Synthesis of potent taxoids for tumor-specific delivery using monoclonal antibodies Michael L. Miller, a, * Elizabeth E. Roller, a Xinyaun Wu, b Barbara A. Leece, a Victor S. Goldmacher, a Ravi V. J. Chari a and Iwao Ojima b, * a ImmunoGen, Inc., 128 Sidney Street, Cambridge, MA 02139, USA b Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA Received 20 April 2004; revised 11 May 2004; accepted 11 May 2004 Available online 17 June 2004 Abstract—The targeted delivery of taxoids, in the form of taxane–antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared. Ó 2004 Elsevier Ltd. All rights reserved. Cancer chemotherapy has long been based on the expectation that cytotoxic agents will preferentially kill rapidly proliferating tumor cells as opposed to healthy normal cells. However, in humans, these agents display only a modest selectivity for the tumor cells. Thus, administration of a large dose of the chemotherapeutic agent is required to ensure delivery of sufficient drug to the tumor site to be clinically effective. Such high doses often result in severe toxicity, and unacceptable damage to normal tissues. Thus, it remains of utmost interest to develop new cytotoxic agents with greater selectivity towards tumor cells and lower systemic toxicity. The discovery that many tumors over-express specific determinants on their cell surface suggests the possibility of selectively targeting tumor cells. 1 Thus, a tumor- associated antigen could be targeted with a monoclonal antibody (mAb) that has shown a high specificity and binding affinity for the antigen. The value of monoclo- nal antibodies in cancer therapy has been recognized with the recent approvals of both Rituxan â , 2 for lym- phoma and Herceptin â , 3 for breast cancer. Despite their high specificity for antigens most naked antibodies are only weakly cytotoxic and thus, are not very effective as anti-cancer agents. However, the antigen-selectivity of these antibodies render them excellent vehicles for the targeted delivery of cytotoxic drugs to the tumor. The linkage of a potent cytotoxic drug to an antibody, such as through a disulfide bond, generates an immunocon- jugate that is stable and nontoxic in circulation in vivo. The conjugate is specifically activated upon binding to the tumor surface, followed by internalization and subsequent cleavage of the disulfide bond between the antibody and the drug to release fully active drug inside the tumor cell. 1 In fact, immunoconjugates have already been shown to exhibit high potency and selectivity with Keywords: Taxoid; Antibody conjugate; Tumor specific; Targeted delivery. * Corresponding authors. Tel.: +1-617-995-2583; fax: +1-617-995-25- 10; e-mail: michael.miller@immunogen.com 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.05.027 Bioorganic & Medicinal Chemistry Letters 14 (2004) 4079–4082