Novel peptides that bind to types of mhc class ii and their use on diagnosis and treatment

a peptide and mhc class technology, applied in the field of new peptides, can solve the problems of irreversible side effects, risk of side effects caused by a generally suppressed immune defense, and the method of diagnosis does not provide the whole picture of the disease in the individual

Inactive Publication Date: 2015-08-06
CURARA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]FIGS. 1-3 provide data from experiments using the peptide...

Problems solved by technology

This drug is, however, associated with both milder and reversible side-effects, such as gastrointestinal and oral mucosal ulceration, but also with more serious, irreversible side effects, such as hepatic toxicity.
However, these novel therapeutics does still not address the specific autoimmune reaction but are non-specific treatments that affect large downstream parts of the immune and inflammation defense system, thereby giving rise to risks for side effects caused by a generally suppressed immune defense.
However, these methods for diagnosis do not provide the whole picture of the disease in the indivi...

Method used

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  • Novel peptides that bind to types of mhc class ii and their use on diagnosis and treatment
  • Novel peptides that bind to types of mhc class ii and their use on diagnosis and treatment
  • Novel peptides that bind to types of mhc class ii and their use on diagnosis and treatment

Examples

Experimental program
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example 1

[0118]The inventors have identified peptides from human collagen type II, alpha-enolase and vimentin that specifically bind to the variants of MHC that are associated with a risk for developing rheumatoid arthritis and with a presence of antibodies to specific citrullinated proteins. These peptides bind to MHC with genotypes HLA DRB1 0101, 0401, 0404, 0405, 0408 and 1001 as indicated in tables 1, 2 and 3. Interestingly, none of the peptides bind to MHC with genotypes HLA-DR 03 and 0402, genotypes that are not associated with developing rheumatoid arthritis.

[0119]Binding of the peptides to recombinant MHC class II protein of various alleles has been confirmed in an in vitro binding assay and the results are shown in Tables 1, 2 and 3. In table 1, 2 and 3, the listing of the allele in the column for the allele indicates binding. Thus “0401” in the “Binds to 0401” column indicates binding of the peptide to MHC class II of the HLA DRB1 0401 genotype. “no” or no data indicates no binding...

example 2

[0122]PBMCs were isolated from several rheumatoid arthritis patients with HLA genotype HLA DRB1-0401. The citrinullated enolase peptide with SEQ ID NO 14 (peptide reference number 287) was added to the cells. As a negative control, cells were incubated without peptide. An influenza peptide was used as a positive control. The peptides were added at concentrations ranging from 5 to 50 ug / ml and after a 5-day incubation in a CO2 incubator, cells were fixed, permeabilized and intracellular cytokine staining were performed. Antibodies for CD3, CD4, viable cells, CD154 (an activation marker) and cytokines IFNgamma, IL-17A and TNF alpha were used for analysis in a multiparameter flow cytometry panel. Cells from all patients exposed to the peptide double stained positive for both CD154 and at least one cytokine, which indicates that activation of T-cells has taken place.

example 3

[0123]PBMCs were isolated from rheumatoid arthritis patients with HLA genotype HLA DRB1-0401. The citrinullated enolase peptide with SEQ ID NO 15 (peptide reference number 289) was added to the cells. As a negative control, cells were incubated without peptide. An influenza peptide was used as a positive control. In addition, the non-citrinullated version of the peptide was used as a negative control. The peptides were added at concentrations ranging from 5 to 50 ug / ml and after a 5-day incubation in a CO2 incubator, cells were fixed, permeabilized and intracellular cytokine staining were performed. Antibodies for CD3, CD4, viable cells, CD154 (an activation marker) and cytokines IFNgamma, IL-17A and TNF alpha were used for analysis in a multiparameter flow cytometry panel. Cells from all patients exposed to the citrinullated peptide double stained positive for both CD154 and at least one cytokine, which indicates that activation of T-cells has taken place. The non-citrinullated pep...

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Abstract

It is provided novel peptides from human alpha-enolase, collagen type II and vimentin that bind to types of MHC class II that is associated with rheumatoid arthritis. There is also provided novel therapies and methods for diagnosis of rheumatoid arthritis.

Description

TECHNICAL FIELD[0001]The present invention relates generally to novel peptides and their use in the treatment of rheumatoid arthritis and other forms of arthritis.BACKGROUND ART[0002]Autoimmune diseases are pathological conditions where an immune response is triggered by tissues and substances naturally present in the body. This unwanted and inappropriate immune reaction can be tissue-specific, organ-specific or systemic. The course of the disease proceeds from mild symptoms to irreversible destruction of specific tissues and / or organs.[0003]Rheumatoid arthritis is a heterogeneous and partially genetically determined inflammatory disease, where autoimmunity is assumed to play an important pathogenic role, but where the specificity of the autoimmune reactions and the genetic determinants of these reactions remains incompletely known. It is a chronic and incurable disease that causes irreversible damage to the articular cartilage and bone, and which leads to progressive physical disab...

Claims

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Application Information

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IPC IPC(8): C12N9/88C07K14/78C07K14/47G01N33/564
CPCA61K38/00G01N2333/70575C12N9/88G01N33/564G01N33/56977G01N2800/102C07K14/70539C07K19/00C07K14/47C12Y402/01011G01N2333/57G01N2333/54G01N2333/525G01N2333/988G01N2800/24G01N2333/70539G01N2333/70514G01N2333/7051C07K14/78A61P29/00A61P37/02A61K39/001A61K39/0008A61K2035/122A61K38/014
Inventor KLARESKOG, LARSMALMSTSTROM, VIVIANNEHOLMDAHL, RIKARD
Owner CURARA
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