Radioiodinated monoclonal antibodies

Abstract

Antibodies were first described by Von Behring almost 100 years ago. Following their early use as putative therapeutic agents in the treatment of infectious and malignant disease (Hericourt and Richet, 1885) their clinical applications dwindled until, at the present day, passive immunotherapy is largely limited to the treatment of such conditions as foetal erythroblastosis, hypergammaglobuminaemia and snake bite. On the other hand, antibodies have become useful tools in the laboratory. The development of Radioimmunoassay by Yallow et al. in the 1950’s and 60’s revolutionised the detection of hormones in biological fluids and has led to the enormous variety of immunoassay systems based on antibodies bearing radioactive, flourescent, enzymic or other markers that today are regarded as indispensible clinical and scientific techniques. However, despite the limited success of antisera as active drugs at the beginning of the century, the concept of using antibodies in-uivo did not go away. These materials were too close to Paul Erhlich’s “Magic Bullet” for people to lose interest in them entirely. Among those who retained an active interest in their properties was David Pressman. He was involved in early radiotracer studies and showed that the purified globulin fraction of an anti-kidney serum would, when radiolabelled and injected into experimental animals, localise in the kidney. He also showed that the localising effect of the antibody was due to the specific antigen combining properties of a particular antiserum and that the biodistribution of unrelated antisera was quite different (Pressman et al., 1957). Thus by a combination of the unique properties of antibodies on the one hand, and radioactivity on the other, Pressman was able to show, for the first time, that materials could be made to home in specifically to a target deep in the body of the animal. Despite the obvious importance of this discovery, there was a lull of several decades before this approach was successfully tried in patients. In the 1970’s, Goldenberg in particular combined developments in the preparation and purification of antibodies with improvements in radiolabelling and radioimaging technology to produce impressive results in the detection of lesions in an extended series of patients with various tumours (Goldenberg et al., 1978). However, medical history is littered with many good ideas that showed early promise but never grew to fruition because they were never developed sufficiently beyond their earliest concepts. Goldenberg’s ideas, however promising, may well have gone the same way were it not for the concurrent development in Cambridge, England, of an entirely novel system for the production of antibodies. Antibody preparations produced by conventional immunisation of animals against an immunogen of choice have a number of practical and theoretical disadvantages. The immune response is an effective one but is rather heavy-handed in its approach. Many different clones of B lymphocytes recognise the immunogen when it appears in the circulation and each lymphocyte clone produces a different antibody that binds to different parts of the antigenic molecule. These antibodies will have a mixture of high and low affinities for their respective antigens and will bear a variety of heavy and light chains. Moreover, the antibodies will recognise a variety of epitopes within the immunogen molecule. Now the aim of the exercise is to produce an antibody that can distinguish between diseased and normal cells. In the context of malignant disease, it is now well established that tumour cells synthesise and frequently secrete a number of substances known generally as tumour-markers. Several different types of tumour-marker exist. In some cases, the tumour cells over-produce large quantities of a normal cellular constituent. In others, the cells aberantly switch on the expression of a material normally present only during foetal development, in others, the cells may synthesise a subtly altered version of a normal molecule. As yet, no tumour-marker that is entirely specific for a malignant process has been described. Such molecules should, therefore, be considered to be tumour-associated rather than tumour-specific. Many cellular constituents share regions of common amino-acid sequence and certain areas of the molecular structure of a tumour-marker will resemble normal cellular componemts. Moreover, some markers differ from their normal counterparts only in terms of post-transcriptional processing, that is they share the same central structure but superficial changes in the addition of carbohydrate or lipid side