1. Academic Validation
  2. Therapeutic potential of a TrkB agonistic antibody for ischemic brain injury

Therapeutic potential of a TrkB agonistic antibody for ischemic brain injury

  • Neurobiol Dis. 2019 Jul;127:570-581. doi: 10.1016/j.nbd.2019.04.009.
Fang Han 1 Xiaoming Guan 2 Wei Guo 3 Bai Lu 4
Affiliations

Affiliations

  • 1 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.
  • 2 4B Technologies Limited, Suzhou BioBay, Suzhou, Jiangsu 215123,China.
  • 3 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: wguo@tsinghua.edu.cn.
  • 4 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.
Abstract

The clinical trials employing neuroprotectants targeting single, early pathogenic mechanisms in stroke have so far been barely successful. We found in human postmortem stroke brains that in addition to Apoptosis, Necroptosis also contributed to neuronal damage. Thus, a new strategy targeting both mechanisms might be necessary. While brain-derived neurotrophic factor (BDNF) is a potent survival factor for neurons, its poor bioavailability including low diffusion rate and short half-life makes it unlikely a therapeutic agent. We recently developed a TrkB agonistic antibody (Ab4B19) that mimicked BDNF functionally but exhibited better physicochemical and pharmacological features. We showed that Ab4B19 halted neuronal death in vitro under multiple conditions that simulate ischemia/reperfusion injury, including oxygen-glucose deprivation (OGD), glutamate toxicity, oxidative stress and nutrient deprivation. In a rat model of ischemia/reperfusion, Ab4B19 suppressed both Apoptosis and Necroptosis, leading to a reduction in infarct volume and acceleration of functional recovery from sensorimotor impairments. In neurons derived from human embryonic stem cells (hESCs), Ab4B19 activated TrkB and its downstream signaling, and rescued neuronal death from OGD at a similar level as that in mouse neurons. Together, our study revealed Necroptosis in human stroke brain, and demonstrated a BDNF-based strategy targeting both Apoptosis and Necroptosis for ischemic stroke treatment.

Keywords

Apoptosis; Drug discovery; Monoclonal antibody; Necroptosis; Receptor tyrosine kinase; Stroke; TrkB agonist.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16701
    99.50%, cIAP1/XIAP Antagonist
    IAP