Phase I study of humanised antibody A33 (Hua33) in patients with colorectal carcinoma - preliminary whole body clearance and tumour dosimetry

A number of clinical trials with mAb A33 have been conducted by Welt and colleagues at Memorial Sloan-Kettering Cancer Centre in New York. An initial Phase I, biopsy based, proof of principle trial with trace 131I-mAbA33 showed excellent targeting of sites of colorectal carcinoma, with uptake levels on biopsy superior to any previously reported antibody trial in this tumour system. A Phase I therapy trial with '131I-mAbA33 also demonstrated excellent targeting (fixed dose of A33, escalating doses of 131I) and some minor responses were seen. Toxicity observed was related to haematological toxicity due to red marrow dose from circulating 131I-mAbA33 (Maximum Tolerated Dose (MTD) was 75mCi/m2), and no gastrointestinal toxicity was observed. Repeat infusions were not possible because of the development of human antimouse antibodies. Due to the internalisation properties of A33 observed in in-vitro and in-vivo systems, a Phase I clinical trial with l25l-mAbA33 was also conducted. Doses up to 350mCi/m2 of l25I-mAbA33 were administered without a MTD being reached. Images of 125I-mAbA33 were obtained up to 35 days post infusion, demonstrating prolonged retention of activity in tumour sites. Four patients demonstrated minor responses, and no bowel toxicity was seen. HuA33 is a fully humanised CDR-grafted IgG1 antibody against the A33 antigen. The development of an immune response directed against this humanised form of the antibody is less likely, and multidosing is therefore theoretically possible. In order that a rational approach can be taken to dose calculation in future therapy trials of radioimmunotherapy with HuA33, it has been necessary to develop, methods for the calculation of whole body clearance and volume-related tumour uptake. Actual tumour radiation dosimetry is the next step, but requires finalization of the above methods prior to their use in calculation of tumour residence times. This paper outlines the methods developed thus far and their application to data already collected by the time of original submission. At that time, 10 patients had been infused with 131I-labelled huA33. The method used to quantify liver tumour uptake assumes that activity is uniformly distributed throughout normal liver and that contribution of activity from the volume of normal liver displaced by tumour is small. Plannar imaging analysis examines the overall tumour radioactivity