Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |
_version_ | 1784754907336671232 |
---|---|
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. |
format | Online Article Text |
id | pubmed-9316817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT yogialvaro braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT hussackgreg braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT vanfaassenhenk braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT haqqaniarsalans braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT delaneychristiee braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT brunetteeric braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT sandhujagdeepk braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT hewittmelissa braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT suleatraian braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT kemmerichkristin braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor AT stanimirovicdanicab braindeliveryofigf1r5asingledomainantibodytargetinginsulinlikegrowthfactor1receptor |