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Clin. Pharmacokinet. 23 (2): 85-89, 1992 0312-5963/92/0008-0085/$02.50/0 © Adis International Limited. All rights reserved. CPK1194

Monoclonal Antibody Administration Current Clinical Pharmacokinetic Status and Future Trends Richard Henry, John Begent and Rosamund Barbara Pedley Cancer Research Campaign Clinical Research Laboratories, Department of Clinical Oncology, Royal Free Hospital School of Medicine, London, England

Monoclonal antibodies are produced from hybridomas generated by fusion of a lymphocyte from an immunised animal with a myeloma cell. The resultant hybridoma cell line produces uniform antibody molecules with a single specificity which can be generated indefinitely, and potentially in large quantities, Monoclonal antibodies have been produced which recognise tumour-associated antigens in many tumour types, They are being widely used for selective delivery of anticancer agents to tumours. The concept dates from the 1890s but application depends on development of successful pharmacokinetics. Recent advances in antibody manipulation give opportunities for enhancing tumour-specific delivery of radionuclide (for radioimmunolocalisation and radioimmunotherapy), cytotoxic drugs and toxins. Most of the data concerning biodistribution of anti tumour antibodies come from tissue studies in nude mice bearing xenografts of human carcinomas (Mach et al. 1974). Examination of radiolabelled antibody levels in tumour and normal tissues has shown selective tumour localisation of intravenously administered specific antitumour antibodies compared with nonspecific antibodies (Pressman et al. 1957). Selective therapy depends on favourable pharmacokinetic profiles covering the whole timecourse from antibody injection until the therapeutic agent is excreted or broken down. The profiles are most readily obtained with radiolabelled anti-

bodies and must show substantial advantages in areas under the tissue concentration-time curve for tumour compared with vulnerable normal tissues.

1. Antibody in Circulation In nude mice bearing xenografts of human carcinomas murine antibodies have a rapid initial distribution (a) phase and then a terminal elimination half-life (t'hJ9) of a few days. High levels of circulating antigen can form complexes with the administered antibody, leading to rapid clearance from the blood and reduction in tumour localisation (Pedley et at. 1989a). The formation of antiglobulin in response to repeated therapy with xenogenic antibodies will also accelerate clearance from blood in humans. 1.1 Normal Tissues

Intact radiolabelled antibodies are principally cleared by liver catabolism but concentrations in most tissues are generally lower than in the circulation. However, lung and spleen are sites at which concentrations of radioactivity commonly exceed the mean for the body. Reasons for this may include nonspecific uptake of radioantibody by the receptors of the reticuloendothelial cells found in these organs. The lower molecular weight of free radio nuclides and antibody breakdown products account for the high levels of radioactivity also

Monoclonal antibody administration. Current clinical pharmacokinetic status and future trends.

LEADING ARTICLE Clin. Pharmacokinet. 23 (2): 85-89, 1992 0312-5963/92/0008-0085/$02.50/0 © Adis International Limited. All rights reserved. CPK1194...
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