Abstract
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 (131)I-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. (131)I-labeled mAb targeting CD45 and MHCII antigens was found to deliver similar doses of radiation to tumor-bearing organ using conventional dosimetry ( approximately 1.0 Gy per MBq when (131)I was labeled to 500 mug mAb and given i.v. per mouse), but when used as radiation vectors in combination therapy only, (131)I-anti-MHCII plus anti-idiotype produced long-term survival. The profound differences in therapy did not seem to be dependent on levels of (131)I-mAb tumor-binding or antibody-dependent cytotoxicity. Instead, the microscopic intratumoral dosimetry seemed to be critical with the (131)I-anti-MHCII, delivering more concentrated and therefore substantially higher radiation dose to tumor cells. When the administered activity of (131)I-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.
Highlights
The use of monoclonal antibody to deliver radioisotopes selectively to tumors is theoretically appealing, and over the last decade, considerable progress has been made in the field of radioimmunotherapy
We have investigated the relationship between tumor dosimetry and successful clearance of lymphoma in radioimmunotherapy
Radioimmunoconjugates of different specificity (131I-anti-MHC class II (MHCII) and 131I-antiCD45) seem to deliver similar doses of radiation to tumor by established dosimetric techniques, there were profound differences in the therapeutic activity between the two monoclonal antibody (mAb) when combined with unlabeled anti-idiotype mAb
Summary
The use of monoclonal antibody (mAb) to deliver radioisotopes selectively to tumors is theoretically appealing, and over the last decade, considerable progress has been made in the field of radioimmunotherapy. Despite a wide variety of mAbs, radionuclides, and study designs, a common theme to emerge from clinical trials investigating radioimmunotherapy in relapsed non– Hodgkin’s lymphoma has been the high response rates with durable remissions seen for significant numbers of patients [1]. Most lymphomas are extremely radiosensitive and generally have good blood perfusion for the delivery of radioimmunoconjugates These favorable characteristics are thought to be important factors relating to the high response rates that have been seen with radioimmunotherapy in lymphomas [3,4,5]. The importance of biodistribution studies and tumor dosimetry to the overall therapeutic response seen in radioimmunotherapy of lymphoma has been very difficult to clarify and remains highly controversial [6,7,8]. Radioimmunotherapy is still regarded by some as little more than sophisticated total body irradiation with little role for antibody targeting and mAbs are considered as vectors for delivering of ‘‘systemic radiotherapy’’ [12]
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