Chemokine mutants in treatment of multiple sclerosis

A chemokine and mutant technology, applied in the field of CC chemokine mutants, can solve problems such as loss of GAG binding ability

Inactive Publication Date: 2006-11-22
MERCK SERONO SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] It has also been reported that only three residues at positions 44, 45 and 47 are replaced by alanine three RANTES triple mutants lost GAG binding ability (A. Proudfoot et al., Chemokine Gordon Conference, Session 1, July 24, 2000 day, personal communication)

Method used

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  • Chemokine mutants in treatment of multiple sclerosis
  • Chemokine mutants in treatment of multiple sclerosis
  • Chemokine mutants in treatment of multiple sclerosis

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Embodiment Construction

[0054] 1. Materials and Methods

[0055] a) Generation of non-heparin-binding RANTES mutants

[0056] Mutagenesis of RANTES was achieved by reverse polymerase chain reaction technique. Point mutations were introduced in opposite directions into one of the two primers used to hybridize to the human RANTES coding sequence (GenBank acc. No. NM_002985). To increase the efficiency of primer annealing (especially when multiple mutations are introduced into the primers), the DNA is denatured with alkali. The denatured DNA was diluted to a concentration of approximately 10 pg / reaction to avoid mixing unmutated DNA in the transformation reaction.

[0057] The amino acid numbering given in the examples and description takes into account the mature protein, ie starts with Ser, which is the amino acid at position 24 according to the sequence listing. Therefore, in order to make the amino acid numbers in the sequence listing and the examples completely consistent, 23 should be added to ...

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Abstract

CC chemokine mutants contain at least two mutations at the cationic site of the 40’S loop (40’s loop), which have lower GAG-binding activity compared with the wild-type molecule. In particular, the present inventors have shown that these mutated chemokines are effective in the treatment of multiple sclerosis and / or other demyelinating diseases. The RANTES triple mutant was the most effective compound.

Description

technical field [0001] The present invention relates to CC chemokine mutants containing at least two mutations in the 40's loop (40's loop), which have lower GAG binding activity compared with wild-type molecules. These mutated chemokines have been found to be effective in the treatment of multiple sclerosis and / or other demyelinating diseases. Background technique [0002] Chemokines constitute a small family of pro-inflammatory cytokines with leukocyte chemotactic and activating properties. According to the position of the first conserved cysteine, chemokine families are divided into C-C, C-X-C and C-X 3 -C chemokine (Baggionlini M. et al., Adv Immunol.1994, 55:97-179; Baggiolini M. et al., Annu Rev Immunol.1997, 15:675-705; Taub D. et al., Cytokine Growth Factor Rev . 1996, 7(4):355-76). [0003] Many C-X-C chemokines, such as interleukin-8 (IL-8), are chemotactic for neutrophils, while C-C chemokines are chemotactic for monocytes, lymphocytes, eosinophils, basophils ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/19A61P25/00C07K14/52C12N15/19C12N15/09A61K38/00C07K14/47C12N1/15C12N1/19C12N1/21C12N5/10C12P21/02
CPCA61K38/00C07K14/523A61P25/00A61P25/28A61K38/19
Inventor A·普罗德富特T·N·C·韦尔斯M·科斯科-维尔博伊斯
Owner MERCK SERONO SA
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