Marshall, Diane; (1997) Investigation of clearance systems in antibody targeted therapy of cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The use of radiolabelled anti-tumour antibodies for the detection and treatment of cancer is limited by their persistence in the circulation. Low tumour to blood ratios delay tumour imaging and also limit the dose which can be safely administered for radioimmunotherapy due to myelotoxicity. An investigation was undertaken to establish whether a streptavidin clearing agent could efficiently complex and clear biotinylated anti-tumour antibodies from the circulation to achieve the higher tumour to blood ratios required for effective radioimmunotherapy. The level of antibody biotinylation at which successful blood clearance could be achieved was first established using a 125I radiolabelled monoclonal anti-CEA antibody, A5B7, in nude mice bearing LS174T colon carcinoma xenografts. A comparison with previously established second antibody clearance of a polyclonal anti- CEA antibody was also investigated. The problem of persistent streptavidin-biotinylated antibody complexes in the spleen was alleviated by conjugation of galactose residues onto streptavidin, which directed complex clearance via the asialoglycoprotein receptors of the liver. Radioimmunotherapy studies were carried out with both intact and F(ab')2 fragments of 131I-biotinylated A5B7 and although some reduction in toxicity was noted following galactosylated streptavidin clearance, the therapeutic capability of the antibody was also diminished. Galactosylated streptavidin was also investigated as a clearing agent for use in antibody directed enzyme prodrug therapy (ADEPT) and was found to be comparable to previously established second antibody clearance. The immunogenicity of galactosylated streptavidin may prevent its repeated use in the clinic. Conjugation of polyethylene glycol (PEG) onto galactosylated streptavidin was found to diminish its immunogenicity in mice, dependent upon the degree of PEG conjugation, but also reduced its antibody clearing capability. Preliminary evidence suggests a PEG modified galactosylated streptavidin may be useful as a tolerising agent before administration of the unmodified galactosylated streptavidin clearing agent.

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