Intraperitoneal pretarget radioimmunotherapy with CC49 fusion protein

Purpose: This study examined a pretarget radioimmunotherapy strategy for treatment of an i.p. tumor model (LS174T). Experimental Design: The strategy used regional administration (i.p.) of a novel targeting molecule composed of four CC49 anti-tumor-associated glycoprotein 72 (TAG-72) single-chain antibodies linked to streptavidin as a fusion protein (CC49 fusion protein); 24 hours later, a synthetic clearing agent was administered i.v. to produce hepatic clearance of unbound CC49 fusion protein/synthetic clearing agent complexes. Four hours later, a low molecular weight radiolabeled reagent composed of biotin, conjugated to the chelating agent 7,10-tetra-azacyclodo-decane-N,N',N '',N'''-tetraacetic acid, (DOTA) complexed with In-111-, Y-90-, or Lu-177-DOTA-biotin was injected. Results: Radiolocalization to tumor sites was superior with i.p. administration of radiolabeled DOTA-biotin as compared with i.v. administration. Imaging and biodistribution studies showed excellent tumor localization of radioactivity with In-111- or Lu-177-DOTA-biotin. Tumor localization of In-177-DOTA-biotin was 43% ID/g and 44% ID/g at 4 and 24 hours with the highest normal tissue localization in the kidney with 6% ID/g at 48 and 72 hours. Therapy studies with Y-90-DOTA-biotin at doses of 400 to 600 mu Ci or Lu-177-DOTA-biotin at doses of 600 to 800 mu Ci produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01). Conclusions: Pretarget radio immunotherapy using regional administration of CC49 fusion protein and i.p. 90Y- or 177Lu-DOTA-biotin represents a successful, therapeutic strategy in the LS174T i.p. tumor model and this strategy may be applicable to human trials in patients with i.p. ovarian cancer.