PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy
Pottayil G. Sasikumar, Naremaddepalli S. Sudarshan, Srinivas Adurthi, Raghuveer Ramachandra, Dodderi S. Samiulla, Anirudha Lakshminarasimhan, Anuradha Ramanathan, T. Chandrasekhar, Amit A. Dhudashiya, Sumalatha Rani Talapati, Nagesh Gowda, Sreenivasulareddy Palakolanu, Jiju Mani, Bandi Srinivasrao, David Joseph, Nigam Kumar, Rashmi Nair, Hanudatta S. Atreya, Nagaraj Gowda, Murali Ramachandra
Abstract
Small molecule immune checkpoint inhibitors targeting PD-1 and other pathways may offer advantages including ease of dosing, ability to manage immune-related adverse events (irAEs) due to their shorter pharmacokinetic exposure and opportunity to target more than one pathway for improving efficacy. Here we describe the identification and characterization of CA-170, an amino acid inspired small molecule inhibitor of PD-L1 and VISTA derived from the interface of PD-1 and PD-L1. CA-170 exhibited potent rescue of proliferation and effector functions of T cells inhibited by PD-L1/L2 and VISTA with selectivity over other immune checkpoint proteins as well as a broad panel of receptors and enzymes. Observed blocking of PD-L1 signaling and binding to PD-L1 in the cellular context without preventing the assembly of PD-1:PD-L1 complex support the formation of a defective ternary complex as the mechanism of action of CA-170. Oral administration of CA-170 resulted in increased proliferation and activation of T cells in the tumor, and significant anti-tumor efficacy in a number of immunocompetent mouse tumor models either as a single agent or in combination with approved therapeutics. These results prompted the advancement of CA-170 to human clinical trials.