CCX559 is a potent, orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• The PD-L1/PD-1 pathway is a critical immune checkpoint inhibiting anti-cancer T cell responses.
• Monoclonal antibodies blocking PD-L1/PD-1 are established cancer therapies.
• Small molecule inhibitors offer potential advantages over antibody therapies for specific patient groups.

Purpose of the Study:

• To characterize the pharmacology of CCX559, an orally available small molecule inhibitor of PD-L1.
• To evaluate the efficacy and mechanism of action of CCX559 in preclinical cancer models.

Main Methods:

• In vitro assays assessed CCX559's inhibition of PD-L1 binding to PD-1 and CD80.
• Primary human T cell activation was measured.
• In vivo studies utilized murine tumor models to assess anti-tumor activity.
• Pharmacodynamic effects were studied in cynomolgus monkeys.

Main Results:

• CCX559 potently and selectively inhibited PD-L1 interactions in vitro.
• Oral CCX559 showed anti-tumor efficacy comparable to an anti-PD-L1 antibody in mice.
• CCX559 induced PD-L1 dimerization and internalization, blocking PD-1 binding.
• Increased plasma soluble PD-L1 was observed in monkeys.

Conclusions:

• CCX559 exhibits promising anti-cancer properties as a small molecule PD-L1 inhibitor.
• The drug's mechanism involves PD-L1 modulation and T cell activation.
• Results support the ongoing clinical development of CCX559 for solid tumors.