Metabolism of an Oxime-Linked Antibody Drug Conjugate, AGS62P1, and Characterization of Its Identified Metabolite
| Autor: | Akihiro Okada, Julien Dugal-Tessier, Maria-Christina Malinao, Brian A. Mendelsohn, John E Atkinson, Banmeet Anand, Josh Snyder |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Antibody-drug conjugate ERG1 Potassium Channel Immunoconjugates medicine.drug_class Metabolite Pharmaceutical Science Phenylalanine Antineoplastic Agents Mice SCID Monoclonal antibody 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Pharmacokinetics Cell Line Tumor Drug Discovery Oximes medicine Animals Humans chemistry.chemical_classification biology Chemistry Primary metabolite Xenograft Model Antitumor Assays Rats Leukemia Myeloid Acute Macaca fascicularis 030104 developmental biology Enzyme Biochemistry fms-Like Tyrosine Kinase 3 030220 oncology & carcinogenesis biology.protein Molecular Medicine Antibody |
| Zdroj: | Molecular pharmaceutics. 15(6) |
| ISSN: | 1543-8392 |
| Popis: | AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time. AGS62P1 metabolism was assessed in xenograft tumor-bearing mice and rats treated with the ADC using liquid chromatography and mass spectrometry-based methods described herein. In this study, we identified the metabolite of AGS62P1 as pAF-AGL-0185-30, which contains a fragment resulting from the catabolism of the antibody component of the ADC and hydrolysis of the terminal amide portion of the linker-payload. We demonstrated that the metabolite of AGS62P1 is tolerated in rats above 1.5 mg/kg and above 0.334 mg/kg in cynomolgus monkeys when given as a single dose. Furthermore, we established in vitro that pAF-AGL-0185-30 does not significantly inhibit hERG or cytochrome P450 family enzymes (CYPs). |
| Databáze: | OpenAIRE |
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