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Publication Number
US-12440544-B2
Publication Date
2025-10-14
Expiration Date
Abstract
Provided herein are methods and compositions for diagnosis and treatment of multiple sclerosis. Compositions and methods are provided, relating to novel peptides involved in autoimmune disease. In the experiments described herein, an unbiased approach was used to screen pathogenic CD4+ T cells from patients with multiple sclerosis (MS), and to determine the antigenic specificity of the T cell receptors (TCR) expressed by these pathogenic cells.
Core Innovation
The disclosure relates to antigen discovery and identification of cross-reactive epitopes in multiple sclerosis (MS). Pathogenic CD4+ T cells are screened using an unbiased approach to identify MHC-restricted cross-reactivity between a human adenovirus peptide and myelin basic protein (MBP) in MHC-relevant contexts, including settings associated with HLA-DR15/DR15.
The disclosure provides specific cross-reactive peptide sequences and defined sets of such peptides, including peptide sequences identified as SEQ ID NO:1-4 and SEQ ID NO:23-75. The cross-reactive peptides are associated with detection of peptide-specific T cell responses and with therapeutic and tolerization strategies that use altered peptide ligands and tolerizing DNA vectors encoding cross-reactive peptides or TCR-derived peptide sequences.
Experimental support is described using yeast DR15 peptide-MHC libraries, TCR clustering (GLIPH), and identification of an adenovirus peptide matching enriched library peptides. Tetramer-based detection is described to enumerate adenovirus-specific CD4 T cells in MS versus controls, including demonstrating TCR cross-reactivity with MBP 85-99, and reporting additional sample findings including CSF TCR clonal expansion and adenovirus titers in serum.
Claims Coverage
The partial record includes two independent claims that cover (i) an isolated cross-reactive peptide defined by specific amino-acid sequences and limited variants, and (ii) an isolated T cell receptor (TCR) peptide defined by specified sequences and limited variants. The independent claims are supported by dependent claims that add immunological presentation constructs (including human MHC/DR15 complexes) and define diagnostic or tolerizing and therapeutic use contexts in multiple sclerosis.
Isolated cross-reactive peptide sequence set with limited variants
An isolated cross-reactive peptide comprising or consisting of an amino acid sequence of ATFTSYRSWYLA (SEQ ID NO:1), ANYGKARSWYLK (SEQ ID NO:2), IDRHMYHSYLK (SEQ ID NO:3), DKGQQYRNWFLK (SEQ ID NO:4), SEQ ID NOs:23-75, or a variant thereof comprising up to 3 amino acid substitutions or deletions, wherein the isolated cross-reactive peptide is up to 40 amino acids in length.
Isolated T cell receptor (TCR) peptide sequence set with limited variants
An isolated T cell receptor (TCR) peptide comprising or consisting of an amino acid sequence set forth in any of SEQ ID NO:5, 7-22 or 76, 78-83 or a variant thereof comprising up to 3 amino acid substitutions or deletions, wherein the isolated cross-reactive peptide is up to 40 amino acids in length.
Overall claim coverage centers on defined isolated peptide sequences (cross-reactive peptides and TCR peptides) limited by variant tolerance (up to 3 substitutions or deletions) and by peptide length (up to 40 amino acids), with dependents covering tolerizing DNA constructs, human MHC protein complexes including DR15, therapeutic use for multiple sclerosis symptom reduction, and detection of pathogenic T cells via peptide-specific T cell responses.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Reducing multiple sclerosis symptoms by administering a tolerogenic dose of a tolerizing DNA construct encoding a cross-reactive peptide.
Reducing multiple sclerosis symptoms by administering an immunogenic dose of a TCR peptide.
Detecting pathogenic T cells in an individual suspected of multiple sclerosis by contacting a T-cell-containing sample with a cross-reactive peptide and determining whether a T-cell response occurs to the peptide.
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