Metabolism of an Oxime-Linked Antibody Drug Conjugate, AGS62P1, and Characterization of Its Identified Metabolite

Molecular Pharmaceutics
Josh T SnyderBrian A Mendelsohn

Abstract

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 ...Continue Reading

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Citations

Jun 5, 2019·Marine Drugs·David J Newman
Mar 3, 2020·Chemical & Pharmaceutical Bulletin·Michinori AkaiwaBrian A Mendelsohn
Mar 21, 2020·SLAS Discovery·Laurence Gauzy-LazoMarie-Priscille Brun
Aug 29, 2020·Expert Opinion on Biological Therapy·Roland B Walter
Oct 22, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Umbreen HafeezAndrew M Scott
Dec 9, 2020·Journal of Hematology & Oncology·Jing Xu, Ting Niu
Dec 9, 2020·Chemical Society Reviews·Stephen J WalshDavid R Spring
Mar 19, 2021·Chemical Society Reviews·Yufei XueNicolas Hans Voelcker
Mar 25, 2021·Nature Reviews. Clinical Oncology·Elias JabbourHagop Kantarjian

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