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Optimization of an Enzymatic Antibody Drug Conjugation Ap-proach based on CoA Analogs

Grunewald, Jan, Jin, Yunho, Vance, Julie, Read, Jessica, Wang, William, Wan, Yongqin, Zhou, Huanfang, Ou, Weijia, Klock, Heath, Peters, Eric, Uno, Tetsuo, Brock, Ansgar and Geierstanger, Bernhard (2017) Optimization of an Enzymatic Antibody Drug Conjugation Ap-proach based on CoA Analogs. Bioconjugate chemistry. ISSN 1520-4812; 1043-1802


Phosphopantetheine transferases (PPTases) can be used to efficiently prepare site-specific antibody-drug-conjugates (ADCs) by enzymatically coupling CoA-linker-payloads to 11-12 amino acid peptide substrates inserted into antibodies. Here, a two-step strategy is established wherein in a first step, CoA analogs with various bioorthogonal reactivities are enzymatically installed on the antibody for chemical conjugation with a cytotoxic payload in a second step. Be-cause of high structural similarity of these CoA analogs to the natural PPTase substrate CoA-SH, the first step pro-ceeds very efficiently and enables using peptide tags as short as 6 amino acids compared to the 11-12 amino acids required for efficient one-step coupling of the payload molecule. Fur-thermore, two-step conjugation provides access to diverse linker chemistries and spacers of varying lengths. The po-tency of the ADCs was largely independent of linker archi-tecture. In mice proteolytic cleavage was observed for some C-terminally linked auristatin payloads. The in vivo stability of these ADCs was significantly improved by reducing the linker length. In addition, linker stability was found to be modulated by attachment site, and this, together with linker length, provides an opportunity for maximizing ADC stabil-ity without sacrificing potency.

Item Type: Article
Date Deposited: 22 Jun 2017 00:45
Last Modified: 22 Jun 2017 00:45