Mojave Therapeutics Inc. released Monday the first results of a Phase I/IIa trial using its Javelin antigen delivery system for the treatment of melanoma.
The study, which began in May 2000, included 27 patients with Stage III and IV melanoma and compared three dosage levels of a therapeutic vaccine. It demonstrated that the Javelin formulations were safe and well tolerated by all patients at each dose level.
Mojave, of Hawthorne, N.Y., presented the results at the 93rd annual meeting of the American Association for Cancer Research in San Francisco.
“I’m thrilled, because it is our first human data,” said Mojave CEO Timothy Cooke, who spent nine years at Merck & Co. Inc., of Whitehouse Station, N.J., with which he held domestic and international positions in its vaccine program. Cooke was a founding member of Aventis Pasteur MSD, a joint venture between Merck and Aventis formed in 1994 to market vaccines in Western Europe.
In the Phase I/IIa study, 78 percent of the patients showed no disease progression after having been followed for 17 months after vaccination. The patients received five subcutaneous injections over an 18-week period. The injections were made of a recombinant human heat shock protein with 1, 10 or 100 micrograms each of tyrosinase and gp 100 peptides two proteins found on the surface of melanoma cells modified with the Javelin sequence, which comprises about 10 amino acids and ensures that antigens can bind to heat shock proteins, which are activated when a cell is exposed to high temperatures or stress. Javelin is necessary, the company said, because not every antigen from which scientists hope to get an immune response can bind to a heat shock protein naturally.
Cooke said that Javelin is used for known human biochemical pathways and allows delivery of an antigen to antigen-presenting cells, which let the body know that disease is present and the body should respond. Ultimately, the antigen presents on the surface of the cell, which activates a killer T cell.
“We think of the Javelin as molecular velcro,” Cooke said, explaining that he considers the company to be in the “antigen delivery business.”
James Rothman, vice chairman at Memorial Sloan-Kettering Cancer Center in New York, discovered all of the intellectual property on which Mojave is based. The company licensed the technology from Sloan-Kettering. Rothman serves on Mojave’s scientific and medical advisory board.
Mojave is focused on treatments for cancer and infectious disease via therapeutic vaccines, including its preclinical work on the human papillomavirus. A collaboration in that indication using a mouse model that has a humanized immune system was initiated with the Paris-based Institut Pasteur in January, Cooke said.
Also pending are Phase I/II trials in prostate cancer. Mojave is now working on the design of such a trial with Memorial Sloan-Kettering and the FDA.
In other news from the conference:
Antigenics Inc., of New York, presented interim results from Phase II trials evaluating Oncophage (HSPPC-96), its personalized cancer vaccine, in the treatment of both advanced melanoma and colorectal cancer. The data showed that treatment with Oncophage can induce expansion of cancer-specific immune responses, and that the induction mechanism is the same for both cancers. Oncophage is derived from each individual patient’s tumor and contains complexes of heat shock proteins.
Antisoma plc, of London, presented data showing that Thioplatin showed promising activity on cisplatin-resistant cells. The company presented data showing Thioplatin was active in three human ovarian carcinoma cell lines with acquired cisplatin resistance. Data also confirmed findings that Thioplatin was potent across a range of cell lines at the more acidic pH levels typically found in the acidic environment around tumors, than at the pH levels found in normal tissues. Thioplatin is a tumor-targeted version of a platin, a class of drugs used to treat a range of solid tumors.
Cell Pathways Inc., of Horsham, Pa., said eight posters presented by scientists from Cell Pathways and its collaborators detail the anticancer properties and mechanism of action for its apoptotic antineoplastic drugs. Presentations concerning the company’s second-generation compound, CP461, include data showing that oral CP461 increased survival in a rat model of human lung cancer equivalent to that produced by injected taxotere (docetaxel). New data being presented show that CP461 exhibits antiproliferative, as well as pro-apoptotic, effects on tumor cells in culture and in animal models, and that the drug is selective for tumor cells over normal cells. Cell Pathways is conducting Phase I/II investigations with CP461 as a single-agent in a variety of cancers.
ChemGenex Therapeutics Inc., of Menlo Park, Calif., is presenting research demonstrating the use of chemical genomics to advance the development of two of its investigational cancer drugs, now in clinical trials. ChemGenex researchers demonstrated the use of high-density expression array analysis to support the development of one drug, Quinamed, being developed as a potential treatment for solid tumors including glioblastoma and hormone-refractory breast and prostate cancers. The company said chemical genomics methods predicted anti-angiogenic properties for ChemGenex’s second product drug, Ceflatonin, a compound in Phase II trials for hematologic malignancies.
Cytokinetics Inc., of South San Francisco, and GlaxoSmithKline plc, of London, said seven abstracts related to their strategic collaboration are being presented. The oral and poster presentations focus on the potential pharmaceutical utility of small molecules specifically directed to kinesin spindle protein, a mitotic kinesin protein essential for proper DNA division in cells. The companies intend to file an investigational new drug application with the FDA in 2002. Cytokinetics and GlaxoSmithKline will present the results of research in the field of mitotic kinesins and small molecules targeting those enzymes for potential applications in the treatment of cancer.
Genaera Corp., of Plymouth Meeting, Pa., presented data on squalamine, its anti-angiogenic agent, for the treatment of breast cancer. The presentation reviewed results indicating that squalamine inhibits growth of human breast tumor xenografts in animals with or without overexpression of the oncogene HER-2/neu. There also is effectiveness in HER-2/neu overexpressing breast tumors when squalamine is combined with Genentech Inc.’s Herceptin, a humanized monoclonal antibody to the HER-2/neu membrane receptor, the company said. The presentation reviews that the anti-angiogenic activity is due, in part, to blockage of vascular endothelial growth factor signaling in the tumor-associated blood vessels.
ImClone Systems Inc., of New York, presented in vitro and in vivo preclinical findings from a study that tested an experimental monoclonal antibody designated E4G10 to evaluate its ability to selectively target the protein vascular endothelial-cadherin (VE-cadherin) to prevent angiogenesis. Findings showed that E4G10 can target tumor-related angiogenesis without interfering with normal blood vessel function. In vitro and in vivo findings demonstrated that E4G10 interferes with the crucial role of VE-cadherin, an endothelial cell-specific adhesion molecule, in the formation of tumor blood vessels. Treatment of mice showed that the monoclonal antibody inhibits growth of mouse and human tumors via an anti-angiogenic mechanism.
Genta Inc., of Berkeley Heights, N.J., said two studies have shown that Genasense, its anticancer compound, enhanced the anticancer activity of two leading anticancer agents, taxotere and Rituxan (rituximab, Genentech Inc., of South San Francisco). The combination of Genasense plus taxotere was explored in a model of human lung cancer. When used individually, the agents showed moderate antitumor activity, but neither single agent produced complete responses. The combination of Genasense and taxotere achieved an increase in tumor reduction, along with complete responses in four of seven animals tested. In a separate study, the effects of Genasense and Rituxan were tested in mice with human lymphoma. In the current study, untreated animals with lymphoma expired at a median time of 44 days. Rituxan alone increased survival to 59 days, whereas Genasense alone increased survival to 71 days. However, neither agent was curative when used by itself. In the combination study, Genasense plus Rituxan increased survival to 150-plus days, and five of seven animals were ultimately proved to be free of disease.
Inex Pharmaceuticals Corp., of Vancouver, British Columbia, said its OligoVax therapeutic vaccine stimulated the immune system to inhibit the growth of melanoma tumors in preclinical studies. Presenters said the result was achieved when an antigen associated with melanoma (tyrosinase-related protein-2, or TRP-2) was combined with Inex’s OligoVax technology. The OligoVax platform was derived from a series of preclinical studies that explored the therapeutic benefits of applying Inex’s drug delivery technology to oligonucleotides.
Lorus Therapeutics Inc., of Toronto, presented data supporting both the mechanism of action and the characterization of its lead immunotherapeutic product, Virulizin. The company presented in vitro and in vivo results of the studies at the meeting. A Lorus scientist reported that mice harboring human melanoma tumors were depleted of macrophages and then treated with either Virulizin or saline control. The antitumor effects of Virulizin were compromised in these macrophage-depressed mice, which demonstrated an important role for macrophages in Virulizin-mediated antitumor efficacy and supported the concept that Virulizin is an activator of macrophages. Also presented were positive data from two separate tests in which isolated tumors from mice harboring human melanoma or pancreatic carcinoma tumors were subjected to flow cytometric analyses using macrophage- and natural killer cell-specific antibodies.
Millennium Pharmaceuticals Inc., of Cambridge, Mass., presented findings from a preclinical trial of its investigational drug, MLN341 (formerly LDP- 341 and PS-341), studying its effects with different chemotherapies against a range of solid tumors in mice. The results demonstrated that MLN341, when combined with chemotherapy, caused greater decreases in tumor size than either treatment given alone, Millennium said. MLN341 is designed to specifically block proteasomes enzymes in the cell responsible for breaking down proteins, including many that regulate cell division.
North American Scientific Inc., of Chatsworth, Calif., said its technology, known as Apomate, may be able to predict whether an individual cancer patient is likely to respond to chemotherapy treatment. Apomate works by measuring changes that occur on the outer membrane of cancer cells early in the cell death process. The test is conducted before chemotherapy begins to measure the natural level of cell death occurring in the cancer cells and another test is done one to three days later. Results are compared to the baseline test. Apomate combines a natural human protein called annexin V, which attaches to phosphatidylserine, with a radioactive tracer called technetium. Technetium can be detected outside the body with a special camera.
Novogen Ltd., of Sydney, Australia, said interim trial results were presented by researchers from the Cleveland Clinic’s Taussig Cancer Center. Results indicated its anticancer product, phenoxodiol, slowed cancer progression in six of 10 patients. Phenoxodiol targets the underlying control mechanism in cells that determines whether a cell will live or die. Patients in the trial have a range of cancers including colon cancer, melanoma, thymic cancer and prostate cancer that have failed to respond to standard anticancer drugs.
Seattle Genetics Inc., of Bothell, Wash., said it will report preclinical data describing the progress of certain of its monoclonal antibody-based therapeutics. The company will present advances in its antibody drug conjugate technology; the genetically engineered monoclonal antibody SGN-30, in Phase I trials; and the observation of synergy between the antibody drug conjugate product candidate SGN-15 and gemcitabine in ovarian cancer models.
Sonus Pharmaceuticals Inc., of Seattle, presented an update on Phase I results with Tocosol paclitaxel, its lead product for cancer therapy. In the study, the company enrolled 36 patients at three clinical sites. Of the 36 patients enrolled to date, 33 are evaluable and 12 have shown a tumor response. Of those 12, three have partial responses (tumor area reduction of more than 50 percent), two patients have minor responses (tumor area reduction of less than 50 percent) and seven patients are in stable disease, meaning that their cancer progression has been halted.