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

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 [1311]huA33(400 MBq: 10 mCi) and [I-125]huA33 (40 MBq: 1 mCi) 1 week before surgery There were four huA33 dose levels (0.25,1.0, 5.0, and 10 mg/m(2)). 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 [I-131] huA33 in metastatic colorectal carcinoma. Pharmacokinetic analysis showed no significant difference in terminal half-life (T1/2 beta) 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.