Targeted Antiangiogenic Therapy for Cancer Using Vitaxin: A Humanized Monoclonal Antibody to the Integrin    3 1 John C. Gutheil, 2 Thomas N. Campbell, Paul R. Pierce, Jeffry D. Watkins, William D. Huse, David J. Bodkin, and David A. Cheresh Department of Clinical Oncology Research, Sidney Kimmel Cancer Center, San Diego, California 92121 [J. C. G., T. N. C., D. J. B.]; MedImmune, Inc., Gaithersburg, Maryland 20878 [P. R. P.]; Applied Molecular Evolution, Incorporated, San Diego, California 92121 [J. D. W., W. D. H.]; and Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037 [D. A. C.] ABSTRACT Angiogenesis plays a central role in the growth and metastasis of cancers. Strategies aimed at interfering with tumor blood supply offer promise for new cancer therapies. Vitaxin (an anti-   3 antibody) interferes with blood vessel formation by inducing apoptosis in newly generated endo- thelial cells. This Phase I study evaluates the safety and pharmacokinetics of Vitaxin in humans with cancer. Eligible patients demonstrated progressive tumors with stage IV disease and an Eastern Cooperative Oncology Group per- formance status <2. Treatment consisted of six weekly in- fusions of Vitaxin. Escalating doses from 0.1 and 4.0 mg/kg/ week were evaluated based on the expectation that plasma levels would bracket the effective in vitro concentration. Escalation beyond 4 mg/kg/week was limited by drug avail- ability. Adverse events were assessed weekly. Pharmacoki- netics were performed weekly through week 9. Clinical re- sponse was assessed at week 9. Of 17 patients treated, 14 were evaluable for response. Treatment was well tolerated with little or no toxicity. The most common side effect was infusion-related fever, which could be controlled with prophylactic antipyretics. Doses >1 mg/kg/week produced plasma concentrations sufficient to saturate the    3 receptor in vitro (25 g/ml). Vitaxin dem- onstrated a half-life in excess of 5 days at higher doses with no accumulation over 6 weeks of therapy. One patient dem- onstrated a partial response, and seven patients demon- strated stable disease. Three patients received Vitaxin be- yond the first cycle of therapy. Each of these patients demonstrated disease stabilization that in one case lasted 22 months. At the doses and schedule studied, Vitaxin appears safe and potentially active, suggesting that vascular integrin    3 represents a clinically relevant antiangiogenic target for prolonged cancer therapy. INTRODUCTION Many disease states (cancer, psoriasis, rheumatoid arthritis, and diabetic retinopathy) are mediated, in part, by a pathological angiogenic response (1– 4). In cancer, the progressive growth of solid tumors is strictly dependent on their ability to stimulate formation of new blood vessels to supply tumor cells with oxygen and essential nutrients. Under normal physiological conditions, the formation of new blood vessels is tightly regu- lated and most tumors persist in a relatively benign or dormant state (5). However, with neovascularization comes tumor growth and the ability to shed tumor cells into the circulation (2, 6). This can lead to metastases. Inhibition of angiogenesis was first proposed as an anti- cancer strategy by Folkman (7) in 1971. Support for this comes from the observation that microvessel density can serve as a prognostic indicator in early-stage breast carcinoma (8). A sim- ilar correlation between microvessel density and prognosis has been made for patients with colon carcinoma, prostate carci- noma, and melanoma (8). In view of this, antiangiogenic therapy appears an attractive and rational approach for the treatment of solid tumors. To date, a number angiogenic inhibitors have been identified (8), some showing promising antitumor effects (4, 9, 10). However, their molecular targets remain unclear (11), and many have been associated with undesirable side effects. Another approach to antiangiogenic therapy is to inhibit the adhesive interactions required by angiogenesis vascular endo- thelial cells. The migration of endothelial cells is dependent on their adhesion to extra cellular matrix proteins, such as vitronec- tin, through a variety of cell adhesion receptors known as integrins. Recent evidence indicates that integrin    3 plays a role in this process (12). Studies have shown the enhanced expression of    3 on newly developing blood vessels in human wound tissue, tumors, diabetic retinopathy, macular degenera- tion, and rheumatoid arthritis. However,    3 is not generally found on blood vessels in normal tissues. In fact, in various animal models, antagonists of    3 , such as the    3 specific antibody, LM609, have been shown to decrease angiogenesis and induce tumor regression (3) or improve arthritic disease (13), and this was associated with the induction of apoptosis within the angiogenic blood vessels (4, 13). Vitaxin (Applied Molecular Evolution, San Diego, CA) is a humanized version of the LM609 monoclonal antibody that functionally blocks the    3 integrin. This antibody has been shown to target angiogenic blood vessels (11) and cause sup- Received 12/23/99; revised 5/2/00; accepted 5/2/00. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by Applied Molecular Evolution, Inc. (San Diego, CA). 2 To whom requests for reprints should be addressed, at Clinical Re- search and Development, Vical Inc., 9373 Towne Centre Drive, Suite 100, San Diego, CA 92121-3088; Phone: (858) 646-1178; E-mail: Jgutheil@vical.com. 3056 Vol. 6, 3056 –3061, August 2000 Clinical Cancer Research Research. on January 20, 2022. © 2000 American Association for Cancer clincancerres.aacrjournals.org Downloaded from