Monoclonal antibodies

Although the management of cancer by exploiting properties distinguishing neoplastic and normal cells has always been an attractive concept, it was the development of hybridoma technology and the resulting tumour-associated monoclonal antibodies (mAbs) that offered new prospects for this strategy. Some of the applications of mAbs in oncology are now part of everyday diagnosis (i.e. immuno-histochemistry, radio-immunodetection).

With regard to cancer therapeutic modalities, unconjugated or native mAbs can activate components of the complement and of cytolytic cells and result in tumour lysis, with a mechanism known as Antibody-Dependent Cellular Cytotoxicity (ADCC). Several studies have been conducted, mainly in patients with haematological malignancies. The responses achieved were generally poor and of short duration: circulating malignant cells were reduced, but with little effect on lymph node or bone marrow disease.

Since the cytotoxic effect of the mAbs was minimal, they have been used as carriers of more potent agents such as conventional cytotoxic drugs, radionuclides, liposomes, and toxins, to achieve specific delivery at the tumour sites and therefore reduced host toxicity. Another approach is to use mAbs-enzymes conjugates to catalyse various substrate conversions at the tumour. The pro-drug is administered after the conjugate has localized to the surface of the malignant cells and cleared from the circulation.

These approaches are currently undergoing clinical evaluation; the major problem seems to be in the immune response elicited by murine antibodies, known as HAMA (Human Anti-Mouse Antiglobulin response). Nevertheless, it is expected that the evolution of genetic engineering and the subsequent production of single-chain, chimaeric and humanized antibodies and of fusion proteins will overcome this problem. Other limiting factors are the low antibody uptake by the tumour, the antigenic heterogeneity of the tumour, the poor tumour penetration, and the poor stability of the immuno-conjugates in vivo.

In conclusion, the use of mAbs as targeting devices for cytotoxic agents is a very attractive approach for tumour immunotherapy. However, there are still several complex issues to be resolved before they become part of the routine practice in oncology.

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