3 years ago

Optimization of an Enzymatic Antibody–Drug Conjugation Approach Based on Coenzyme A Analogs

Optimization of an Enzymatic Antibody–Drug Conjugation Approach Based on Coenzyme A Analogs
Yongqin Wan, Ansgar Brock, Jessica Read, Weijia Ou, Xing Wang, Eric C. Peters, Huanfang Zhou, Tetsuo Uno, Heath E. Klock, Yunho Jin, Bernhard H. Geierstanger, Julie Vance, Jan Grünewald
Phosphopantetheine transferases (PPTases) can be used to efficiently prepare site-specific antibody–drug conjugates (ADCs) by enzymatically coupling coenzyme A (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. Because of the high structural similarity of these CoA analogs to the natural PPTase substrate CoA-SH, the first step proceeds very efficiently and enables the use of 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. Furthermore, two-step conjugation provides access to diverse linker chemistries and spacers of varying lengths. The potency of the ADCs was largely independent of linker architecture. In mice, proteolytic cleavage was observed for some C-terminally linked auristatin payloads. The in vivo stability of these ADCs was significantly improved by reduction of 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 stability without sacrificing potency.

Publisher URL: http://dx.doi.org/10.1021/acs.bioconjchem.7b00236

DOI: 10.1021/acs.bioconjchem.7b00236

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.