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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

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 orcid and Ellmark, Peter LU (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.

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author
; ; ; ; ; ; ; and
organization
publishing date
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
2024-12-22 09:17:54
@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}},
}