A phase I biodistribution and pharmacokinetic trial of humanized monoclonal antibody Hu3s193 in patients with advanced epithelial cancers that express the Lewis-Y antigen

Andrew M. Scott, Niall Tebbutt, Fook Thean Lee, Tina Cavicchiolo, Zhanqi Liu, Sanjeev Gill, Aurora M.T. Poon, Wendie Hopkins, Fiona E. Smyth, Carmel Murone, Duncan MacGregor, Anthony T. Papenfuss, Bridget Chappell, Timothy H. Saunder, Martin W. Brechbiel, Ian D. Davis, Roger Murphy, Geoffrey Chong, Eric W. Hoffman, Lloyd J. Old

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Abstract

Purpose: We report a first-in-man trial of a humanized antibody (hu3S193) against the Ley antigen. Experimental Design: Patients with advanced Ley-positive cancers received four infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20, and 40 mg/m2). The first infusion of hu3S193 was trace labeled with Indium-111, and biodistribution, pharmacokinetics, tumor uptake, and immune response were evaluated in all patients. Results: A total of 15 patients (7 male/8 female; age range, 42-76 years; 6 breast, 8 colorectal cancer, and 1 non-small-cell lung cancer) were entered into the study. Transient grade 1 to 2 nausea and vomiting was observed following infusion of hu3S193 at the 40mg/m2 dose level only. There was one episode of dose-limiting toxicity with self-limiting Common Toxicity Criteria grade 3 elevated alkaline phosphatase observed in one patient with extensive liver metastases. The biodistribution of 111In-hu3S193 showed no evidence of any consistent normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node, and hepatic metastases. Hu3S193 displayed a long serum half-life (T 1/2β=189.63 ± 62.17 h). Clinical responses consisted of 4 patients with stable disease and 11 patients with progressive disease, although one patient experienced a 89% decrease in a lymph node mass, and one patient experienced inflammatory symptoms in cutaneous metastases, suggestive of a biological effect of hu3S193. No immune responses (human anti-human antibody) to hu3S193 were observed. Conclusion: Hu3S193 is well tolerated and selectively targets tumors, and the long half-life and biological function in vivo of this antibody makes it an attractive potential therapy for patients with Le y-expressing cancers.

Original languageEnglish
Pages (from-to)3286-3292
Number of pages7
JournalClinical Cancer Research
Volume13
Issue number11
DOIs
Publication statusPublished - 1 Jun 2007

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