Local hyperthermia improves uptake of a chimeric monoclonal antibody in a subcutaneous xenograft model.
This study was undertaken to determine the effect of local hyperthermia on the tissue distribution of a chimeric human/mouse IgG2 monoclonal antibody, 81C6, reactive with the extracellular matrix protein tenascin, which is expressed at high levels in gliomas, carcinomas of the breast and prostate, and other neoplasms. The D-54 MG s.c. glioma xenograft was treated with hyperthermia by immersion of the tumor-bearing leg in a circulating water bath. By 4 h after injection (immediately after heating), administration of chimeric 125I-labeled 81C6 (ch81C6) concomitantly with a 4-h local hyperthermia treatment at 41.8 degreesC resulted in an increase in tumor uptake of monoclonal antibody from a median of 12% of injected dose/g of tumor in normothermic mice to 42% of injected dose/g in mice receiving local hyperthermia. The increased level of uptake persisted in the heated tumors over the first 48 h and at 96 h. Additionally, heating increased the tumor:blood ratio of ch81C6 more than 7-fold at 4 h postinjection. The rate of uptake was also dramatically improved, with 60 and 90% of the maximum level of uptake achieved by 4 and 24 h, respectively, in the hyperthermia-treated mice, whereas the normothermic mice reached only 31 and 69% of their maximum uptake at those time points. In summary, local hyperthermia enhanced the absolute level and the rate of tumor uptake as well as tumor:normal tissue ratios for ch81C6. This approach may facilitate the clinical application of radionuclides with shorter half-lives, such as 211At, for the therapy of solid malignancies.
Hauck
M L
ML
Departments of Pathology, Radiology, and Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dewhirst
M W
MW
Bigner
D D
DD
Zalutsky
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics*; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D019063:Tenascin / Q000276:immunology; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; D019063:Tenascin