PD-1 Derived CA-170 is an Oral Immune Checkpoint Inhibitor That Exhibits Preclinical Anti-tumor Efficacy

Overview

Journal Commun Biol

Specialty Biology

Date 2021 Jun 9

PMID 34103659

Citations 57

Authors

Pottayil G Sasikumar

Naremaddepalli S Sudarshan

Srinivas Adurthi

Raghuveer K Ramachandra

Dodderi S Samiulla

Anirudha Lakshminarasimhan

Anuradha Ramanathan

Talapaneni Chandrasekhar

Amit A Dhudashiya

Sumalatha R Talapati

Nagesh Gowda

Sreenivasulareddy Palakolanu

Jiju Mani

Bandi Srinivasrao

David Joseph

Nigam Kumar

Rashmi Nair

Hanudatta S Atreya

Nagaraj Gowda

Murali Ramachandra

Affiliations

Soon will be listed here.

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.

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