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Microscopic Intratumoral Dosimetry of Radiolabeled Antibodies Is a Critical Determinant of Successful Radioimmunotherapy in B-Cell Lymphoma

¹ Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, United Kingdom; ² Cancer Studies Division, Cancer Research UK Paterson Institute, School of Medicine, University of Manchester, Manchester, United Kingdom; and ³ Institute of Nuclear Medicine, University College London Hospital, London, United Kingdom

Requests for reprints: Tim Illidge, Cancer Studies Division, School of Medicine, University of Manchester, Manchester M20 4BX, United Kingdom. Phone: 44-161-446-8095; Fax: 44-161-446-8111; E-mail: tmi{at}manchester.ac.uk.

Radioimmunotherapy is a highly effective treatment for some hematologic malignancies; however, the underlying mechanisms of tumor clearance remain poorly understood. We have previously shown that both targeted radiation using ¹³¹I-labeled anti–MHC class II (MHCII) monoclonal antibody (mAb) plus mAb signaling with unlabeled anti-idiotype are required for the long-term clearance of tumor in syngeneic murine lymphoma models. In this study, we have investigated how the microdistribution of the targeted radiation component of this combination affects the long-term clearance of lymphoma. ¹³¹I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry (1.0 Gy per MBq when ¹³¹I was labeled to 500 µg mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, ¹³¹I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of ¹³¹I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the ¹³¹I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of ¹³¹I-anti-CD45 was increased, a radiation dose response was shown in the presence of anti-idiotype and long-term survival was seen. We believe that these new insights should influence the selection of new antigen targets and the design of dosimetric methods in radioimmunotherapy of lymphoma. [Cancer Res 2007;67(3):1335–43]