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

NEUROBIOLOGY OF DISEASE

卷:132

Article

Guo, Wei^1,2  Pang, Keliang^1,2  Chen, Yanbo¹  Wang, Shudan^1,2  Li, Heng⁴  Xu, Yihua^1,2  Han, Fang^1,2  Yao, Hongyang¹  Liu, Hang^1,2  Lopes-Rodrigues, Vanessa^5,6  Sun, Dang¹  Shao, Jingyu¹  Shen, Jianying^1,7  Dou, Yang¹  Zhang, Wen¹  You, He¹  Wu, Wutian^3,4  Lu, Bai^1,2 

[1] Tsinghua Univ, IDG McGovern Inst Brain Res, Sch Pharmaceut Sci, Beijing 100084, Peoples R China

[2] Tsinghua Univ Shenzhen, Res Inst, R&D Ctr Diag & Treatment Major Brain Dis, Shenzhen, Guangdong 518057, Peoples R China

[3] Jinan Univ, Guangdong Hong Kong Macau Inst CNS Regenerat, Guangzhou, Guangdong, Peoples R China

[4] Univ Hong Kong, Div Anat, Sch Biomed Sci, Pokfulam, Hong Kong, Peoples R China

[5] Natl Univ Singapore, Dept Physiol, Singapore, Singapore

[6] Natl Univ Singapore, Life Sci Inst, Singapore, Singapore

[7] China Acad Chinese Med Sci, Inst Chinese Mat Med, Artemisinin Res Ctr, Beijing 100084, Peoples R China

关键词: Receptor tyrosine kinase;    Neurotrophin;    BDNF;    TrkB signaling;    Agonistic antibody;    Monoclonal antibody;    p75(NTR);    Drug discovery;    Motoneuron degeneration;    ALS;   

DOI  :  10.1016/j.nbd.2019.104590

来源: Elsevier

【 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 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 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.

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