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-11045529-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 disclosure describes Tregitopes as T-cell epitope peptides or polypeptides derived from common proteins, with immunoglobulin proteins noted as a source of such epitope peptides or polypeptides. The Tregitopes are defined using in-silico criteria including EpiMatrix, EpiBar, and ClustiMer for HLA class II binding and MHC presentation that activates pre-existing natural regulatory T-cells (CD4+CD25+FOXP3) to suppress antigen-specific effector responses.
The disclosure further provides chimeric or fusion constructs to induce regulatory T-cells and suppress immune responses in a subject. A chimeric polypeptide includes a first and second polypeptide chain linked together, where the first polypeptide chain is an immunoglobulin fragment including an amino acid sequence of SEQ ID NO: 5 and the second polypeptide chain comprises a biologically active molecule that is not an immunoglobulin polypeptide.
The disclosure also describes therapeutic compositions and delivery formats for Tregitope-based and chimeric polypeptide constructs, including pharmaceutical compositions, nucleic acids encoding Tregitopes, vectors and cells, and kits. Additional construct concepts described include Tregitope-antigen fusions, including FVIII-Tregitopes and multi-Tregitope fusions, and vaccine-vector enhancement by modifying Fc or the Tregitope to alter MHC II binding and regulatory activation.
Claims Coverage
The partial content identifies one independent claim. The claim coverage centers on a chimeric polypeptide architecture that links an immunoglobulin-fragment chain to a non-immunoglobulin biologically active molecule to induce regulatory T-cells that suppress an immune response; dependent claims further narrow fusion orientation and add specified T-cell epitope sequences and molecule-type selections.
Chimeric polypeptide inducing regulatory T-cells via immunoglobulin fragment and non-immunoglobulin biologically active molecule
A chimeric polypeptide comprising a first and a second polypeptide chain linked together, where the first polypeptide chain is a fragment of an immunoglobulin consisting of the amino acid sequence of SEQ ID NO: 5, and where the second polypeptide chain comprises a biologically active molecule that is not an immunoglobulin polypeptide, to induce regulatory T-cells that suppress an immune response in a subject.
Fusion orientation at the immunoglobulin-fragment chain N-terminus
The second polypeptide chain is fused to the N-terminus of the first polypeptide chain.
Fusion orientation at the immunoglobulin-fragment chain C-terminus
The second polypeptide chain is fused to the C-terminus of the first polypeptide chain.
Incorporation of defined T-cell epitope sequences
The chimeric polypeptide includes at least one isolated T-cell epitope polypeptide with an amino acid sequence chosen from SEQ ID NOS: 6-58.
Biologically active molecule selected from specified entity types
The biologically active molecule is chosen from a group consisting of a viral protein, a bacterial protein, an FVIII molecule, an autoimmune antigen, or an allergen.
Non-immunoglobulin constraint for the second chain biologically active molecule
The second polypeptide chain is a biologically active molecule that is not an immunoglobulin polypeptide.
Overall, claim coverage is directed to inducing regulatory T-cells to suppress an immune response by administering a chimeric polypeptide with an immunoglobulin-fragment chain linked to a second chain carrying a non-immunoglobulin biologically active molecule, with dependent claims refining fusion orientation, adding T-cell epitope sequences, and restricting the biologically active molecule to listed entity types.
Stated Advantages
Induces regulatory T-cells that suppress an immune response in a subject.
Activates pre-existing natural regulatory T-cells (CD4+CD25+FOXP3) to suppress antigen-specific effector responses.
Documented Applications
Allergy, including dust-mite allergen.
Autoimmunity, including Graves’ disease.
Transplantation and graft-versus-host disease (GVHD).
Therapy involving protein therapeutics immunogenicity, including FVIII and insulin.
Infections.
Cancer.
Infertility.
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