Characterization of in vivo biotransformations for trastuzumab emtansine by high-resolution accurate-mass mass spectrometry. Issue 7 (3rd October 2018)

• Record Type: Journal Article
• Authors: He, Jintang; Yu, Shang-Fan; Yee, Sharon; Kaur, Surinder; Xu, Keyang
• Is Part Of: MAbs. Volume 10:Issue 7(2018)
• Page Start: 960
• Page End: 967
• Publication Date: 2018-10-03
• Subjects: T-DM1 -- biotransformation -- catabolites -- maleimide exchange -- hydrolysis -- high resolution -- mass spectrometry; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2018.1494487
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) designed for the treatment of HER2-positive cancers. T-DM1 is composed of the humanized monoclonal antibody trastuzumab connected to a maytansine derivative cytotoxic drug, via a nonreducible thioether linker at random lysine residues, and therefore has a very complex molecular structure. It was anticipated that T-DM1 undergoes biotransformations in circulation. However, there was limited knowledge on these structural changes due to bioanalytical challenges. Here, we have investigated the in vivo biotransformations of T-DM1 using a high-resolution accurate-mass (HR/AM) mass spectrometry approach. Three types of biotransformations were characterized for T-DM1 in circulation in tumor-bearing mice, including cysteine or glutathione adduct formation via maleimide exchange, loss of maytansinol via ester hydrolysis, as well as addition of H2 O via linker-drug hydrolysis. These results provide new insights into in vivo catabolism of T-DM1.