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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Variations of this approach (e.g., Gene Directed Enzyme Prodrug Therapy [or GDEPT] and Virus Directed Enzyme Prodrug Therapy [or VDEPT]) were later established in which the activating enzyme is introduced through organ-specific gene therapy or other means rather than through an antibody-enzyme conjugate. GDEPT is one of the most successful prodrug delivery approaches that utilize transgenes to encode enzymes that can convert prodrugs into active therapeutic metabolites. Systems that use viral vectors to deliver the gene are known as VDEPT (i.e., Viral-Directed Enzyme-Produg Therapy). The most well-known carboxypeptidase G2-based ADEPT system that reached clinical trials is described in more detail below.
Respiratory, endocrine, cardiac, and renal topics
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
In case of poisoning occurring during the administration of high doses of methotrexate, hyper-hydration is continued, the doses of folinic acid are increased, and one can use carboxypeptidase G2 [14,15], which is now commercially available (Voraxase®). This is an enzyme, which hydrolyses methotrexate into its non toxic DAMPA metabolite.
Selective Drug Delivery Using Targeted Enzymes For Prodrug Activation
Published in Siegfried Matzku, Rolf A. Stahel, Antibodies in Diagnosis and Therapy, 2019
Nathan O. Siemers, Peter D. Senter
A number of in vivo experiments have been reported using bacterial carboxypeptidase G2 (CPG2) for prodrug activation. ICR12, a mAb that recognizes the HER-2 antigen on some breast carcinomas was covalently linked to CPG2, and tested for in vivo antitumor activity (Eccles et al., 1994). In this case, conjugate cleared very slowly from the blood, requiring a 12-14 day delay before a nitrogen mustard prodrug could be administered. Even after such a delay, the conjugate tumor: blood ratio was only 2:1. Despite this poor localization, a single dose of a glutamic acid mustard prodrug resulted in long term regressions in the animals treated with the anti HER-2-CPG2 conjugate (Figure 3D).
Treatment of two cases on the same day of intrathecal methotrexate overdose using cerebrospinal fluid exchange and intrathecal instillation of carboxypeptidase-G2
Published in Pediatric Hematology and Oncology, 2018
Ole Mikal Wormdal, Trond Flægstad, Tore Stokland
Several sources indicate that the preferred treatment of this medical emergency is intrathecal administration of the enzyme glucarpidase.2,8,11 Glucarpidase is a recombinant form of the bacterial enzyme carboxypeptidase-G2 which rapidly converts MTX to glutamate and 2,4-diamino-N(10)-methylpteroic acid.12 These substances are much less toxic compared to MTX. Glucarpidase is mainly used in cases of delayed excretion of MTX after intravenous treatment, or after intravenous MTX overdoses. In such circumstances, the treatment with glucarpidase is less urgent, and thus the substance was not present in our hospital at the time of this overdose. Widemann et al reports fast and extensive (>98%) elimination of MTX from CSF after intrathecal administration of glucarpidase in seven patients. There were no significant toxicity.8 We ordered the medicine transported to us when the error was discovered. As expected, many of the symptoms disappeared quickly after IT administration of glucarpidase.
Prodrugs for targeted cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Carla Souza, Diogo Silva Pellosi, Antonio Claudio Tedesco
The majority of enzyme ADEPT systems only reach the preclinical stage, and only the carboxypeptidase G2 (CPG2) system has progressed to clinical trial [123]. The ADEPT strategy using CPG2 and a bis-iodo phenol mustard prodrug was evaluated in a phase I study. The system was formed by the conjugation of the antibody-enzyme fusion protein MFECP1 and 4[di(2-iodoethyl)amino]phenyloxy-carbonyl-L-glutaminate as a prodrug (ZD2767P). MFECP1 is a recombinant fusion protein of CPG2, a bacterial enzyme isolated from Pseudomonas sp. that has no known human analog and converts the bis-iodo phenol mustard prodrug into an active drug by the cleavage of the glutamate moiety. But this system showed short half-life with quick elimination and limited normal tissue toxicity [130,131].
The role of therapeutic drug monitoring in the management of safety of anticancer agents: a focus on 3 cytotoxics
Published in Expert Opinion on Drug Safety, 2019
Dominique Levêque, Guillaume Becker
Methotrexate (MW: 454) is an antifolate agent used at high dose (i.e. >1g/m2 intravenously) in the treatment of various types of cancers (acute lymphoblastic leukemia, non Hodgkin lymphomas, osteosarcomas, medulloblastoma) [38]. Methotrexate is mostly cleared by the kidneys (90%) with a small contribution of hepatic metabolism generating 7-hydroxy methotrexate. The terminal half-life varies between 8 and 15 h and the systemic clearance is around 50–135 mL/min/m2 [38]. The major side effects are hematologic (anemia, leucopenia, thrombocytopenia), hepatic, gastrointestinal, mucosal [39]. At high dose (>1 g/m2), methotrexate may also induce acute kidney injury due to crystallization in the nephrons leading to a delay in the elimination and consequently to an increase in the systemic toxicity [38]. High-dose methotrexate side effects are prevented by the addition of folinate and measures favoring optimal renal elimination (hyperhydration and urine alkalinization to optimize the solubility of the parent drug and the metabolite). In case of delayed elimination associated with severe renal injury, the use of the costly antidote glucarpidase (previously referred as carboxypeptidase G2) an enzyme that cleaves methotrexate rapidly in the vascular space must be considered [38]. Methotrexate clearance displayed great variations (intrapatient variability: 48%; interpatient variability: 52%) [38]. However, in routine practice, methotrexate plasma concentration analysis is used only to monitor the elimination. Despite the implementation of measures that optimize the renal elimination after high-dose administration, it remains a risk of overexposure. Initially, R Stoller et al. [10] defined as 0.9 µM the 48 h methotrexate plasma concentration above which severe myelotoxicity occurred. Threshold concentrations and time points may differ according to protocols or publications. Thus, a pediatric consensus conference has defined the methotrexate plasma concentrations associated with nephrotoxicity in children with acute lymphoblastic leukemia (above 20 µM at 36 h, 10 µM at 42 h and/or 5 µM at 48 h) [39]. The standard procedure is to administer folinate (rescue agent) at 50 mg/m2 intravenously every 6 h for 48 h after the start of methotrexate infusion. According to methotrexate plasma concentrations, supplemental injections of folinate are provided generally until they fell under 0.1 µM.