Fusion of heterooligomeric mycobacterial antigens
Inventors
Marchand, Jean-Baptiste • Silvestre, Nathalie • Penin, François
Assignees
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Publication Number
US-10765731-B2
Publication Date
2020-09-08
Expiration Date
Abstract
The present invention relates generally to novel immunogenic combinations comprising or encoding at least two heterooligomeric mycobacterial antigens and preferably a fusion polypeptide comprising said two heterooligomeric mycobacterial antigens, where the mycobacterial antigens are selected from the group of Esx, PE and PPE antigens of a Mycobacterium species, particularly a Mycobacterium of the tuberculosis complex such as Mycobacterium tuberculosis (Mtb). The present invention also relates to vectors, host cells and compositions comprising or encoding said immunogenic combination as well as to methods for expressing and producing it. The present invention also relates to methods of using said immunogenic combination, fusion polypeptide, vector, host cell, composition particularly for inducing or stimulating an immune response with the goal of providing a protective response against a Mycobacterium infection or any disease caused by or associated with a Mycobacterium infection.
Core Innovation
The disclosed invention relates to an immunogenic TB-antigen strategy in which at least two heterooligomeric mycobacterial antigens are used, including ESAT6 and CFP10, with one or more other mycobacterial antigens from specified ESAT6/CFP10-related heterooligomeric systems. The antigen design is focused on preserving heterodimer formation by using fusion polypeptides based on heterooligomeric partners from Mycobacterium tuberculosis, including ESAT6 (Rv3875) with CFP10 (Rv3874).
The strategy further incorporates one or more additional mycobacterial antigens selected from Ag85B (Rv1886), RpfB, RpfD, Rv1813, Rv2626, Rv3407, and a mycobacterial antigen comprising an amino acid sequence as set forth in SEQ ID NO: 3 or 4. Particular pairs are emphasized, including TB10.4 (Rv0288) together with TB9.8 (Rv0287), and PE antigens together with PPE partners, with additional antigens across infection phases (active/resuscitation/latent) described as part of preferred antigen sets.
The disclosure provides viral vectors and nucleic acid molecules encoding fusion constructs and related antigen combinations, with formulations and prophylactic/therapeutic use for preventing or treating TB and for reactivation/latent infection contexts, including BCG booster and co-therapy context. Experimental examples include viral vector constructs expressing fused heterodimeric partners and additional antigens, with Western blot/solubility findings indicating improved folding/solubility when fused to natural partners, and mouse IFNγ ELISpot results demonstrating antigen-specific cellular immunogenicity.
Claims Coverage
The independent claim covers a viral vector encoding a fusion of heterooligomeric mycobacterial antigens ESAT6 and CFP10, plus one or more additional mycobacterial antigens selected from a specified group, including named antigens and antigens defined by SEQ ID NO:3 or 4. Two inventive features are identified across the independent claim set.
Fusion of ESAT6 with CFP10 in a viral vector
A viral vector comprising a nucleic acid molecule encoding a fusion of the heterooligomeric mycobacterial antigens ESAT6 with CFP10.
Additional mycobacterial antigens with specified selection
A viral vector further including nucleic acid molecule(s) encoding one or more additional mycobacterial antigen(s) selected from Ag85B (Rv1886), RpfB, RpfD, Rv1813, Rv2626, Rv3407, and a mycobacterial antigen comprising an amino acid sequence as set forth in SEQ ID NO: 3 or 4.
Across the independent claim set, the core coverage is a viral vector encoding an ESAT6/CFP10 heterooligomeric fusion together with additional selected mycobacterial antigens, with dependent claims further refining vector antigen designs and expression constraints.
Stated Advantages
Improved folding/solubility when fused to natural heterooligomeric partners, as indicated by Western blot/solubility findings in the disclosure.
Antigen-specific cellular immunogenicity, as indicated by mouse IFNγ ELISpot results demonstrating antigen-specific cellular responses.
Documented Applications
Prophylactic use for preventing TB.
Therapeutic use for treating TB.
Use for preventing or treating TB reactivation/latent infection, including latent infection and reactivation contexts.
Contextual use including BCG booster and co-therapy context.
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