한빛사논문
- 조회1,328
Jong Youl Leea,1, Taehoon Parkb,1, Eunmi Hongc, Reeju Amatyab, Kyung-Ah Parka, Young-Hoon Parkc, Kyoung Ah Mind, Minki Jind, Sumi Leed, Seungmi Hwangd, Gu Seob Roha,*, Meong Cheol Shinb,*
aDepartment of Anatomy and Convergence Medical Science, Bio Anti-Aging Medical Research Center, Institute of Health Sciences, College of Medicine, Gyeongsang National University, Jinju, Gyeongnam, 52727, Republic of Korea
bCollege of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, 501 Jinju Daero, Jinju, Gyeongnam, 660-701, Republic of Korea
cNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, 41061, Republic of Korea
dCollege of Pharmacy and Inje Institute of Pharmaceutical Sciences and Research, Inje University, Gimhae, Gyeongnam, 50834, Republic of Korea
1Jong Youl Lee and Taehoon Park contributed equally to the manuscript.
*Corresponding author.
Abstract
A common bottleneck challenge for many therapeutic proteins lies in their short plasma half-lives, which often makes the treatment far less compliant or even disables achieving sufficient therapeutic efficacy. To address this problem, we introduce a novel drug delivery strategy based on the genetic fusion of an albumin binding domain (ABD) and an anti-neonatal Fc receptor (FcRn) affibody (AFF) to therapeutic proteins. This ABD-AFF fusion strategy can provide a synergistic effect on extending the plasma residence time by, on one hand, preventing the rapid glomerular filtration via ABD-mediated albumin binding and, on the other hand, increasing the efficiency of FcRn-mediated recycling by AFF-mediated high-affinity binding to the FcRn. In this research, we explored the feasibility of applying the ABD-AFF fusion strategy to exendin-4 (EX), a clinically available anti-diabetic peptide possessing a short plasma half-life. The EX-ABD-AFF produced from the E. coli displayed a remarkably (241-fold) longer plasma half-life than the SUMO tagged-EX (SUMO-EX) (0.7 h) in mice. Furthermore, in high-fat diet (HFD)-fed obese mice model, the EX-ABD-AFF could provide significant hypoglycemic effects for over 12 days, accompanied by a reduction of body weight. In the long-term study, the EX-ABD-AFF could significantly reverse the obesity-related metabolic complications (hyperglycemia, hyperlipidemia, and hepatic steatosis) and, moreover, improve cognitive deficits. Overall, this study demonstrated that the ABD-AFF fusion could be an effective strategy to greatly increase the plasma half-lives of therapeutic proteins and thus markedly improve their druggability.
논문정보
- Research article
- 2020년 07월 (BRIC 등록일 2020-07-27)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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