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A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice

Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the th...

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Autores principales: Seo, Songyi, Kim, Koung Li, Yeo, Yeongju, Kim, Ryul-I, Jeong, Hayoung, Kim, Jin-Ock, Song, Sun-Hwa, An, Mi-Jin, Kim, Jung-Woong, Hong, Hye Kyoung, Ham, Min Hee, Woo, Se Joon, Sung, Jong-Hyuk, Park, Sang Gyu, Suh, Wonhee
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400730/
https://www.ncbi.nlm.nih.gov/pubmed/34452268
http://dx.doi.org/10.3390/pharmaceutics13081308
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author Seo, Songyi
Kim, Koung Li
Yeo, Yeongju
Kim, Ryul-I
Jeong, Hayoung
Kim, Jin-Ock
Song, Sun-Hwa
An, Mi-Jin
Kim, Jung-Woong
Hong, Hye Kyoung
Ham, Min Hee
Woo, Se Joon
Sung, Jong-Hyuk
Park, Sang Gyu
Suh, Wonhee
author_facet Seo, Songyi
Kim, Koung Li
Yeo, Yeongju
Kim, Ryul-I
Jeong, Hayoung
Kim, Jin-Ock
Song, Sun-Hwa
An, Mi-Jin
Kim, Jung-Woong
Hong, Hye Kyoung
Ham, Min Hee
Woo, Se Joon
Sung, Jong-Hyuk
Park, Sang Gyu
Suh, Wonhee
author_sort Seo, Songyi
collection PubMed
description Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD.
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spelling pubmed-84007302021-08-29 A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice Seo, Songyi Kim, Koung Li Yeo, Yeongju Kim, Ryul-I Jeong, Hayoung Kim, Jin-Ock Song, Sun-Hwa An, Mi-Jin Kim, Jung-Woong Hong, Hye Kyoung Ham, Min Hee Woo, Se Joon Sung, Jong-Hyuk Park, Sang Gyu Suh, Wonhee Pharmaceutics Article Stem cell factor (SCF) and its receptor, cKIT, are novel regulators of pathological neovascularization in the eye, which suggests that inhibition of SCF/cKIT signaling may be a novel pharmacological strategy for treating neovascular age-related macular degeneration (AMD). This study evaluated the therapeutic potential of a newly developed fully human monoclonal antibody targeting cKIT, NN2101, in a murine model of neovascular AMD. In hypoxic human endothelial cells, NN2101 substantially inhibited the SCF-induced increase in angiogenesis and activation of the cKIT signaling pathway. In a murine model of neovascular AMD, intravitreal injection of NN2101 substantially inhibited the SCF/cKIT-mediated choroidal neovascularization (CNV), with efficacy comparable to aflibercept, a vascular endothelial growth factor inhibitor. A combined intravitreal injection of NN2101 and aflibercept resulted in an additive therapeutic effect on CNV. NN2101 neither caused ocular toxicity nor interfered with the early retinal vascular development in mice. Ocular pharmacokinetic analysis in rabbits indicated that NN2101 demonstrated a pharmacokinetic profile suitable for intravitreal injection. These findings provide the first evidence of the potential use of the anti-cKIT blocking antibody, NN2101, as an alternative or additive therapeutic for the treatment of neovascular AMD. MDPI 2021-08-20 /pmc/articles/PMC8400730/ /pubmed/34452268 http://dx.doi.org/10.3390/pharmaceutics13081308 Text en © 2021 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
Seo, Songyi
Kim, Koung Li
Yeo, Yeongju
Kim, Ryul-I
Jeong, Hayoung
Kim, Jin-Ock
Song, Sun-Hwa
An, Mi-Jin
Kim, Jung-Woong
Hong, Hye Kyoung
Ham, Min Hee
Woo, Se Joon
Sung, Jong-Hyuk
Park, Sang Gyu
Suh, Wonhee
A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title_full A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title_fullStr A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title_full_unstemmed A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title_short A Fully Human Monoclonal Antibody Targeting cKIT Is a Potent Inhibitor of Pathological Choroidal Neovascularization in Mice
title_sort fully human monoclonal antibody targeting ckit is a potent inhibitor of pathological choroidal neovascularization in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400730/
https://www.ncbi.nlm.nih.gov/pubmed/34452268
http://dx.doi.org/10.3390/pharmaceutics13081308
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