Genetically Modified Salmonella Lack Ability to Induce TNF-Alpha and Cause Sepsis According to Nature Biotechnology Publication
NEW HAVEN, CT (December 29, 1998): New research demonstrates that genetic modification of a cell wall component of tumor-targeting Salmonella bacteria can greatly reduce the bacteria's potential for virulence and ability to cause septic shock, announced Vion Pharmaceuticals, Inc. (Nasdaq: VION). Vion is developing the modified bacteria, the heart of the company's TAPET technology, as vectors for the targeted, systemic delivery of anti-cancer agents to tumors throughout the body.
A publication detailing the research, entitled "Lipid A mutant Salmonella with suppressed virulence and TNF-alpha induction retain tumor-targeting in vivo," will appear in the January issue of the journal Nature Biotechnology. The article is authored by scientists at Vion and their collaborators at Yale University School of Medicine; Texas A&M University, College of Veterinary Medicine; and the University of Washington Health Sciences Center.
Vion researchers and their collaborators have previously reported the development of Salmonella that specifically target tumors over normal tissues. However the clinical utility of such bacteria was potentially limited by the ability of lipid A in the bacteria's cell walls to elicit the production of TNF-alpha and trigger septic shock. Now the researchers have shown that a disruption of the Salmonella msbB gene involved in the production of lipid A reduces, by 10,000 fold, the ability of the bacteria's lipid to induce TNF-alpha and cause death in animal models. At the same time, the msbB-minus Salmonella retain their tumor-targeting properties, exhibiting the ability to accumulate in tumors at ratios in excess of 1000:1 compared with normal tissues.
"Administration of these modified bacteria to mice bearing melanoma tumors results in tumors that are less than six percent the size of tumors in untreated control animals," said David Bermudes, Ph.D., associate director of biology at Vion and an author of the publication. "Thus, the anti-tumor activity that we previously demonstrated using tumor-targeting bacteria with normal lipid A is retained. At the same time, the modified bacteria's potential for causing septic shock is essentially eliminated." Septic shock from bacterial infection can produce a variety of potentially life-threatening complications.
"Our results with msbB-minus Salmonella in both laboratory and animal models are consistent with the idea that these organisms should be safe for use in humans," Dr. Bermudes continued. "In addition the msbB-minus bacteria that we are developing as anticancer vectors remain fully sensitive to a wide range of antibiotics, adding an additional level of safety and control." Vion expects to begin human clinical safety studies using the modified TAPET organisms in the first quarter of 1999. Ultimately, the company plans to develop the TAPET bacteria as systemically administered vectors for the selective delivery of anticancer agents and pro-drug converting enzymes to tumors.
Additional Research Results
The researchers tested the msbB-minus bacteria in several cell culture and
animal models of TNF-alpha induction and septic shock, comparing results with
the modified organisms to those elicited by wild-type Salmonella. Their reported
findings included:
• Purified lipopolysaccharide (LPS) from the msbB-minus mutant bacteria showed at least a 10,000-fold reduction in the induction of TNF-alpha by human monocytes compared to LPS from wild-type organisms.
• The ability of live msbB-minus bacteria to elicit TNF-alpha in animals was significantly reduced compared to wild type organisms. In a standard swine model of septic shock, msbB-minus bacteria induced only 14 percent of the TNF-alpha induced by wild type organisms.
• Ninety minutes after injection, respiration was significantly increased in swine injected with wild-type bacteria compared to controls, but not in swine injected with the msbB-minus bacteria.
• The msbB-minus bacteria exhibited reduced survival in mouse macrophages compared to wild-type bacteria. This implies that, except in tumors where bacteria are sequestered from the immune system, the TAPET organisms will be eliminated by the immune system.
• Injection of the mutated Salmonella into mice and swine caused no deaths, while administration of wild-type bacteria produced mortality in all of the mice within four days and 90 percent of the treated swine within 28 days.
Vion Pharmaceuticals, Inc. is a biopharmaceutical company engaged in the discovery, development and commercialization of novel products and technologies for the treatment of cancer and viral diseases. The company has an extensive research and development pipeline focused on five principal projects: Promycin (porfiromycin), a hypoxic cancer cell therapy currently undergoing Phase III clinical testing; TAPET, the company's platform cancer treatment technology; Triapine, a ribonucleotide reductase inhibitor currently in a Phase I clinical trial; Beta-L-FD4C, a novel nucleoside analog for the treatment of viral diseases; and arylsufonyl hydrazine prodrugs, for the treatment of cancer. The company has licensed its non-core MELASYN(synthetic melanin) technology to San-Mar Laboratories, who plans to market its first OTC cosmeceutical preparations for vitiligo through the company's subsidiary, Vitiligo Solution, Inc. For additional information on Vion and its research and product development programs, visit the company's Internet web site at http://www.vionpharm.com.
Statements included in this press release which are not historical in nature are forward-looking statements made pursuant to the safe-harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements regarding the Vion Pharmaceuticals future business prospects, plans, objectives, expectations and intentions are subject to certain risks, uncertainties and other factors that could cause actual results to differ materially from those projected or suggested in the forward-looking statements, including, but not limited to those contained in the Vion Pharmaceuticals Registration Statement filed on Form S-3 (file no. 333-37941).
John Spears
President and CEO
Vion Pharmaceuticals, Inc.
(203) 498-4210
Email: vioninfo@vionpharm.com
Joan Kureczka
J. Kureczka Associates
(415) 821-2413
Email: JKureczka@aol.com
Journal
Nature Biotechnology