BioWorld International Correspondent
Biovitrum AB moved into oncology by acquiring a preclinical platform targeting the insulin-like growth factor-1 receptor (IGF-1R) from Axelar AB for an undisclosed sum.
Axelar, founded by Magnus Axelson and Olle Larsson, both professors at the Karolinksa Institute in Stockholm, Sweden, identified a series of orally active, small-molecule allosteric inhibitors of IGF-1R that showed anticancer activity in a series of animal models. A lead compound, BVT.5104, has been selected and will shortly enter clinical development.
"We plan to move this compound into the clinic during 2005," said Terje Kalland, chief scientific officer at Stockholm-based Biovitrum.
The company was attracted to the project, he said, because of its uniqueness. IGF-1R, a membrane-bound tyrosine kinase that acts as a growth factor during development, is well recognized as a cancer target.
"The target is very interesting because it controls both the way tumor cells grow and how they die," he said. It appears to be active in around 80 percent to 90 percent of all breast, lung, prostate and colon cancers.
Finding inhibitors with sufficient selectivity has proved difficult, however, as most screens tend to result in the detection of non-selective ATP competitors that inhibit the activity of multiple kinases. "That's what you get if you screen a library from a pharmaceutical company - you get ATP competitors," Kalland said. A particular problem with many inhibitors of IGF-1R is that they also affect the insulin receptor, a closely related tyrosine kinase with an identical ATP-binding pocket. Typically, they achieve a 10- to 25-fold reduction in IGF-1R activity as compared with that of the insulin receptor.
"Normally you like to see at least a 100-fold [reduction]," Kalland said.
Axelar's series of leads are not ATP competitors, but bind outside the ATP-binding pocket and induce a conformational change that results in a 1,000-fold reduction of IGF-1R activity relative to the insulin receptor. Moreover, they have demonstrated tumor regression, as well as inhibition, in animal models.
Several other companies have preclinical projects targeting IGF-1R with biologics. Immunogen Inc., of Cambridge, Mass., licensed an anti-IGF-1R antibody to Sanofi-Aventis, of Paris, last year, while Insmed Inc., of Glen Allen, Va., is developing insulin-like growth factor binding protein-3, which it describes as a naturally occurring tumor agent.
"The potential advantage of a small molecule is that it will freely penetrate a tumor," Kalland said.