Cross-reactive epitope for multiple sclerosis

Patent metadata

Field	Value
Publication number	US-12440544-B2
Application number	US-202017638005-A
Country	US
Kind code	B2
Filing date	Sep 3, 2020
Priority date	Sep 4, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

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.

First claim

What is claimed is:

1. An isolated cross-reactive peptide that comprises or consists of an amino acid sequence of any one 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.

2. The cross-reactive peptide according to claim 1 fused to a non-native protein sequence.

3. A pharmaceutical composition comprising the isolated cross-reactive peptide of claim 1 and a pharmaceutically acceptable excipient.

4. A protein complex comprising a human MHC protein and the cross-reactive peptide of claim 1 .

5. The protein complex of claim 4 , wherein the MHC protein is a Class II MHC protein.

6. The protein complex of claim 5 , wherein the MHC protein is DR15.

7. An altered peptide ligand of the cross-reactive peptide of claim 1 .

8. A method of reducing the symptoms of multiple sclerosis, the method comprising administering a tolerogenic dose of the pharmaceutical composition of claim 3 .

9. The method of claim 8 , wherein the pharmaceutical composition is administered orally, nasally, intradermally, transdermally or intramuscularly.

10. A tolerizing DNA construct encoding the cross-reactive peptide of claim 1 .

11. The tolerizing DNA construct of claim 10 , wherein the construct is in a modified plasmid backbone.

12. A method of reducing the symptoms of multiple sclerosis, the method comprising administering a tolerogenic dose of the tolerizing DNA construct of claim 10 .

13. The method of claim 12 , wherein the tolerizing DNA construct is administered intramuscularly.

14. An isolated T cell receptor (TCR) peptide that comprises or consists 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.

15. The isolated TCR peptide according to claim 14 fused to a non-native protein sequence.

16. A pharmaceutical composition comprising the isolated TCR peptide of claim 14 .

17. The pharmaceutical composition of claim 16 , further comprising an adjuvant.

18. A method of reducing the symptoms of multiple sclerosis, the method comprising administering an immunogenic dose of the TCR peptide according to claim 14 .

19. An antibody that specifically binds to:
a protein complex of claim 4 .

20. A method of determining the presence of pathogenic T cells in an individual suspected of having multiple sclerosis, the method comprising:
contacting a sample comprising T cells from the individual with the cross-reactive peptide of claim 1 ; and
determining the presence of a T cell response to the cross-reactive peptide.

Assignees

• Univ Leland Stanford Junior

Inventors

• Saligrama Naresha
• Davis Mark M

Classifications

• G01N2800/285

  Demyelinating diseases; Multipel sclerosis · CPC title

• G01N33/564

  for pre-existing immune complex or autoimmune disease {, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9} · CPC title

• G01N33/505

  involving T-cells · CPC title

• C07K19/00

  Hybrid peptides {, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes} · CPC title

• C07K16/2833

  against MHC-molecules, e.g. HLA-molecules · CPC title