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Feature Articles : Jan 15, 2006 ( )
New Biomolecules for Cancer Treatment
Real Hope for Safer Drugs on the Horizon
At the recent 9th European Biotech Crossroads meeting in Lille, France, Nigel Courtenay-Luck, Ph.D., CSO of Antisoma (www.anti soma.com), presented encouraging safety data from a Phase I study of a new type of biomolecule known as an aptamer.
According to Dr. Courtenay-Luck, an aptamer has similar properties to an antibody in that it can recognize and bind to antigens, it has low nanomolar binding, and the pKa of this type of molecule can be easily modified. Since aptamers are 3-D structures, Dr. Courtenay-Luck stated, they can bind well but because they are small they show no evidence of eliciting an immunogenic response, which makes them ideal as therapeutics.
Dr. Courtenay-Luck presented preclinical and Phase I trial results for Antisomas lead aptamer, designated AS1411. This aptamer recognizes and binds to nucleolin, a major nuclear phosphoprotein found on the surface of many solid tumors yet not generally expressed on the surface of noncancerous cells.
In preclinical studies exposure of four days or more provided optimal killing of lung and prostate cancer cells. In the Phase I study, 17 patients with various solid tumors were dosed with 110 mg/kg per day for up to 7 days. No evidence of serious toxicities was observed at doses where signs of anticancer activity, including one near-complete response, were seen.
AS1411 is cleared so quickly from the blood, that its half life is less than 20 minutes. In fact my colleagues working in pharmacokinetics say it escapes quicker than Houdini, and you would have to be a magician to find it. This is why we believe we see little if any toxicity, Dr. Courtenay-Luck explained.
We want to use AS1411 to treat renal cell and other tumor types, and are proceeding to evaluate the drug through clinical trials.
Another novel approach to cancer treatment was presented by Jacques Bartholeyns, Ph.D., director of strategy and IP at IDM Pharma (www.idm-biotech.com). The first immunotherapies being developed by IDM are designed to activate macrophage activity (either in vivo or in vitro) so that macrophages recognize and destroy tumor cells.
Dr. Bartholeyns presented results of a Phase III clinical trial of Junovan, a small molecule based on a synthetic analogue of bacterial cell wall component that activates macrophages in the body. The trial showed that out of 664 patients with osteosarcoma, a significant increase in their disease-free survival and in the survival was seen in patients treated with Junovan.
Since Junovan is stimulating the bodys own defenses, the treatment was well tolerated, even combined with standard chemotherapy, Dr. Bartholeyns stated. Junovan has been granted orphan drug status in the United States and the European Union, and we expect this drug to come to market in 2007.
Dr. Bartholeyns also presented an alternative method of inducing specific anticancer immunity into the body. We use dendritic cells derived from the patients own white blood cells and expose them to tumor cell antigens. We then obtained up to 20 doses of these activated white blood cells and injected them back into the patient in order to stimulate the immune system to recognize and kill tumor cells that display these antigens on their surface. Using this approach we have three products being tested in the clinic.
Phase II trial data on the therapeutic vaccine effect of Uvidem, a treatment for melanoma, which is being jointly developed with Sanofi-Aventis, was also presented. The data shows that 10 of the 15 patients treated with Uvidem presented immune responses, and some presented stabilization of their melanomas, according to Dr. Bartholeyns.
Our approach aims at boosting anti-tumor immunity, and we have five products in clinical trials, one of which could be available in as little as two years. We believe this approach will not only prolong life for cancer patients, but will make the treatments less unpleasant for patients to take, thus preserving their quality of life, Dr. Bartholeyns stated.
Better Monoclonal Antibodies
Christian Behrens Ph.D., a program manager at LFB (www.lfb.fr), presented data on how to engineer recombinant monoclonal antibodies to have greater cytotoxic effects.
We set up FcgR-based assays to select for antibodies with specific effector functions, a research effort leading eventually to the development of the EMABling platform to produce highly cytotoxic antibodies, Dr. Behrens said. One candidate, anti-CD20 EMABling antibody, has a 50100 fold higher cytotoxic activity against cells from patients with B-cell chronic lymphocytic leukemia than Rituxan, the current antibody treatment for CD20-positive Non-Hodgkins lymphoma. Therefore, this technology has the potential to produce more effective monoclonal antibodies for cancer treatment.
The Answer is Beer?
Another more unusual presentation of promising preclinical studies on biomolecules discussed the use of the hop-flavonoid xanthohumol, a component of beer, as a cancer treatment.
Barbara Vanhoecke, Ph.D., a researcher at the University Hospital Ghent (www.ugent.be) in Belgium, presented preclinical data from cell-based assays showing how xanthohumol has a selective cytotoxic effect against MCF-7/6 invasive mammary carcinoma cells.
These results are promising, and we now understand the mechanism of how xanthohumol induces apoptosis in breast cancer cells, Dr. Vanhoecke stated. But we have a lot of work to do looking at the biodistribution and pharmacokinetics of the compound after oral ingestion in humans before we can say this compound has potential as a breast cancer treatment.
The need for new molecules to treat cancer was summed up by Najoua Dendouga, Ph.D., a scientist at Johnson & Johnson Pharmaceuticals (www .jnj.com). Even with the most effective current treatments some cancer cells evade apoptosis, and the best cancer cell is a dead one. Additionally, many of the drugs on the market do not have a selective toxic effect so there is plenty of room for improvement.
The cross section of biomolecules and biomolecular technologies for the treatment of cancer presented at the European Biotech Crossroads did show good safety profiles but, as Dr. Courtenay-Luck pointed out, In due course, targeted therapies may come to be used on their own. In the near term, however, most of the benefits provided by these agents will be seen through use in conjunction with chemotherapy.
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