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

• Published in: Neurobiology of disease 2019-12, Vol.132, p.104590-104590, Article 104590
• Main Authors: Guo, Wei, Pang, Keliang, Chen, Yanbo, Wang, Shudan, Li, Heng, Xu, Yihua, Han, Fang, Yao, Hongyang, Liu, Hang, Lopes-Rodrigues, Vanessa, Sun, Dang, Shao, Jingyu, Shen, Jianying, Dou, Yang, Zhang, Wen, You, He, Wu, Wutian, Lu, Bai
• Format: Article
• Language: English
• Subjects: Agonistic antibody; ALS; BDNF; Drug discovery; Monoclonal antibody; Motoneuron degeneration; Neurotrophin; p75NTR; Receptor tyrosine kinase; TrkB signaling
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.104590

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. •Unlike BDNF, TrkB agonistic antibodies selectively bind TrkB but not p75NTR.•They exhibit longer blood half-life of days and diffuse readily in neural tissues.•A candidate antibody (Ab4B19) binds to a domain on TrkB distinct from that by BDNF.•Ab4B19elicitsa longer signaling and works cooperatively with endogenous BDNF.•Ab4B19 enhances motoneuron survival in both in vitro and in vivo models.