Journal
NEUROBIOLOGY OF DISEASE
Volume 132, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.104590
Keywords
Receptor tyrosine kinase; Neurotrophin; BDNF; TrkB signaling; Agonistic antibody; Monoclonal antibody; p75(NTR); Drug discovery; Motoneuron degeneration; ALS
Categories
Funding
- National Natural Science Foundation of China [81501105, 31730034]
- Ministry of Education (Thousand Talent Program)
- Shenzhen Science Technology and Innovation Commission [JCYJ20170411152419928, GJHZ20170314151528005]
- Beijing Municipal Science & Technology Commission [Z151100003915118]
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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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