By Frances Bishopp

SIGA Pharmaceuticals Inc., which focuses on the treatment of infectious disease through the development of vaccines, antibiotics and anti-infectives, will collaborate with Wyeth-Ayerst Pharmaceuticals to discover and develop anti-infectives for prevention and treatment of human and veterinary gram-positive bacterial infections.

The privately held, Manhattan, N.Y.-based company could potentially receive up to $25 million in up-front and milestone payments under terms of the agreement. Wyeth-Ayerst, a division of American Home Products Corp., located in Radnor, Pa., will fund product development and make royalty payments based on sales of any marketed products.

The collaboration will use two-year-old SIGA's technology in disarming pathogenic gram-positive bacteria by interfering with their ability to attach to and colonize mucosal surfaces. The two companies will use high-throughput screening procedures to identify protease inhibitors that block normal surface protein anchoring, thereby preventing bacterial attachment, colonization and infection.

In the antibiotic area, SIGA has developed a group of targets that interfere with the placement of surface proteins on bacteria, David de Weese, president and CEO of SIGA, told BioWorld Today.

"What we have provided to Wyeth-Ayerst is a target, an enzyme that we have identified and patented, and a high-throughput screen which incorporates this enzyme," de Weese said.

"Wyeth-Ayerst will take its compound libraries and screen, looking for an inhibitor of that enzyme or protease," de Weese said.

SIGA is developing protein production systems based on its understanding of the mechanisms used by gram-positive bacteria to export and anchor surface proteins. Methods have been developed to engineer gram-positive bacteria to produce and secrete commercially useful proteins such as antigens or enzymes into the culture medium in a form requiring minimal purification.

"These surface proteins are involved in all parts of the infection process and have never been used as targets for intervention before," de Weese said.

"If you look at a healthy gram-positive, it looks like a brand-new fuzzy tennis ball," de Weese said. "We're trying to turn it into a billiard ball. It doesn't have any of those proteins on the surface and it basically becomes a non-infective organism.

"We can engineer almost any gram-positive organism. We have very good data on the genetic make-up of gram-positives in various parts of the mucosal tracts. We can put a gene into almost any one of these and allow it to recolonize the area where it would normally live," deWeese said.

"We picked one that would colonize the same place that a pathogen would take up residence so that part of the mucosal system is armed against that pathogen," de Weese said.

In the vaccine area, SIGA is focused on mucosal vaccines. The company's lead vaccine candidate is for the prevention of group A streptococcal pharyngitis (strep throat), a recurrent infection affecting between seven million and 20 million children in the U.S. every year. Currently there is no vaccine available for strep throat because more than 100 different serotypes of group A streptococcus are known to cause the disease.

SIGA's antigen addresses the challenge of multiple serotypes in it is common to most types of bacteria that cause strep throat. When a vaccine incorporating this antigen was orally administered to animals, it was shown to provide protection against multiple types of group A strep infections.

In a vaccine collaboration, SIGA is working with Chiron Corp., of Emeryville, Calif., on the treatment of sexually transmitted diseases. The agreement constitutes a one-year major feasibility study designed to establish proof in animal models using SIGA's vector system and Chiron's antigens.

SIGA's lead vaccine candidate for strep throat soon will enter Phase I clinical trials, which will be sponsored and paid for by the National Institutes of Health, of Bethesda. Md.

SIGA also is working on a vaccine for periodontal disease, which is in preclinical studies.

De Weese said SIGA's gross consumption of cash over the next two years should not exceed $4.5 million per year. "We expect much of that to be covered by corporate collaborations. Our own burn rate is substantially below that number," de Weese said. *