PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy

Pottayil G Sasikumar,Raghuveer K Ramachandra,Sreenivasulareddy Palakolanu,Nagaraj Gowda,Srinivas Adurthi,Rashmi Nair,Hanudatta S Atreya,Naremaddepalli S Sudarshan,Anirudha Lakshminarasimhan,T Chandrasekhar ,Nigam Kumar,Sumalatha Rani Talapati ,Anuradha Ramanathan,Nagesh Gowda,Bandi Srinivasrao,Amit A Dhudashiya,Dodderi S Samiulla,Jiju Mani,David Joseph,Murali Ramachandra

doi:10.1038/s42003-021-02191-1

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.

Highlights

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 due to their shorter pharmacokinetic exposure and opportunity to target more than one pathway for improving efficacy
Apart from these pathways, there are other checkpoint pathways such as VISTA expressed in the tumor microenvironment (TME) that play a role in dampening the anti-tumor immune response and come in the way of achieving effective therapy[3,4,5]
In comparison to the most of reported antibodies and small molecule agents, the reports of potent and pharmacologically active anti-PD-1 antibodies despite their inability to block the interaction of PD-1 with PD-L112,13 support the possibility of identifying agents with a distinct mechanism of action

Summary

Introduction

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. Development, and clinical practice of inhibitory antibodies targeting CTLA-4 and PD-1 pathways are acknowledged with the well-deserved nobel prize in Physiology or Medicine in 20182 Apart from these pathways, there are other checkpoint pathways such as VISTA expressed in the tumor microenvironment (TME) that play a role in dampening the anti-tumor immune response and come in the way of achieving effective therapy[3,4,5]. Deficiencies of antibody-based inhibitors underscore the need for alternate approaches including small molecule agents that are amenable for oral dosing, capable of targeting more than one immune checkpoint protein for greater clinical response rate and allow better management of irAEs due to a shorter pharmacokinetic (PK) profile and suitable for combination with other approved chemotherapeutic drugs. Rational design based on the interface sequence substituted for the large compound library screening, while the use of a functional assay using the native system to assess the compound replaced the binding assay using recombinant proteins

Methods

Results

Conclusion