Radioimmunotherapy of Metastatic Disease - Studies of Alpha- and Beta-particle-Emitting Radionuclides in a Preclinical Model
Sammanfattning: In radioimmunotherapy, monoclonal antibodies (mAbs) are used as a targeting agent carrying a toxic payload consisting of radionuclides. This treatment allows the irradiation of small lesions, even on the microscopic level. In the present work, two radionuclides with different properties were used. Lutetium-177 (177Lu) is a beta-particle-emitting radionuclide (t½=6.7 days) and astatine-211 (211At) emits alpha particles (t½=7.2 h). These radionuclides were used to label a mAb targeting the Lewis Y antigen expressed on many carcinomas. A syngeneic rat colon carcinoma model was used in all the studies. The aim of the work described in this thesis was to evaluate the therapeutic effects and toxicity of mAbs labeled with different activities of these two radionuclides, administered separately, or administration of 177Lu-mAbs, followed by administration of the unlabeled mAbs, 177Lu-mAbs or 211At-mAbs. The intratumoral distribution of radioimmunoconjugates was examined over time using digital autoradiography and was related to tumor histology. The results show that the tumor response was dose dependent after treatment with 177Lu-mAbs alone. Both evaluated activities of 211At-mAbs resulted in similar tumor response rate as the highest tested activity of 177Lu-mAbs (400 MBq/kg). Metastases were detected in approximately half the animals, regardless of the radionuclide or administered activity. The toxicity was deemed tolerable as the numbers of white blood cells and platelets recovered to initial levels. Administration of the minimal effective activity of 177Lu-mAbs followed by treatment with unlabeled mAbs, 177Lu-mAbs, or 211At-mAbs resulted in a small increase in the number of tumors showing complete response. No effect was seen on the development of metastases. The additional treatment with unlabeled mAbs did not show any toxic effects. Repeated treatment with 177Lu-mAbs resulted in a prolonged period of low white blood cell counts and a second decrease in platelet counts. Sequential administration of minimal effective activities of first 177Lu-mAbs and then 211At-mAbs also resulted in prolonged myelotoxicity, but with faster recovery of the white blood cells than following the repeated treatment with 177Lu-mAbs. Studies on the intratumoral distribution of the radioimmunoconjugates are important for our understanding of the response to treatment. The results showed that the activity was initially located in the tumor margins, and did not reach the more central parts until 24 h after administration. The distribution of activity was heterogeneous despite the expression of the antigen on all tumor cells. The tumor histology changed from dense tumor growth to areas of stromal tissue in some tumors after 24 h, while other tumors continued to grow. Calculations of the dose rate indicate that the tumors are treated most efficiently during the first 24 h after injection. In summary, these results show that single treatment with alpha- and beta-particle-emitting radionuclides results in comparable toxicity at activities giving the same rate of tumor response. The studies on combined treatment showed that although a higher number of tumors showed complete response, there was no effect on the development of metastatic disease or survival.
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