Isolated donor MHC-derived peptide and uses thereof

Patent metadata

Field	Value
Publication number	US-10137181-B2
Application number	US-201515300331-A
Country	US
Kind code	B2
Filing date	Apr 1, 2015
Priority date	Apr 1, 2014
Publication date	Nov 27, 2018
Grant date	Nov 27, 2018

Abstract

The invention relates to an peptide derived from a polymorphic region of donor MHC class II molecules which induces tolerance and thus prevents transplant rejection in a patient in need thereof. The invention relates to isolated peptide of length ranging between 11 and 16 amino acids comprising the amino acid sequence: SDVGEYR (SEQ ID NO: 1) or a function-conservative variant thereof for use as drug. The invention relates to an in vitro method for determining whether a transplanted patient is tolerant, comprising a step of determining the presence of CD8+CD45RC low Tregs in a biological sample obtained from said transplanted patient, wherein the presence of CD8 + CD45RC low Tregs is indicative of tolerance.

First claim

The invention claimed is:

1. An isolated peptide derived from a MHC class II molecule comprising an amino acid sequence of SDVGEYR (SEQ ID NO: 1) or DSDVGEYR (SEQ ID NO: 21), wherein the isolated peptide has an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 13)

YLRYDSDVGEYR;

(SEQ ID NO: 16)

YLRYDSDVGEYRAV;

(SEQ ID NO: 17)

SDVGEYRAVTELGR; 

and

(SEQ ID NO: 18)

LRYDSDVGEYRAVTE.

2. A nucleic acid sequence encoding the peptide of claim 1 .

3. An expression vector comprising the nucleic acid sequence of claim 2 .

4. A host cell comprising the expression vector of claim 3 .

5. A MHC/peptide multimer, comprising a peptide sequence encoding multiple peptides, wherein at least one peptide of the multiple peptides is derived from a MHC class II molecule, and wherein the at least one peptide is YLRYDSDVGEYR (SEQ ID NO: 13).

6. An in vitro or ex vivo method for generating a population of CD8+CD45RC low Tregs, comprising a step of
culturing a population of CD8+ Tregs with a culture medium comprising a peptide derived from a MHC class II molecule, wherein the peptide comprises an amino acid sequence: SDVGEYR (SEQ ID NO: 1),
and has an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 2)

YLRYDSDVGEYRAVTE;

(SEQ ID NO: 3)

DSDVGEYRAVTELGRP;

(SEQ ID NO: 13)

YLRYDSDVGEYR;

(SEQ ID NO: 16)

YLRYDSDVGEYRAV;

(SEQ ID NO: 17)

SDVGEYRAVTELGR; 

and

(SEQ ID NO: 18)

LRYDSDVGEYRAVTE;

 and

wherein the step of culturing is performed in the presence of a population of plasmacytoid dendritic cells.

7. The in vitro or ex vivo method of claim 6 ,
wherein the peptide is an isolated peptide.

8. A method of inducing tolerance in a patient in need thereof, comprising the steps of
administering to the patient a prophylactically effective amount of a peptide derived from a MHC class II molecule comprising an amino acid sequence of SDSVGEYR (SEQ ID NO: 1), wherein the peptide has an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 2)

YLRYDSDVGEYRAVTE;

(SEQ ID NO: 3)

DSDVGEYRAVTELGRP;

(SEQ ID NO: 13)

YLRYDSDVGEYR;

(SEQ ID NO: 16)

YLRYDSDVGEYRAV;

(SEQ ID NO: 17)

SDVGEYRAVTELGR; 

and

(SEQ ID NO: 18)

LRYDSDVGEYRAVTE,

 and
inducing tolerance to at least one organ, tissue or cell.

9. A pharmaceutical composition comprising:
a) a peptide derived from a MHC class II molecule, wherein the peptide comprises an amino acid sequence: SDVGEYR (SEQ ID NO: 1) and wherein the peptide has an amino acid sequence selected from the group consisting of:

(SEQ ID NO: 2)

YLRYDSDVGEYRAVTE;

(SEQ ID NO: 3)

DSDVGEYRAVTELGRP;

(SEQ ID NO: 13)

YLRYDSDVGEYR;

(SEQ ID NO: 16)

YLRYDSDVGEYRAV;

(SEQ ID NO: 17)

SDVGEYRAVTELGR;

Assignees

• Inst Nat Sante Rech Med
• Univ Nantes
• Univ Nantes

Inventors

• Guillonneau Carole
• Anegon Ignacio
• Picarda Elodie

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K39/001 Primary

  Preparations to induce tolerance to non-self, e.g. prior to transplantation · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C12N2502/1121

  Dendritic cells · CPC title

• G01N33/505

  involving T-cells · CPC title