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A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake

Authors' Affiliations: ¹ Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch; Departments of ² Nuclear Medicine and Centre for PET, ³ Surgery, ⁴ Anatomical Pathology, and ⁵ Medical Physics, Austin Hospital, Melbourne, Victoria, Australia and ⁶ Ludwig Institute for Cancer Research, New York, New York

Requests for reprints: Andrew M. Scott, Tumour Targeting Program, Ludwig Institute for Cancer Research, Level 1, Harold Stokes Building, Austin Hospital, 143-165 Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5876; Fax: 61-3-9496-5892; E-mail: andrew.scott{at}ludwig.edu.au.

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 (T1/2ß) 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.

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