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Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library

Merkouris, Spyridon, Barde, Yves-Alain, Binley, Kate E., Allen, Nicholas D., Stepanov, Alexey V., Wu, Nicholas C., Grande, Geramie, Lin, Chih-Wei, Li, Meng, Nan, Xinsheng, Chacon-Fernandez, Pedro, DiStefano, Peter S., Lindsay, Ronald M., Lerner, Richard A. and Xie, Jia 2018. Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library. Proceedings of the National Academy of Sciences 115 (30) , E7023-E7032. 10.1073/pnas.1806660115

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Abstract

The diverse physiological roles of the neurotrophin family have long prompted exploration of their potential as therapeutic agents for nerve injury and neurodegenerative diseases. To date, clinical trials of one family member, brain-derived neurotrophic factor (BDNF), have disappointingly failed to meet desired endpoints. Contributing to these failures is the fact that BDNF is pharmaceutically a nonideal biologic drug candidate. It is a highly charged, yet is a net hydrophobic molecule with a low molecular weight that confers a short t1/2 in man. To circumvent these shortcomings of BDNF as a drug candidate, we have employed a function-based cellular screening assay to select activating antibodies of the BDNF receptor TrkB from a combinatorial human short-chain variable fragment antibody library. We report here the successful selection of several potent TrkB agonist antibodies and detailed biochemical and physiological characterization of one such antibody, ZEB85. By using a human TrkB reporter cell line and BDNF-responsive GABAergic neurons derived from human ES cells, we demonstrate that ZEB85 is a full agonist of TrkB, comparable in potency to BDNF toward human neurons in activation of TrkB phosphorylation, canonical signal transduction, and mRNA transcriptional regulation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: National Academy of Sciences
ISSN: 0027-8424
Date of First Compliant Deposit: 10 July 2018
Date of Acceptance: 2 July 2018
Last Modified: 14 Jun 2019 13:32
URI: http://orca.cf.ac.uk/id/eprint/113078

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