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Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor

The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to inc...

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Autores principales: Yogi, Alvaro, Hussack, Greg, van Faassen, Henk, Haqqani, Arsalan S., Delaney, Christie E., Brunette, Eric, Sandhu, Jagdeep K., Hewitt, Melissa, Sulea, Traian, Kemmerich, Kristin, Stanimirovic, Danica B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316817/
https://www.ncbi.nlm.nih.gov/pubmed/35890347
http://dx.doi.org/10.3390/pharmaceutics14071452
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author Yogi, Alvaro
Hussack, Greg
van Faassen, Henk
Haqqani, Arsalan S.
Delaney, Christie E.
Brunette, Eric
Sandhu, Jagdeep K.
Hewitt, Melissa
Sulea, Traian
Kemmerich, Kristin
Stanimirovic, Danica B.
author_facet Yogi, Alvaro
Hussack, Greg
van Faassen, Henk
Haqqani, Arsalan S.
Delaney, Christie E.
Brunette, Eric
Sandhu, Jagdeep K.
Hewitt, Melissa
Sulea, Traian
Kemmerich, Kristin
Stanimirovic, Danica B.
author_sort Yogi, Alvaro
collection PubMed
description The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to increase drug delivery to the brain. In this study, we characterized IGF1R5, which is a single-domain antibody (sdAb) that binds to insulin-like growth factor-1 receptor (IGF1R) at the BBB, as a ligand that triggers RMT and could deliver cargo molecules that otherwise do not cross the BBB. Surface plasmon resonance binding analyses demonstrated the species cross-reactivity of IGF1R5 toward IGF1R from multiple species. To overcome the short serum half-life of sdAbs, we fused IGF1R5 to the human (hFc) or mouse Fc domain (mFc). IGF1R5 in both N- and C-terminal mFc fusion showed enhanced transmigration across a rat BBB model (SV-ARBEC) in vitro. Increased levels of hFc-IGF1R5 in the cerebrospinal fluid and vessel-depleted brain parenchyma fractions further confirmed the ability of IGF1R5 to cross the BBB in vivo. We next tested whether this carrier was able to ferry a pharmacologically active payload across the BBB by measuring the hypothermic and analgesic properties of neurotensin and galanin, respectively. The fusion of IGF1R5-hFc to neurotensin induced a dose-dependent reduction in the core temperature. The reversal of hyperalgesia by galanin that was chemically linked to IGF1R5-mFc was demonstrated using the Hargreaves model of inflammatory pain. Taken together, our results provided a proof of concept that appropriate antibodies, such as IGF1R5 against IGF1R, are suitable as RMT carriers for the delivery of therapeutic cargos for CNS applications.
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spelling pubmed-93168172022-07-27 Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor Yogi, Alvaro Hussack, Greg van Faassen, Henk Haqqani, Arsalan S. Delaney, Christie E. Brunette, Eric Sandhu, Jagdeep K. Hewitt, Melissa Sulea, Traian Kemmerich, Kristin Stanimirovic, Danica B. Pharmaceutics Article The ability of drugs and therapeutic antibodies to reach central nervous system (CNS) targets is greatly diminished by the blood–brain barrier (BBB). Receptor-mediated transcytosis (RMT), which is responsible for the transport of natural protein ligands across the BBB, was identified as a way to increase drug delivery to the brain. In this study, we characterized IGF1R5, which is a single-domain antibody (sdAb) that binds to insulin-like growth factor-1 receptor (IGF1R) at the BBB, as a ligand that triggers RMT and could deliver cargo molecules that otherwise do not cross the BBB. Surface plasmon resonance binding analyses demonstrated the species cross-reactivity of IGF1R5 toward IGF1R from multiple species. To overcome the short serum half-life of sdAbs, we fused IGF1R5 to the human (hFc) or mouse Fc domain (mFc). IGF1R5 in both N- and C-terminal mFc fusion showed enhanced transmigration across a rat BBB model (SV-ARBEC) in vitro. Increased levels of hFc-IGF1R5 in the cerebrospinal fluid and vessel-depleted brain parenchyma fractions further confirmed the ability of IGF1R5 to cross the BBB in vivo. We next tested whether this carrier was able to ferry a pharmacologically active payload across the BBB by measuring the hypothermic and analgesic properties of neurotensin and galanin, respectively. The fusion of IGF1R5-hFc to neurotensin induced a dose-dependent reduction in the core temperature. The reversal of hyperalgesia by galanin that was chemically linked to IGF1R5-mFc was demonstrated using the Hargreaves model of inflammatory pain. Taken together, our results provided a proof of concept that appropriate antibodies, such as IGF1R5 against IGF1R, are suitable as RMT carriers for the delivery of therapeutic cargos for CNS applications. MDPI 2022-07-12 /pmc/articles/PMC9316817/ /pubmed/35890347 http://dx.doi.org/10.3390/pharmaceutics14071452 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yogi, Alvaro
Hussack, Greg
van Faassen, Henk
Haqqani, Arsalan S.
Delaney, Christie E.
Brunette, Eric
Sandhu, Jagdeep K.
Hewitt, Melissa
Sulea, Traian
Kemmerich, Kristin
Stanimirovic, Danica B.
Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title_full Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title_fullStr Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title_full_unstemmed Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title_short Brain Delivery of IGF1R5, a Single-Domain Antibody Targeting Insulin-like Growth Factor-1 Receptor
title_sort brain delivery of igf1r5, a single-domain antibody targeting insulin-like growth factor-1 receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316817/
https://www.ncbi.nlm.nih.gov/pubmed/35890347
http://dx.doi.org/10.3390/pharmaceutics14071452
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