Ledermann, Jonathan Andrew; (1990) Investigation of two methods to improve the therapeutic potential of radiolabelled antibodies: Use of an anti-antibody and suppression of the host anti-antibody response. Doctoral thesis (M.D), UCL (University College London).

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Abstract

The aim of targeting therapy with radiolabelled antitumour antibody is to increase the quantity of cytotoxic agent delivered to the tumour relative to normal tissues. But the administration of antibody conjugates with 131- iodine (131I) is limited by myelosuppression. The purpose of this thesis was to investigate two methods of reducing myelotoxicity so that a larger amount of radiolabelled antibody could be given. An anti-antibody ('second antibody') that binds to the primary antitumour antibody was given to patients with colorectal cancer 24 hours after 131-iodine (131I) labelled antibody to carcinoembryonic antigen (CEA). This led to an acceleration in the removal of radioactivity from blood but not the body. The dose to bone marrow, estimated from the radioactivity in blood was reduced after 'second antibody' was given (p<0.05). Although, the total bone marrow radiation dose was not significantly reduced by 'second antibody' up to 152 mCi 131I anti-CEA was given without life-threatening toxicity. A second approach examined whether 131I anti-CEA could be given in divided doses allowing the bone marrow to recover between treatments. However, a single intravenous injection of polyclonal or monoclonal anti-CEA led to an increase in the concentration of serum human IgG antiantibody in 13 out of 24 (54.2%) patients. Treatment in the presence of anti-antibodies detected before therapy did not prevent uptake of radioactivity in the tumour. But therapy repeated following a rise in the concentration of anti-antibody led to allergic reactions and rapid elimination of the radiolabelled antibody. Cyclosporin A was found to suppress the anti-antibody response in rabbits and man. Up to four injections of approximately 50 mCi of anti-CEA were given before small amounts of human anti-antibody appeared. However, myelosuppression was seen in 4 out of 6 patients. As almost half the bone marrow radiation was delivered before 24 hours a greater improvement in therapeutic ratio may result from giving 'second antibody' earlier and in combination with repeated courses immunconjugate and cyclosporin A.

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