PMID- 28351853
OWN - NLM
STAT- MEDLINE
DCOM- 20170613
LR  - 20181119
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 361
IP  - 3
DP  - 2017 Jun
TI  - Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic 
      Antibodies on Human Induced Pluripotent Stem (hiPS) Cell-Derived Neurons.
PG  - 355-365
LID - 10.1124/jpet.117.240184 [doi]
AB  - Brain-derived neurotrophic factor (BDNF) is a central modulator of neuronal 
      development and synaptic plasticity in the central nervous system. This renders 
      the BDNF-modulated tropomyosin receptor kinase B (TrkB) a promising drug target 
      to treat synaptic dysfunctions. Using GRowth factor-driven expansion and 
      INhibition of NotCH (GRINCH) during maturation, the so-called GRINCH neurons were 
      derived from human-induced pluripotent stem cells. These GRINCH neurons were used 
      as model cells for pharmacologic profiling of two TrkB-agonistic antibodies, 
      hereafter referred to as AB2 and AB20 In next-generation sequencing studies, AB2 
      and AB20 stimulated transcriptional changes, which extensively overlapped with 
      BDNF-driven transcriptional modulation. In regard to TrkB phosphorylation, both 
      AB2 and AB20 were only about half as efficacious as BDNF; however, with respect 
      to the TrkB downstream signaling, AB2 and AB20 displayed increased efficacy 
      values, providing a stimulation at least comparable to BDNF in respect to VGF 
      transcription, as well as of AKT and cAMP response element-binding protein 
      phosphorylation. In a complex structure of the TrkB-d5 domain with AB20, 
      determined by X-ray crystallography, the AB20 binding site was found to be 
      allosteric in regard to the BDNF binding site, whereas AB2 was known to act 
      orthosterically with BDNF. In agreement with this finding, AB2 and AB20 acted 
      synergistically at greater concentrations to drive TrkB phosphorylation. Although 
      TrkB downstream signaling declined faster after pulse stimulation with AB20 than 
      with AB2, AB20 restimulated TrkB phosphorylation more efficiently than AB2. In 
      conclusion, both antibodies displayed some limitations and some benefits in 
      regard to future applications as therapeutic agents.
CI  - Copyright (c) 2017 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Traub, Stefanie
AU  - Traub S
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Stahl, Heiko
AU  - Stahl H
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Rosenbrock, Holger
AU  - Rosenbrock H
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Simon, Eric
AU  - Simon E
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Florin, Lore
AU  - Florin L
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Hospach, Lisa
AU  - Hospach L
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Horer, Stefan
AU  - Horer S
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.).
FAU - Heilker, Ralf
AU  - Heilker R
AD  - Trenzyme GmbH, Konstanz (S.T.) Germany, Lead Identification and Optimization 
      Support (L.H., S.H., R.H.), Immunological and Respiratory Diseases Research 
      (H.S.), CNS Diseases Research (H.R.), and Target Discovery Research (E.S.), 
      Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; and Biotherapeutics 
      Discovery, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut 
      (L.F.) Ralf.Heilker@boehringer-ingelheim.com.
LA  - eng
PT  - Journal Article
DEP - 20170328
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Immunoglobulin G)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/chemistry/metabolism/*pharmacology
MH  - Brain-Derived Neurotrophic Factor/chemistry/metabolism/pharmacology
MH  - CHO Cells
MH  - Cricetinae
MH  - Cricetulus
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Immunoglobulin G/chemistry/metabolism/pharmacology
MH  - Induced Pluripotent Stem Cells/*drug effects/metabolism
MH  - Neurons/*drug effects/metabolism
MH  - Protein Binding/physiology
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Receptor, trkB/*agonists/chemistry/metabolism
EDAT- 2017/03/30 06:00
MHDA- 2017/06/14 06:00
CRDT- 2017/03/30 06:00
PHST- 2017/01/10 00:00 [received]
PHST- 2017/03/23 00:00 [accepted]
PHST- 2017/03/30 06:00 [pubmed]
PHST- 2017/06/14 06:00 [medline]
PHST- 2017/03/30 06:00 [entrez]
AID - jpet.117.240184 [pii]
AID - 10.1124/jpet.117.240184 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2017 Jun;361(3):355-365. doi: 10.1124/jpet.117.240184. Epub 
      2017 Mar 28.