Intraperitoneal Co-Delivery of Claudin18.2×41BB and EpCAM×CD3 Bispecific Antibodies via mRNA-LNPs Synergistically Suppresses Gastric Cancer Peritoneal Metastasis Through T Cell Co-Activation - PubMed
6 hours ago
- #mRNA-LNP
- #Gastric Cancer Therapy
- #Bispecific Antibodies
- Developed E3C4, a single mRNA-LNP co-encoding EpCAM×CD3 and Claudin18.2×4-1BB bispecific antibodies, for localized dual-antigen T cell co-activation against gastric cancer peritoneal metastasis (GCPM).
- In vitro, E3C4 demonstrated high binding affinity (KD ~10^-10 M) and synergistic T cell activation, achieving 80.9% cytotoxicity, significantly higher than EpCAM×CD3 alone (29.1%, P<0.001).
- In subcutaneous tumor models, 3 μg E3C4 induced 98.5% tumor growth inhibition with enhanced T cell infiltration and granzyme B expression; intraperitoneal delivery showed 96.4% tumor-localized expression and superior efficacy in orthotopic models.
- E3C4 was safe with no mortality or cytokine release syndrome, only transient elevations in IL-6, AST, ALT, and body weight loss >10% that resolved within 2 weeks; maximum tolerated dose exceeded therapeutic dose by >200-fold.
- Conclusion: E3C4 offers a localized, synergistic platform for dual-antigen T cell co-activation in the peritoneal cavity, maximizing antitumor efficacy while minimizing systemic toxicity as a novel immunotherapy for GCPM.