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Research ArticleDrug Discovery and Translational Medicine

Pharmaceutical Characterization of Tropomyosin Receptor Kinase B-Agonistic Antibodies on Human Induced Pluripotent Stem (hiPS) Cell–Derived Neurons

Stefanie Traub, Heiko Stahl, Holger Rosenbrock, Eric Simon, Lore Florin, Lisa Hospach, Stefan Hörer and Ralf Heilker
Journal of Pharmacology and Experimental Therapeutics June 2017, 361 (3) 355-365; DOI: https://doi.org/10.1124/jpet.117.240184
Stefanie Traub
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.)
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Heiko Stahl
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.)
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Holger Rosenbrock
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.)
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Eric Simon
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.)
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Lore Florin
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.)
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Lisa Hospach
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.)
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Stefan Hörer
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.)
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Ralf Heilker
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.)
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Abstract

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.

Footnotes

    • Received January 10, 2017.
    • Accepted March 23, 2017.
  • ↵https://doi.org/10.1124/jpet.117/240184.

  • Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 361 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 361, Issue 3
1 Jun 2017
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Research ArticleDrug Discovery and Translational Medicine

TrkB-Agonistic Antibodies on Human iPS Cell-Derived Neurons

Stefanie Traub, Heiko Stahl, Holger Rosenbrock, Eric Simon, Lore Florin, Lisa Hospach, Stefan Hörer and Ralf Heilker
Journal of Pharmacology and Experimental Therapeutics June 1, 2017, 361 (3) 355-365; DOI: https://doi.org/10.1124/jpet.117.240184

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Research ArticleDrug Discovery and Translational Medicine

TrkB-Agonistic Antibodies on Human iPS Cell-Derived Neurons

Stefanie Traub, Heiko Stahl, Holger Rosenbrock, Eric Simon, Lore Florin, Lisa Hospach, Stefan Hörer and Ralf Heilker
Journal of Pharmacology and Experimental Therapeutics June 1, 2017, 361 (3) 355-365; DOI: https://doi.org/10.1124/jpet.117.240184
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