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Methods for reducing immunogenicity of polypeptides

An immunogenic and biologically active technology, applied in chemical instruments and methods, biochemical equipment and methods, peptides, etc., can solve problems such as loss of HLA-DM activity

Inactive Publication Date: 2004-08-25
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HLA-DO binding at pH 6 inactivates HLA-DM activity

Method used

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Embodiment Construction

[0076] In particular, the invention provides modified polypeptides with reduced ability to be presented to the immune system via the MHC class II pathway. In a first embodiment, the polypeptide is modified by amino acid substitutions which alter one or more specific amino acid residues in the polypeptide chain to their respective D-isomeric forms.

[0077] Inclusion of a single D-amino acid in a polypeptide is known to disrupt binding to the MHC class II binding groove. US 5,679,640 shows that D-amino acid substitutions need to be made at critical contact sites of peptide MHC complexes, and that substitutions at non-critical sites are tolerated in MHC / peptide complexes. The aim of the present invention is to use D-amino acid substitutions to disrupt binding in the MHC class II binding pocket so that the peptide cannot be presented to the TCR. This differs significantly from the approach taught in US5,679,640, where substitutions occur at non-critical binding residues, where t...

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Abstract

This invention relates to the fields of immunology and protein therapeutics. The therapeutic proteins are polypeptides to be administered especially to humans. The polypeptides are modified whereby the modification results in a reduced propensity for the polypeptide to elicit an immune response upon administration to the human subject. The invention therefor provides methods for the development of therapeutic polypeptides that are less immunogenic than any non-modified counterpart when used in vivo. The modifications used according to this invention relate, for example, to the introduction of protease cleavage sites, attachment of different molecules or insertion of non-natural amino acids.

Description

field of invention [0001] The present invention relates to the fields of immunology and protein therapeutics. A therapeutic protein is a polypeptide specifically administered to humans. The polypeptide has been modified such that the polypeptide has a reduced immune response when administered to a human. The present invention thus provides methods for developing therapeutic polypeptides that are less immunogenic when used in vivo than any unmodified corresponding polypeptide. Background of the invention [0002] There are many examples where the efficacy of therapeutic proteins is limited by interfering immune responses directed against them. Several mouse monoclonal antibodies have shown promise for the treatment of a variety of human diseases, but in some cases have not been successfully used due to the induction of substantial human anti-mouse antibody (HAMA) responses [Schroff, R.W. et al. (1985) Cancer Res. 45:879-885; Shawler, D.L. et al. (1985) J. Immunol. 135:1530...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/09A61K38/00A61K38/02C07K7/08C07K14/00C07K14/47C12N9/64
CPCC12N9/6472C07K14/47C07K14/435
Inventor F·J·卡尔G·卡特K·海伦多尔恩
Owner MERCK PATENT GMBH