title: Effect of pre-irradiation on radiopharmaceutical localization in human colon tumor xenografts using mono- and bispecific monoclonal antibodies.
abstract: In previous investigations we found that pre-irradiation of a tumor can significantly increase site-specific accumulation of radiolabeled monoclonal antibodies (MAb). The aims of the present study were to compare the effects of radiation on the localization of conventional MAb and a bifunctional delivery system and to evaluate a new time-dose schedule. T380 human colon tumors in athymic nude mice were irradiated (60Co, 10 Gy single dose) and the antibodies were injected 2 hours later. For mice given 111In-ZCE025, an anti-carcinoembryonic antigen (CEA) MAb, the biodistribution of activity was determined 7 days later. The animals receiving ECA001, a bispecific antibody binding to CEA and to a hapten on 111In-DBX, were injected with the radiolabeled hapten 5 days after cold annbody and sacrificed 2 days later. The mean percentage of injected dose (%ID/g) within tumors was significantly increased (p < 0.05) for both anti-CEA antibodies after pre-irradiation compared to their respective nonirradiated controls (%ID/g = 22.8 versus 47.8 for conventional MAb; %ID/g = 12.5 versus 25.9 for bifunctional system). Tumor-to-normal tissue ranos were also higher in the pre-irradiated groups. The data show that pre-irradiation can increase the delivery of conventional MAb within solid tumors by over 200%. In addition, the efficacy of the approach can be enhanced by manipulation of the time-dose schedule. The results with the bispecific antibody system were unexpectedly confounded by significant differences in tumor growth rate after treatment a phenomenon not seen in the groups receiving the conventional MAb.
authors.affiliation: Department of Microbiology and Molecular Genetics, Loma Linda University/Independent Order of Foresters Cancer Research Laboratory, Loma Linda University School of Medicine, CA 92350, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Gridley
authors.forename: J B
authors.initials: JB
authors.lastname: Slater
authors.forename: D G
authors.initials: DG
authors.lastname: Mackensen
authors.forename: J M
authors.initials: JM
authors.lastname: Slater
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D003037:Cobalt Radioisotopes; D018796:Immunoconjugates; D007205:Indium Radioisotopes