Background Immune checkpoint blockade (ICB) is a promising cancer immunotherapy, among which targeting the PD-1/PD-L1 pathway has been one of the widely studied ICB strategies. Anti-PD-L1 antibodies targeted at cancer cells or tumor-associated immune cells are currently used in the treatment of various cancers. However, their use is severely limited due to the low response rate of certain cancers, immune-related toxicity, and acquired drug resistance. Therefore, combination therapy with other therapies such as chemotherapy is currently being tried to overcome these limitations. STING (Stimulator of interferon genes) agonists efficiently induce anti-tumor activity and are being studied as attractive targets for immunotherapy, but there are safety concerns about the systemic administration of STING agonists. In this study, STING agonists were conjugated to several types of PD-L1 antibodies to manufacture antibody-immune modulator conjugates (AICs) that cross-react with human and mouse PD-L1, making them suitable for both mouse model studies and human clinical trials. These PD-L1 AICs showed potent anti-tumor efficacy in syngeneic models and were well tolerated in ICR mice.
Methods The activity of PD-L1 AICs was conducted through co-culture of cancer cells with immune cells. The in vivo anti-tumor efficacy of PD-L1 AICs was evaluated by tumor growth inhibition (TGI) after a single administration in CT26 or 4T-1 syngeneic models. Additionally, an in vivo toxicity study of PD-L1 AIC was evaluated in ICR mice for 2 weeks.
Results In vitro THP-1 reporter assay under co-culture conditions with cancer cells confirmed the efficacy of STING-mediated PD-L1 AIC. In co-culture of cancer cells and PBMCs, immune cell-mediated cancer cell killing was increased compared to atezolizumab only when treated with PD-L1 AICs. In the 4T-1 syngeneic model, PD-L1 AIC induced a significant TGI of 88.5% at 14 days, whereas atezolizumab did not show effective anti-tumor effect. In addition, it showed a superior anti-tumor effect compared to the administration of the same dose of the STING agonist. In the CT26 syngeneic model, PD-L1 AIC (1mg/kg) induced 103.8% TGI on the 14th day, and 80% of administered subjects achieved a complete response (CR). Finally, administration of AIC to ICR mice by intravenous injection at 20 mg/kg was well tolerated with no effects on body weight.
Conclusions Our studies show that PD-L1 AICs, which are a combination of immune checkpoint antibodies and immune modulators, demonstrated significant anti-tumor activity, as well as a favorable safety profile. Furthermore, we plan to conduct intensive pre-clinical studies using novel PD-L1 AICs.
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