Generation of an Intensely Potent Anthracycline by a Monoclonal Antibody−β-Galactosidase Conjugate

Abstract

The L49 monoclonal antibody against the p97 antigen on melanomas and carcinomas was chemically conjugated to E. coli β-galactosidase (β-gal), forming a largely monomeric conjugate with preserved enzymatic activity. The resulting L49−β-gal conjugate was used to activate (N-[(4‘ ‘R,S)-4‘ ‘-hexyloxy-4‘ ‘-(1‘ ‘‘-O-β-d-galactopyranosyl)butyl]daunorubicin) (1), a derivative of daunorubicin that has low cytotoxicity and high chemical stability. Addition of the conjugate to the prodrug resulted in an increase in cytotoxicity of approximately 10⁵-fold, a level of activation that is higher than any mAb−enzyme/prodrug combination yet described. Furthermore, the released drug had an IC₅₀ value of approximately 10 pM, making it significantly more potent than the vast majority of clinically approved anticancer drugs. The potential of this enzyme/prodrug combination for cancer therapy is discussed.