Abstract 5529: In vivo efficacy evaluation of ASC61, an oral PD-L1 inhibitor, in two tumor mouse models

Abstract

Abstract Background: ASC61 is an oral inhibitor prodrug of programmed cell death-ligand 1 (PD-L1). ASC61 is converted to its pharmacologically active metabolite ASC61-A in the plasma. In vitro studies showed that ASC61-A could activate PD-L1 dimerization and membrane PD-L1 protein internalization, interfere PD-1/PD-L1 interaction and enhance T-cell activation. Here we report the in vivo efficacy of ASC61 in two tumor mouse models. ASC61 was found to have the best antitumor activity among all test drugs in the syngeneic tumor mouse model, BALB/c mice bearing CT-26-hPD-L1 tumors. Then a humanized mouse model, PD-1/PD-L1 dKI HuGEMM bearing hPD-L1 MC38 tumor, was used to further validate the therapeutic efficacy of ASC61. Methods: In the BALB/c mouse model, mice were inoculated subcutaneously with CT-26-hPD-L1 cells. When the average tumor volume reached approximately 69 mm3, mice were randomly assigned and treated twice a day (BID) with vehicle, reference drug (Atezolizumab), ASC61, GLC01-589 or GLC01-633 for 19 days. In the PD-1/PD-L1 dKI HuGEMM mouse model, MC38 hPD-L1 cells were subcutaneously inoculated in the right rear flank region of mice. Once the mean tumor size reached approximately 78.3 mm3, mice were randomized and treated BID for 16 days with vehicle, Atezolizumab, ASC61 (50 or 100 mg/kg). In both models, body weights and tumor volumes were measured regularly, and tumor growth inhibitions (TGI) of different groups were compared. Results: All mice showed a gradually increase in body weight during the study and no significant difference of body weight or body weight change was found among different groups in both mouse models. In the BALB/c mouse model, ASC61 50 mg/kg showed significantly inhibitory effects on the tumor growth with the best TGI value of 52.9% (p < 0.05) on Day 19, even better than that of the reference drug (40.77%). In the PD-1/PD-L1 dKI HuGEMM mouse model, Group 2 to 4 showed TGI values of 69.62%, 33.62% and 63.15% on Day 16, respectively. Atezolizumab 5 mg/kg BIW and ASC61 100 mg/kg BID produced similar significant antitumor efficacies (both p < 0.001). Survival analysis showed significant differences between Group 1 and Group 2 to 4 (p = 0.0002, 0.0338 and 0.0027, respectively). Conclusion: Results of this study show that ASC61 is well tolerated in both mouse models, and ASC61 has comparable antitumor efficacies as the FDA-approved PD-L1 antibody, Atezolizumab. ASC61 is an oral PD-L1 inhibitor, and thus will have better patient compliance than injective PD-1/PD-L1 antibody. ASC61 first in human clinical trial will begin soon. Citation Format: Jinzi J. Wu, Handan He. In vivo efficacy evaluation of ASC61, an oral PD-L1 inhibitor, in two tumor mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5529.