Regulatory T cell epitopes, compositions and uses thereof
Inventors
De Groot, Anne • Martin, William • Rivera, Daniel S.
Assignees
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Publication Number
US-11045531-B2
Publication Date
2021-06-29
Expiration Date
Abstract
The invention is directed to T cell epitopes wherein said epitopes comprises a peptide or polypeptide chain comprising at least a portion of an immunoglobulin constant or variable region. The invention also relates to methods of using and methods of making the epitopes of the invention.
Core Innovation
The invention relates to Tregitopes, i.e., T-cell epitope peptides/polypeptides derived from IgG constant/variable regions, and their use to selectively engage and activate natural regulatory T cells (Tregs). The disclosed compositions are described as enabling an increased functional phenotype associated with CD4+CD25+FOXP3 Tregs and MHC class II/APC presentation through TCR recognition of the Tregitopes.
The document describes eligibility and design criteria for selecting T-cell epitope clusters using predicted HLA class II binding and epitope clustering metrics (EpiMatrix/EpiVax, Clustimer, and EpiBar). Functional requirements are described in terms of MHC class II binding and APC presentation, together with measured outcomes such as increased IL-10, TGF-β, TNF-α, and MCP-1.
The described functional outcomes include suppression of antigen-specific effector Th1/Th2 responses and reduced proliferation, with the document also discussing peptide modifications that can affect function. The invention additionally includes example chimeric/constructs such as Fc-fusion and Factor VIII-Tregitope, as well as multi-Tregitope constructs, including vaccine-vector related examples with optimization by modifying Fc-associated Tregitopes to reduce MHC II binding.
The document further supports the claimed concept by describing experimental validation narratives including in vitro suppression in human PBMCs and in vivo suppression in murine models. It also summarizes pharmaceutical and delivery concepts that include nucleic-acid/vector/kits and broad therapeutic indications, and it includes ex vivo expansion/stimulation of Tregs.
Claims Coverage
Two independent claims are identified. Collectively, they cover a chimeric polypeptide construct defined by a linked immunoglobulin fragment and a second non-immunoglobulin biologically active molecule, and a method of inducing regulatory T-cells by administering that chimeric polypeptide to a subject for suppression of immune response.
Chimeric polypeptide with immunoglobulin fragment linked to a non-immunoglobulin biologically active molecule
A chimeric polypeptide comprising a first and a second polypeptide chain linked together, wherein the first polypeptide chain is a fragment of an immunoglobulin consisting of the amino acid sequence of SEQ ID NO: 31, and wherein the second polypeptide chain comprises a biologically active molecule that is not an immunoglobulin polypeptide.
Method of inducing regulatory T-cells to suppress immune response by administering the chimeric polypeptide
A method of inducing regulatory T-cells to suppress immune response in a subject comprising administrating to the subject a therapeutically effective amount of a chimeric polypeptide, wherein the chimeric polypeptide comprises a first and a second polypeptide chain linked together, the first polypeptide chain is a fragment of an immunoglobulin consisting of the amino acid sequence of SEQ ID NO: 31, and the second polypeptide chain comprises a biologically active molecule that is not an immunoglobulin polypeptide.
The claim coverage centers on administering and/or using a chimeric polypeptide with an immunoglobulin fragment (SEQ ID NO: 31) linked to a second polypeptide chain containing a biologically active molecule that is not an immunoglobulin polypeptide, with the method claim framing use for inducing regulatory T-cells to suppress an immune response in a subject.
Stated Advantages
Suppresses antigen-specific effector Th1/Th2 responses and proliferation.
Increases IL-10, TGF-β, TNF-α, and MCP-1.
Induces regulatory T-cells to suppress immune response in a subject.
Documented Applications
Therapeutic use for autoimmunity, allergy, transplantation/GVHD, protein therapeutics immunogenicity, and infections.
Inducing regulatory T-cells to suppress immune response in a subject by administering a therapeutically effective amount of a chimeric polypeptide.
Ex vivo expansion/stimulation of Tregs.
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