2. Academic Validation
  3. Fully human agonist antibodies to TrkB using autocrine cell-based selection from a combinatorial antibody library

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

  • Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7023-E7032. doi: 10.1073/pnas.1806660115.
Spyros Merkouris 1,  Yves-Alain Barde 1,  Kate E Binley 1,  Nicholas D Allen 1,  Alexey V Stepanov 2,  Nicholas C Wu 3,  Geramie Grande 3,  Chih-Wei Lin 3,  Meng Li 1,  Xinsheng Nan 1,  Pedro Chacon-Fernandez 1,  Peter S DiStefano 4,  Ronald M Lindsay 4,  Richard A Lerner 5,  Jia Xie 5
Affiliations

Affiliations

  • 1 School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
  • 2 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
  • 3 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
  • 4 Zebra Biologics, Concord, MA 01742.
  • 5 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; [email protected] [email protected].
PMID: 29987039 DOI: 10.1073/pnas.1806660115
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.

Keywords

TrkB; agonist; antibody; combinatorial library; membrane tethered.

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