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Proinsulin peptides for type 1 diabetes

A type 1 diabetes and disease technology, applied in the direction of insulin, hormone peptides, peptides, etc., can solve the problems of not being disclosed

Pending Publication Date: 2022-05-10
KING'S COLLEGE LONDON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The claimed peptides of the present invention, which have significant therapeutic potential, especially in the DR3-DQ2 haplotype, are not disclosed in the prior art

Method used

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  • Proinsulin peptides for type 1 diabetes
  • Proinsulin peptides for type 1 diabetes
  • Proinsulin peptides for type 1 diabetes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Materials and methods

[0088] animal

[0089] Make HLA-DR3-DQ2-transgenic animals (B6.hCD4.DR3-DQ2.DQ2.MHCII - / - Mice (described in the past (de Kauwe AL et al. (2009) J Immunol 182 (12): 7440-7450) and obtained from J. McCluskey) with RIP-B7.1 transgenic animals (B6.Cg- Tg(Ins2-CD80)3B7Flv / Orl, EMMA, Orleans, France; ID00216) hybridization to obtain HLA-DR3-DQ2 + huCD4 + IA / IE - / - RIP.B7.1 + mouse, hereinafter referred to as DR3DQ2xRIP-B7.1. By making B6.129S2-H2-Ab1 tm1Gru DR4xRIP-B7.1 mice produced by crossing Tg(HLA-DRA / H2-Ea,HLA-DRB1*0401 / H2-Eb)1Kito mice with B6.Cg-Tg(Ins2-CD80)3B7Flv / Orl have been used in the past described (Verhagen J, et al. (2018) Sci Rep 8(1):14106). All animals were housed under specific pathogen-free conditions in individually ventilated cages in the KCL Biological Services Unit on a 12-h light / dark cycle with food and water provided ad libitum. Experiments were carried out under a project license held by M.Peakman in accordanc...

Embodiment 2

[0110] Spontaneous diabetes onset in DR3DQ2xRIP-B7.1 mice

[0111] Unlike our previously described DR4xRIP-B7.1 model (VerhagenJ, et al. (2018) Sci Rep 8(1):14106), which did not display spontaneous insulitis or diabetes, DR3DQ2xRIP-B7.1 mice spontaneously developed diabetes ( figure 1 a). Although both models exhibited relatively high baseline levels of blood glucose at any age, only DR3DQ2xRIP-B7.1 mice developed levels >16.7 mmol / l in addition to glycosuria. By 35 weeks of age, 46% (26 of 56) of all animals monitored had developed autoimmune diabetes. Disease incidence (16 / 32 vs. 10 / 24, respectively) and mean age of onset (24.2 weeks ± 7.3 (SD) vs. 24.8 ± 8.5, respectively) were similar in male and female animals. No overt signs of other immune-mediated disorders were detected, as evidenced by splenomegaly, cachexia, lethargy, or skin / ocular abnormalities. All mice with diabetes showed severe immune infiltration in islets. This infiltrate is highly diverse, with both...

Embodiment 3

[0113] Proinsulin is a diabetogenic antigen in DR3DQ2xRIP-B7.1 mice

[0114] Spontaneous diabetes onset in mice carrying high-risk transgenic HLA suggests that autoimmune processes are central to disease development and prompted us to address the question of whether specific autoantigens are disease drivers. The hypothesis that priming an animal with an adjuvant against a candidate molecule will accelerate disease progression has been tested if the antigen has 'driver' properties. Thus, single 30-mer peptides overlapping and spanning the length of murine proinsulin 2 in TiterMax Gold adjuvant; recombinant human GAD65; the 377 amino acid intracellular region of human islet antigen-2 (IA-2) or individual Mice were first immunized with PBS ( figure 2 a-f)( figure 2 a-f). Importantly, in these conditions, primary immunization with proinsulin peptide alone significantly accelerated the onset of diabetes and increased morbidity beyond that observed with control stimulation or...

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Abstract

The present invention relates to a peptide. The peptides can be used for the treatment or prevention of Type 1 diabetes mellitus (T1D), in particular patients having a DR3-DQ2 haplotype. The invention also relates to a method for diagnosing or determining the efficacy of a treatment using said peptide, and to a method for identifying a TID-associated antigen driver, a method for identifying a subject as being at T1D high risk and a method for identifying a patient as being suitable for and / or responsive to T1D treatment.

Description

technical field [0001] The present invention relates to one or more peptides useful in the treatment or prevention of type 1 diabetes (T1D). Background technique [0002] Type 1 diabetes (T1D) is an autoimmune disease characterized by metabolic dysfunction, most notably dysregulated glucose metabolism, with characteristic long-term vascular and neurological complications. T1D is one of the most common autoimmune diseases, affecting 1 in 250 individuals in the United States, where approximately 10,000 to 15,000 new cases are reported each year, and the incidence is increasing. The region with the highest T1D prevalence is Northern Europe. [0003] T1D is characterized by absolute insulin deficiency, making patients dependent on exogenous insulin for survival. Before the acute clinical onset of T1D with hyperglycemic symptoms, there is a long asymptomatic clinical phase during which insulin-producing beta cells are progressively destroyed. [0004] Once onset, treatment wit...

Claims

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Application Information

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IPC IPC(8): C07K14/62C12N15/17C12N15/864A61K38/10A61K38/28A61P3/10C12Q1/02G01N33/569G01N33/74A01K67/027C12N15/12
CPCC07K14/62C12N15/86A61K38/10A61K38/28A61P3/10G01N33/505G01N33/56977G01N33/74A01K67/0278C07K14/70532G01N2800/042G01N2333/62G01N2800/52G01N2800/50C12N2750/14143C12N2800/107A01K2227/105A01K2267/0362G01N33/56972G01N33/6878A61K2300/00A61K9/146A61K31/198
Inventor 马克·皮克曼乔汉·维尔哈根马丁·埃希曼
Owner KING'S COLLEGE LONDON
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