, endocrine, and cancer - Each antigen can be cross-reactive with antibodies raised to others in the set - Affinity of antibodies for antigens is less than 10−7 M - The method includes delivering nucleic acids encoding antigens via viral or lipid vectors, and delivery via different administration routes.
The claim coverage focuses on methods comprising the delivery and design of antigen ensembles that direct the immune response to a conserved target epitope by exploiting variable non-target surfaces and sub-immunogenic individual antigen dosing, ensuring epitope-specific immunization.
Stated Advantages
Enhances the focus of the immune response to a specific, conserved target epitope, reducing responses to variable or immunodominant but non-essential regions.
Reduces the potential for vaccine evasion by pathogens that use antigenic drift or variation to escape detection.
Can be broadly applied to generate antibodies or immune responses against a wide range of antigens, including those relevant to infectious disease, cancer, and other diseases.
Allows for more selective and predictable antibody generation, facilitating applications in diagnostics, therapeutics, and research tools.
Enables the production of vaccine compositions where no individual antigen is immunogenic alone, improving safety and specificity.
Documented Applications
Development of vaccines for infectious diseases, including those caused by viruses, bacteria, fungi, and parasites.
Generation of vaccines for cancer by targeting tumor or cancer antigens with conserved epitopes.
Development of immunogenic compositions for autoimmune, inflammatory, neurological, addiction, cardiovascular, endocrine diseases, and those involving chemical/bio-warfare agents.
Production of specific antibodies for therapeutic use, including the creation of monoclonal and humanized antibodies.
Use in generating antibody-based tools for diagnostics, detection, quantification, protein purification, characterization, and structural domain mapping.
Development of diagnostic assays to detect exposure to pathogens or immune threats by assessing antibody responses to defined epitopes.
Use for generating immunogenic compositions for in vitro or in vivo immune cell training or selection, including use in hybridomas and immune cell therapeutics.
Application in generation of virus-like particles (VLPs) comprising epitope-focused immunogenic compositions for vaccination or study.
Use in generating bispecific T-cell engagers (BiTEs) and other engineered therapeutic antibodies with targeted epitope specificity.
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