Novel agonist monoclonal antibodies activate TrkB receptors and demonstrate potent neurotrophic activities
Novel agonist monoclonal antibodies activate TrkB receptors and demonstrate potent neurotrophic activities
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DOI：
10.1523/jneurosci.1118-06.2006
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发表时间：
2006-09-13
影响因子：
5.3
通讯作者：
Cho, Seongeun
中科院分区：
文献类型：
--
作者：
Qian, Ming D.;Zhang, Jie;Cho, Seongeun
酪氨酸激酶受体B（Trk B）介导脑源性神经营养因子（BDNF）的神经营养作用，以增加神经元的存活、分化、突触可塑性和神经发生。使用BDNF激活TrkB的治疗潜力已经在CNS疾病的几种临床前模型中得到很好的证明，验证了TrkB作为有前途的药物靶标。因此，我们旨在通过使用单克隆抗体方法开发TrkB特异性受体激动剂。在产生杂交瘤克隆并评估其结合和功能活性后，我们鉴定了五种小鼠单克隆抗体，其显示出对TrkB的高度选择性结合并诱导TrkB信号传导的稳健活化。使用竞争分析的表位作图研究表明，每个单克隆抗体识别TrkB上的独特结合位点，其中一些与BDNF对接位点不同。这些抗体基于其激活TrkB受体下游的近端和次级信号传导分子并促进神经元存活和神经突生长的能力而表现为真正的激动剂。这些抗体的结合亲和力和功能功效与BDNF的那些相当，而它们根本不与p75低亲和力神经营养因子受体结合。因此，它们可以代表新的试剂来探索TrkB的病理生理作用及其在治疗CNS疾病中的潜在治疗效用。
Tyrosine kinase receptor B (TrkB) mediates neurotrophic effects of brain-derived neurotrophic factor (BDNF) to increase neuronal survival, differentiation, synaptic plasticity, and neurogenesis. The therapeutic potential of TrkB activation using BDNF has been demonstrated well in several preclinical models of CNS diseases, validating TrkB as a promising drug target. Therefore, we aimed to develop TrkB-specific receptor agonists by using a monoclonal antibody approach. After generation of hybridoma clones and assessment of their binding and functional activity, we identified five mouse monoclonal antibodies that show highly selective binding to TrkB and that induce robust activation of TrkB signaling. Epitope mapping studies using competition analysis showed that each of the monoclonal antibodies recognizes a unique binding site on TrkB, some of which are distinct from BDNF docking sites. These antibodies behave as true agonists based on their ability to both activate proximal and secondary signaling molecules downstream of TrkB receptors and promote neuronal survival and neurite outgrowth. The binding affinities and the functional efficacy of these antibodies are comparable to those of BDNF, whereas they do not bind to the p75 low-affinity neurotrophin receptor at all. Therefore, they could represent novel reagents to explore the pathophysiological roles of TrkB and its potential therapeutic utility in treating CNS disorders.