San Diego-based Maxim Pharmaceuticals Inc. said its new program for Maxamine, now Ceplene (histamine dihydrochloride), appeared promising in a preclinical study.

The effort to remake the adjuvant to interleukin-2 for the treatment of patients with advanced metastatic melanoma with liver metastases into an immunotherapy adjuvant was supported by preclinical data presented at the American Association for Cancer Research meeting in New Orleans. The data indicated the therapeutic significantly increased expression of CD86, a molecule that triggers activation of antitumor lymphocytes.

The in vitro study showed that monocytes incubated with histamine showed a significantly increased expression of CD86.

The study also evaluated the combination of histamine and granulocyte macrophage-colony stimulating factor (GM-CSF), and showed the combination boosted the upregulation of CD86 by monocytes by more than 350 percent compared to GM-CSF alone.

Ceplene is being studied in two Phase III trials as an anticancer agent for advanced metastatic melanoma and acute myelogenous leukemia, and in Phase II trials for treatment of hepatitis C and advanced renal cell carcinoma. An FDA advisory panel in December recommended against approval of the product for advanced metastatic melanoma that has metastasized to the liver. (See BioWorld Today, Dec. 14, 2000.)

In other news from the American Association for Cancer Research meeting:

¿ AEterna Laboratories Inc., of Toronto, presented data from a Phase I/II trial of the anti-angiogenic Neovostat. Trial results showed a twofold increase (p<0.01) in median survival time for metastatic renal cell carcinoma patients refractory to standard treatments who were treated with a higher dose of Neovostat, compared to patients treated with the standard dose level. Patients treated with 120 ml twice a day showed a median survival time of 16.3 months, compared with 7.1 months for patients treated with 30 ml twice a day.

¿ AltaRex Corp., of Waltham, Mass., presented additional data indicating its OvaRex antibody effectively activates T cells. The in vitro data demonstrated that the uptake of antibody/antigen complexes by antigen-presenting cells is receptor mediated and results in two immunological responses. Data also indicated that uptake is most efficient in the presence of AltaRex's fully murine monoclonal antibodies, and that an effective T-cell response is generated only in the presence of foreign/self complex, not with antibody alone, antigen alone, or complexes with humanized or chimeric antibodies.

¿ Cell Pathways Inc., of Horsham, Pa., said preclinical data supports the ongoing investigation of Aptosyn (exisulind) in non-small-cell lung cancer. Researchers said the combination of Aptosyn and Taxotere increased survival in an animal model compared to Taxotere alone. Aptosyn is in Phase III study comparing Aptosyn and Taxotere to Taxotere alone.

¿ Cyternex Inc., of San Diego, said scientists from the University of Arizona updated research at the meeting on the role of higher-order DNA structures in regulating genes. The scientists are examining knots in DNA as potential targets for novel cancer therapeutics. Research has focused on developing compounds that help a quadraplex implicated in the unregulated expression of the known cancer gene c-myc form. A compound that binds to and stabilizes the quadraplex could turn off the c-myc gene. Cyternex will take the most promising leads into clinical development.

¿ EntreMed Inc., of Rockville, Md., released data from a preclinical study that indicated its anti-angiogenic Panzem (2-methoxyestradiol) effectively inhibits metastasis in mice in addition to significantly reducing primary tumor size. Panzem showed dose-dependent anti-angiogenic and antitumor activity. Panzem is under investigation in two Phase I trials in patients with refractory, drug-resistant breast cancer.

¿ ImClone Systems Inc., of New York, said preclinical findings indicate its novel recombinant hTRPx3 protein-based melanoma vaccine, a chimeric vaccine consisting of human melanoma proteins TRP-1, TRP-2 and tyrosinase, produces antibody and cellular immune responses in vaccinated nontumor-challenged mice. Researchers at the meeting presented posters announcing that the suppression of lung metastases was significantly enhanced in vaccinated mice compared to controls. The company also released findings from a study of its anticancer agent, IMC-C225, which is designed to block epidermal growth factor receptor. That study indicated the agent, as a single-agent therapy and in combination with irinotecan, significantly inhibited the growth of xenografts compared to controls in two colorectal carcinoma xenograft models. The combination therapy further demonstrated enhanced antitumor activity compared to IMC-C225 or irinotecan alone.

¿ Immunomedics Inc., of Morris Plains, N.J., said that using a new peptide-based linking method reduces degradation of iodine-131 from its attached antibody after it is bound to the target tumor. The advance addresses one of the major limitations to using I-131-labeled antibodies for cancer therapy. The company said the change showed significantly increased retention and improved targeting properties.

¿ Matritech Inc., of Newton, Mass., said a study of 384 cervical samples showed the company's cervical cancer test, NMP179, demonstrated high sensitivity at detecting high-grade squamous intraepithelial lesions (HSIL) and may provide a cost-effective way to manage low-grade squamous intraepithelial lesions and equivocal Pap smears. NMP179 was positive in 92.8 percent of samples diagnosed as HSIL, compared to 85.7 percent using Hybird Capture II.

¿ MetaPhore Pharmaceuticals Inc., of St. Louis, said animal studies indicated the synthetic enzyme M40403 reversed the extreme blood-pressure drops associated with high-dose interleukin-2 cancer therapy. Research also showed the compound enhanced IL-2's anticancer efficacy.

¿ Miravent Medical Technologies Inc., of Santa Barbara, Calif., said preclinical study results indicate its PhotoPoint therapy for solid tumor treatment selectively destroys tumor neovasculature with minimum effect on surrounding normal blood vessels. Additional studies are under way, the company said, to evaluate the selective effects and efficacy of PhotoPoint.

¿ Onyx Pharmaceuticals Inc., of Richmond, Calif., and collaborator Bayer AG, of Leverkusen, Germany, presented Phase I results of their oral Raf kinase inhibitor, BAY 43-9006. The results demonstrated the compound's mechanism of action and potential applicability in multiple tumor types. BAY 43-9006 is a selective agent designed to block the Ras signaling pathway in cells by inhibiting Raf kinase. The companies also reported preclinical results that indicated that the compound inhibited Raf kinase signal transduction.

¿ Targeted Genetics Corp., of Seattle, said preclinical evaluation of tgLOC71, its metastatic cancer gene therapy candidate designed to deliver the E1A gene, indicated that the therapy may have utility in treatment of metastatic disease when local-regional delivery is not feasible. The study data indicated that delivery of tgLOC71 via tail injection in mice resulted in E1A gene expression within tumor cells when delivered as a single agent or in combination with paclitaxel. Both administration options produced a reduction in the expression of HER-2/neu compared to controls.

¿ Telik Inc., of South San Francisco, presented additional data supporting the potential of TLK199, a small molecule that activates elements of the signaling pathway responsible for the therapeutic effects of hematologic growth factors. The molecule accelerated recovery of circulating neutrophil levels in rodents following treatment with the common anticancer agent 5-fluorouracil in one study presented at the meeting, and the company said another study indicated similar elevations in rodents that were not treated with 5-fluorouracil. Telik continues evaluating the compound in preclinical study in preparation for filing an investigational new drug application later this year.

¿ Vion Pharmaceuticals Inc., of New Haven, Conn., said preclinical results indicated its lead sulfonyl hydrazine prodrug candidate, VNP40101M, exhibited unique properties compared to existing alkylating (DNA damaging) agents. Vion plans to initiate a 20- to 30-patient Phase I trial of the compound to assess safety and maximum tolerated dose in about two months. n

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