June 1, 2005 (Vol. 25, No. 11)
John F. Wong Ph.D.
Monoclonal Antibodies and Novel Drug Delivery Methods Top List of Biotech Innovations
Genentech (San Francisco) had a banner year from 1997 to 1998, when it received FDA approval to market its two monoclonal antibodies for treating cancers. In November 1997, Genentech received FDA approval to commercialize Rituxan (rituximab), to treat B-cell non-Hodgkin lymphoma along with its co-marketing partner Biogen Idec (Cambridge, MA).
Rituxan is a humanized monoclonal antibody that binds to the B-cell surface epitope, CD 20, and kills the marked B cells by recruiting the body’s natural defenses. The mechanism of action for Rituxan is through antibody-mediated cytotoxicity and the complement pathway.
In September 1998, the FDA approved Genentech’s Herceptin (trastuzumab) to treat metastatic breast cancer in patients overexpressing the HER2 protein in combination with paclitaxcel. Herceptin is another monoclonal antibody that binds to the epidermal growth factor receptor (HER2). This epidermal growth factor receptor is over expressed on malignant cells in 2530% of the patient population with breast cancer.
During the last six years, Rituxan has reached blockbuster drug status, with the company reporting revenues of $1.71 billion from sales in 2004. Herceptin is well on its way to becoming another blockbuster product for the company, with a reported $483 million in revenues from sales for 2004.
Genentech’s strategy is to broaden the clinical application of Herceptin to other forms of cancer expressing the HER2 protein. The company is currently preparing to file another application with the FDA to approve Herceptin as an adjuvant to chemotherapy in early-stage breast cancer patients with positive HER2 tumors and in combination with Taxotere as a front-line therapy to treat metastatic breast cancers in patients positive for HER2.
At this year’s “96th Annual Meeting of the American Association for Cancer Research (AACR)” held in Anaheim, CA, angiogenesis and its inhibitors generated great interest as a therapeutic approach to treat solid tumors.
Napoleone Ferrara, M.D., described how, in 1989, he discovered a vascular endothelial factor from pituitary glands and developed a humanized monoclonal antibody (bevacizumab/Avastin) to inhibit its activity as a side project at Genentech.
In February 2004, the FDA approved Avastin for marketingthe first antiangiogenesis drug approved by the agency. Avastin is approved for use in combination with 5-fluorouracil as a front-line therapy to treat metastatic colorectal cancers.
In less than a year, Avastin generated product sales of $555 million. Avastin is also in Phase III clinical studies for treating non-squamous, non-small cell lung cancers and metastatic breast cancers. Genentech reported that an interim analysis of the Phase III study demonstrated that Avastin with chemotherapy prolonged disease-free survival in metastatic breast cancer patients.
Last month, Genentech presented Phase III data at ASCO demonstrating that non-small-cell lung cancer patients receiving Avastin with paclitaxel and carboplatin had 30% greater improvement in overall survival than patients just receiving the chemotherapy.
Judah Folkman, M.D., professor of surgery at Children’s Hospital (Boston) and cell biology at Harvard University (Cambridge, MA), first proposed the concept of inhibiting vascularization of tumors over 40 years ago to treat solid tumors. He discovered two anti-angiogenic factors, endostatin and angiostatin, which he licensed to EntreMed (Rockville, MD).
However, endostatin is still languishing in the early stages of clinical development as EntreMed refocused its product development strategy to small molecules.
Due to its low toxicity, drug resistance and side effects, monoclonal antibodies are finally fulfilling their promise as anticancer agents. At the time of their discover by Milstein and Kohler in 1975, monoclonal antibodies were thought to be the magic bullet to cure cancer. However, it was over 30 years before biotech companies were able to figure out how to use these reagents in the clinic.
With ImClone’s (New York City) Erbitux and Genentech’s three approved drugs, biotech companies that are developing monoclonal antibody-based therapeutics are emerging as the key players in oncology.
Another novel approach to treating various forms of cancers is to develop drug delivery technologies that can deliver anticancer agents to targeted cancer cells. American Pharmaceutical Partners (APP; Los Angeles) presented data at AACR on Abraxane, for treating metastatic breast cancers. The gold standard for treating such cancers is paclitaxcel. Abraxane is an encapsulated form of paclitaxcel with particles sizes in the nanometer range.
Paclitaxcel is part of a class of compounds known as taxanes, which are highly insoluble compounds that require solubizing excipients such as Cremophors (polyoxyethylene castor oils) in order to infuse such agents into a patient while preventing the reticulo-endothelial system from clearing the circulating particulates.
APP chairman and chief executive, Patrick Soon-Shiong, M.D., noted that albumin encapsulation technology is an ideal drug delivery system that uses nanoparticles and the biology of neovascularization for concentrating highly toxic agents within cancer cells.
The mechanism for delivering Abraxane is through the albumin receptor, gp60, which is upregulated and expressed on the surface of endothelial cells during neovascularization. The particles bound to the albumin receptor undergo transcytosis within endothelial cells and are released into tumor interstitium.
The encapsulated albumin particles are subsequently bound to a glycoprotein (osteonectin/SPARC) that is secreted and expressed on the surface of tumor cells. The bound nanoparticles are eventually internalized and the drugs released into the cytoplasm of the cancer cells.
Dr. Soon-Shiong noted that this could be the ideal operating system for concentrating generic anticancer agents into neoplastic cells, while simultaneously lowering the toxicities and side effects normally associated with these chemotherapeutic agents.
In a 460-patient Phase III clinical studies for metastatic breast cancers, anticancer response rate was 33% among the patients treated with Abraxane, compared to 19% of the patients receiving paclitaxcel. Median time to disease progression was 22 weeks for Abraxane-treated patients, compared to 16 weeks for patients treated with paclitaxcel. These results along with its lower toxicity and side effects were the basis for the FDA to give APP approval to market the drug.
Biotech’s Power Alley
Oncology and developing new anticancer agents are in the power alley for biotech companies. With new tools to uncover putative molecular pathways for understanding the natural history of cancers, biotech companies seem more poised to innovate therapeutic regimens, such as inhibitors of angiogenesis, than traditional pharmaceutical companies.
Using the system biology approach, it may be only a matter of time before anticancer therapies becomes the province of biotechnology and biotech companies develop drugs that can cure cancers.