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To activate prodrugs for cancer treatment, an anti-TAG-72 antibody (HuCC49DeltaCH2) was used for delivery of an activation enzyme (beta-galactosidase) to specifically activate a geldanamycin prodrug (17-AG-C2-Gal) against colon cancer. The geldanamycin prodrug 17-AG-C2-Gal was synthesized by coupling a galactose-amine derivative with geldanamycin at the C-17 position. Molecular docking with two different programs (Affinity and Autodock) showed that the prodrug (17-AG-C2-Gal) was unable to bind to Hsp90; however, the product (17-AG-C2), enzymatically cleaved by beta-galactosidase conjugate, bound to Hsp90 in a similar way as geldanamycin and 17-AG. The computational docking results were further confirmed in experimental testing by the tetrazolium [3-(4,5-dimethythiazol-2-yl)]-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and mass spectrometry. HuCC49DeltaCH2 was chemically conjugated to beta-galactosidase. The antibody-enzyme conjugate was able to target tumor antigen TAG-72 with the well-preserved enzymatic activity to activate 17-AG-C2-Gal prodrug. The released active drug 17-AG-C2 was demonstrated to induce up to 70% AKT degradation and enhance anticancer activity by more than 25-fold compared to the prodrug.

Enzyme Specific Activation of Benzoquinone Ansamycin Prodrugs Using HuCC49ΔCH2−β-Galactosidase Conjugates