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.
School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.
Neurobiol Dis. 2019 Dec;132:104590. doi: 10.1016/j.nbd.2019.104590. Epub 2019 Aug 27.
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, 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. 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.
脑源性神经营养因子（BDNF）长期以来一直被认为可用于治疗神经疾病，但重组 BDNF 蛋白在多项临床试验中均以失败告终。除了不稳定和粘性的性质外，BDNF 还可以激活 p75，这是一种介导与 TrkB 相反的细胞功能的受体。我们现在已经确定了几种具有优于 BDNF 的特性的 TrkB 激动性抗体（TrkB-agoAbs）：它们的血液半衰期为几天而不是几小时，在神经组织中的扩散距离为几厘米而不是几毫米，并且与 TrkB 结合并激活 TrkB，但不与 p75 结合。此外，与 BDNF 相比，TrkB-agoAbs 引发的 TrkB 激活时间更长，TrkB 内化减少，细胞内降解减少。更重要的是，其中一些 TrkB-agoAbs 与 BDNF 结合的 TrkB 表位不同，并且与内源性 BDNF 协同作用。与 BDNF 不同，TrkB-agoAbs 的半衰期为几天/几周，并且很容易在神经组织中扩散。我们进一步测试了一种 TrkB-agoAbs，并表明它可以增强脊髓神经根撕脱模型中体内运动神经元退化的运动神经元存活。因此，TrkB-agoAbs 是治疗神经损伤的有前途的药物候选物。
