BioWorld International Correspondent
LONDON - Ark Therapeutics plc claimed a breakthrough in gene-based drug targeting saying conventional radiotherapy or chemotherapy delivered via its Scavidin technology is effective in killing tumor cells at one-tenth of normal doses.
Delivery by Scavidin stopped tumor development in two treatment models using the radioisotope yttrium 90 in one, and the chemotherapeutic paclitaxel in another.
Nigel Parker, CEO, said the results "indicate that Scavidin has the potential both to improve the therapeutic effect and to reduce unpleasant side effects of a wide variety of drugs, most obviously chemotherapy and other potent anticancer agents, but also in many other therapies where the side effects are high and thus dose-limiting."
Scavidin is based on the gene that codes for the scavenger receptor on white blood cells. That receptor is responsible for collecting waste fats and damaged cells and membranes from the blood for subsequent removal and disposal.
Ark has modified the gene so that the receptor is expressed with the protein avidin as the "collecting head." Avidin binds only to biotin, another protein, with a bonding strength that is twice that of an antibody-antigen bond. Biotin easily can be linked to a wide variety of therapeutic agents.
After Scavidin is transfected into tumors using a viral vector, it generates the avidin-expressing receptor. The therapeutic agent tagged with biotin is then administered intravenously.
Scavidin binds to the biotin, extracting the drug from the bloodstream. The therapeutic is released into the tumor cell, and the receptor goes back to the cell surface to collect more.
Ark said that molecular shuttle system concentrates the drug from a low and ineffective dose in the blood to a therapeutic dose in the target tissue. The London-based company believes this will minimize dose-limiting side effects.
Seppo Yla-Herrtuala, director of molecular medicine said, "Scavidin targeting could markedly reduce side effects and enable treatment to be repeated more easily. An additional advantage is that the anticancer drug can be concentrated in the tumor at higher levels and thus its cancer killing efficacy can be very substantially increased." The approach has been tested in two animal models featuring aggressive tumors growing under the skin.
Treatment with subtherapeutic doses of biotin tagged Yttrium 90 and biotin tagged paclitaxel eliminated tumor growth during the seven-to-10-day study, with a clear and rapid response to treatment and no observable side effects. Tumors in non-treated controls showed a fivefold increase in size in the same period.
Ark now intends to optimize dosing and test efficacy in other models, and to commence final preclinical toxicity work.
It also plans to further develop the therapeutic potential of Scavidin. In vitro and in vivo tests have shown the construct is able to concentrate a wide range of biotinylated agents ranging from small radioisotopes to large biomolecules such as immunoglobulin.
Evidence of the binding strength between biotin and avidin on the genetically modified scavenger receptor has been confirmed in atomic force microscopy. Scavidin can be further modified to hold a therapeutic agent on the cell surface, or to slowly or rapidly internalize it. It has been administered with a range of standard gene therapy vectors including adenovirus and retrovirus.