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

Spyros Merkouris, Yves Alain Barde, Kate E. Binley, Nicholas D. Allen, Alexey V. Stepanov, Nicholas C. Wu, Geramie Grande, Chih Wei Lin, Meng Li, Xinsheng Nan, Pedro Chacon-Fernandez, Peter S. DiStefano, Ronald M. Lindsay, Richard A. Lerner, Jia Xie

Research output: Contribution to journalArticlepeer-review

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 pharmaceu-tically 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.

Original languageEnglish (US)
Pages (from-to)E7023-E7032
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number30
DOIs
StatePublished - Jul 24 2018
Externally publishedYes

Keywords

  • Agonist
  • Antibody
  • Combinatorial library
  • Membrane tethered
  • TrkB

ASJC Scopus subject areas

  • General

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