CD40 is broadly expressed on APCs (dendritic cells, B cells, monocytes), stromal cells, endothelial cells, and certain tumors . Agonistic CD40 recombinant mAbs mimic the natural CD40 ligand (CD40L) to:
Activate APCs: Upregulate MHC class II and costimulatory molecules (e.g., CD86), promoting T-cell priming .
Induce cytotoxic myeloid cells: Enable macrophage-mediated tumor stroma destruction .
Direct antitumor effects: Trigger apoptosis in CD40+ malignancies (e.g., B-cell lymphomas) .
Synergize with chemotherapy: Enhance antigen cross-presentation and T-cell infiltration via tumor cell death .
Antagonistic CD40 mAbs (e.g., lucatumumab) block CD40-CD40L interactions, suppressing autoimmune or inflammatory responses .
In murine models, agonistic CD40 mAbs eradicated bulk tumors and established long-term immunity .
CP-870,893 induced rapid B-cell activation and margination, correlating with melanoma-specific T-cell responses .
Combination therapy: Gemcitabine + CD40 mAbs cured 50% of pancreatic cancer patients, with stromal destruction enhancing chemotherapy delivery .
Next-generation CD40 mAbs focus on improving tumor selectivity and reducing systemic toxicity:
Fc engineering: Modified Fc regions (e.g., IgG2 for CP-870,893) optimize CD40 clustering and agonism without excessive CRS .
Bispecific formats: Targeting CD40 + tumor antigens (e.g., CD40-HER2) enhances tumor-localized immune activation .
In situ vaccination: Chemotherapy + CD40 mAbs convert "cold" tumors to "hot," enabling checkpoint inhibitor efficacy .