With four therapeutic viral vector-based products in development, Transgene (www.transgene.fr) is pursuing the cancer and infectious disease markets. Its vaccine strategy involves introducing immunostimulatory molecules and viral or tumor-associated antigens.
Transgene’s lead product, TG4010, targets non-small-cell-lung cancer in combination with chemotherapy and is in a Phase IIb study in Europe in patients with advanced-stage disease. The vaccine is comprised of an MVA-based vector and the MUC1 tumor-associated antigen.
“MVA is a very safe vector—nonreplicative and nonintegrative,” says Jean-Yves Bonnefoy, Ph.D., vp of R&D. “This virus allows you to bring into it quite a significant chunk of foreign DNA. Additionally, based on data we are accumulating in man, immunity to MVA does not seem to be a handicap—and that is a major plus.”
Transgene’s TG4001 vaccine is indicated for the treatment of HPV-induced precancerous cervical lesions. The MVA vector expresses the E6 and E7 antigens of HPV16 together with IL-2. Phase II results were reported in April: 18 women with high-grade cervical intraepithelial neoplasia (CIN 2/3) related to HPV16 infection received three injections of the vaccine. Of the 18 women, 10 had normal colposcopic evaluations of the cervix at six months, nine had no evidence of CIN 2/3, and nine had no HPV16 mRNA. “This is the first time it has been shown that a therapeutic vaccine has worked on a chronic infection,” says Philippe Poncet, CFO. Larger studies are planed to confirm these results.
TG1042, an adenovirus-vectored vaccine expressing interferon-g, has completed a Phase I/II trial in patients with cutaneous B-cell or T-cell lymphoma who have failed radiotherapy. The goal is to induce a nonspecific local immune response.
Over the past year, Dr. Bonnefoy has also observed growing recognition of the potential value of combining new classes of therapeutic vaccines with existing cancer treatment strategies to take advantage of their complementary and sometimes synergistic effects. The addition of immunotherapy may allow for the use of lower doses of chemotherapeutic agents with improved outcomes.
Avant Immunotherapeutics (www.avantimmune.com) collaborated with GSK on the development of Rotarix and is producing several oral, single-dose vaccines against bacterial targets aimed at preventing diarrhea and enteric diseases. Although the company’s bacterial vector platform is based on live attenuated cholera or typhoid fever vaccines, it believes that it can use this technology to vector viral antigens to protect against viral disease, according to Una S. Ryan, Ph.D., president and CEO of Avant.
Following promising Phase II results of its CholeraGarde® cholera vaccine this summer, Avant reported that the International Vaccine Institute had received a $21-million grant from the Bill & Melinda Gates Foundation for a Cholera Vaccine Initiative that will include further trials of CholeraGarde, including immunization concurrent with measles vaccination and use in HIV-positive patients. Phase III trials planned for Bangladesh are designed to compare vaccinated villages (vaccination of adults, children, and infants) with unvaccinated villages for disease incidence.
Avant’s typhoid fever vaccine is in Phase I/II testing, with a Phase II study anticipated to get under way in the first half of 2007. Its cholesterol ester transfer protein (CETP) vaccine aims to raise levels of HDL and has completed Phase II testing. The company has reformulated the CETP vaccine with a new adjuvant, a TLR ligand, and is now testing this new vaccine formulation.
The company plans to apply its bacterial vaccine platform as vectors for delivering various disease antigens, such as enterotoxigenic E. coli or plague. According to Dr. Ryan, one of the company’s ultimate goals is to combine several of its vaccines to create a super-protectant against the many potential causes of traveler’s diarrhea. Another planned application of the technology is to develop a preventive vaccine for pandemic flu.
Lentigen (www.lentigen.com) is leveraging its LentiMax™ lentiviral vector system in a recently announced partnership with Dharmacon (www.dharmacon.com) to develop and manufacture lentiviral expression reagents for gene-silencing applications. The lentiviral reagents will deliver shRNA expression vectors into cells for RNAi-mediated gene silencing.
On the therapeutic front, Lentigen continues to develop its lentiviral vector system as a manufacturing platform for vaccine, Mab, and therapeutic protein production. Its lead target is pandemic and seasonal influenza. Within five weeks the company can produce virus-like particle-based vaccines containing three to four viral proteins, including a hemagglutinin neuraminidase targeting the desired virus strain, according to Boro Dropulic, Ph.D., founder and CEO of Lentigen.
Other advantages of the lentiviral platform include the ability to produce virus-like particles (VLPs) in standard manufacturing cell lines and long harvest times, because VLPs do not kill the cells. Ongoing collaborations in the area of gene therapy focus mainly on cancer with additional projects in regenerative medicine and infectious diseases.