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

Sasikumar, PG and Sudarshan, NS and Adurthi, S and Ramachandra, RK and Samiulla, DS and Lakshminarasimhan, A and Ramanathan, A and Chandrasekhar, T and Dhudashiya, AA and Talapati, SR and Gowda, N and Palakolanu, S and Mani, J and Srinivasrao, B and Joseph, D and Kumar, N and Nair, R and Atreya, HS and Gowda, N and Ramachandra, M (2021) PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy. In: Communications Biology, 4 (1).

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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. © 2021, The Author(s).

Item Type:	Journal Article
Publication:	Communications Biology
Publisher:	Nature Research
Additional Information:	The copyright for this article belongs to Authors
Department/Centre:	Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility)
Date Deposited:	27 Aug 2021 10:03
Last Modified:	27 Aug 2021 10:03
URI:	http://eprints.iisc.ac.in/id/eprint/69295

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