September 15, 2008 (Vol. 28, No. 16)

Helix BioPharma Utilizes Biphasix and DOS47 Technology to Advance Cancer-Related Drugs

The overall goal at Helix BioPharma is to develop treatments for cancer and precancerous conditions. The company’s two major drug candidates tackle that challenge through different technology platforms.

The lead drug candidate, an interferon cream, fights human papilloma virus (HPV). The second product in preclinical development consists of an enzyme attached to an antibody to treat adenocarcimona of the lung. The underlying methods behind both of these products hold the potential to be expanded to other conditions.

“HPV lesions of the genital tract can lead to cancer, but there are no pharmaceutical treatments today,” says John Docherty, president of Helix BioPharma. HPV causes abnormal squamous cells or cervical dysplasia, which are precursors to the development of cervical cancer.

Researchers at Helix BioPharma started with Schering-Plough’s interferon alpha for injection and created a topical formulation. The company’s technology, called Biphasix™, delivers interferon into the cervical epidermis where HPV resides, something injections of interferon cannot accomplish, Docherty says.

Proteins like interferon oxidize readily unless they are kept stable in solution, like the liquid interferons sold for injection. “To make interferon stable in a cream requires a lot of formulation chemistry,” explains Docherty.

The Biphasix technology was acquired from PharmaDerm, now a wholly owned subsidiary of Helix BioPharma. Biphasix uses special lipid vescicles to deliver proteins, peptides, and even small molecules into the skin. “We’re keeping our eyes open for other opportunities to use the technology,” Docherty adds.

Recent positive results from a Phase II study of the company’s Topical Interferon Alpha-2b in women with low-grade cervical lesions induced by HPV are encouraging. Nearly half the women in the treatment group had their abnormal PAP smears revert to normal after six weeks of self-administering the cream intravaginally three times a week. In a group of untreated controls, only 16% of PAP smears improved.

“We’re pleased to see statistically significant clinical results from cytology and colposcopy,” notes Docherty, “and we’re moving into more advanced studies in larger populations.”

Helix BioPharma is also testing Topical Interferon Alpha-2b in a Phase II trial against anogenital warts caused by non-cancerous strains of HPV. The Biphasix technology could potentially be used to deliver drugs to treat premalignant skin conditions like basal cell carcinoma and actinic keratosis.

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.

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