Hard prodrug a hard prodrug is a biologically active compound with a high lipid solubility or high water solubility having along biologic half life eg. Antibodydirected enzymeprodrug therapy adept biochemical. This chapter focuses on a relatively new method for cancer treatment named antibody directed enzyme prodrug therapy adept. The design and synthesis of potent thiocarbamate inhibitors for carboxypeptidase g2 are described. Antibody directed enzyme prodrug therapy, adept, is a recent approach to targeted cancer chemotherapy intended to diminish the nonspecific toxicity associated with many commonly used chemotherapeutic agents.
The key limitation has been immunogenicity of the enzyme. Translating antibody directed enzyme prodrug therapy. We have, therefore, combined two complementary therapies. The therapeutic responses observed so far in the clinic are modest but. Pdf antibody directed enzyme prodrug therapy adept a promising cancer therapy approach antibody directed enzyme prodrug therapy adept a promising cancer therapy approach chapter pdf. In antibodydirected enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.
A phase i trial of antibody directed enzyme prodrug therapy adept. Studies on the adept approach over the last 6 years have indicated its general feasibility. Enhancement of antibodydirected enzyme prodrug therapy. Siteselective prodrug activation results in reduced side effects in remote tissue. Toward antibodydirected enzyme prodrug therapy with the. An antibody designeddeveloped against a tumor antigen is linked to an enzyme and injected to the blood, resulting in selective binding of the enzyme in the tumor. When the discrimination between tumor and normal tissue enzyme levels is sufficient, a prodrug is. First, an antibody enzyme is targeted to the tumour. A phase i trial of antibody directed enzyme prodrug therapy adept in patients with advanced colorectal carcinoma or other cea producing tumours. Systems biology and the mathematical modelling of antibody. Most adept systems incorporate a bacterial enzyme, and thus their potential is reduced because of the immunogenicity of that component of the conjugate. Enzyme prodrug therapy an overview sciencedirect topics. The antibody directed enzyme prodrug therapy, adept, was developed for selective delivery of lethal levels of drugs to tumors, without concomitant damage to normal tissues 108.
Mfecp, an anticarcinoembryonic antibody fragment fused to the enzyme carboxypeptidase g2. The prodrugs substrates for carboxypeptidase g2 cpg2 and yield more cytotoxic drugs than known products of cpg2 catalysed. Antibodydirected enzyme prodrug therapy adept can generate highly localised concentrations of cytotoxic agents directly in a tumour, thereby reducing the collateral toxicity associated with normal tissue exposure. Antibodydirected enzyme prodrug therapy springerlink. Pdf the concept of generating cytotoxic agents from nontoxic prodrugs at tumour sites by antibody vectored enzyme introduces a wide range. Us5587161a prodrugs for antibody directed enzyme prodrug. Sorry, we are unable to provide the full text but you may find it at the following locations. Antibody directed enzyme prodrug therapy adept delivers chemotherapeutic agents in high concentration to tumor tissue while minimizing systemic drug exposure. Although numerous enzyme prodrug combinations have been reported over the last two decades, only. Antibodydirected enzyme prodrug therapy adept was conceived as a means of reducing the toxicity of chemotherapy and improving its efficacy by. In vivoactivity in a catalytic antibodyprodrug system. Important first indications of this potential were demonstrated over 20 years ago, for.
Prodrug cancer therapy is a two step process, the first step. Enhancement of antibodydirected enzyme prodrug therapy in. Nitroreductase genedirected enzyme prodrug therapy. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Pdf antibody directed enzyme prodrug therapy adept. Prodrugs, of generic formula i, are disclosed for use in antibody directed enzyme prodrug therapy adept. This allows for selective activation of a nontoxic prodrug to a cytotoxic agent at the tumor site for cancer therapy. In antibody directed enzyme prodrug therapy, an enzyme conjugated to an. The central part of enzyme prodrug cancer therapy is to deliver drugactivating enzyme. The expanding role of prodrugs in contemporary drug design. In antibody directed enzyme prodrug therapy adept an antibody bound enzyme is targeted to tumor cells. First, a nontoxic antibody enzyme fusion protein is localised in the tumour matrix by binding a specific antigen expressed only on the. Potentiation of antitumor immunity by antibodydirected.
The premise of adept is to target an enzyme of interest specifically to tumor cells by coupling it to a tumorspecific antibody. Antibody directed enzyme prodrug therapy adept adept is a strategy to overcome the problems of lack of tumor selectivity. Antibody directed enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been targeted to the tumour by an antibody. Introduction antibodydirected enzymeprodrug therapy advances in adept conclusion 2 3. Antibody directed enzyme prodrug therapy adept, which targets tumor cells, and an agent that selectively destroys tumor vasculature. Antibodydirected enzyme prodrug therapy adept was conceived as a means of reducing the toxicity of chemotherapy and improving its efficacy by generating the. Antibody directed enzyme prodrug therapy adept is designed to overcome these obstacles to successful therapy bagshawe et al, 1988.
A novel and promising strategy for targeted therapy is the use of moabs to direct enzymes to tumor tissue, which then convert relatively nontoxic prodrugs into active cytostatic agents adept, antibody directed enzyme prodrug therapy. University of groningen studies on superantigens and. These compounds 25a,b,c and 32a,b,c have been designed to generate cytotoxic drugs after activation with. A prodrug is administrated into the blood circulation. Agents that can be administered systemically but that act selectively against cancer cells have been intensively sought but have thus far proved elusive. The antibodydirected enzyme prodrug therapy, adept, was developed for selective delivery of lethal levels of drugs to tumors, without concomitant damage to normal tissues 108. First, an antibodyenzyme is targeted to the tumour. An antibody directed enzyme prodrug therapy adept system against ceapositive tumours is currently in phase i clinical trials. The irregular nature of solid tumor vasculature produces a heterogeneous distribution of antibody targeted therapies within the tumor mass, which frequently results in reduced therapeutic efficacy.
Zd2767p is converted by antibody targeted cpg2 into an. The aim was to measure plasma levels of the prodrug 42chloroethyl2mesyloxyethyl amino benzoyllglutamic acid cmda and the bifunctional alkylating drug cjs11 released from it by the action of tumourlocalised carboxypeptidase g2 cpg2 enzyme. To understand the complexity and to explore optimal therapeutic regimens for adept in vivo, a physiologicallybased pharmacokinetic model pbpk is applied to analyze each anatomical componentorgan. The selective activation of prodrug s in tumor tissues by exogenous enzyme s for cancer therapy can be accomplished by several ways, including gene directed enzyme prodrug therapy gdept, virus directed enzyme prodrug therapy vdept, and antibody directed enzyme prodrug therapy adept. Antibodydirected enzyme prodrug therapy adept springerlink. A phase i trial of antibody directed enzyme prodrug. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibodydirected enzyme prodrug therapy with a5b7 fab. Antibodydirected enzyme prodrug therapy adept has been studied in a human ovarian carcinoma xenograft grown subcutaneously in nude mice. Clinical studies with cpg2 system have shown the feasibility of this approach. Antibodydirected enzyme prodrug therapy adept is a system that aims to restrict the action of a high concentration of a cytotoxic drug to cancer sites. Antibody directed enzyme prodrug therapy adept is an experimental cancer treatment. Predictive physiologicallybased pharmacokinetic pbpk. Glucarpidase has proved particularly useful in antibody directed enzyme prodrug therapy adept, in which it accumulates at the site of a tumor via a tumorspecific antibody, after that it converts a prodrug into an active drug. To understand the complexity and to explore optimal therapeutic regimens for adept in vivo, a physiologically based pharmacokinetic model pbpk is applied to analyze each anatomical componentorgan.
This antibodydirected enzyme prodrug therapy is based upon the use of monoclonal antibody to target an enzyme at the tumor cell surface which ultimately is expected to selectively deliver an. Lectindirected enzymeactivated prodrug therapy pnas. Prodrugs of anthracyclines for use in antibodydirected. Directed enzyme prodrug therapy and adapt antibody directed abzyme prodrug therapy are in initial stages. Antibody directed enzyme prodrug therapy adept, which targets tumor cells, and an agent that selectively destroys tumor. Both native and genetically engineered forms of the pancreatic carboxypeptidases have been used in this cancer therapy. Lactamases are particularly useful enzymes for adept systems due to their unique substrate specificity that allows the activation of a variety of lactambased prodrugs with minimal interference from mammalian enzymes. The therapeutic effectiveness of lectin directed enzyme activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, rhadox, and its application to reduce tumor burden in a hepatocellular carcinoma hepg2 disease model.
Pdf a phase i trial of antibody directed enzyme prodrug. As with other antibody based systems the pharmacokinetics and biodistribution of the antibody. Antibodydirected enzyme prodrug therapy is a targeted therapy in which a prodrug is activated selectively at the tumour site by an enzyme, which has been. Antibody directed enzyme prodrug therapy an overview. Both native and genetically engineered forms of the pancreatic carboxypeptidases have been used in this cancer therapy 86,109. Antibodydirected enzyme prodrug therapy adept is an experimental cancer treatment. In the form of antibody directed enzyme prodrug therapy adept, this approach has shown feasibility in the clinic. The best thiocarbamate inhibitor npmethoxybenzenethiocarbonylaminolglutamic acid 6d, chosen for preliminary investigations of in vitro antibody directed enzyme prodrug therapy adept, abrogated the cytotoxicity of a combination of a5b7.
The tumour located enzyme activates a subsequently administered prodrug. We cover the relevant technologies such as antibody directed enzyme prodrug therapy adept, gene directed enzyme prodrug therapy gdept as well as related therapies such as clostridial cdept and polymer directed enzyme prodrug therapy pdept with emphasis on prodrug converting enzymes, prodrugs and drugs. Systemic administration of a nontoxic agent results in the antibody s conversion to a toxic drug, resulting in a cytotoxic effect that can be targeted at malignant cells. In antibodydirected enzyme prodrug therapy, an enzyme conjugated to an. The generation of cytotoxic drugs, selectively within tumours, from nontoxic prodrugs by targeted enzymes provides a powerful system for cancer therapy. The first step involves the administration of an antibody enzyme conjugate, which targets the tumour. It consists of a prodrug, 4n,nbis2iodoethyl amino phenoxycarbonyl lglutamic acid zd2767p and a conjugate of the fab 2 anticea antibody a5b7 and the bacterial enzyme carboxypeptidase g2 cpg2. Antibody directed enzyme prodrug therapy has the potential to be an effective therapy for most common solid cancers. Antibody directed enzyme prodrug therapy adept adept is a strategy to overcome the problems of lack of tumour selectivity. Regression of established breast carcinoma xenografts with. Construction and characterization of a fusion protein of. Antibody directed enzyme prodrug therapy adept and. The development of fusion proteins has provided the means of making consistent antibody enzyme constructs on an adequate scale, and glycosylation has provided the.
Antibody directed enzyme prodrug therapy adept aims to restrict the cytotoxic action to tumour sites. Directed enzyme prodrug therapy adept ucl discovery. This method has a number of advantages, including the reduction of. Antibodydirected enzyme prodrug therapy for cancer. Strategies for enzymeprodrug cancer therapy clinical. As expected, recovery of the active drug was observed after enzymatic cleavage by escherichia coli. The important aspect of prodrug cancer therapy is to deliver drugactivating enzyme or gene or functional protein to tumor tissues, followed by systemic administration of a prodrug 2. After clearance from healthy tissue, a prodrug is administered and activated by the enzyme. The use of antibody enzyme conjugates directed at tumorassociated antigens to achieve sitespecific activation of prodrugs to potent cytotoxic species, termed antibody directed enzyme prodrug therapy adept, has attracted considerable interest since the concept was first described in 1987. Soft prodrug a soft prodrug is a biologically active.
A series of new prodrugs of daunorubicin and doxorubicin which are candidates for antibodydirected enzyme prodrug therapy adept is reported. An example for such approach is the antibodydirected enzyme prodrug therapy adept or antibody directed catalysis, antigens expressed on tumors cells are utilized to target enzym es to the tumor. Antibodydirected enzyme prodrug therapy adept sciencedirect. The obstacles to achieve this were recognised at the outset, but time and experience have given these better definition.
Blumenkopf, michael cory, joan humphreys, ronald m. Antibody directed enzyme prodrug therapy adept using antitag72 antibody and geldanamycin ga prodrug was validated in vitro. Antibody directed enzyme prodrug therapy adept involves the application of cancerassociated monoclonal antibodies that are linked to a drugactivating enzyme. Adept antibodydirected enzyme prodrug therapy is a novel therapeutic approach that targets an enzyme into tumors to convert a relatively nontoxic prodrug into an active cytotoxic agent. Predictive physiologically based pharmacokinetic model for. Auld, in handbook of proteolytic enzymes third edition, 20.