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.
Hampus AnderssonAastha SobtiDavid Gomez JimenezYago Pico de CoañaSumeet Vijay AmbarkhaneKarin HägerbrandKarin Enell SmithMalin LindstedtPeter EllmarkPublished in: Cells (2023)
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.
Keyphrases
- dendritic cells
- single cell
- natural killer cells
- end stage renal disease
- ejection fraction
- peripheral blood
- extracellular matrix
- newly diagnosed
- induced apoptosis
- peritoneal dialysis
- regulatory t cells
- monoclonal antibody
- cell cycle arrest
- rna seq
- clinical trial
- cell death
- electronic health record
- study protocol
- cell proliferation
- endothelial cells
- multiple myeloma
- machine learning
- cancer therapy
- open label
- pi k akt
- cerebral ischemia