Rodent hepadnavirus cores with reduced carrier-specific antigenicity
Inventors
Milich, David R. • WHITACRE, David C.
Assignees
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Publication Number
US-10300124-B2
Publication Date
2019-05-28
Expiration Date
Abstract
The present disclosure generally relates to hepadnavirus core antigens in which one or more endogenous b cell epitopes have been effectively removed. More specifically, the present disclosure relates to rodent hepadnavirus cores modified to diminish the antibody response to the core so as to enhance the antibody response to heterologous polypeptides included therein.
Core Innovation
The patent describes an antigenic composition comprising a hybrid woodchuck hepadnavirus core antigen in the form of a fusion protein. The fusion protein includes a heterologous antigen fused to a woodchuck hepadnavirus core antigen comprising the amino acid sequence of SEQ ID NO:12 with a serine at position 61, and the fusion protein is capable of assembling as a hybrid virus-like particle (VLP).
The patent addresses obtaining enhanced antibody responses to heterologous inserts by reducing carrier-specific B-cell epitope antigenicity of the rodent hepadnavirus core antigen. Reduced-antigenicity core variants and specific carrier modifications are defined, including substitutions and residue-region replacement, to reduce endogenous B-cell epitope binding while maintaining hybrid VLP assembly and heterologous antigen presentation.
The hybrid VLP architecture is further defined by permitted heterologous antigen lengths and insertion positions within the woodchuck core antigen, including N-terminus, internal sites numbered according to SEQ ID NO:1, and C-terminus. Hybrid VLPs are used to assess binding and antibody specificity toward the heterologous antigen, including comparisons with nonhybrid or devoid-of-insert controls.
Claims Coverage
The document presents one independent claim and multiple dependent claims. The inventive coverage centers on a hybrid woodchuck hepadnavirus core antigen fusion capable of forming a hybrid VLP, with defined reduced-antigenicity core sequence or modification choices and controlled heterologous antigen insertion parameters.
Hybrid woodchuck hepadnavirus core antigen fusion capable of assembling as a hybrid VLP
An antigenic composition comprising a hybrid woodchuck hepadnavirus core antigen, wherein the hybrid core antigen is a fusion protein comprising a heterologous antigen and a woodchuck hepadnavirus core antigen comprising the amino acid sequence of SEQ ID NO:12 with a serine at position 61, and the fusion protein is capable of assembling as a hybrid virus-like particle (VLP).
Heterologous antigen length in the hybrid fusion
The heterologous antigen in the antigenic composition is 4 to 50 amino acids long.
Heterologous antigen insertion position within the core
A heterologous antigen inserted at a specified position within a core antigen at either N-terminal or C-terminal locations or at selected internal positions numbered according to SEQ ID NO:1.
One through five defined woodchuck core modifications with specified substitutions or residue-region replacement
The antigenic composition includes woodchuck hepadnavirus core antigen having one through five specified modifications, where each modification corresponds to particular listed amino-acid substitutions or a residue-region replacement with a heterologous antigen, and the modification numbering follows SEQ ID NO:1.
Vaccine comprising the hybrid antigenic composition and an adjuvant
A vaccine that includes the antigenic composition together with an adjuvant.
Screening anti-heterologous antigen antibodies using hybrid versus nonhybrid core antigen binding
A method for screening anti-heterologous antigen antibodies by measuring their binding to a hybrid woodchuck hepadnavirus core antigen versus a nonhybrid core antigen devoid of the heterologous antigen, and determining antibody specificity for the heterologous antigen based on binding to the hybrid but not the nonhybrid antigen.
The claims coverage is directed to a hybrid woodchuck hepadnavirus core antigen fusion protein with a defined core sequence (SEQ ID NO:12 with a serine at position 61) that assembles into a hybrid VLP, with dependent claim coverage specifying heterologous antigen length, insertion positions, and defined reduced-antigenicity core modifications. Additional dependent coverage specifies vaccine formulations that include an adjuvant and a hybrid-versus-nonhybrid binding workflow to screen for anti-heterologous antigen antibody specificity.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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