Phase I Study of Intrapleural AD32 for Management of MPE

We will test a new approach to management of malignant pleural effusions (MPE) based on chemotherapintrapleural administration of AD 32 rather than pleurodesis. There are about 100,000 cases p.a. ofcauses significant morbidity in patients with advanced malignancies. MPE is currently treated primarpleurodesis, a procedure that obliterates the pleural cavity with adherence of the lung to the chestcompromises respiratory functioning. AD 32 is a lipophilic anthracycline analog that has shown a goominimal local toxicity and evidence of antitumor activity in clinical studies for intracavitary therand ovarian cancer. Compared to other chemotherapeutic drugs, AD 32 has superior tissue penetrationlittle sclerosing activity. Thus if AD 32 proves active in treatment of MPE, this activity is likelyeffect that does not permanently damage normal pleural tissue and may spare respiratory function. Ianimal model for pleural effusions, we will sponsor a Phase I safety and tolerance study of intraplewith MPE.TITLE OF PROJECT: Angiostatin--Recombinant Therapeutic for Metastatic CancPRINCIPAL INVESTIGATOR: Sim, KimRECIPIENT ORGANIZATION: Entremed, Inc.9610 Medical Center Drive, Suite 200Rockville, MD 20850TELEPHONE NUMBER: (301)217-9858AWARD NUMBER AND AMOUNT: 1 R43 CA67641-01, $100,000Angiostatin was identified by scientists at Harvard Children's Hospital, under a Sponsored Researchfunded by EntreMed, as the endogenous antiangiogenic factor responsible for the phenomenon of suppregrowth by tumor mass. The systemic suppression of metastatic tumor growth was caused by a 38 kD circangiogenesis inhibitor isolated from urine of primary tumor-bearing mice. The sequence of this molechomology to an internal fragment of plasminogen of both mouse and man, and a corresponding fragmentplasminogen has similar inhibitory activity in vitro and in vivo. Murine and human cDNAs encoding thinhibitor were cloned by the PI in EntreMed laboratories. The specific aim of this proposal is to derecombinant system for production and expression of biologically active human angiostatin. When theprocess is identified, a Phase II proposal will address issues related to large-scale production andnaturally-occurring cancer therapeutic. The long term goal is to provide sufficient angiostatin in pconduct preclinical studies and clinical safety and efficacy tests in man. In this Phase I proposal,expression of human recombinant angiostatin in Escherichia coli and determine its biological activitthe methylotropic yeast, Pichia pastoris, as a system for producing large quantities of glycosylatedcompare the quality and biological activity of the angiostatin produced by recombinant techniques in(eukaryotic and prokaryotic). The commercial potential for angiostatin as a therapeutic for inhibitigrowth is enormous.