Antibody directed enzyme prodrug therapy (ADEPT)

Abstract

The concept of generating cytotoxic agents from non-toxic prodrugs at tumour sites by antibody vectored enzyme introduces a wide range of opportunities. Various prodrug-enzyme combinations have been described and encouraging results reported in xenograft models. Whilst the mouse model is a valuable tool in this approach translation to the human patient may expose more complex issues. The objective of restricting drug action to tumour sites and thus allowing greatly increased cytotoxic action requires more precise restriction of enzyme activity to tumour sites than has been achieved with an antibody vector and natural clearance alone. Assisted clearance mechanisms have been found effective. Alternatively, or additionally, the difference between prodrug and active drug creates the opportunity to degrade active drug selectively in blood and thus protect normal tissues. In order to give more than one cycle of treatment it will be necessary for the antibody-enzyme conjugate to be nonimmunogenic or for the concurrent administration of immunosuppressive agents. A pilot scale clinical trial with a prototype prodrug indicated the feasibility of antibody directed enzyme prodrug therapy (ADEPT).

Agentes antineoplásicos biorredutíveis: uma nova alternativa para o tratamento de tumores sólidos

“…A partir de então, a mostarda (17) vem sendo estudada utilizando-se o sistema ADEPT (AntibodyDirected Enzyme Prodrug Therapy) 89 . Esta terapia fundamenta-se na ativação enzimática de um pró-fármaco usando um conjugado anticorpo-enzima (AEC) específico para antígenos presentes na membrana das células tumorais 90,91 . Neste caso, a enzima utilizada é a nitrorredutase de E. coli.…”

“…Neste caso, a enzima utilizada é a nitrorredutase de E. coli. Em linhas gerais, após administração e distribuição pelo organismo, o AEC liga-se às células tumorais e, em seguida, administra-se a mostarda (17) (pró-fármaco) 90 . Esta é, então, reduzida pela nitrorredutase acoplada ao anticorpo, liberando a mostarda na sua forma ativa (Figura 15), na região do tumor 89 .…”

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 …”

A Fusion Protein of RGD4C and β-Lactamase Has a Favorable Targeting Effect in Its Use in Antibody Directed Enzyme Prodrug Therapy

“…Antibody directed enzyme prodrug therapy (ADEPT) is a targeted therapeutic method based on antibody-enzyme conjugates and prodrugs [1,2], which is a promising approach for targeting treatment of cancer. It is designed to restrict the action of cytotoxic agents at the tumor sites.…”