Selective Drug Delivery Using Targeted Enzymes For Prodrug Activation
Siegfried Matzku, Rolf A. Stahel in Antibodies in Diagnosis and Therapy, 2019
Unfortunately, the efficiencies of the catalytic antibodies described so far are probably orders of magnitude lower than what would be necessary for clinical efficacy. For example, a catalytic antibody has been described that is capable of hydrolyzing an ester prodrug of the cytotoxic drug 5-fluorodeoxyuridine (Campbell et al., 1994). The prodrug consisted of a D-valine ester, which was intended to be stable towards endogenous esterases. It was demonstrated that the prodrug/abzyme combination was capable of exerting an antibacterial effect under conditions where either prodrug or antibody alone had no activity. However, the conditions described to achieve the results employed a 5% mole ratio of antibody, which is equal to a 20: 1 ratio of mAb to prodrug by weight. Also, the study does not provide evidence for true catalysis in the therapy model, as less than one turnover of each antibody variable region would have been required to produce the observed effects. It therefore seems apparent that further progress in the field of catalytic antibodies is required before the technology will be applicable for prodrug activation.
Prodrugs for targeted cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Carla Souza, Diogo Silva Pellosi, Antonio Claudio Tedesco
The antibody-directed abzyme prodrug therapy (known as ADAPT) has been applied for this purpose. It avoids any additional antibody purification stages and reduces the enzymatic activity of the antibody with the conjugate [3,131]. In this case, bacterial enzymes are replaced with catalytic antibodies (known as abzymes) using recombinant DNA technology, producing a fusion protein with specific characteristics to activate the prodrug. The conjugate antibody-ß-lactamase fusion protein, for example, for the activation of cephalosporin prodrugs, was developed by fusion of ß-lactamase to a single-chain fragment (scFv) based on antibody CC49. In addition, a cyclic RGD4C peptide was fused into the NH2 terminus of ß-lactamase, known to target integrin αvβ3 [3]. This conjugate demonstrates lower immunogenicity than intact antibodies, better tissue penetration, and more specific activation of the prodrug, which results in a high local concentration of the drug in the cancer tissue.