Summary A humanised IgGl/k version of A33 (hA33) has been constructed and expressed with yields up to 700 mg 1' in mouse myeloma NS0 cells in suspension culture. The equilibrium dissociation constant of hA33 (KD= 1.3 al., 1990, 1994). A phase I/II study has been conducted (Welt et al., 1994) with this murine antibody, in which some tumour responses were observed at the maximum tolerated dose (75 mCi m-2). The major limiting toxicity was haematological, as observed in almost all therapy studies with radioimmunoconjugates. All patients treated developed a human anti-mouse antibody (HAMA) response after one administration, and this led to very rapid clearance of the conjugate upon retreatment, consistent with all previous results with rodent antibodies. These data suggest that A33 is a promising antibody for successful radioimmunotherapy of colon cancer, and the purpose of this study has been to design and develop a second generation reagent based upon it. The key to the development of successful radioimmunotherapy will be the identification of reagents capable of delivering a killing dose to tumour cells without unacceptable toxicity to normal tissues. To this end we are evaluating several alternative radioimmunotherapeutic strategies including the use of isotopes which require internalisation into the cell for cytotoxicity, such as 125I (which are less toxic to normal tissues), and engineering the antibody for the optimal delivery of highly cytotoxic agents such as 90Y.The radioisotope 9'Y has been used in several radioimmunotherapy studies and is an attractive isotope for this purpose owing to its appropriate physical properties. As a pure high-energy P-emitter 9Y has advantages over the more

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