Abstract 2330: Discovery of EP4 receptor antagonist KF-0210 for the treatment of cancers
Authors: Deng Yongqi , Tian Yuan , Rong Tao , Gan Xiangdong , Qin Shuai , Zhou Yuanqi , Wang Xiaomei , Jia Yanlin 
Published: April 2023

Abstract
Background: It is known that tumors with more infiltrated immune cells have better responses to PD-1/PD-L1 antibody therapy. PGE2 is involved in the regulation of the cancer microenvironment and tumor growth, mainly through the EP4 receptor. Inhibition of the EP4 receptor may increase tumor-killing immune cell infiltration and thus increase the response to PD-1/PD-L1 antibody therapy. Here we reported a potent and selective EP4 receptor antagonist, KF-0210, for the treatment of cancers.
Methods: Multiple experiments were conducted to characterize KF-0210 and to evaluate its anti-tumor activities in vitro and in vivo, including receptor binding assay, cAMP release in cultured cells, and in vivo pharmacokinetic and toxicity studies. Syngeneic mouse tumor models were used to evaluate the effect of KF-0210 on immune cell infiltration and tumor growth.
Results: In the EP4 receptor binding assay, KF-0210 showed a potent binding to EP4 receptor (IC50=18.6nM). Its binding potency to EP4 receptor was &gt;500 fold higher than to other prostaglandin receptors, including EP1, EP2, EP3, IP, DP1, and FP. PGE2-induced cAMP production was inhibited by KF-0210 in MCF-7 cells (IC50 = 1.06 nM) and in Flpin-293-mEP4 cells (IC50 = 0.915 nM). In human PBMCs, KF-0210 increased LPS-induced TNFα release (IC50 = 4.5 nM) in the presence of PGE2. Oral administration of KF-0210 showed superior plasma exposure in rats and mice compared to E7046, another EP4 antagonist under clinical development. In the CT26 mouse model of colorectal cancer, KF-0210 increased the tumor-killing immune cells in the tumor. Tumor growth was attenuated by 16%, 36%, and 42% respectively when treated with 10mg/kg, 30 mg/kg/, and 150 mg/kg KF-0210. In the combination therapy studies, when animals were treated with KF-0210 or anti-PD-1 antibody alone, tumor growth was attenuated by 68% and 83% respectively. While combination treatment of KF-0210 and PD-1 antibody achieved 95% inhibition of tumor growth (P&lt;0.001), superior to the monotherapy of either KF-0210 or PD-1 antibody. Similar results were also observed when KF-0210 was combined with PD-L1 antibody in the same model. In the mouse EMT6 breast cancer model, the combination treatment of KF-0210 and PD-1 antibody also showed a superior effect in inhibiting tumor growth. No significant safety issues were identified in toxicity and safety studies in vivo.
Conclusion: KF-0210 is a potent and selective EP4 antagonist with a good PK and safety profile. It shows the inhibitory effect on tumor growth in mouse models of colorectal and breast cancers. The combination treatment of KF-0210 and PD-1/PD-L1 antibodies shows a superior therapeutic effect compared to the monotherapy of each treatment. These results support the clinical development of KF-0210 for cancer therapy, especially the combination therapy with PD-1/PD-L1 antibodies. KF-0210 is currently in phase 1 clinical study and the preliminary data showed good safety and PK profile.
Citation Format: Yongqi Deng, Yuan Tian, Tao Rong, Xiangdong Gan, Shuai Qin, Yuanqi Zhou, Xiaomei Wang, Yanlin Jia. Discovery of EP4 receptor antagonist KF-0210 for the treatment of cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2330.