RADIOIMMUNOTHERAPY OF COLORECTAL-CARCINOMA XENOGRAFTS IN NUDE-MICE WITH Y-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 i n the clinic where selective localisation to hepatic metastases has be en demonstrated [Welt ei al. (1994) J. Clin. Oncol. 12, 1561-1571]. A3 3 and an A33 tri-fab fragment (TFM) were labelled with Y-90 via a stab le macrocyclic ligand for biodistribution and therapy studies in nude mice bearing SW1222 colon carcinoma xenografts. Biodistribution studie s demonstrated tumour localisation for both A33 IgG and TFM with low b one, 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% fo r 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 with in tumour tissue which was not observed with other anti-colorectal tum our antibodies. TFM penetrated into the tumour tissue more rapidly tha n IgG. In therapy studies, a single dose of Y-90-A33 IgG (250 mu Ci pe r mouse) or Y-90-A33 TFM (300 mu Ci per mouse) led to complete regress ion of 2-week-old tumour xenografts with long-term tumour-free survivo rs. A transient drop in white blood cell count was observed with both IgG and TFM but was significantly more pronounced with Igc. The cell c ount fell to 8.4% of control for IgG, whereas with TFM cell counts fel l to 51% of control before recovery. These results indicate that the m ore rapid blood clearance of Y-90-TFM confers reduced toxicity compare d with Y-90-IgG although similar therapeutic effects are achieved. Whe n the dose of Y-90-IgG was adjusted to give the same dose to tumour ac hieved with 300 mu Ci Y-90-TFM, a lesser therapeutic effect was observ ed. This may be owing to more rapid tumour penetration achieved with T FM. Both A33 IgG and TFM demonstrated potent anti-tumour effects again st human tumour xenografts in this mouse model system. The stability o f these Y-90-labelled conjugates and their effective tumour penetratio n are promising for the development of humanised reagents for clinical studies.