A phase I trial of humanized monoclonal antibody A33 in patients with colorectal carcinoma: Biodistribution, pharmacokinetics, and quantitative tumor uptake

Andrew M Scott, Fook-Thean Lee, Robert Jones, Wendie Hopkins, Duncan MacGregor, Jonathon S Cebon, Anthony Hannah, Geoffrey Chong, Paul U, Anthony Papenfuss, Angela Rigopoulos, Susan Sturrock, Roger Murphy, Veronika Wirth, Carmel Murone, Fiona E Smyth, Simon Knight, Sydney Welt, Gerd Ritter, Elizabeth RichardsEdouard C Nice, Anthony W Burgess, Lloyd J Old

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PURPOSE: To determine the in vivo characteristics of huA33, a CDR-grafted humanized antibody against the A33 antigen, we have conducted an open-label, dose escalation, biopsy-based phase I trial of huA33 in patients with colorectal carcinoma. EXPERIMENTAL DESIGN: Patients with colorectal carcinoma were infused with [131I]huA33 (400 MBq: 10 mCi) and [125I]huA33 (40 MBq: 1 mCi) 1 week before surgery. There were four huA33 dose levels (0.25, 1.0, 5.0, and 10 mg/m2). Adverse events, pharmacokinetics, biodistribution, tumor biopsies, and immune responses to huA33 were evaluated. RESULTS: There were 12 patients entered into the trial (6 males and 6 females; age range, 39-66 years). No dose-limiting toxicity was observed. The biodistribution of huA33 showed excellent uptake of [131I]huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2beta) between dose levels (mean +/- SD, 86.92 +/- 22.12 hours). Modeling of colon uptake of huA33 showed a T1/2 of elimination of 32.4 +/- 8.1 hours. Quantitative tumor uptake ranged from 2.1 x 10(-3) to 11.1 x 10(-3) ID/g, and tumor/normal tissue and tumor/serum ratios reached as high as 16.3:1 and 4.5:1, respectively. Biosensor analysis detected low-level human anti-human antibody responses in four patients following huA33 infusion. CONCLUSIONS: huA33 shows selective and rapid localization to colorectal carcinoma in vivo and penetrates to the center of large necrotic tumors, and colon elimination half-life of huA33 is equivalent to basal colonocyte turnover. The excellent targeting characteristics of this humanized antibody indicate potential for the targeted therapy of metastatic colorectal cancer in future trials.
Original languageEnglish
Pages (from-to)4810 - 4817
Number of pages8
JournalClinical Cancer Research
Issue number13
Publication statusPublished - 2005
Externally publishedYes

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