A Phase I Study of Single Administration of Antibody-Directed Enzyme Prodrug Therapy with the Recombinant Anti–Carcinoembryonic Antigen Antibody-Enzyme Fusion Protein MFECP1 and a Bis-Iodo Phenol Mustard Prodrug

Abstract

Purpose: Antibody-directed enzyme prodrug therapy is a two-stage treatment whereby a tumor-targeted antibody-enzyme complex localizes in tumor for selective conversion of prodrug. The purpose of this study was to establish optimal variables for single administration of MFECP1, a recombinant antibody-enzyme fusion protein of an anti^carcinoembryonic antigen singlechain Fv antibody and the bacterial enzyme carboxypeptidase G2 followed by a bis-iodo phenol mustard prodrug. MFECP1 is manufactured in mannosylated form to facilitate normal tissue elimination. Experimental Design: Pharmacokinetic, biodistribution, and tumor localization studies were used to test the hypothesis that MFECP1localizes in tumor and clears from normal tissue via the liver. Firstly, safety of MFECP1 and a blood concentration of MFECP1 that would avoid systemic prodrug activation were tested. Secondly, dose escalation of prodrug was done. Thirdly, the dose of MFECP1and timing of prodrug administration were optimized. Results: MFECP1was safe and well tolerated, cleared rapidly via the liver, and was less immunogenic than previously used products. Eighty-fold dose escalation from the starting dose of prodrug was carried out before dose-limiting toxicity occurred. Confirmation of the presence of enzyme in tumor and DNA interstrand cross-links indicating prodrug activation were obtained for the optimal dose and time point. A total of 28 of 31patients was evaluable for response, the best response being a 10% reduction of tumor diameter, and 11of 28 patients had stable disease. Conclusions: Optimal conditions for effective therapy were established. A study testing repeat treatment is currently being undertaken.

Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo

“…A number of similar VDEPT systems have also been developed, including the carboxypeptidase G2 (CPG2)/ZD2767P combination. 23 ZD2767P has been used in clinical trials of antibody-directed enzyme prodrug therapy, 24 and a future trial of a replicationcompetent adenoviral vector expressing CPG2 is in the planning stages. Interestingly, ZD2767P is metabolized by CPG2 into a potent alkylating agent that is highly likely to enhance the effects of radiation.…”

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

“…Several scFvs are now in different stages of clinical trials for the treatment of various cancers [127,128]. An Anti-CD22 scFv [129] and an anti-mesothelin scFv [130] have been conjugated to Pseudomonas exotoxin A (PE), whereas others, such as an anti-CEA scFv [128], are fused to an enzyme and are used in antibody-directed enzyme prodrug therapy (ADEPT) as pre-targeting agents.…”

“…An Anti-CD22 scFv [129] and an anti-mesothelin scFv [130] have been conjugated to Pseudomonas exotoxin A (PE), whereas others, such as an anti-CEA scFv [128], are fused to an enzyme and are used in antibody-directed enzyme prodrug therapy (ADEPT) as pre-targeting agents. For the scFv-PE fusion protein, each scFv molecule carries a payload of one high potency PE molecule.…”

“…For the scFv-PE fusion protein, each scFv molecule carries a payload of one high potency PE molecule. For less potent therapeutics, the dose of scFv needed for therapeutic efficacy may become excessively high, which would not only become prohibitively expensive, but could also increase the frequency of adverse effects, such as the immunogenic reactions reported by Mayer [128]. Nevertheless, the success of scFv-targeted alternative therapeutics will pave the way for the clinical acceptance of scFvtargeted SIL drugs.…”

Attenuated Salmonella Targets Prodrug Activating Enzyme Carboxypeptidase G2 to Mouse Melanoma and Human Breast and Colon Carcinomas for Effective Suicide Gene Therapy

“…CPG2 plus another prodrug, 1 (4-[bis(2-iodoethyl)amino]-phenyloxycarbonyl-L-glutamic acid), is the second antibody-directed enzyme prodrug therapy system to reach clinical trials (25). The safe dose of 4-[bis(2-iodoethyl)amino]-phenyloxycarbonyl-L-glutamic acid depended on dose of CPG2 antibody and time allowed for blood clearance, but typically 537.6 mg/m 2 was safe when circulating enzyme was <0.005 units CPG2/mL, giving rise to an AUC inf of 3,408 Ag/mL min, dose-limiting toxicities being liver, kidney, and marrow (25). Gene-directed enzyme prodrug therapy with CPG2 has also been developed and we have recently described a conditionally replicating oncolytic adenoviral vector that leads to expression of CPG2 selectively in telomerase-positive tumor cells.…”