Suppression of tumour growth in mice by a drug–antibody conjugate using a novel approach to linkage

Abstract

THE possibility of using cytotoxic drugs linked to tumour-specific antibodies as a form of cancer chemotherapy has been revived recently. In theory the antibodies would selectively transport the drugs to the target tumour site. The demonstration by Ghose et al.^1,2 and also by Flechner³ that chlorambucil and antibody combined produce an augmented antitumour effect can, however, be explained by an additive or synergistic effect of drugs and antibody uncombined, since there is a high probability of in vivo dissociation^4–6. Although this synergistic drug–antibody effect has been studied in detail^7–9, the original aim of preparing a stable drug–antibody conjugate has also been pursued and evidence of in vivo tumour suppression has been obtained with covalent conjugates of rabbit antitumour immunoglobulin (Ig) and alkylating agents^10,11. In these studies, direct conjugation of the drugs with Ig was carried out using a water-soluble carbodiimide. Successful tumour suppression was, however, dependent on using large amounts of linked material since severe limitations are imposed on the degree of drug substitution by the physico-chemical changes induced in the immunoglobulin by linkage. These changes are reflected in loss of antibody activity and poor water solubility of the preparations thus limiting the clinical potential of complexes in this form. Here we describe a method of overcoming these problems. Instead of direct substitution of the drugs on the Ig, an intermediate carrier molecule is heavily substituted and the drug carrier then linked to Ig. By minimising interference with the chemical structure of Ig in this linkage step, a conjugate is produced with both a high concentration of drug and little loss of antibody activity. This conjugate has proved effective in suppressing tumour growth in mice.