Biomega Laboratories, Inc.

In the summer of 1966 the Beach Boys and the Beatles topped the popular music charts, the nowclassic television show Star Trek first aired, and a young physi­cian-scientist by the name of George Lipkin filed for an National Cancer Institute grant to study melanoma. He held the belief that melanoma could actually be a reversible disease. This was considered quite a radical idea at that time and Dr. Lipkin had never received his own grant before. Nevertheless, the grant was awarded and a lifelong pursuit was underway. This work became the foundation of Biomega Laboratories, Inc. (“Biomega”), a company devoted to development of a substance that might just make that original idea a reality.

Not a lot was known at that time about the biological charac­teristics that distinguished cancer from normal cells. Dr. Lipkin began by transfect­ing hamster melanoma cells (melanoma is malignancy in thepigment producing cells of the skin) with DNA or RNA from blue nevi. Blue nevi are heavily pigmented, benign cells that most people would recognize as birthmarks. Although the next three years were mainly spent optimizing the methods for transfection of the DNA or RNA, the results seemed to justify the effort. Dr. Lipkin was able to reintroduce pigmentation to non-pigmented melanoma cells. Even more encouraging, these same cells displayed a 400 % decrease in their growth rate, making them more like normal skin cells. He also discovered melanoma cells that did not reacquire the ability to produce pigmentation but behaved like normal melanocytes in another very important way.

Normal cells exhibit contact inhibition - they cease to grow or divide any further once they encounter another cell. Malignant cells no longer dis­play this behavior. Fortuitously, during one transfection experi­ment, Dr. Lipkin came upon a non-pigmented cell line thatcontinued to display contact inhibition. These new cells became the subject of his studies for the next several years, but they failed to reveal the agent conferring contact inhibition. However, a break-through would occur during a sabbatical in Switzerland.

While working in a labora­tory at the Abteilung für Krebsforschlung, in Zurich, Dr. Lipkin decided to try somethingvery different. He took a sample of the medium that bathed this new cell line and added it to a fresh culture of hamster malig­nant melanoma cells. Within 48 hours these cells also began to exhibit contact inhibition and more normal growth. What he had witnessed was the passive transfer of contact inhibition by an unknown element found in the media of the transfected hamster melanoma cells. This element was named “Contact Inhibitory Factor”, or “CIF^™”. Upon exposure to hamster cell-derived CIF, contact inhibition and “normalization of growth” was also apparent in a wide

	variety of human, mouse and rat cancer cell lines including melanoma, colon carcinoma, neuroblastoma, neurinoma, glioma, mammary carcinoma, rhabdomyosarcoma, prostate carcinoma, lung carcinoma, and several other solid tumors. Upon his return from Zurich Dr. Lipkin, then joined by Dr. Martin Rosenberg, conducted further in vitro experiments. They demonstrated that CIF restores the three main analoguesof normalin vivo growth to can­cer cells. In addition to density dependent growth, or contact inhibition, the cells also displayed serum dependent growth and anchorage dependent growth. Microscopic examination of theCIF treated cells revealed a morenormal appearing cytoskeleton,	important for normal cell signal­ing and growth regulation. In order to determine CIF’s effectiveness in vivo, hamster melanomas were implanted subcutaneously into hamsters and a formulation of partially purified CIF injected twice weekly around the tumor. Despite the termination of treatment after 30 days, the tumors began to recede, eventu­ally disappearing. While all of the control hamsters perished by week 9 with massive tumors, the CIF-treated hamsters lived full life spans with no evidenceof cancer. Pathology showed only the presence of necrotic tissue where the tumor had been with no evidence of overt local or systemic toxicity. A similar experiment done in	mice with implanted Lewis lung carcinoma led to regression in 75 % of tumors after only 10 days of CIF treatment. Only fluid and necrotic debris remained at the site of the tumors. These in vitro and in vivo experiments suggested that Dr. Lipkin had discovered an endogenous and apparently non-toxic factor that restores normalgrowth controls to cancer cells and causes permanent regres­sion of tumors. Furthermore, itseffects were neither species nor tissue specific. His focus then turned towards understanding the mechanisms behind these effects. Dr. Lipkin thought thatthe first clue might lie in surveil-lance. Whereas cancer cells will often go undetected by the
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body’s circulating defenses, reversion of the malignant phenotype by CIF led to an increased immune response inboth humoral and cellular arms. Increased expression of class I Major Histocompatability Complex antigens made the tumor cells more susceptible to detection and destruction by cytotoxic T lymphocytes. In melanoma cells CIF also inducedthe expression of pigmentation antigens that have been shown to enhance antibody-dependent cytotoxicity.

CIF also displays anti-angio­genic activity, interfering withthe creation of new blood vesselsthat may have served a progress­ing tumor.In vitro, CIF almost completely shuts down the ability of melanoma cells to secrete VEGF, a common angiogenic factor. At the same time, CIF inhibits response of blood vessel endothelial cells to another angiogenic factor, ßFGF.

Finally, data provided by a chick embryo model suggest­ed that CIF might interfere with metastasis as well.

Biomega Laboratories Inc. wasincorporated in 1999 with the expressed purpose of bringingCIF to market for the treatmentof cancer. Currently the companyhas three members on its team -its two scientific founders, Dr.George Lipkin and Dr. MartinRosenberg (both are faculty atNYU) and Dr. Richard Glaser,the company’s chief executive officer. Biomega supports the effort to investigate and developCIF as a therapeutic candidatethrough the work carried out inDr. Lipkin’s laboratory as well as collaborations with other groups both within and outsideof NYU. One of the most recent and important results of these collaborations has been the isolation and characterization of the single, active constituent of CIF. In addition to seed funding by angel investors, the company has been awarded a NYSTAR grant.

In regard to the future, Drs. Lipkin and Rosenberg believe that given the animal and in vitro data collected thus far (Table 1) CIF may be effectiveagainst a wide variety of cancers.

Other possible markets for CIF are ophthalmology (diabetic retinopathy, macular degenera­tion due to aging), dermatology (psoriasis) and the research laboratory. But the first indication will most likely be for malignant melanoma. This disease is the seventh most common cancer in the U.S. and the most common among women ages 25-29. Response rates with currently available therapies are only 20 %. The company believes that this makes it an ideal candidate forFast Track approval by the FDA.

More than 560,000 Americans will die of cancer in 2004. That’s nearly twice the number of victims reported in 1966, when Dr. Lipkin began to think about a new therapeutic approach.

www.biomegalaboratories.com

Andrew Koopman, M.S., is a Business Venture Analyst at NYU’s Office of Industrial Liaison/TechnologyTransfer.