Human trials(Ph I) on TAPET to start 1Q '99. Research looks very promising!
Vion's TAPET Organisms Demonstrate Reduced Virulence,
Increased Safety While Retaining Ability to Specifically Target
Tumors
PR Newswire - December 29, 1998 08:30
Genetically Modified Salmonella Lack Ability to Induce TNF-Alpha and Cause Sepsis According to Nature
Biotechnology Publication
NEW HAVEN, Conn., Dec. 29 /PRNewswire/ -- 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(R)
(porfiromycin), a hypoxic cancer cell therapy currently undergoing Phase III clinical testing; TAPET(R), the
company's platform cancer treatment technology; Triapine(TM), 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
arylsulfonyl hydrazine prodrugs, for the treatment of cancer. The company has licensed its non-core
MELASYN(R) (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 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 Joan Kureczka
President & CEO J. Kureczka Associates
Vion Pharmaceuticals, Inc. 415-821-2413
203-498-4210 Email: Jkureczka@aol.com
Email: vioninfo@vionpharm.com
SOURCE Vion Pharmaceuticals, Inc.
/CONTACT: John Spears, President & CEO of Vion Pharmaceuticals, Inc.,
203-498-4210, or vioninfo@vionpharm.com; or Joan Kureczka of J. Kureczka
Associates, 415-821-2413, or Jkureczka@aol.com, for Vion Pharmaceuticals,
Inc./
/Web site: vionpharm.com |
