김대성 (아주대학교) | 한빛사논문 > 한빛사

한빛사논문

조회98

아주대학교

인터뷰 보기

J. Control. Release, Apr 11 2025, S0168-3659(25)00347-5 | https://doi.org/10.1016/j.jconrel.2025.113727 Engineering IgG antibodies for intracellular targeting and drug delivery

Dae-Seong Kim ^a,1, Seung-Eun Kim^a,1, Jeong-Seon Byeon ^a,1, Hyun-Jin Lee ^a, Ji-Won Kim ^b, Haelyn Kim ^c, Byeong-Ho Chae ^a, Deok-Han Ko^a, Seul-Gi Lee ^a, Sang-Rok Yoon ^a, Juyong Lee ^c,d, Jeong-Sun Kim ^b, Yong-Sung Kim^a,e

^aDepartment of Molecular Science and Technology, College of Engineering, Ajou University, Suwon 16499, Republic of Korea
^bDepartment of Chemistry, Chonnam National University, Gwangju 61186, Republic of Korea
^cDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
^dResearch Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
^eAdvanced college of Bio-Convergence Engineering, Ajou University, Suwon 16499, Republic of Korea
¹These authors contributed equally to this work.
Corresponding author: Yong-Sung Kim

Abstract

Enabling immunoglobulin G (IgG)-format antibodies to autonomously internalize and localize in the cytosol of targeted cells-referred to as cytosol-penetrating antibodies (cytotransmab, CT)-is challenging yet highly promising. A primary barrier to cytosolic access for CT is limited endosomal escape. Herein, we developed a second-generation (2G) CT, named in2CT4.1, featuring an endosomal acidic pH-responsive endosomal escape motif (R-W/E motif) with Arg-Trp pairs and a Glu patch in the CH3 and CL domains of IgG1/κ antibody. This motif selectively destabilizes endosomal membranes at endosomal acidic pH to facilitate cytosolic access while remaining inactive at neutral pH. The 2G CT, in2CT4.1, achieves efficient cytosolic localization at nanomolar concentrations, demonstrating approximately 3-fold higher endosomal escape efficiency compared to the first-generation CT. The potential of 2G CT is validated by engineering a cytosolic α-tubulin-targeting CT via an α-tubulin-specific variable domain in in2CT4.1. Additionally, the 2G CT effectively delivers the catalytic domain of diphtheria toxin to the cytosol of epidermal growth factor receptor-overexpressing tumor cells, resulting in near-complete suppression of tumor growth in a xenograft mouse model. These results establish 2G CT as a versatile platform for targeting cytosolic proteins and delivering therapeutic payloads, with broad potential in targeted cancer therapy and other applications.

논문정보

형식Research article
게재일2025년 04월 (BRIC 등록일 2025-04-14)
연구진국내 연구진
분야 의약학 > 면역의학

댓글 작성 로그인

CV 열람하기

연락처 보기