TrkB agonistic antibodies superior to BDNF: Utility in treating motoneuron degeneration

Neurobiology of Disease

Wutian Wu¹  Shudan Wang²  Vanessa Lopes-Rodrigues²  Wen Zhang²  Jingyu Shao²  Fang Han²  Keliang Pang²  He You³  Hongyang Yao⁴  Hang Liu⁵  Jianying Shen⁵  Heng Li⁵  Yihua Xu⁵  Wei Guo⁵  Bai Lu⁵  Yanbo Chen⁵  Dang Sun⁵  Yang Dou⁵ 

[1] Life Sciences Institute, National University of Singapore, Singapore;R&D Center for the Diagnosis and Treatment of Major Brain Diseases, Research Institute of Tsinghua University in Shenzhen, Shenzhen, Guangdong 518057, China;Department of Physiology, National University of Singapore, Singapore;School of Biomedical Sciences, Division of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China;School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China;

关键词: Receptor tyrosine kinase;    Neurotrophin;    BDNF;    TrkB signaling;    Agonistic antibody;    Monoclonal antibody;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 p75NTR, 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 p75NTR. 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.

【 授权许可】

Unknown