UBC Theses and Dissertations
Monoclonal antibodies and cancer: photoimmunotherapy and radioimmunoimagery Mew, Daphne Jung Yen
The advantage of using monoclonal antibodies in the treatment of malignancies lies in its potential to make cancer therapy or detection more tumour specific. Tumour specific antibodies linked to chemotherapeutic drugs or radionuclides would aid in the transportation of the drugs' cytotoxic activity to tumour targets or make it possible to accurately map the spread of primary tumour and metastasis radioactively. The term "photoimmunotherapy" describes an anti-cancer treatment that combines the phototoxic effects of chemicals such as haematoporphyrin and the target seeking ability of antibodies. By homing in on their designated targets, monoclonal antibodies conjugated to haematoporphyrin are able to localize the photodynamic activity to the tumour site, minimizing nonspecific dispersal through the body and therefore decreasing the potential for normal tissue toxicity. Haematoporphyrin chemically coupled to monoclonal antibodies directed to DBA/2J rhabdomyosarcoma M-l was assayed for tumour specific phototoxicity in vitro and in vivo. When conjugated to monoclonal antibodies (CAHAL-1) directed against a human myelogenous leukaemia-associated antigen (CAMAL), the photoimmuno-therapeutic activity of haematoporphyrin-CAMAL-1 antibodies was examined as a potential method for specifically purging leukaemic cells from a normal haematopoeitic cell population in vitro. Administration of anti-M-l-Haematoporphyrin conjugates intravenously to M-l tumour-bearing animals followed by exposure to light resulted in suppression of M-l growth. The time interval between injection and lightexposure was an important parameter in terms of tumour suppression. Tumour-bearing animals maintained in the dark for 96 to 196 hrs after haematoporphyrin-antibody injection followed by 4 hr light exposure demonstrated significantly lower tumour incidence and longer latency periods, in comparison to conjugate treated animals instantly exposed to light. The growth inhibiting properties of the conjugate appeared to be M-l specific since it had no effect on the growth of a C5BL/6J lymphoma EL4. In addition, conjugates made with a non-specific monoclonal antibody did not have any specific anti-tumour effect on M-l growth. Treatment with equivalent doses of haematoporphyrin or antibody had no significant inhibiting effect on tumour growth. Clearly, the homing ability of the specific monoclonal antibody - haematoporphyrin conjugate was essential for effective drug delivery and inhibition of tumour growth. In vitro experiments with haematoporphyrin-CAMAL-1 demonstrated that the conjugate specifically eliminated CAMAL bearing cells in myelogenous leukaemic cell populations. The cytotoxicity of Hp-CAMAL-1 was shown to be target specific since irrelevant conjugates (Hp-anti-M-1 or Hp-anti-L1210) had minimal effect on the leukaemic cell samples. In addition, Hp-CAMAL-1 had no activity on normal bone marrow cells, normal peripheral blood lymphocytes, CAMAL negative ALL bone marrow or lymphoma cells. These results indicated that Hp-CAMAL-1 photoimmunotherapy may be a potential method for specifically eliminating tumour cells from bone marrow suspensions prior to autologous transplantation. In radioimmunoimagery, labelled antibodies are used to detect cancer in vivo. By combining the specificity of anti-tumour antibodies and thesensitivity of radioisotope tracer technology, a higher level of detection was created for cancer diagnosis. The potential of radioimmunoimagery was examined in vivo murine tumour studies with [sup 99m]technetium labelled anti-M-1 monoclonal antibodies [sup 99m]Tc-anti-M-1 antibodies were able to detect and localize M-l tumours as small as 0.3 g (< 1 cm²) 6 - 18 hrs after intravenous administration. Radionuclide localization was M-l tumour specific since EL4 lymphomas were not detected with [sup 99m]Tc-anti-M-l. Sensitivity of the radioimmunoimaging approach was diminished by the high backgrounds observed in normal tissues such as liver, kidneys, and spleen. Biochemical examination of the labelled antibody preparations indicated that the background problem could be due to the highly aggregated nature of the injected immunotracer. Improvement of the radioimmunoimaging scans might be achieved if the labelled antibodies could be administered in a nonaggregated form.
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