Antibody-Directed Enzyme Prodrug Therapy (ADEPT)

New approaches to antibody therapy

“…The initial example of this strategy was antibody-directed enzyme prodrug therapy (ADEPT), in which an antitumor antibody-enzyme conjugate is administered systemically, and then allowed to clear from normal tissues. An inactive chemotherapy prodrug is then administered that rapidly clears from the host, but is selectively retained at tumor sites by the antibodytargeted enzyme to liberate the active chemotherapy agent at tumor sites (Bagshawe et al, 1993). Various iterations of this strategy have been tested in preclinical models and in human clinical trials (Bagshawe et al, 1991;Martin et al, 1997;Siemers et al, 1997).…”

“…The capacity to employ multiple radionuclides indicates that this core strategy oers the potential to function as a delivery system for diverse radionuclides and other chelated substances (Goodwin et al, 1988;Paganelli et al, 1988). The general pretargeting concept can be applied to direct the delivery of chemotherapy agents (Juweid et al, 1992;Wu et al, 1996;Bagshawe, 1993), toxins, cytokines or other tumor-modulatory agents.…”

Anti-tumour effects of an antibody-carboxypeptidase G2 conjugate in combination with phenol mustard prodrugs

“…The phenol mustard drug liberated from PGP andFTP by CPG2 is some 50-to 100-fold more potent than the benzoic acid mustard drug liberated from the CMDA prodrug (Springer et al, 1991b;Blakey et al, 1993) which is currently in chnical trials combination with the F(ab%A5B7-CPG2 conjugate (Bagshawe et al, , 1995Bagshawe, 1993 (Springer et al, 1991b Previously, Wallace and Senter (1991) reported an ADEPT system which incorporated a different prodrug of the phenol mustard drug used in these studies. The prodrug wasp[NVNBis(2chothyl)aminonyl phosphate (POMP) and the enzyme used to cleave the phosphate residue to release the drug was alkaline phosphatase.…”

“…The activity of this system was probablylimited by endogenous alkaline phosphatase causing conversion of prodrug to drug and so enhancing toxicity. Since CPG2 is a bacterial enzyme and no active drug has been detected following the administration of the CMDA prodrug to patients in the absence of conjugate (Bagshawe, 1993;Bagshawe et al, 1995 …”

“…The amide bond in the glutamate derivatives of benzoic acid mustards are also cleaved by CPG2 to release the benzoic acid mustard drug. A series of studies has shown that the combination of these benzoic acid mustard-glutamate prodrugs and a conjugate of CPG2 linked to either the anti-$-hCG antibody, W14 (Bagshawe et al, 1988;Springer et al, 1991a) Bagshawe, 1993).…”