EntreMed Signs Contract Manufacturing Agreement for Angiostatin Protein
Angiostatin protein, a naturally occurring antiangiogenic substance, was discovered in 1994 by Judah Folkman and Michael O'Reilly of Children's Hospital, Boston. In preclinical studies in mice, the protein inhibits the growth of a variety of metastatic and primary cancerous tumors, apparently with no drug resistance or toxicity.
EntreMed and Covance began technology transfer for the production of Angiostatin protein in the first quarter of this year. With the technology transfer process now complete, the two firms have jointly demonstrated success in numerous small and medium-scale fermentation runs.
Larger GMP fermentations of Angiostatin protein at the 2,000 liter scale are scheduled to take place at Covance early this quarter. Under the terms of the agreement, Covance will produce enough recombinant protein for the Phase I clinical trials and further preclinical studies.
EntreMed plans eventually to contract out full production of Angiostatin protein, according to company spokeswoman Mary Sundeen. "We demonstrated scalability, purification, and activity for shaker flask to 150-liter batches of the protein," Sundeen said. "To go to the next step would require giant biofermenters, which are too expensive for us to purchase right now. We were so pleased at the job Covance did last year using the same yeast expression system for [our other anti-angiogenisis protein] endostatin, that we decided to go with Covance on Angiostatin protein as well."
EntreMed CEO John Holaday commented on his firm's deal with Covance: "After EntreMed's initial evaluation of five separate recombinant expression systems in 1995 and 1996, the Pichia pastoris yeast system emerged as the clear choice for the scale-up expression of Angiostatin protein for human clinical trials. As a result of the molecular engineering of the angiostatin molecule, and the knowledge gained from biochemical studies performed by our scientists, we can now report that recombinant human Angiostatin protein is being readily synthesized and purified at Covance." Pichia pastoris is a methylotropic yeast that secretes large quantities of foreign proteins into the fermentation broth in which it lives. This microorganism is an industry accepted production system already being used for several protein-based biopharmaceutical agents currently in clinical trials.
EntreMed first reported on the generation of recombinant human Angiostatin protein in 1997. Since then, the company has followed an active research and development program that has significantly refined knowledge of this potent antiangiogenic molecule. Through Entremed's efforts, the recombinant human molecule was engineered with features that enable protein production at scales required for clinical testing (and beyond). EntreMed's research team has also concentrated on the Angiostatin protein receptor, and the potential for a gene-based delivery system. As of year-end 1998, more than 92 publications from groups all over the world confirmed the protein's antiangiogenic properties.
In 1995, EntreMed signed a Research, Collaboration and License Agreement with Bristol-Myers Squibb for Angiostatin protein. As reported by EntreMed in February 1999, the agreement was subsequently modified, granting EntreMed development rights for the protein and rights with respect to future partnering and commercialization.
For more information: Mary Sundeen, Director, EntreMed Inc., 9640 Medical Center Dr., Rockville, MD 20850. Tel: 301-738-2490. Fax: 301-217-9594. Email: marys@entremed.com.
By Angelo DePalma