By Charles Craig

Most genetic licensing deals focus on a gene and its protein, which of course are part of a more complex series of biological activities.

But Exelixis Pharmaceuticals Inc., a functional genomics company whose business is identifying biochemical pathways, has gone several steps farther, claiming title to a complete signaling cascade of molecular events implicated in cell differentiation.

Exelixis said Thursday it acquired an exclusive license to the "entire" Notch regulatory pathway, which is involved in differentiation of cells for the formation of the various tissues and organs of the body.

The privately held Cambridge, Mass., start-up firm assembled the intellectual property from discoveries of scientists associated with Yale University, of New Haven, Conn., Indiana University, of Bloomington, and the Imperial Cancer Research Fund, of London. Financial terms were not disclosed.

Yale developmental geneticist Spyros Artavanis-Tsakonas, who also is a co-founder of Exelixis, completed most of the research identifying the Notch signal transduction pathways using fruit flies.

Twelve patent applications have been filed to cover the Notch genes and their uses. So far two notices of allowances have been issued by the U.S. Patent and Trademark Office.

Artavanis-Tsakonas said a Notch pathway has five core genes involved in delivering an extracellular signal to the nucleus of a cell. And there are four Notch pathways, each responsible for formation of different tissues of the body.

"Notch is, to our surprise," said Artavanis-Tsakonas, "very fundamental in regulating stem cell differentiation. It may be possible to use the pathways to manipulate stem cells in all sorts of tissues."

George Scangos, Exelixis president and CEO, said gene malfunctions in Notch pathways are implicated in leukemia, cancer, stroke and dementia, such as that characteristic of Alzheimer's disease.

"Notch also may be involved in the proper development of solid organs," Scangos said.

With commercial rights to the Notch signal transduction pathways, Exelixis next will attempt to identify genetic targets for manipulation.

"We already know how each molecule talks to the other molecule," said Exelixis' chief operating officer, Remi Barbieri. "What is not known is how that results in abnormal tissue development and function of cells."

Once targets are selected, Exelixis can determine a strategy for intervening, such as using small molecule drugs to generate and block events or replacing mis-expressed proteins.

Barbieri said Exelixis does not intend to conduct clinical drug development, but could prepare candidates for Phase I testing by pharmaceutical company collaborators.

Exelixis was set up to try to identify all genes of specific pathways involved in diseases, not just single molecules, such as a protein. In addition to fruit flies, the company uses worms and yeast to plot the course of cellular signaling cascades.

Potential drug development partners, Barbieri said, would license commercial rights to an entire cell signaling pathway, rather than a specific molecule, such as a therapeutic protein.

For example, Amgen Inc., of Thousand Oaks, Calif., agreed to pay Rockefeller University, of New York, up to $90 million to develop the protein leptin to treat obesity. The leptin gene and its protein are implicated in regulating fat content in the body. Amgen then agreed to spend another $42 million to get rights to the leptin receptor discovered by Progenitor Inc., of Columbus, Ohio.

If the leptin piece of the biochemical puzzle for obesity is worth more than $132 million, what price would an entire genetic pathway command? Barbieri asked.

"We think we can identify the components of one to three pathways a year," he added.

In addition to the Notch cascade, Exelixis is researching other signaling pathways involved in cancer, Alzheimer's disease and obesity.

In its most recent financing round in April 1996, Exelixis raised more than $12 million. (See BioWorld Today, April 8, 1996, p. 1.) *