PMID- 29987039
OWN - NLM
STAT- MEDLINE
DCOM- 20180917
LR  - 20240329
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 115
IP  - 30
DP  - 2018 Jul 24
TI  - Fully human agonist antibodies to TrkB using autocrine cell-based selection from 
      a combinatorial antibody library.
PG  - E7023-E7032
LID - 10.1073/pnas.1806660115 [doi]
AB  - 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 
      t(1/2) 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.
CI  - Copyright (c) 2018 the Author(s). Published by PNAS.
FAU - Merkouris, Spyros
AU  - Merkouris S
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Barde, Yves-Alain
AU  - Barde YA
AUID- ORCID: 0000-0002-7627-461X
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Binley, Kate E
AU  - Binley KE
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Allen, Nicholas D
AU  - Allen ND
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Stepanov, Alexey V
AU  - Stepanov AV
AD  - Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of 
      Sciences, 117997 Moscow, Russia.
FAU - Wu, Nicholas C
AU  - Wu NC
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
FAU - Grande, Geramie
AU  - Grande G
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
FAU - Lin, Chih-Wei
AU  - Lin CW
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037.
FAU - Li, Meng
AU  - Li M
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Nan, Xinsheng
AU  - Nan X
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - Chacon-Fernandez, Pedro
AU  - Chacon-Fernandez P
AD  - School of Biosciences, Cardiff University, CF10 3AX Cardiff, United Kingdom.
FAU - DiStefano, Peter S
AU  - DiStefano PS
AD  - Zebra Biologics, Concord, MA 01742.
FAU - Lindsay, Ronald M
AU  - Lindsay RM
AD  - Zebra Biologics, Concord, MA 01742.
FAU - Lerner, Richard A
AU  - Lerner RA
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; 
      rlerner@scripps.edu jiaxie@scripps.edu.
FAU - Xie, Jia
AU  - Xie J
AD  - Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; 
      rlerner@scripps.edu jiaxie@scripps.edu.
LA  - eng
GR  - MR/L023784/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/L023784/2/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180709
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Single-Chain Antibodies)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.10.1 (tropomyosin-related kinase-B, human)
SB  - IM
MH  - *Autocrine Communication
MH  - Cell Line
MH  - GABAergic Neurons/*metabolism
MH  - *Gene Library
MH  - Humans
MH  - Membrane Glycoproteins/*agonists/genetics/metabolism
MH  - Phosphorylation/drug effects
MH  - Receptor, trkB/*agonists/genetics/metabolism
MH  - Signal Transduction/*drug effects
MH  - *Single-Chain Antibodies/genetics/pharmacology
MH  - Transcription, Genetic/*drug effects
PMC - PMC6065019
OTO - NOTNLM
OT  - TrkB
OT  - agonist
OT  - antibody
OT  - combinatorial library
OT  - membrane tethered
COIS- Conflict of interest statement: This work was supported by Zebra Biologics. 
      P.S.D. and R.M.L. are affiliated with Zebra Biologics.
EDAT- 2018/07/11 06:00
MHDA- 2018/09/18 06:00
PMCR- 2018/07/09
CRDT- 2018/07/11 06:00
PHST- 2018/07/11 06:00 [pubmed]
PHST- 2018/09/18 06:00 [medline]
PHST- 2018/07/11 06:00 [entrez]
PHST- 2018/07/09 00:00 [pmc-release]
AID - 1806660115 [pii]
AID - 201806660 [pii]
AID - 10.1073/pnas.1806660115 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7023-E7032. doi: 
      10.1073/pnas.1806660115. Epub 2018 Jul 9.