IntraVec Inc. foresees therapeutic solutions for cancer and infectious diseases that would eliminate surgery, recurrent drug and vaccine administrations, chemotherapy and radiation - interventions that often require protracted treatments and which IntraVec considers to have limited utility in remediating chronic disease.
The company, which is developing three genetic engineering therapeutic platforms and a gene screening process, started last August with seed capital from Wake Forest University and is operating as an incubator company under the auspices of university technology transfer company QED Technologies Ltd. (Malvern, Penn.).
IntraVec's platforms are based on the work of cancer biologist Si-Yi Chen and colleagues during Chen's tenure at Wake Forest. Chen, a company founder, is now associate professor at the Center for Cell and Gene Therapy at Baylor College of Medicine (Houston, Texas). There, he and Malcolm Brenner - scientific founder of IntraVec and director of the center - are overseeing clinical development of therapies for AIDS and cancer, with Phase I and II trials to be funded by Baylor. Brenner has transferred his genetic engineering discoveries to IntraVec.
The platforms include toxic cell technology, in which normal cells are genetically modified to produce a toxin that attacks and kills cancer cells but which does not harm the carrier or normal cells. IntraVec also is developing the use of cellular chemokines, or intrakines, to target AIDS (see Technology Briefing, BioCentury, Oct. 20, 1997); and the production of therapeutic proteins that can be used to treat diseases involving activation of the cellular immune response.
In addition, the company's Gene Screen project screens genes for which no function is known to identify those coding for proteins that elicit an immune response, which would form the basis for the development of small molecules and peptidomimetics.
President and CEO Annette Tobia, a QED partner, said the company's first priority will be to start Phase I/II trials with intrakines in early stage AIDS patients and with toxic cell technology in terminal brain cancer patients. The clinical program is expected to begin next summer.
The intrakine technology genetically alters lymphocytes from HIV-infected patients with vectors to make them impervious to entry by the virus, after which the lymphocytes are reinfused into the patient.
"Ordinarily, the HIV binds to the host cell through interaction with chemokine co-receptors on the surface of the cell. But some people have what we call a defective CCR-5 gene, which does not produce the chemokine that permits docking by HIV," Tobia said. "We have mimicked that natural HIV resistance by causing T cells to act as if they are resistant mutants."
Tobia noted that other gene therapies attempt to interfere with viral replication after the virus has been incorporated into host cells, and after the immune system has been compromised.
IntraVec said its approach also addresses the dilemma of using chemokines themselves as drugs due to their short half life - less than 10 minutes. In the trial, patients will be given two intrakine injections at about three-month intervals, eliminating the need for frequent, repeated injections of drug.
IntraVec also is developing engineered cells to produce and secrete a protein that binds to HIV receptors on surrounding cells, thus masking the docking sites for HIV on both macrophages and lymphocytes. Such a product would address late stage as well as early stage HIV infections.
Another project is a second-generation "breakthrough" vector aimed at transducing those stem cells that differentiate into T lymphocytes, monocytes and macrophages to make the differentiated cells resistant to HIV infection by making them look like CCR-5 gene defective cells.
IntraVec's brain cancer trial will assess the effect of the toxic cell technology on survival. The approach, which IntraVec said can be used on any type of solid tumors, is based on the modification of normal cells to produce and secrete a toxin that kills tumor cells.
"We insert into the normal neuronal cell a vector that encodes a fusion protein that is a chimera - having one portion coding for an antibody to an antigen on the tumor and the other portion coding for a toxin which, when released in a cell, will destroy it," said Tobia. "The engineered cells are injected directly into the solid tumor. The antibody, which directs the toxin to antigens that are present on tumor cells but not on normal cells, has an added benefit of not recognizing either modified or normal cells."
Because neuronal cells have a long life compared to other types of cells, Tobia said only a single injection may be required.
Tobia calls the third platform "the genetic and cellular education of proteins." In this approach, normal cells are transduced so that they produce a protein, such as an antiviral that can treat infection. "These proteins are collected, harvested and then re-injected to the patient, where they continuously activate immune response," Tobia said. Hepatitis B is the company's initial target in this area.
In addition to fund-raising efforts, IntraVec hopes to obtain revenues from Gene Screen sales, which will be used to fund the therapeutic proteins program. The strategy for the toxic cell and intrakine technologies will be to partner the programs for Phase III development.