As the American Association for Cancer Research meeting in Los Angeles wrapped up Wednesday, Peregrine Pharmaceuticals Inc. was among a number of firms presenting promising preclinical and early clinical data.
Tustin, Calif.-based Peregrine reported that a preclinical study of 2aG4, described as a mouse equivalent to its anti-phosphatidylserine antibody bavituximab, demonstrated vaccine-like activity in a brain cancer model and suggested a potential for inducing a curative response. Researchers presenting the data demonstrated that the improvement in survival for 2aG4-treated animals likely was attributable to the antibody's ability to help the treated animals mount an effective immune response against an aggressive cancer type.
Rats in the study were injected with irradiated glioma cells along with 2aG4. Among those that were pretreated with the 2aG4-treated irradiated cells, 57 percent achieved long-term survival vs. zero percent of animals receiving no prior treatment. However, a group receiving irradiated control antibodies, without the anti-PS activity of 2aG4, only achieved a 16 percent long-term survival rate. In calculating long-term survival, researchers determined that those animals receiving the 2aG4 regimen had more than 99.99 percent of the glioma cells destroyed by their immune systems, indicating that the 2aG4 vaccine-like regimen resulted in a strong immune response not seen in controls.
Based on those data, Peregrine said it intends to continue evaluating bavituximab as a vaccine-like regimen for potential application against a variety of cancers.
Bavituximab is a targeted monoclonal antibody that binds to phospholipids called phosphatidylserine, which becomes exposed on the outside of cells that line the blood vessels of tumors. Once bound to the blood vessel, the antibody is designed to alert the body's immune system to attack the tumor's blood supply, resulting in cell death. The compound is in a Phase Ib trial in combination with docetaxel and other chemotherapy agents in patients with advanced solid cancers, including prostate, breast and lung cancers. Based on interim data, more than half the patients to complete treatment to date demonstrated stable disease or an objective response.
In separate news, Peregrine reported preclinical data showing that fusion proteins combining the cytokines alpha interferon and interleukin 2 with 2aG4 demonstrated anticancer activity in models of B-cell lymphoma and melanoma. In those studies, the antibody-cytokine fusion proteins generated an antitumor response without any observable toxicity.
Immunocytokine fusion proteins incorporating antibodies that target the blood vessels of tumors are being developed under the company's Vascular Targeting Agent technology platform.
In other AACR news:
• Adventrx Pharmaceuticals Inc., of San Diego, reported positive preclinical results of a multidrug treatment regimen that included ANX-510 (CoFactor) along with 5-fluorouracil and capecitabine, showing that superior inhibition of tumor growth and longer survival, with lower systemic toxicity, were seen in the treatment groups with Co-Factor compared to those containing leucovorin or capecitabine alone in a colorectal tumor model. Tumor-bearing mice treated with CoFactor, 5-FU and capecitabine had the greatest inhibition of tumor growth compared to the other drug regimens tested in the study. The company continues to evaluate treatment combinations to identify additional commercial opportunities for CoFactor, a folate-based biomodulator designed to replace leucovorin as the preferred method to enhance the activity and reduce associated toxicity of chemotherapy.
• Alfacell Corp., of Bloomfield, N.J., reported that its lead candidate, Onconase (ranpirnase), might have potential as a chemopreventive agent. A researcher presented data showing that the early detection in patients at high risk for developing malignant mesothelioma is becoming more prevalent via the presence of certain biological markers in blood samples, and that Onconase's favorable toxicity profile and mechanism of action position it as a potential early treatment to at-risk populations. Onconase is based on Alfacell's ribonuclease technology and is designed to target cancer cells to induce apoptosis through multiple molecular mechanisms of action.
• Avalon Pharmaceuticals Inc., of Germantown, Md., reported data showing the antiproliferative activity of AVN944 in human endothelial cells and showing that the compound prevents blood vessel formation in a mouse model. Avalon said the suppression of blood vessel growth without adverse effects to the mice provides strong rationale to include solid tumors in AVN944's Phase II program. The compound is designed to inhibit inosine monophosphate dehydrogenase 1 and 2.
• CombinatoRx Inc., of Cambridge, Mass., said data from its first biologic/small-molecule combination high-throughput screening effort identifying drug classes that synergistically enhance activity of the TRAIL (TNF-related apoptosis inducing ligand) cytokine found that certain cytostatic agents, DNA cross-linking agents and topoisomerase inhibitors were particularly efficacious in overcoming TRAIL resistance while maintaining selectivity toward non-small-cell lung cancer cell lines. CombinatoRx's combination High Throughput Screening platform is designed to search millions of combinations across a large portfolio of phenotypic disease models to identify patterns of activity against both known and new targets in a range of disease areas.
• Cytokinetics Inc., of South San Francisco, said non-clinical data of ispinesib, a kinesin spindle protein inhibitor, in models of multiple myeloma demonstrated that the KSP inhibition with ispinesib was able to induce growth arrest and apoptosis in myeloma cells and to overcome resistance to both conventional drugs and agents such as bortezomib (Velcade, Millennium Pharmaceuticals Inc.) Ispinesib is in Phase II trials with partner London-based GlaxoSmithKline plc in breast, lung and ovarian cancers. Cytokinetics also reported data from a preclinical study evaluating GSK-923295, an inhibitor of centrosome-associated protein E (CENP-E), which showed that the compound selectively inhibits CENP-E. Data also support the conclusion that GSK-923295 elicits dose-dependent increases in mitotic index in Colo205 tumor xenografts and an associated increase in apoptotic index.
• Enzon Pharmaceuticals Inc., of Bridgewater, N.J., said preclinical data showed that treatment with PEG-SN38, its PEGylated SN38 compound, resulted in significant tumor growth inhibition in mice resistant to Camptosar (irinotecan HCl injection) and outperformed Camptosar in mice when given as a second-round therapy. Results showed that when the product was given to Camptosar-resistant mice, there was a 25 percent decrease in tumor volume. PEG-SN38 also demonstrated long-lasting antitumor activity in mouse models of human breast and pancreatic cancers.
• Favrille Inc., of San Diego, said data from a study of insect cell-derived idiotype (Id) proteins showed enhanced activity compared to Id proteins produced using mammalian cells. Results indicated that the production of recombinant Id proteins via an insect cell system produces a structurally different antigen with improved immunogenicity compared to mammalian cell-derived Id proteins. Id proteins are a key component of the company's Id/KLH immunotherapy product candidate FavId, which recently completed enrollment in a pivotal Phase III trial following Rituxan induction in patients with follicular B-cell non-Hodgkin's lymphoma.
• Gemin X Biotechnologies Inc., of Montreal, reported positive preclinical data of its lead compound, GX15-070 (obatoclax) in infant acute lymphoblastic leukemia, showing that the drug demonstrated single-agent activity against ALL blast cells and also enhanced chemosensitivity and was synergistic with cytotoxic drugs. Blast cells from five infants and one child that were exposed to the compound in vitro for three days showed that GX15-070 exhibited activity in all six cases. GX15-070 is a small molecule designed to specifically inhibit all relevant members of the Bcl-2 protein family to restore apoptosis.
• Gloucester Pharmaceuticals Inc., of Cambridge, Mass., reported data from a preclinical study examining the combination of romidepsin, the company's histone deacetylase (HDAC) inhibitor, and erlotinib (Tarceva) in non-small-cell lung cancer cell lines derived from human cancer patients. Results from the in vivo arm of the study showed that romidepsin synergistically enhanced erlotinib sensitivity in wide type NSCLC cell lines by induction of profound apoptosis. That synergy also was shown in the nude mice xenografts, but was not observed in epidermal growth factor (EGFR) mutant cell lines.
• Idera Pharmaceuticals Inc., of Cambridge, Mass., reported data from a preclinical study showing that its lead candidate, IMO-2055, in combination with the multi-kinase inhibitor, sorafenib (Nexavar, Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp.) showed enhanced antitumor activity compared to either agent alone in a mouse xenograft model. Results from a second preclinical study involving an analogue of IMO-2055 optimized for mice and administered intranasally showed antitumor activity in mouse models of lung metastases of colon carcinoma and melanoma. IMO-2055 is a Toll-like receptor 9 agonist and is in Phase II testing in cancer.
• Innovive Pharmaceuticals Inc., of New York, said data from a preclinical evaluation of INNO-206, a doxorubicin prodrug for treatment of a variety of tumor types, showed that the compound is much better tolerated in animal models than doxorubicin alone. Results from a rat model concluded that INNO-2056 has the potential of inducing less acute and chronic cardiotoxicity in humans compared to doxorubicin and that low-dose and high-dose groups of INNO-206 did not differ from controls with regard to clinical symptomatology and mortality, whereas animal subjects exposed to doxorubicin had a severe clinical and histopathological cardiomyopathy. Innovive expects to begin a Phase II trial of INNO-206 in small-cell lung cancer this quarter.
• Introgen Therapeutics Inc., of Austin, Texas, reported that a cancer-suppressing gene was delivered successfully into the tumors of Stage IV lung cancer patients via the company's intravenously administered lipid nanoparticle product candidate, INGN 401. In a Phase I trial, the gene, FUS1, was found to be active in patients' metastatic non-small-cell lung cancer tumors. Thirteen patients were treated, with no significant drug-related toxicity, and data showed that median survival time for all patients was 14.6 months, compared to a seven-month median survival time for patients receiving second-line therapy.
• Kosan Biosciences Inc., of Hayward, Calif., said preclinical data showed induction of fast-acting and long-lasting anticancer activity with its nuclear export inhibitors (NEIs), which also showed a high degree of tolerability in multiple human tumor xenograft cancer models. NEIs are specific inhibitors of CRMI, a conserved, essential protein that exports regulatory proteins from the nucleus to the cytoplasm. Kosan anticipates selecting a lead compound from its family of NEIs to advance into investigational new drug-enabling studies.
• Micromet Inc., of Carlsbad, Calif., and MedImmune Inc., of Gaithersburg, Md., reported preclinical data showing that BiTE molecules targeting carcinoembryonal antigen (CEA) prevent subcutaneous tumor growth and formation of lung metastases. A class of drugs that function as bi-specific T-cell engagers, BiTE molecules are designed to enable the body' killer T cells to recognize and attack tumor and target cells, leaving normal cells unharmed. In addition to demonstrating in vitro and in vivo antitumor activity, certain CEA-specific BiTE molecules also showed resistance to inhibition by soluble CEA. CEA is the second target in the research collaboration between Micromet and MedImmune, which also is targeting tyrosine kinase receptor EphA2.
• Myriad Genetics Inc., of Salt Lake City, presented data from a technology that might be used to determine the original location of a metastatic tumor, and said that work also could prove helpful in determining whether any two tumors are related. Preliminary data came from patient specimens with diagnoses of simultaneous ovarian and endometrial cancers, which were collected, included one specimen from the ovarian tumor, one from the endometrial tumor and one from normal unaffected tissue. Those specimens were analyzed for DNA copy number from each patient. The copy number analysis either confirmed conclusions from pathological examination or provided new information that could be used to give a more positive determination of tumor source. In Myriad's dataset, copy number conclusions subsequently were confirmed by re-sequencing the PTEN tumor suppressor gene for mutations.
• Pharmacyclics Inc., of Sunnyvale, Calif., said data from an in vitro study demonstrated that its histone deacetylase (HDAC) inhibitor, PCI-24781, inhibits homologous recombination, a cellular mechanism of DNA repair, by both downregulating RAD51 gene expression and by affecting the ability of the cell to form RAD51 foci at the site of the lesion. PCI-24781 is in Phase I trials in both solid and hematological malignancies. In a separate study, researchers testing the effects of the company's Bruton's tyrosine kinase (BTK) inhibitor, PCI-31523, on a variety of B-cell receptor-expressing lymphoma cell lines found that multiple diffuse large B-cell lymphoma lines and follicular lymphoma lines are sensitive to the drug, with growth arrest and apoptosis occurring at concentrations as low as 0.5uM.
• Seattle Genetics Inc., of Bothell, Wash., reported preclinical data describing how changes in the structure of the attached drugs can affect antibody-drug conjugate (ADC) efficacy and tolerability, the impact that linker structure and those modifications can have on ADC activity and the ability of the company's ADC technology to effectively deliver active drugs to target tissue while avoiding nontargeted drug release. In addition, other preclinical data demonstrated that ADCs targeted to glypican-3, CD133/prominin-1 and Lewis-Y are active and have therapeutic potential in the treatment of multiple solid tumor types. ADCs are monoclonal antibodies linked to cell-killing drugs.
• Telik Inc., of Palo Alto, Calif., reported preclinical data of Telcyta (canfosfamide HCl, TLK286) supporting clinical evaluation of the triplet combination of Telcyta, carboplatin and paclitaxel in advanced non-small-cell lung cancer and ovarian cancer patients. That combination demonstrated a significantly enhanced cancer cell cycle arrest compared to the single agents alone or the carboplatin/paclitaxel doublet combination. Telik also reported studies demonstrating the anti-angiogenic activity of Telcyta alone and in combination with bevacizumab (Avastin, Genentech Inc.).
• Viventia Biotech Inc., of Toronto, said it generated a fully human cancer antibody, VBI-050, and identified the antibody's target, which is a mutant form of the protein Glut-8, the overexpression of which is associated with the likelihood of disease metastasis and poor patient prognosis. VBI-050, an IgG monoclonal antibody, was generated from pooled lymphocytes of cancer patient samples using the company's Hybridomics platform. Further research is ongoing to assess the potential clinical exploitation of the compound. In separate news, Viventia reported results of in vitro cytotoxicity and in vivo pharmacokinetic studies of Proxinium, an antibody therapeutic, in combination with first-line standard-of-care therapy for squamous-cell carcinoma of the head and neck. The combination of Proxinium with cisplatin, carboplatin, paclitaxel, 5-fluorouracil and docetaxel resulted in a significant additive cytotoxic effect as compared to the chemotherapeutic agents administered alone. Proxinium is in a Phase III trial in late-stage, locally advanced head and neck cancer.