Table 3.
Preclinical studies of CD40 agonistic antibodies in cancer treatment, alone or in combination with other treatments.
| Therapy | Interventions | Route of Delivery |
Cancer Type | Dosage (mg/kg ) |
Outcome | Side Effects | Reference |
|---|---|---|---|---|---|---|---|
| Anti-mouse CD40 mAb (FGK45) | w/w.o nab-nabpaclitaxel and gemcitabine (CD40/Gem or Gem/CD40) w/w.o anti-CSF-1R | IP | PDA | 5 or 15 | No reduction in tumor volume. aCD40 was lethal when administered before chemotherapy (40%). Lethal hepatotoxicity was abrogated when macrophage activation was blocked using anti-CSF-1R mAb | 42% mice treated with 0.3mg/kg followed by Gem died vs. 58.1% in the 0.1 mg/kg group. In all mice: multifocal granulomatous and neutrophilic infiltration; significant increase in ALT and AST. Higher hepatotoxicity in CD40/Gem group. | [9] |
| Diphtheria toxin (DT) (Treg depletion) w/w.o TNF neutralization | IP | Mammary carcinoma (4T1.2) and Colon adenocarcinoma (MC38) | 5 | Mice with Treg depletion had higher TNF and IL-6 production. Concomitant TNF neutralization may reduce irAEs but also antitumor efficacy | DT + aCD40: significant weight loss, increase in clinical score, ALT and the proinflammatory cytokines. Concomitant anti-TNF abrogated weight loss, liver damage and colitis, resulting in an improved clinical score. | [126] | |
| + Radiotherapy + PDL1 | NDES or IP | Mammary carcinoma (4T1) | 5 | Localized immunotherapy via NDES + radiotherapy demonstrated an abscopal effect, augmented CD8+ T cells | IP vs. NDES CD40/PDL1: significant weight loss, worsened pathologic liver inflammation. | [127] | |
| w/w.o anti-PD-1, anti-CTLA4 | IP | Colon adenocarcinoma (MC38) | 5 | IL-12 and IFN-γ interdependently drive tissue-damaging effects in the liver and other tissues in a neutrophil-dependent way | IrAEs at liver and the GI tract. Portal and prominent lobular hepatitis and broad, confluent areas of necrosis. Colon crypt hyperplasia. | [131] | |
| + IL-2 w/w.o T-cell adoptive transfer | IP | Melanoma (B16) and Colon adenocarcinom a (MC38) | 10 | CD40 agonist expanded transferred T cell in vivo and improved antitumor effects | N/A | [130] | |
| monotherapy | IP | Melanoma (B16-OVAMO4) | 1.5 | Antitumor activity was significantly higher for mice treated with CD40 antibody with enhanced FcγRIIB binding | N/A | [51] | |
| monotherapy | IP | Breast cancer (4T1) and Hepatocellular carcinoma (RIL-175) | 5 | CD40 agonist matured murine and human hepatic MDSCs, relieving immunosuppression. | Liver damage occurred within 24h: ALT and AST elevations, and ROS-mediated hepatotoxicity. | [129] | |
| monotherapy | subcutanous or peritumoral or intravenous | Bladder cancer (MB49) | 0.5, 1.5, 5 | local peritumoral at low dose (0.01 and 0.03 mg.kg) improved survival and reduced toxicity than the intravenous systemic treatment | [100] | ||
| Human anti-CD40 agonist antibody | monotherapy | Intratumoral injectionor IP | Colon adenocarcinoma (MC38) | 0.1 | Intratumoral delivery led to a significantly lower tumor burden. | Dosage > 0.1 mg/led to profound increase in AST, ALT, and hepatotoxicity. Increasing dose worsened thrombocytopenia. | [128] |
NDES: nanofluidic drug-eluting seed; IrAE: immune-related adverse events; ALT: aminotransferase; AST: aspartate aminotransferase