Chemokine mutants in treatment of multiple sclerosis

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 ...

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[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)

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