Making Tumors Alkaline
The company’s other technology, DOS47, combines urease with a specific single domain antibody that targets the enzyme to adenocarcinoma cells in the lungs. The cancer therapeutic, dubbed L-DOS47 to designate its specificity for lung cancer, acts through the urea cycle to change the local pH of cancer cells. Because of their aberrant metabolism, many solid tumors have acidic extracellular compartments relative to healthy tissues. The acid environment helps cancer cells to invade, grow, and metastasize.
“We recognized that urease can act on urea like a prodrug to produce two key byproducts, hydroxyl ions and ammonia,” says Docherty. The hydroxyl ions raise the pH and make the local tumor environment more alkaline, while ammonia, a potent cytotoxic agent, readily diffuses into cancer cells and destroys them by interfering with critical metabolic functions.
To deliver urease to tumors, researchers built an immunoconjugate molecule that specifically binds lung adenocarcinoma tissue, yet it does not bind healthy tissue or other tumors. The bulk of the development work on the novel immunoconjugate was done at Sensium Technologies, a subsidiary of Helix BioPharma.
Preclinical studies of L-DOS47 are under way, and the company plans to file an IND application by the end of 2008. The technology can be adapted for other solid tumors by changing the attached antibody to direct urease to different types of tumors. “The beauty of DOS47 is that we can attach other tumor targeting agents even if they don't have therapeutic potential themselves,” explains Docherty.
Helix BioPharma plans to partner with researchers who are developing highly specific antibodies for cancerous cells to create a portfolio of conjugated DOS47-based cancer therapeutics.
Additionally, the DOS47 method may improve the action of other chemotherapy drugs and radiation, Docherty says. The acid microenvironment of tumors prevents alkaloid chemotherapy agents from functioning optimally.
In vitro studies suggest that a more alkaline environment allows drugs to penetrate cells and perform better. “Adding DOS47 to standard chemotherapeutics could produce synergistic effects,” Docherty notes.
Radiation therapy acts on free radicals like oxygen in surrounding cells, but an acidic microenvironment limits the availability of these free radicals.
In theory, “DOS47 may modulate and potentiate radiation therapy, too,” says Docherty.