Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A

Ling Liu,1 Jirong Lu,1 Barrett W Allan,2 Ying Tang,2 Jonathan Tetreault,1 Chi-kin Chow,1 Barbra Barmettler,2 James Nelson,2 Holly Bina,1 Lihua Huang,3 Victor J Wroblewski,4 Kristine Kikly1 1Biotechnology Discovery Research, Indianapolis, IN, 2Applied Molecular Evolution, Lilly Biotechnology...

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Autores principales:	Liu L, Lu J, Allan BW, Tang Y, Tetreault J, Chow C, Barmettler B, Nelson J, Bina H, Huang L, Wroblewski VJ, Kikly K
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	ixekizumab IL-17A monoclonal antibody anti-IL-17A Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/5e331cf6122443a39273d7248c25dc03
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spelling	oai:doaj.org-article:5e331cf6122443a39273d7248c25dc032021-12-02T01:56:22ZGeneration and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A1178-7031https://doaj.org/article/5e331cf6122443a39273d7248c25dc032016-04-01T00:00:00Zhttps://www.dovepress.com/generation-and-characterization-of-ixekizumab-a-humanized-monoclonal-a-peer-reviewed-article-JIRhttps://doaj.org/toc/1178-7031Ling Liu,1 Jirong Lu,1 Barrett W Allan,2 Ying Tang,2 Jonathan Tetreault,1 Chi-kin Chow,1 Barbra Barmettler,2 James Nelson,2 Holly Bina,1 Lihua Huang,3 Victor J Wroblewski,4 Kristine Kikly1 1Biotechnology Discovery Research, Indianapolis, IN, 2Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, 3Bioproduct Research and Development, 4Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA Abstract: Interleukin (IL)-17A exists as a homodimer (A/A) or as a heterodimer (A/F) with IL-17F. IL-17A is expressed by a subset of T-cells, called Th17 cells, at inflammatory sites. Most cell types can respond to the local production of IL-17A because of the near ubiquitous expression of IL-17A receptors, IL-17RA and IL-17RC. IL-17A stimulates the release of cytokines and chemokines designed to recruit and activate both neutrophils and memory T-cells to the site of injury or inflammation and maintain a proinflammatory state. IL-17A-producing pathogenic T-cells contribute to the pathogenesis of autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. This study describes the generation and characterization of ixekizumab, a humanized IgG4 variant IL-17A-neutralizing antibody. Ixekizumab binds human and cynomolgus monkey IL-17A with high affinity and binds rabbit IL-17A weakly but does not bind to rodent IL-17A or other IL-17 family members. Ixekizumab effectively inhibits the interaction between IL-17A and its receptor in binding assays and potently blocks IL-17A-induced GRO or KC secretion in cell-based assays. In an in vivo mouse pharmcodynamic model, ixekizumab blocks human IL-17A-induced mouse KC secretion. These data provide a comprehensive preclinical characterization of ixekizumab, for which the efficacy and safety have been demonstrated in human clinical trials in psoriasis and psoriatic arthritis.Keywords: ixekizumab, IL-17A monoclonal antibody, anti-IL-17ALiu LLu JAllan BWTang YTetreault JChow CBarmettler BNelson JBina HHuang LWroblewski VJKikly KDove Medical PressarticleixekizumabIL-17A monoclonal antibodyanti-IL-17APathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol 2016, Iss Issue 1, Pp 39-50 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	ixekizumab IL-17A monoclonal antibody anti-IL-17A Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	ixekizumab IL-17A monoclonal antibody anti-IL-17A Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Liu L Lu J Allan BW Tang Y Tetreault J Chow C Barmettler B Nelson J Bina H Huang L Wroblewski VJ Kikly K Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
description	Ling Liu,1 Jirong Lu,1 Barrett W Allan,2 Ying Tang,2 Jonathan Tetreault,1 Chi-kin Chow,1 Barbra Barmettler,2 James Nelson,2 Holly Bina,1 Lihua Huang,3 Victor J Wroblewski,4 Kristine Kikly1 1Biotechnology Discovery Research, Indianapolis, IN, 2Applied Molecular Evolution, Lilly Biotechnology Center, San Diego, CA, 3Bioproduct Research and Development, 4Drug Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA Abstract: Interleukin (IL)-17A exists as a homodimer (A/A) or as a heterodimer (A/F) with IL-17F. IL-17A is expressed by a subset of T-cells, called Th17 cells, at inflammatory sites. Most cell types can respond to the local production of IL-17A because of the near ubiquitous expression of IL-17A receptors, IL-17RA and IL-17RC. IL-17A stimulates the release of cytokines and chemokines designed to recruit and activate both neutrophils and memory T-cells to the site of injury or inflammation and maintain a proinflammatory state. IL-17A-producing pathogenic T-cells contribute to the pathogenesis of autoimmune diseases, including psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. This study describes the generation and characterization of ixekizumab, a humanized IgG4 variant IL-17A-neutralizing antibody. Ixekizumab binds human and cynomolgus monkey IL-17A with high affinity and binds rabbit IL-17A weakly but does not bind to rodent IL-17A or other IL-17 family members. Ixekizumab effectively inhibits the interaction between IL-17A and its receptor in binding assays and potently blocks IL-17A-induced GRO or KC secretion in cell-based assays. In an in vivo mouse pharmcodynamic model, ixekizumab blocks human IL-17A-induced mouse KC secretion. These data provide a comprehensive preclinical characterization of ixekizumab, for which the efficacy and safety have been demonstrated in human clinical trials in psoriasis and psoriatic arthritis.Keywords: ixekizumab, IL-17A monoclonal antibody, anti-IL-17A
format	article
author	Liu L Lu J Allan BW Tang Y Tetreault J Chow C Barmettler B Nelson J Bina H Huang L Wroblewski VJ Kikly K
author_facet	Liu L Lu J Allan BW Tang Y Tetreault J Chow C Barmettler B Nelson J Bina H Huang L Wroblewski VJ Kikly K
author_sort	Liu L
title	Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
title_short	Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
title_full	Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
title_fullStr	Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
title_full_unstemmed	Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A
title_sort	generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17a
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/5e331cf6122443a39273d7248c25dc03
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Generation and characterization of ixekizumab, a humanized monoclonal antibody that neutralizes interleukin-17A

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