Radioimmunotherapy of colorectal carcinoma xenografts in nude mice with yttrium-90 A33 IgG and tri-fab (TFM)

The monoclonal antibody A33 recognises a tumour-associated antigen on human colorectal carcinoma, and has undergone preliminary evaluation in the clinic where selective localisation to hepatic metastases has been demonstrated [Welt ei al. (1994) J. Clin. Oncol. 12, 1561-1571]. A33 and an A33 tri-fab fragment (TFM) were labelled with Y-90 via a stable macrocyclic ligand for biodistribution and therapy studies in nude mice bearing SW1222 colon carcinoma xenografts. Biodistribution studies demonstrated tumour localisation for both A33 IgG and TFM with low bone, liver and kidney levels. Clearance of TFM from the blood was much faster than IgG and this led to lower tumour accumulation for TFM but superior tumour-blood ratios. The maximum per cent injected dose per g localised to tumour was 35.9%+/-5.3% for A33 IgG and 12.9%+/-4.6% for A33 TFM with tumour-blood ratios at 48 h after administration of 5.6+/-1.8 and 29.2+/-9.8 respectively. Autoradiography studies with I-125-labelled A33 IgG and TFM demonstrated a homogeneous distribution within tumour tissue which was not observed with other anti-colorectal tumour antibodies. TFM penetrated into the tumour tissue more rapidly than IgG. In therapy studies, a single dose of Y-90-A33 IgG (250 mu Ci per mouse) or Y-90-A33 TFM (300 mu Ci per mouse) led to complete regression of 2-week-old tumour xenografts with long-term tumour-free survivors. A transient drop in white blood cell count was observed with both IgG and TFM but was significantly more pronounced with Igc. The cell count fell to 8.4% of control for IgG, whereas with TFM cell counts fell to 51% of control before recovery. These results indicate that the more rapid blood clearance of Y-90-TFM confers reduced toxicity compared with Y-90-IgG although similar therapeutic effects are achieved. When the dose of Y-90-IgG was adjusted to give the same dose to tumour achieved with 300 mu Ci Y-90-TFM, a lesser therapeutic effect was observed. This may be owing to more rapid tumour penetration achieved with TFM. Both A33 IgG and TFM demonstrated potent anti-tumour effects against human tumour xenografts in this mouse model system. The stability of these Y-90-labelled conjugates and their effective tumour penetration are promising for the development of humanised reagents for clinical studies.