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RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

INTRODUCTION: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human st...

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Autores principales: Tripp, Catherine S., Cuff, Carolyn, Campbell, Andrew L., Hendrickson, Barbara A., Voss, Jeff, Melim, Terry, Wu, Chengbin, Cherniack, Andrew D., Kim, Kenneth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Healthcare 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487860/
https://www.ncbi.nlm.nih.gov/pubmed/28455782
http://dx.doi.org/10.1007/s12325-017-0525-8
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author Tripp, Catherine S.
Cuff, Carolyn
Campbell, Andrew L.
Hendrickson, Barbara A.
Voss, Jeff
Melim, Terry
Wu, Chengbin
Cherniack, Andrew D.
Kim, Kenneth
author_facet Tripp, Catherine S.
Cuff, Carolyn
Campbell, Andrew L.
Hendrickson, Barbara A.
Voss, Jeff
Melim, Terry
Wu, Chengbin
Cherniack, Andrew D.
Kim, Kenneth
author_sort Tripp, Catherine S.
collection PubMed
description INTRODUCTION: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study. METHODS: Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma. RESULTS: In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo. CONCLUSION: RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis). FUNDING: AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-017-0525-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-54878602017-07-03 RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study Tripp, Catherine S. Cuff, Carolyn Campbell, Andrew L. Hendrickson, Barbara A. Voss, Jeff Melim, Terry Wu, Chengbin Cherniack, Andrew D. Kim, Kenneth Adv Ther Original Research INTRODUCTION: A unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study. METHODS: Anti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma. RESULTS: In the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo. CONCLUSION: RPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis). FUNDING: AbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12325-017-0525-8) contains supplementary material, which is available to authorized users. Springer Healthcare 2017-04-28 2017 /pmc/articles/PMC5487860/ /pubmed/28455782 http://dx.doi.org/10.1007/s12325-017-0525-8 Text en © The Author(s) 2017 https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Tripp, Catherine S.
Cuff, Carolyn
Campbell, Andrew L.
Hendrickson, Barbara A.
Voss, Jeff
Melim, Terry
Wu, Chengbin
Cherniack, Andrew D.
Kim, Kenneth
RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title_full RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title_fullStr RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title_full_unstemmed RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title_short RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study
title_sort rpc4046, a novel anti-interleukin-13 antibody, blocks il-13 binding to il-13 α1 and α2 receptors: a randomized, double-blind, placebo-controlled, dose-escalation first-in-human study
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487860/
https://www.ncbi.nlm.nih.gov/pubmed/28455782
http://dx.doi.org/10.1007/s12325-017-0525-8
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