Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study
Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targ...
Saved in:
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2023-12-01
|
| Series: | mAbs |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2022.2156317 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1839619426260877312 |
|---|---|
| author | Dmitry Shchelokov Oleg Demin Jr |
| author_facet | Dmitry Shchelokov Oleg Demin Jr |
| author_sort | Dmitry Shchelokov |
| collection | DOAJ |
| description | Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays: measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies. |
| format | Article |
| id | doaj-art-f80140490d5f4fac96e56b16b9fca76c |
| institution | Matheson Library |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-f80140490d5f4fac96e56b16b9fca76c2025-07-23T08:11:50ZengTaylor & Francis GroupmAbs1942-08621942-08702023-12-0115110.1080/19420862.2022.2156317Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case studyDmitry Shchelokov0Oleg Demin Jr1InSysBio UK Limited, Edinburgh, UKInSysBio UK Limited, Edinburgh, UKReceptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays: measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies.https://www.tandfonline.com/doi/10.1080/19420862.2022.2156317Receptor occupancyPD-1nivolumabmodeling |
| spellingShingle | Dmitry Shchelokov Oleg Demin Jr Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study mAbs Receptor occupancy PD-1 nivolumab modeling |
| title | Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study |
| title_full | Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study |
| title_fullStr | Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study |
| title_full_unstemmed | Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study |
| title_short | Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study |
| title_sort | receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology nivolumab case study |
| topic | Receptor occupancy PD-1 nivolumab modeling |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2022.2156317 |
| work_keys_str_mv | AT dmitryshchelokov receptoroccupancyassessmentandinterpretationintermsofquantitativesystemspharmacologynivolumabcasestudy AT olegdeminjr receptoroccupancyassessmentandinterpretationintermsofquantitativesystemspharmacologynivolumabcasestudy |