Nautilus Biotech and Creabilis Therapeutics research on pathologies, including hepatitis B, melanoma, inflammation, and diabetes complications, has found increased biological activity and resistance to proteolysis in vitro of the HMGB1 Box A protein.
HMGB1 (High Mobility Group Box One ) 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 for Advanced Glycation End products) 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 druggable variant of native HMBG1 Box A with improved PK/PD characteristics to be used as a direct antagonist of HMGB1 and/or as inhibitor of RAGE.
Using its 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. Creabilis is now testing these improved molecules in vivo and plans to select the lead molecule for preclinical development in Q1 2007.