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
Affiliations
Yunjin Song
Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
Hoibin Jeong
Chuncheon Center, Korea Basic Science Institute (KBSI), Chuncheon 24341, South Korea
Song-Rae Kim
Chuncheon Center, Korea Basic Science Institute (KBSI), Chuncheon 24341, South Korea
Yiseul Ryu
Institute of Life Sciences (ILS), Kangwon National University, Chuncheon 24341, South Korea
Jonghwi Baek
Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
Jinhak Kwon
Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
Hyeongjun Cho
Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea
Kil-Nam Kim
Chuncheon Center, Korea Basic Science Institute (KBSI), Chuncheon 24341, South Korea; Corresponding author
Joong-jae Lee
Department of Biochemistry, Kangwon National University, Chuncheon 24341, South Korea; Institute of Life Sciences (ILS), Kangwon National University, Chuncheon 24341, South Korea; Global/Gangwon Innovative Biologics-Regional Leading Research Center (GIB-RLRC), Kangwon National University, Chuncheon 24341, South Korea; Corresponding author
Summary: 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.
