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Title: Studies in targeted radiotherapy
Author: Lashford, Linda Suzanne
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 1990
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Advances in the treatment of patients with cancer, have come from the use of relatively toxic agents. Therapists are constantly searching for ways to reduce the side effects of treatment, whilst maintaining therapeutic efficacy. One route to this objective is to attempt site specific delivery of a cytotoxic agent. This thesis examines the potential of two methods of targeting radiotherapy; monoclonal antibodies, and a small molecular weight radiopharmaceutical 131I meta- Iodobenzylguanidine (mIBG). The data presented in this thesis characterises the pharmacokinetics of a monoclonal antibody UJ13A, in children with neuroblastoma. Radiation dose estimates ITT are presented, and a Phase I study of 131I UJ13A is reported in children with relapsed neuroblastoma. A number of strategies are explored to improve the therapeutic index of 131I UJ13A. These include methods to improve quality control of the administered radiopharmaceutical, and attempts to reduce whole body irradiation and immunogenicity by the preparation of radiolabelled antibody, F(ab')2 and Fab fragments. Changes in the biodistribution of UJ13A and its fragments are explored in the common marmoset, and correlated with changing levels of anti-murine immunoglobulin. Advantages for the antibody fragments are established, although problems are identified in preparing a stable F(ab')2 digest. Methods for improving the stability and purity of the F(ab')2 digest are explored. An alternative vector of 131I is available in neuroblastoma. MIBG accumulates in greater than 90% of neuroblastomas at diagnosis. A direct comparison of the pharmacokinetics of mIBG to whole immunoglobulin is undertaken in both the marmoset and patient population. The data demonstrates the wider tissue distribution of mIBG, and predicts a lower bone marrow dosage at equivalent doses of The validity of this result is tested for mIBG of differing specific activity in the marmoset model. One theoretical method for improving the therapeutic index of monoclonal antibody therapy, is to restrict its application to a clinical situation where tumour is confined to a body cavity. This is investigated in a study of intrathecal administration of 131I monoclonal antibody, as treatment for leptomeningeal tumour. The pharmacokinetics and biodistribution of intrathecally administered conjugate is reported for patients and animal models, and a Phase I study 131I of monoclonal antibody is described for 15 patients with neoplastic meningitis. Problems with a specific monoclonal antibody UJ181.4, are reported and an alternative monoclonal antibody M340, is described and characterised for clinical use in a new Phase I/II study of intrathecal, radiolabelled antibody in relapsed medulloblastoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available