Synergestic Tumor-Killing Effect by Cross-Hybrid IgGA Fc

Despite the success of immune checkpoint inhibitors in the clinic, only a fraction of patients benefit from these therapies. A theoretical strategy to increase efficacy would be to enhance such antibodies with Fc-mediated effector mechanisms. We designed a cross-hybrid Fc-fusion peptide against PD-L1 able to elicit effector mechanisms of an IgG1 but also IgA consequently activating PMNs, a population neglected by IgG1, in order to combine multiple effector mechanisms. Moreover, to prevent toxicity, these Fc-fusion peptides were cloned in oncolytic adenoviruses whose replication is restricted to the tumor. These oncolytic adenoviruses were able to secrete the cross-hybrid Fc-fusion peptides able to bind to PD-L1 and activate multiple immune components enhancing tumor cytotoxicity, compared to FDAapproved immune checkpoint inhibitors, in various cancer cell lines and renal cell carcinoma patient derived organoids. In conclusion, these cross-hybrid Fc-fusion peptides demonstrate that activating multiple immune effector populations increases tumor cytotoxicity potentially leading to improved clinical outcomes.