A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

Abstract The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential bindi...

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Autores principales:	Katherine E. Harris, Kyle J. Lorentsen, Harbani K. Malik-Chaudhry, Kaitlyn Loughlin, Harish Medlari Basappa, Sharon Hartstein, Ghenima Ahmil, Nicole S. Allen, Brian C. Avanzino, Aarti Balasubramani, Andrew A. Boudreau, Karen Chang, Maria-Cristina Cuturi, Laura M. Davison, Dennis M. Ho, Suhasini Iyer, Udaya S. Rangaswamy, Preethi Sankaran, Ute Schellenberger, Roland Buelow, Nathan D. Trinklein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6280e71ffa694c31a509b1afcf87bff2
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spelling	oai:doaj.org-article:6280e71ffa694c31a509b1afcf87bff22021-12-02T15:45:31ZA bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells10.1038/s41598-021-90096-82045-2322https://doaj.org/article/6280e71ffa694c31a509b1afcf87bff22021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90096-8https://doaj.org/toc/2045-2322Abstract The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.Katherine E. HarrisKyle J. LorentsenHarbani K. Malik-ChaudhryKaitlyn LoughlinHarish Medlari BasappaSharon HartsteinGhenima AhmilNicole S. AllenBrian C. AvanzinoAarti BalasubramaniAndrew A. BoudreauKaren ChangMaria-Cristina CuturiLaura M. DavisonDennis M. HoSuhasini IyerUdaya S. RangaswamyPreethi SankaranUte SchellenbergerRoland BuelowNathan D. TrinkleinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Katherine E. Harris Kyle J. Lorentsen Harbani K. Malik-Chaudhry Kaitlyn Loughlin Harish Medlari Basappa Sharon Hartstein Ghenima Ahmil Nicole S. Allen Brian C. Avanzino Aarti Balasubramani Andrew A. Boudreau Karen Chang Maria-Cristina Cuturi Laura M. Davison Dennis M. Ho Suhasini Iyer Udaya S. Rangaswamy Preethi Sankaran Ute Schellenberger Roland Buelow Nathan D. Trinklein A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
description	Abstract The use of recombinant interleukin-2 (IL-2) as a therapeutic protein has been limited by significant toxicities despite its demonstrated ability to induce durable tumor-regression in cancer patients. The adverse events and limited efficacy of IL-2 treatment are due to the preferential binding of IL-2 to cells that express the high-affinity, trimeric receptor, IL-2Rαβγ such as endothelial cells and T-regulatory cells, respectively. Here, we describe a novel bispecific heavy-chain only antibody which binds to and activates signaling through the heterodimeric IL-2Rβγ receptor complex that is expressed on resting T-cells and NK cells. By avoiding binding to IL-2Rα, this molecule circumvents the preferential T-reg activation of native IL-2, while maintaining the robust stimulatory effects on T-cells and NK-cells in vitro. In vivo studies in both mice and cynomolgus monkeys confirm the molecule’s in vivo biological activity, extended pharmacodynamics due to the Fc portion of the molecule, and enhanced safety profile. Together, these results demonstrate that the bispecific antibody is a safe and effective IL-2R agonist that harnesses the benefits of the IL-2 signaling pathway as a potential anti-cancer therapy.
format	article
author	Katherine E. Harris Kyle J. Lorentsen Harbani K. Malik-Chaudhry Kaitlyn Loughlin Harish Medlari Basappa Sharon Hartstein Ghenima Ahmil Nicole S. Allen Brian C. Avanzino Aarti Balasubramani Andrew A. Boudreau Karen Chang Maria-Cristina Cuturi Laura M. Davison Dennis M. Ho Suhasini Iyer Udaya S. Rangaswamy Preethi Sankaran Ute Schellenberger Roland Buelow Nathan D. Trinklein
author_facet	Katherine E. Harris Kyle J. Lorentsen Harbani K. Malik-Chaudhry Kaitlyn Loughlin Harish Medlari Basappa Sharon Hartstein Ghenima Ahmil Nicole S. Allen Brian C. Avanzino Aarti Balasubramani Andrew A. Boudreau Karen Chang Maria-Cristina Cuturi Laura M. Davison Dennis M. Ho Suhasini Iyer Udaya S. Rangaswamy Preethi Sankaran Ute Schellenberger Roland Buelow Nathan D. Trinklein
author_sort	Katherine E. Harris
title	A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
title_short	A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
title_full	A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
title_fullStr	A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
title_full_unstemmed	A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells
title_sort	bispecific antibody agonist of the il-2 heterodimeric receptor preferentially promotes in vivo expansion of cd8 and nk cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6280e71ffa694c31a509b1afcf87bff2
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A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells

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