Dissecting the impact of target-binding kinetics of protein binders on tumor localization

Yunjin Song; Hoibin Jeong; Song-Rae Kim; Yiseul Ryu; Jonghwi Baek; Jinhak Kwon; Hyeongjun Cho; Kil-Nam Kim; Joong-Jae Lee

doi:10.1016/j.isci.2021.102104

Dissecting the impact of target-binding kinetics of protein binders on tumor localization

iScience. 2021 Jan 29;24(2):102104. doi: 10.1016/j.isci.2021.102104. eCollection 2021 Feb 19.

Authors

Yunjin Song¹, Hoibin Jeong², Song-Rae Kim², Yiseul Ryu³, Jonghwi Baek¹, Jinhak Kwon¹, Hyeongjun Cho¹, Kil-Nam Kim², Joong-Jae Lee^{1

3

4}

Affiliations

¹ Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea.
² Chuncheon Center, Korea Basic Science Institute (KBSI), Chuncheon 24341, South Korea.
³ Institute of Life Sciences (ILS), Kangwon National University, Chuncheon 24341, South Korea.
⁴ Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon 24341, South Korea.

Abstract

Systematic control of in vivo behavior of protein-based therapeutics is considered highly desirable for improving their clinical outcomes. Modulation of biochemical properties including molecular weight, surface charge, and binding affinity has thus been suggested to enhance their therapeutic effects. However, establishing a relationship between the binding affinity and tumor localization remains a debated issue. Here we investigate the influence of the binding affinity of proteins on tumor localization by using four repebodies having different affinities to EGFR. Biochemical analysis and molecular imaging provided direct evidence that optimal affinity with balanced target binding and dissociation can facilitate deep penetration and accumulation of protein binders in tumors by overcoming the binding-site-barrier effect. Our findings suggest that binding kinetics-based protein design can be implicated in the development of fine-tuned protein therapeutics for cancers.

Keywords: biochemistry; immunology; molecular medicine.