PMID- 31470106 OWN - NLM STAT- MEDLINE DCOM- 20200806 LR - 20200806 IS - 1095-953X (Electronic) IS - 0969-9961 (Linking) VI - 132 DP - 2019 Dec TI - TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration. PG - 104590 LID - S0969-9961(19)30258-X [pii] LID - 10.1016/j.nbd.2019.104590 [doi] AB - While Brain-derived Neurotrophic Factor (BDNF) has long been implicated in treating neurological diseases, recombinant BDNF protein has failed in multiple clinical trials. In addition to its unstable and adhesive nature, BDNF can activate p75(NTR), a receptor mediating cellular functions opposite to those of TrkB. We have now identified TrkB agonistic antibodies (TrkB-agoAbs) with several properties superior to BDNF: They exhibit blood half-life of days instead of hours, diffuse centimeters in neural tissues instead millimeters, and bind and activate TrkB, but not p75(NTR). In addition, TrkB-agoAbs elicit much longer TrkB activation, reduced TrkB internalization and less intracellular degradation, compared with BDNF. More importantly, some of these TrkB-agoAbs bind TrkB epitopes distinct from that by BDNF, and work cooperatively with endogenous BDNF. Unlike BDNF, the TrkB-agoAbs exhibit a half-life of days/weeks and diffused readily in nerve tissues. We tested one of TrkB-agoAbs further and showed that it enhanced motoneuron survival in the spinal-root avulsion model for motoneuron degeneration in vivo. Thus, TrkB-agoAbs are promising drug candidates for the treatment of neural injury. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Guo, Wei AU - Guo W AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Pang, Keliang AU - Pang K AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Chen, Yanbo AU - Chen Y AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Wang, Shudan AU - Wang S AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Li, Heng AU - Li H AD - School of Biomedical Sciences, Division of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. FAU - Xu, Yihua AU - Xu Y AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Han, Fang AU - Han F AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Yao, Hongyang AU - Yao H AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Liu, Hang AU - Liu H AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. FAU - Lopes-Rodrigues, Vanessa AU - Lopes-Rodrigues V AD - Department of Physiology, National University of Singapore, Singapore; Life Sciences Institute, National University of Singapore, Singapore. FAU - Sun, Dang AU - Sun D AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Shao, Jingyu AU - Shao J AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Shen, Jianying AU - Shen J AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100084, China. FAU - Dou, Yang AU - Dou Y AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Zhang, Wen AU - Zhang W AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - You, He AU - You H AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China. FAU - Wu, Wutian AU - Wu W AD - Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou, Guangdong Province, China; School of Biomedical Sciences, Division of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China. FAU - Lu, Bai AU - Lu B AD - School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China; R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China. Electronic address: bai_lu@tsinghua.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190827 PL - United States TA - Neurobiol Dis JT - Neurobiology of disease JID - 9500169 RN - 0 (Antibodies, Monoclonal) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Neuroprotective Agents) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Antibodies, Monoclonal/*pharmacology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Humans MH - Motor Neurons/*drug effects/pathology MH - Nerve Degeneration/*pathology MH - Neuroprotective Agents/*pharmacology MH - Receptor, trkB/*agonists OTO - NOTNLM OT - ALS OT - Agonistic antibody OT - BDNF OT - Drug discovery OT - Monoclonal antibody OT - Motoneuron degeneration OT - Neurotrophin OT - Receptor tyrosine kinase OT - TrkB signaling OT - p75(NTR) EDAT- 2019/08/31 06:00 MHDA- 2020/08/07 06:00 CRDT- 2019/08/31 06:00 PHST- 2019/07/07 00:00 [received] PHST- 2019/08/18 00:00 [revised] PHST- 2019/08/26 00:00 [accepted] PHST- 2019/08/31 06:00 [pubmed] PHST- 2020/08/07 06:00 [medline] PHST- 2019/08/31 06:00 [entrez] AID - S0969-9961(19)30258-X [pii] AID - 10.1016/j.nbd.2019.104590 [doi] PST - ppublish SO - Neurobiol Dis. 2019 Dec;132:104590. doi: 10.1016/j.nbd.2019.104590. Epub 2019 Aug 27.