title: Microscopic intratumoral dosimetry of radiolabeled antibodies is a critical determinant of successful radioimmunotherapy in B-cell lymphoma.
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.
authors.affiliation: Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
authors.forename: Martin
authors.initials: M
authors.lastname: Glennie
authors.forename: Peter
authors.initials: P
authors.lastname: Johnson
authors.forename: Tim
authors.initials: T
authors.lastname: Illidge
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics; D000920:Antibody-Dependent Cell Cytotoxicity; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D018796:Immunoconjugates / Q000493:pharmacokinetics / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000008:administration & dosage*; D017493:Leukocyte Common Antigens / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D016499:Radioimmunotherapy / Q000379:methods*; D011874:Radiometry
chemical_list: D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; D018796:Immunoconjugates; D007457:Iodine Radioisotopes; D017493:Leukocyte Common Antigens