Endosomal acidic pH-induced conformational changes of a cytosol-penetrating antibody mediate endosomal escape

Ji Sun Kim, Dong Ki Choi, Ju Yeon Shin, Seung Min Shin, Seong Wook Park, Hyun Soo Cho, Yong Sung Kim

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


Endosomal escape after endocytosis is a critical step for protein-based agents to exhibit their effects in the cytosol of cells. However, antibodies internalized into cells by endocytosis cannot reach the cytosol due to their inability to escape from endosomes. Here, we report a unique endosomal escape mechanism of the IgG-format TMab4 antibody, which can reach the cytosol of living cells after internalization. Dissociation of TMab4 from its cell surface receptor heparan sulfate proteoglycan by activated heparanase in acidified early endosomes and then local structural changes of the endosomal escape motif of TMab4 in response to the acidified endosomal pH were critical for the formation of membrane pores through which TMab4 escaped into the cytosol. Identification of structural determinants of endosomal escape led us to generate a TMab4 variant with ~ 3-fold improved endosomal escape efficiency. Our finding of the endosomal escape mechanism of the cytosol-penetrating antibody and its improvement will establish a platform technology that enables a full-length IgG antibody to directly target cytosolic proteins.

Original languageEnglish
Pages (from-to)165-175
Number of pages11
JournalJournal of Controlled Release
Publication statusPublished - 2016 Aug 10

Bibliographical note

Funding Information:
This work was supported by grants from the Pioneer Research Center Program ( 2014M3C1A3051470 ) and the Global Frontier Project ( 2013M3A6A4043874 ) from the National Research Foundation funded by the Korean government.

Publisher Copyright:
© 2016 Elsevier B.V.

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science


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