Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody
(2023) In Cells 12(19).- Abstract
CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed... (More)
CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8+ T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.
(Less)
- author
- Andersson, Hampus LU ; Sobti, Aastha LU ; Jimenez, David Gomez LU ; de Coaña, Yago Pico ; Ambarkhane, Sumeet Vijay ; Hägerbrand, Karin LU ; Smith, Karin Enell ; Lindstedt, Malin LU and Ellmark, Peter LU
- organization
- publishing date
- 2023-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cancer, CD40, mitazalimab, pharmacodynamics, RNA sequencing
- in
- Cells
- volume
- 12
- issue
- 19
- article number
- 2365
- publisher
- MDPI AG
- external identifiers
-
- pmid:37830579
- scopus:85173856593
- ISSN
- 2073-4409
- DOI
- 10.3390/cells12192365
- language
- English
- LU publication?
- yes
- id
- fc6e7af5-c4e5-473e-950c-fa7a29f025ce
- date added to LUP
- 2024-01-12 12:09:40
- date last changed
- 2024-04-13 05:38:33
@article{fc6e7af5-c4e5-473e-950c-fa7a29f025ce,
abstract = {{<p>CD40-targeting therapies can enhance the dendritic cell priming of tumor-specific T cells and repolarize intratumoral macrophages to alleviate the tumoral immunosuppressive environment and remodel the extracellular matrix. Mitazalimab is a potent agonistic CD40 monoclonal IgG1 antibody currently under clinical development. This study used RNA sequencing of blood samples from a subset of patients from a Phase I trial with mitazalimab (NCT02829099) to assess peripheral pharmacodynamic activity. We found that mitazalimab induced transient peripheral transcriptomic alterations (at 600 µg/kg and 900 µg/kg dose administered intravenously), which mainly were attributed to immune activation. In particular, the transcriptomic alterations showed a reduction in effector cells (e.g., CD8<sup>+</sup> T cells and natural killer cells) and B cells peripherally with the remaining cells (e.g., dendritic cells, monocytes, B cells, and natural killer cells) showing transcription profiles consistent with activation. Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.</p>}},
author = {{Andersson, Hampus and Sobti, Aastha and Jimenez, David Gomez and de Coaña, Yago Pico and Ambarkhane, Sumeet Vijay and Hägerbrand, Karin and Smith, Karin Enell and Lindstedt, Malin and Ellmark, Peter}},
issn = {{2073-4409}},
keywords = {{cancer; CD40; mitazalimab; pharmacodynamics; RNA sequencing}},
language = {{eng}},
number = {{19}},
publisher = {{MDPI AG}},
series = {{Cells}},
title = {{Early Pharmacodynamic Changes Measured Using RNA Sequencing of Peripheral Blood from Patients in a Phase I Study with Mitazalimab, a Potent CD40 Agonistic Monoclonal Antibody}},
url = {{http://dx.doi.org/10.3390/cells12192365}},
doi = {{10.3390/cells12192365}},
volume = {{12}},
year = {{2023}},
}