Background Mitazalimab is a human FcgR crosslinking-dependent human IgG1 CD40 agonistic antibody developed for cancer immunotherapy.1–3 Mitazalimab has demonstrated a manageable safety profile when administered once every 2 weeks both with or without corticosteroid pre-treatment.3 Treatment with mitazalimab induces transient increases in levels of selected chemokines and activation of peripheral B cells.3 An ongoing phase 2 study (OPTIMIZE-1) is currently evaluating the efficacy of mitazalimab in patients with metastatic pancreatic cancer (NCT04888312).
Methods Cell-free RNA from whole blood was collected from subjects both pre- and post-treatment in a dose escalation study of mitazalimab in patients with solid tumors (NCT02829099). The whole transcriptome sequencing was conducted according to Illumina TruSeq Stranded protocol. Samples obtained pretreatment and one day after treatment from cohorts receiving 75, 200, 600 and 900 µg/kg mitazalimab without corticosteroid pretreatment (pre/post treatment;75 µg: n=3/3, 200 µg: n=5/5, 600 µg: n=10/11 and 900 µg: n= 13/14) and 600 µg/kg mitazalimab with corticosteroid pretreatment were analyzed (pre/post treatment; n=10/5). The normalized data was analyzed utilizing the edgeR limma workflow on R software. Differentially expressed genes were analyzed according to dose level and corticosteroid (yes vs no) administration. Cell phenotyping was conducted according to CIBERSORTX and Xcell cell signatures. Gene expression results were further correlated with peripheral blood concentrations of 15 cytokines 24 hours after treatment.
Results Significant mitazalimab treatment-induced transcriptional activity was identified using pre-selected gene signatures related to event associated to CD40 biology at the 600 and 900 µg/kg dose levels without corticoid pre-treatment. In contrast, the number of significantly expressed genes in the lower dose groups were limited. Gene signatures related to activation of B cell- and myeloid/dendritic activation were upregulated post treatment, confirming the CD40 agonistic activity of mitazalimab. Additionally, corticosteroid pre-treatment significantly reduced the magnitude of the mitazalimab treatment induced changes in gene expression in circulating immune cells in patients. This was confirmed at the protein level for circulating cytokines.
Conclusions The analysis of RNAseq data obtained from whole blood clearly demonstrated that mitazalimab induce strong CD40-mediated responses, such as activation of myeloid cells and B cells in patients. Furthermore, corticosteroid pretreatment reduced the immune stimulatory activity of mitazalimab. The presented gene expression data confirms the biological activity of mitazalimab, further strengthening the proof of mechanism.
Mangsbo SM, Broos S, Fletcher E, et al. The human agonistic CD40 antibody ADC-1013 eradicates bladder tumors and generates T-cell-dependent tumor immunity. Clin Cancer Res 2015;21:1115–1126.
Irenaeus SMM, Nielsen D, Ellmark P, et al. First-in-human study with intratumoral administration of a CD40 agonistic antibody, ADC-1013, in advanced solid malignancies. Int J Cancer 2019.
Calvo E, Moreno V, Perets R, et al. A phase I study to assess safety, pharmacokinetics (PK), and pharmacodynamics (PD) of JNJ-64457107, a CD40 agonistic monoclonal antibody, in patients (pts) with advanced solid tumors. Journal of Clinical Oncology 2019;37:2527–2527.
Ethics Approval The study protocol and amendments were reviewed and approved by an Independent Ethics Committee. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Subjects or their legally acceptable representatives provided their written consent to participate in the study after having been informed about the nature and purpose of the study, participation/termination conditions, and risks and benefits of treatment. ClinicalTrial ID: NCT02829099
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