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Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein

Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) wa...

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Autores principales: Yang, Zheng, Loy, James, Poirson, Brian, Dai, Yanshan, Rajendran, Surendran, Xu, Shihua, Spires, Vanessa, Gururajan, Murali, Lin, Zheng, Arbanas, Jaren, Carl, Stephen, Pace, Samantha, Wang, Yun, Mehl, John, Vasudevan, Krishna, Spires, Thomas, Novosiadly, Ruslan, Coker, Shodeinde, Perez, Raymond, Covello, Kelly, Morin, Paul, Graziano, Robert, Broz, Miranda, Lehman-McKeeman, Lois
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251408/
https://www.ncbi.nlm.nih.gov/pubmed/35795558
http://dx.doi.org/10.3389/fphar.2022.829063
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author Yang, Zheng
Loy, James
Poirson, Brian
Dai, Yanshan
Rajendran, Surendran
Xu, Shihua
Spires, Vanessa
Gururajan, Murali
Lin, Zheng
Arbanas, Jaren
Carl, Stephen
Pace, Samantha
Wang, Yun
Mehl, John
Vasudevan, Krishna
Spires, Thomas
Novosiadly, Ruslan
Coker, Shodeinde
Perez, Raymond
Covello, Kelly
Morin, Paul
Graziano, Robert
Broz, Miranda
Lehman-McKeeman, Lois
author_facet Yang, Zheng
Loy, James
Poirson, Brian
Dai, Yanshan
Rajendran, Surendran
Xu, Shihua
Spires, Vanessa
Gururajan, Murali
Lin, Zheng
Arbanas, Jaren
Carl, Stephen
Pace, Samantha
Wang, Yun
Mehl, John
Vasudevan, Krishna
Spires, Thomas
Novosiadly, Ruslan
Coker, Shodeinde
Perez, Raymond
Covello, Kelly
Morin, Paul
Graziano, Robert
Broz, Miranda
Lehman-McKeeman, Lois
author_sort Yang, Zheng
collection PubMed
description Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC(50) for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (K(d)) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC(50) by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro K(d). The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2–3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein.
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spelling pubmed-92514082022-07-05 Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein Yang, Zheng Loy, James Poirson, Brian Dai, Yanshan Rajendran, Surendran Xu, Shihua Spires, Vanessa Gururajan, Murali Lin, Zheng Arbanas, Jaren Carl, Stephen Pace, Samantha Wang, Yun Mehl, John Vasudevan, Krishna Spires, Thomas Novosiadly, Ruslan Coker, Shodeinde Perez, Raymond Covello, Kelly Morin, Paul Graziano, Robert Broz, Miranda Lehman-McKeeman, Lois Front Pharmacol Pharmacology Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed to quantitatively integrate preclinical pharmacology and toxicology data for determining the therapeutic index (TI) of an interleukin-10 (IL-10) fragment crystallizable (Fc) fusion protein. Mouse Fc fused with mouse IL-10 (mFc-mIL-10) was studied in mice for antitumor efficacy, and the elevation of interleukin-18 (IL-18) was examined as a PD biomarker. The in vivo mFc-mIL-10 EC(50) for the IL-18 induction was estimated to be 2.4 nM, similar to the in vitro receptor binding affinity (K(d)) of 3.2 nM. The IL-18 induction was further evaluated in cynomolgus monkeys, where the in vivo induction EC(50) by a human IL-10 human Fc-fusion protein (hFc-hIL-10) was 0.08 nM vs. 0.3 nM measured as the in vitro K(d). The extent of the IL-18 induction correlated with mouse antitumor efficacy and was used to connect mouse efficacy to that in monkeys. The PD-based efficacious dose projected in monkeys was comparable to the results obtained using a PK-based method in which mouse efficacious exposure was targeted and corrected for affinity differences between the species. Furthermore, PK/PD relationships were developed for anemia and thrombocytopenia in monkeys treated with hFc-hIL-10, with thrombocytopenia predicted to be dose-limiting toxicity. Using quantitative pharmacology and toxicology information obtained through modeling work in the same species, the TI of hFc-hIL-10 in monkeys was determined to be 2.4 (vs. PD-based efficacy) and 1.2–3 (vs. PK-based efficacy), indicating a narrow safety margin. The model-based approaches were proven valuable to the developability assessment of the IL-10 Fc-fusion protein. Frontiers Media S.A. 2022-06-20 /pmc/articles/PMC9251408/ /pubmed/35795558 http://dx.doi.org/10.3389/fphar.2022.829063 Text en Copyright © 2022 Yang, Loy, Poirson, Dai, Rajendran, Xu, Spires, Gururajan, Lin, Arbanas, Carl, Pace, Wang, Mehl, Vasudevan, Spires, Novosiadly, Coker, Perez, Covello, Morin, Graziano, Broz and Lehman-McKeeman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Yang, Zheng
Loy, James
Poirson, Brian
Dai, Yanshan
Rajendran, Surendran
Xu, Shihua
Spires, Vanessa
Gururajan, Murali
Lin, Zheng
Arbanas, Jaren
Carl, Stephen
Pace, Samantha
Wang, Yun
Mehl, John
Vasudevan, Krishna
Spires, Thomas
Novosiadly, Ruslan
Coker, Shodeinde
Perez, Raymond
Covello, Kelly
Morin, Paul
Graziano, Robert
Broz, Miranda
Lehman-McKeeman, Lois
Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title_full Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title_fullStr Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title_full_unstemmed Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title_short Application of Pharmacokinetic/Pharmacodynamic Modeling to Bridge Mouse Antitumor Efficacy and Monkey Toxicology Data for Determining the Therapeutic Index of an Interleukin-10 Fc Fusion Protein
title_sort application of pharmacokinetic/pharmacodynamic modeling to bridge mouse antitumor efficacy and monkey toxicology data for determining the therapeutic index of an interleukin-10 fc fusion protein
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9251408/
https://www.ncbi.nlm.nih.gov/pubmed/35795558
http://dx.doi.org/10.3389/fphar.2022.829063
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