BioWorld International Correspondent

Creabilis Therapeutics Srl entered what founder and CEO Silvano Fumero described as its "first important" deal with another company, a pact with Nautilus Biotech SA to develop variants of a naturally occurring protein, CT500, that acts as an antagonist against high-mobility group box-1 (HMGB-1) protein.

Terms were not disclosed, but each company will benefit from any subsequent licensing.

"There are plans to share eventual milestone payments and royalties in case of positive results," Fumero said. Nautilus, of Paris, is bringing its protein-evolution technology to the collaboration in order to generate leads with better protease resistance and improved pharmacokinetic properties.

"Nautilus has already done this for two interferons and a series of other molecules," Fumero said. He declined to divulge details of CT500, other than to say it is a naturally occurring small protein that is highly conserved. It mediates its antagonistic effect by blocking the receptor for advanced glycation end products (RAGE), thereby preventing HMGB-1 from binding.

HMGB-1 has several roles, depending on the physiological status of the cell. Under normal conditions, it functions as a chromatin-binding factor within the nucleus, and appears to facilitate transcription by causing a distortion of DNA's double helical structure. It also is passively secreted by cells following necrosis and actively secreted by macrophages in response to stimulation by lipopolysaccharide, tumor necrosis factor or interleukin-1. Extracellular HMGB-1 has multiple effects. It prolongs and sustains inflammation, and it plays a role in cellular differentiation and in cell migration.

Creabilis is not the only company active in the HMGB-1 field. Critical Therapeutics Inc., of Cambridge, Mass., last year licensed an HMGB-1 project to MedImmune Inc., of Gaithersburg, Md. (See BioWorld Today, Aug. 1, 2003.)

Fumero said CTI's approach is based on generating antibodies to the target. Creabilis, in addition to the CT500 project, has generated a series of duplex chimeras and hybrids, comprising single strands of DNA and an analogue, peptide nucleic acid, which also interferes with HMGB-1 signaling. The company also has in-licensed CT301, a small molecule of microbial origin that inhibits HMGB-1 activity through an unknown mechanism.

Fumero said those programs have potential application in multiple indications, including autoimmune disease and inflammation, cancer, infectious disease and in preventing restenosis. None will be ready to enter clinical development before 2006. CT301, an inhibitor of the nerve growth factor tyrosine kinase receptor, also is in development as a treatment for psoriasis, while the company also has an HIV program, based on the use of peptides to block a second, previously undescribed mechanism of entry of the virus into T cells.

Creabilis is based in Ivrea, Italy. Fumero established the company last year, after six years as senior executive vice president and head of research and pharmaceutical development at Geneva-based Serono SA. The company has funding from private sources, he said, and it will not require venture capital investment for another 18 months.

"The freedom that we have now is fantastic," he said. "If possible, it's better to continue [without it]."

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