Novel Agonist Monoclonal Antibodies Activate TrkB Receptors and Demonstrate Potent Neurotrophic Activities

Overview

Journal J Neurosci

Specialty Neurology

Date 2006 Sep 15

PMID 16971523

Citations 34

Authors

Ming D Qian

Jie Zhang

Xiang-Yang Tan

Andrew Wood

Davinder Gill

Seongeun Cho

Affiliations

Soon will be listed here.

Abstract

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.

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References

Encinas M, Iglesias M, Llecha N, Comella J . Extracellular-regulated kinases and phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor-mediated survival and neuritogenesis of the neuroblastoma cell line SH-SY5Y. J Neurochem. 1999; 73(4):1409-21. DOI: 10.1046/j.1471-4159.1999.0731409.x. View

Friedman W, Greene L . Neurotrophin signaling via Trks and p75. Exp Cell Res. 1999; 253(1):131-42. DOI: 10.1006/excr.1999.4705. View

Robinson R, Radziejewski C, Spraggon G, Greenwald J, Kostura M, Burtnick L . The structures of the neurotrophin 4 homodimer and the brain-derived neurotrophic factor/neurotrophin 4 heterodimer reveal a common Trk-binding site. Protein Sci. 2000; 8(12):2589-97. PMC: 2144242. DOI: 10.1110/ps.8.12.2589. View

Schabitz W, Sommer C, Zoder W, Kiessling M, Schwaninger M, Schwab S . Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke. 2000; 31(9):2212-7. DOI: 10.1161/01.str.31.9.2212. View

Ochs G, Penn R, York M, Giess R, Beck M, Tonn J . A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 1(3):201-6. DOI: 10.1080/14660820050515197. View

Banfield M, Naylor R, Robertson A, Allen S, Dawbarn D, Brady R . Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Structure. 2001; 9(12):1191-9. DOI: 10.1016/s0969-2126(01)00681-5. View

Wong S, Henley J, Kanning K, Huang K, Bothwell M, Poo M . A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat Neurosci. 2002; 5(12):1302-8. DOI: 10.1038/nn975. View

Iglesias M, Segura M, Comella J, Olmos G . Mu-opioid receptor activation prevents apoptosis following serum withdrawal in differentiated SH-SY5Y cells and cortical neurons via phosphatidylinositol 3-kinase. Neuropharmacology. 2003; 44(4):482-92. DOI: 10.1016/s0028-3908(03)00024-8. View

Jing S, Tapley P, Barbacid M . Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron. 1992; 9(6):1067-79. DOI: 10.1016/0896-6273(92)90066-m. View

10.

Comelli M, Seren M, Guidolin D, Manev R, Favaron M, Rimland J . Photochemical stroke and brain-derived neurotrophic factor (BDNF) mRNA expression. Neuroreport. 1992; 3(6):473-6. DOI: 10.1097/00001756-199206000-00004. View

11.

Kurozumi K, Nakamura K, Tamiya T, Kawano Y, Kobune M, Hirai S . BDNF gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther. 2004; 9(2):189-97. DOI: 10.1016/j.ymthe.2003.10.012. View

12.

Koda M, Hashimoto M, Murakami M, Yoshinaga K, Ikeda O, Yamazaki M . Adenovirus vector-mediated in vivo gene transfer of brain-derived neurotrophic factor (BDNF) promotes rubrospinal axonal regeneration and functional recovery after complete transection of the adult rat spinal cord. J Neurotrauma. 2004; 21(3):329-37. DOI: 10.1089/089771504322972112. View

13.

Leeds P, Leng Y, Chalecka-Franaszek E, Chuang D . Neurotrophins protect against cytosine arabinoside-induced apoptosis of immature rat cerebellar neurons. Neurochem Int. 2004; 46(1):61-72. DOI: 10.1016/j.neuint.2004.07.001. View

14.

Williams G, Williams E, Maison P, Pangalos M, Walsh F, Doherty P . Overcoming the inhibitors of myelin with a novel neurotrophin strategy. J Biol Chem. 2004; 280(7):5862-9. DOI: 10.1074/jbc.M411121200. View

15.

Beck M, Flachenecker P, Magnus T, Giess R, Reiners K, Toyka K . Autonomic dysfunction in ALS: a preliminary study on the effects of intrathecal BDNF. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005; 6(2):100-3. DOI: 10.1080/14660820510028412. View

16.

TOCCO G, Lapchak P, Pasinetti G, Najm I, Baudry M, Hefti F . Regionally specific and rapid increases in brain-derived neurotrophic factor messenger RNA in the adult rat brain following seizures induced by systemic administration of kainic acid. Neuroscience. 1992; 47(2):303-15. DOI: 10.1016/0306-4522(92)90246-x. View

17.

Zhang J, Chen D, Gong X, Ling H, Zhang G, Wood A . Cyclic-AMP response element-based signaling assays for characterization of Trk family tyrosine kinases modulators. Neurosignals. 2006; 15(1):26-39. DOI: 10.1159/000094385. View

18.

Muragaki Y, Timothy N, Leight S, Hempstead B, Chao M, Trojanowski J . Expression of trk receptors in the developing and adult human central and peripheral nervous system. J Comp Neurol. 1995; 356(3):387-97. DOI: 10.1002/cne.903560306. View

19.

McDonald N, Chao M . Structural determinants of neurotrophin action. J Biol Chem. 1995; 270(34):19669-72. DOI: 10.1074/jbc.270.34.19669. View

20.

Shelton D, Sutherland J, Gripp J, Camerato T, Armanini M, PHILLIPS H . Human trks: molecular cloning, tissue distribution, and expression of extracellular domain immunoadhesins. J Neurosci. 1995; 15(1 Pt 2):477-91. PMC: 6578290. View