Nautilus Biotech and Creabilis Therapeutics Achieve Technical Milestone in Collaboration
Improvement of HMGB1 Box A for the Treatment of Rage- and HMGB1-Related Pathologies
Nautilus Biotech SA and Creabilis Therapeutics SpA have announced that they have shown increased biological activity and resistance to proteolysis in vitro of the High Mobility Group Box One (HMGB1) Box A protein, an important technical milestone in their collaboration to identify a potential candidate drug for the treatment of RAGE- (Receptor for Advanced Glycation End products) and HMGB1-related pathologies, which include hepatitis B, rheumatoid arthritis, melanoma and sepsis.
HMGB1 is an abundant nuclear and cytoplasmic protein present in mammalian cells, which, when released, is known to play an important role in the pathogenesis of several diseases. Native HMGB1 Box A (a DNA-binding domain of HMGB1) is a specific antagonist of whole HMGB1 on the RAGE receptor. Highly purified native Box A has been shown to successfully protect against sepsis and other RAGE and HMGB1-related diseases in animal models.
Nautilus Biotech and Creabilis Therapeutics entered into collaboration in September 2004 with the aim to develop a drugable variant of native HMBG1 Box A with improved PK/PD characteristics to be used as a direct antagonist of HMGB1 to treat related pathologies including hepatitis B, rheumatoid arthritis, SLE, melanoma, sepsis and MS and/or as inhibitor of RAGE to treat diabetes complications and inflammatory diseases. Using its proprietary protein engineering technology, Nautilus Biotech created a series of single amino acid variants of the native Box A protein. Creabilis has now completed testing of all the variants and has shown that a limited number of these have increased biological activity in vitro and greater resistance to proteolysis, according to the company. Creabilis is now testing these improved molecules in vivo and plans to select the lead molecule for preclinical development in Q1 2007.
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