Page 8 - P. Molecular medicine and imaging

[P. Molecular medicine and imaging-5]

Target-switchable Intracellular Bacterial Toxin Delivery

Systems with improved therapeutic efficacy against target

tumor

Seong Guk Park¹˙#, Bongseo Choi¹˙²˙#, Yoonji Bae¹, Yu Geon Lee¹, Soo Ah Park³, Young Chan Chae¹˙*,

Sebyung Kang¹˙*

¹Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology

(UNIST), Ulsan 44919, Korea, ²Department of Radiology, Feinberg School of Medicine, Northwestern University,
Chicago 60611, United States, ³In Vivo Research Center, Ulsan National Institute of Science and Technology
(UNIST), Ulsan 44919, Korea

Targeted cancer therapies have been extensively developed to selectively suppress tumor growth as well as to avoid
harming healthy tissues. However, failure to escape endosome upon endocytosis is a major obstacle limiting the

efficacy of protein-based targeted cancer therapeutics. Here, we developed novel target-switchable intracellular
toxin delivery systems (TiTDS) by using diphtheria toxin (DTA) as an intracellular toxin delivery platform and affinity

molecules targeting human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR)
as target-specific ligands. These modules were post-translationally ligated by protein ligation system to form

complete TiTDS (DTA/HER2Afb or DTA/EGFRAfb). They were selectively endocytosed to their corresponding target
cancer cells, successfully escaped endosome, released to the cytosol, and killed them. With versatile target-

switchability, they exhibited high cytotoxicity without any significant off-target effect in vitro and significantly
suppressed growth of target tumors in vivo. The TiTDS developed here would be promising targeted cancer
therapeutic platforms because of their high target specificity with improved therapeutic efficacy.