Nautilus and Creabilis demonstrate positive HMGB1 results
demonstrated the increase in biological activity and resistance to
proteolysis in vitro of a protein that could play a role in
hepatitis B, rheumatoid arthritis, melanoma and sepsis treatments.
Proteolysis refers to a process in which a protein is broken down partially, into peptides, or completely, into amino acids, by proteolytic enzymes, present in bacteria and in plants but most abundant in animals.
The collaboration's approach has centred on HMGB1, a 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.
Creabilis is now testing these improved molecules in vivo and plans to select the lead molecule for preclinical development in Q1 2007.
"We are very pleased with the results so far achieved in this project as they are a confirmation of the potential of Nautilus' proprietary technology when applied to early development stage proteins," said Dr. Silvano Fumero, CEO Creabilis Therapeutics.
"Native Box A has been demonstrated to be active in experimental models but with a very poor PK profile. Some of the variants obtained with Nautilus' technology are now potential drugable compounds."
Increasing resistance to proteolysis and improving biological activity offers important improvements in drug profiles and has the potential to create highly differentiated therapeutic products with better patient compliance.
"I am delighted to announce the achievement of this important milestone in our collaboration with Creabilis Therapeutics, which represents further external validation of Nautilus core technology for protein engineering," said Dr Manuel Vega, CEO Nautilus Biotech.
Nautilus Biotech's technology has wide applicability across many therapeutic protein families and this collaboration has demonstrated the success of our technology when applied to small proteins such as HMGB1 Box A, opening the way to other small proteins and peptides of big clinical potential and market value.
