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Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform

For many years, clinical research in Alzheimer’s disease (AD) has focused on attempts to identify the most explicit biomarker, namely amyloid beta. Unfortunately, the numerous therapies that have been developed have failed in clinical practice. AD arises as a consequence of multiple factors, and as...

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Autores principales: Karelina, Tatiana, Lerner, Stepan, Stepanov, Alexandr, Meerson, Mark, Demin, Oleg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213414/
https://www.ncbi.nlm.nih.gov/pubmed/33818905
http://dx.doi.org/10.1002/psp4.12628
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author Karelina, Tatiana
Lerner, Stepan
Stepanov, Alexandr
Meerson, Mark
Demin, Oleg
author_facet Karelina, Tatiana
Lerner, Stepan
Stepanov, Alexandr
Meerson, Mark
Demin, Oleg
author_sort Karelina, Tatiana
collection PubMed
description For many years, clinical research in Alzheimer’s disease (AD) has focused on attempts to identify the most explicit biomarker, namely amyloid beta. Unfortunately, the numerous therapies that have been developed have failed in clinical practice. AD arises as a consequence of multiple factors, and as such it requires a more mechanistic analytical approach than statistical modeling. Quantitative systems pharmacology modeling is a valuable tool for drug development. It utilizes in vitro data for the calibration of parameters, embeds them into physiologically based structures, and explores translation between animals and humans. Such an approach allows for a quantitative study of the dynamics of the interactions between multiple factors or variables. Here, we present an overview of the quantitative translational model in AD, which embraces current preclinical and clinical data. The previously published description of amyloid physiology has been updated and joined with a model for tau pathology and multiple intraneuronal processes responsible for cellular transport, metabolism, or proteostasis. In addition, several hypotheses regarding the best correlates of cognitive deterioration have been validated using clinical data. Here, the amyloid hypothesis was unable to predict the aducanumab clinical trial data, whereas simulations of cognitive impairment coupled with tau seeding or neuronal breakdown (expressed as caspase activity) matched the data. A satisfactory validation of the data from multiple preclinical and clinical studies was followed by an attempt to predict the results of combinatorial treatment with targeted immunotherapy and activation of autophagy using rapamycin. The combination is predicted to yield better efficacy than immunotherapy alone.
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spelling pubmed-82134142021-06-28 Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform Karelina, Tatiana Lerner, Stepan Stepanov, Alexandr Meerson, Mark Demin, Oleg CPT Pharmacometrics Syst Pharmacol Reviews For many years, clinical research in Alzheimer’s disease (AD) has focused on attempts to identify the most explicit biomarker, namely amyloid beta. Unfortunately, the numerous therapies that have been developed have failed in clinical practice. AD arises as a consequence of multiple factors, and as such it requires a more mechanistic analytical approach than statistical modeling. Quantitative systems pharmacology modeling is a valuable tool for drug development. It utilizes in vitro data for the calibration of parameters, embeds them into physiologically based structures, and explores translation between animals and humans. Such an approach allows for a quantitative study of the dynamics of the interactions between multiple factors or variables. Here, we present an overview of the quantitative translational model in AD, which embraces current preclinical and clinical data. The previously published description of amyloid physiology has been updated and joined with a model for tau pathology and multiple intraneuronal processes responsible for cellular transport, metabolism, or proteostasis. In addition, several hypotheses regarding the best correlates of cognitive deterioration have been validated using clinical data. Here, the amyloid hypothesis was unable to predict the aducanumab clinical trial data, whereas simulations of cognitive impairment coupled with tau seeding or neuronal breakdown (expressed as caspase activity) matched the data. A satisfactory validation of the data from multiple preclinical and clinical studies was followed by an attempt to predict the results of combinatorial treatment with targeted immunotherapy and activation of autophagy using rapamycin. The combination is predicted to yield better efficacy than immunotherapy alone. John Wiley and Sons Inc. 2021-05-02 2021-06 /pmc/articles/PMC8213414/ /pubmed/33818905 http://dx.doi.org/10.1002/psp4.12628 Text en © 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Reviews
Karelina, Tatiana
Lerner, Stepan
Stepanov, Alexandr
Meerson, Mark
Demin, Oleg
Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title_full Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title_fullStr Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title_full_unstemmed Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title_short Monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: Predictions using an integrated Alzheimer’s Disease Platform
title_sort monoclonal antibody therapy efficacy can be boosted by combinations with other treatments: predictions using an integrated alzheimer’s disease platform
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213414/
https://www.ncbi.nlm.nih.gov/pubmed/33818905
http://dx.doi.org/10.1002/psp4.12628
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