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Intraperitoneal Pretarget Radioimmunotherapy with CC49 Fusion Protein

Authors' Affiliations: Departments of ¹ Radiation Oncology, ² Medicine, and ³ Radiology, University of Alabama at Birmingham, Birmingham, Alabama and ⁴ NeoRx Corp., Seattle, Washington

Requests for reprints: Donald J. Buchsbaum, Department of Radiation Oncology, University of Alabama at Birmingham, 1530 3rd Avenue South, WTI 674, Birmingham, AL 35294-6832. Phone: 205-934-7077; Fax: 1-205-975-7060; E-mail: djb{at}uab.edu.

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-azacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) complexed with ¹¹¹In-, ⁹⁰Y-, or ¹⁷⁷Lu-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 ¹¹¹In- or ¹⁷⁷Lu-DOTA-biotin. Tumor localization of ¹¹¹In-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 ⁹⁰Y-DOTA-biotin at doses of 400 to 600 µCi or ¹⁷⁷Lu-DOTA-biotin at doses of 600 to 800 µCi produced significant prolongation of survival compared with controls (P = 0.03 and P < 0.01).

Conclusions: Pretarget radioimmunotherapy 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.

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