Antigenic peptides deriving from secretogranin V and uses thereof for the diagnosis and treatment of type 1 diabetes

Patent metadata

Field	Value
Publication number	US-12492230-B2
Application number	US-201916981352-A
Country	US
Kind code	B2
Filing date	Mar 15, 2019
Priority date	Mar 16, 2018
Publication date	Dec 9, 2025
Grant date	Dec 9, 2025

Abstract

Despite the notion that human CD8 + T cells are the final mediators of autoimmune β-cell destruction in type 1 diabetes (TID), none of their target epitopes has been demonstrated to be naturally processed and presented by β cells. The inventors therefore performed an epitope discovery study combining HLA Class I peptidomics and transcriptomics strategies. Inflammatory cytokines increased β-cell peptide presentation in vitro, paralleling upregulation of HLA Class I expression. Peptide sources included known β-cell antigens and several insulin granule proteins. Secretogranin V (SCG5/7B2) was identified as a novel β-cell antigen, which was processed into HLA-A2- and HLA-A3-restricted epitopes recognized by circulating naïve CD8 + T cells in type 1 diabetic and healthy donors. HLA-A2-bound neo-epitopes were also represented and originated from an alternative SCG5-009 mRNA splice isoform. Accordingly, the present invention relates to antigenic peptides derived from secretogranin V and uses thereof for the diagnosis and treatment of T1D.

First claim

The invention claimed is:

1 . A composition comprising
an isolated peptide derived from secretogranin V comprising: at least 8 consecutive amino acids in the sequence ranging from the amino acid residue at position 171 to the amino acid residue at position 215 in SEQ ID NO:2 (SCG5-009) and an adjuvant, wherein the length of the peptide consists of 8-21 amino acids.

2 . A composition comprising an isolated peptide derived from secretogranin V
and an adjuvant, wherein the peptide consists of the amino acid sequence as set forth in SEQ ID NO:38 (RLKPSLVGK) or SEQ ID NO:35 (SFLSGAVNRL).

3 . A composition comprising an isolated peptide derived from secretogranin V
and an adjuvant, wherein the peptide consists of the amino acid sequence as set forth in SEQ ID NO: 3 (RMVSTMLSGL); SEQ ID NO:4 (STMLSGLLFWL); SEQ ID NO:5 (TMLSGLLFWL); SEQ ID NO:6 (TMLSGLLFWLA); SEQ ID NO:7 (MLSGLLFWL); SEQ ID NO:8 (MLSGLLFWLA); SEQ ID NO:9 (FWLASGWTPA); SEQ ID NO:10 (WLASGWTPA); SEQ ID NO:11 (FWLASGWTPAF); SEQ ID NO:12 (MVSRMVSTMLSGLLF); SEQ ID NO:13 (VSRMVSTMLSGLLFW); SEQ ID NO:14 (SRMVSTMLSGLLFWL); SEQ ID NO:15 (RMVSTMLSGLLFWLA); SEQ ID NO:16 (SGLLFWLASGWTPAF); SEQ ID NO:17 (GLLFWLASGWTPAFA); SEQ ID NO:18 (LLFWLASGWTPAFAY); SEQ ID NO:19 (MVSRMVSTMLSGLLF); SEQ ID NO:20 (GWTPAFAYSPRTPDRVSEA); SEQ ID NO:26 (MKGGERRKRRSVNPYLQGQRL); SEQ ID NO:27 (WLASGWTPA); SEQ ID NO:28 (FWLASGWTPA); SEQ ID NO:29 (FWLASGWTPAF); SEQ ID NO:30 (GLLFWLASGWTPAFA); SEQ ID NO:31 (LLFWLASGWTPAFAY); SEQ ID NO:32 (SGLLFWLASGWTPAF); SEQ ID NO:33 (GWTPAFAYSPRTPDRVSEA); SEQ ID NO:34 (FLSGAVNRL); SEQ ID NO:35 (SFLSGAVNRL); SEQ ID NO:36 (FLSGAVNRLK); SEQ ID NO:37 (NRLKPSLVGK); SEQ ID NO:38 (RLKPSLVGK); SEQ ID NO:39 (RLKPSLVGKS); SEQ ID NO:40 (SPEKHWSM); SEQ ID NO:41 (CGDAWSFLSGAVNRL); SEQ ID NO:42 (GDAWSFLSGAVNRLK); SEQ ID NO:43 (DAWSFLSGAVNRLKP); SEQ ID NO:44 (AWSFLSGAVNRLKPS); SEQ ID NO:45 (WSFLSGAVNRLKPSL); SEQ ID NO:46 (SFLSGAVNRLKPSLV); SEQ ID NO:47 (FLSGAVNRLKPSLVG); SEQ ID NO:48 (LSGAVNRLKPSLVGK); SEQ ID NO:49 (SGAVNRLKPSLVGKS); SEQ ID NO:50 (GAVNRLKPSLVGKSQ); SEQ ID NO:51 (AVNRLKPSLVGKSQN); SEQ ID NO:52 (CGDAWSFLSGAVNRL); SEQ ID NO:53 (GDAWSFLSGAVNRLK); SEQ ID NO:54 (DAWSFLSGAVNRLKP); SEQ ID NO:55 (AWSFLSGAVNRLKPS); SEQ ID NO:56 (WSFLSGAVNRLKPSL); SEQ ID NO:57 (SFLSGAVNRLKPSLV); SEQ ID NO:58 (FLSGAVNRLKPSLVG); SEQ ID NO:59 (LSGAVNRLKPSLVGK); SEQ ID NO:60 (SGAVNRLKPSLVGKS); SEQ ID NO:61 (GAVNRLKPSLVGKSQ); SEQ ID NO:62 (MKGGERRKRR); SEQ ID NO:63 (NRL); or SEQ ID NO:64 (PSLVGKSQNPPLCSPEKHWS).

4 . A fusion protein comprising the peptide of claim 1 fused to a heterologous
polypeptide.

5 . An immunoconjugate comprising an antibody fused or conjugated to the
peptide of claim 1 .

6 . The immunoconjugate of claim 5 wherein the antibody is directed against a
surface antigen of an antigen presenting cell so that the peptide is targeted to said antigen presenting cell to elicit an immune response.

7 . An aptamer or an antibody having specificity for the peptide of claim 1 , either
alone or complexed with HLA molecules that are permissive for peptide binding.

8 . A chimeric antigen receptor (CARs) comprising an antigen binding domain of
the antibody of claim 7 .

9 . A T-cell receptor (TCR) having specificity for the peptide of claim 1 .

10 . A nucleic acid molecule that encodes the peptide of claim 1 .

11 . A host cell comprising the nucleic acid of claim 10 .

12 . The host cell of claim 11 which is T cell.

13 . A MHC class I or Class II multimer loaded with the peptide of claim 1 .

14 . A method of treating type 1 diabetes in a subject in need thereof, comprising
administering to the subject a therapeutically effective amount of the peptide of claim 1 .

15 . The host cell of claim 12 wherein the T cell is a Treg cell.

16 . A pharmaceutical or vaccine composition comprising a population of host
cells comprising a nucleic acid encoding the peptide of claim 1 , a fusion protein comprising the peptide, a chimeric antigen receptor comprising an antigen binding domain of an antibody having specificity for the peptide or a TCR having specificity for the peptide.

17 . A pharmaceutical or vaccine composition comprising a population of host
cells comprising an MHC class I or Class II multimer loaded with the peptide of claim 1 .

18 . A pharmaceutical or vaccine composition comprising the peptide of claim 1 , a
fusion protein comprising the peptide, or an immunoconjugate comprising an antibody fused or conjugated to the peptide.

Assignees

• Inst Nat Sante Rech Med
• Univ Paris
• Centre Nat Rech Scient
• Ecole Superieure Physique & Chimie Ind Ville De Paris
• Univ Bruxelles
• Centre Nat Rech Scient

Inventors

• Mallone Roberto
• Vinh Joëlle
• Verdier Yann
• Laks Eizirik Decio
• Colli Maikel Luis
• Afonso Georgia
• Gonzalez-Duque Sergio

Classifications

• C07K2319/40

  containing a tag for immunodetection, or an epitope for immunisation · CPC title

• C07K2319/33

  fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies · CPC title

• C07K16/18

  against material from animals or humans · CPC title

• C07K14/70539

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

• A61K2039/572

  cytotoxic response · CPC title