Abstract B006: Functional antagonism of VSIG8-mediated immune suppression by oral VISTA agents

Abstract

With the remarkable success of antibodies focusing on PD-1/PD-L1, the immune checkpoint blockade approach has established itself as a cornerstone to cancer therapy. While PD-1/PD-L1 antibodies primarily focus on T cells to achieve antitumor efficacy, other cells in the tumor microenvironment such as myeloid cells, including MDSCs, also play a role in immune evasion, thus contributing to the lack of response in 70-80% of patients. To overcome the immune resistance induced by MDSCs, V-domain Ig suppressor of T-cell activation (VISTA) expressed predominantly on myeloid cells and tumor-infiltrating lymphocytes is considered as an ideal target. Recent findings also support the role of VISTA pathway in clearance of apoptotic bodies and prevention of autoimmunity. VISTA is reported to mediate immune suppression through homophillic interaction as well as interaction with V-Set and immunoglobulin domain containing 8 (VSIG8). We sought to discover and develop an orally available, small-molecule VISTA antagonist targeting both VISTA and VSIG8 pathways. Unlike antibodies targeting VISTA in early clinical trials, an oral agent potentially offers the convenience and flexibility to adjust the dose and schedule to address any emergent adverse events and ease of combination therapy. Since VISTA belongs to B7 family and the extracellular Ig domain of VISTA shares significant sequence homology with the B7 family ligands PD-L1 and PD-L2, a focused library of compounds mimicking the interaction of checkpoint proteins of B7 family was designed and synthesized. Screening and analysis of the resulting library led to the identification of hits capable of functional disruption of the checkpoint protein(s) signaling, depending upon the pockets of sequence similarity of interacting proteins. Further optimization resulted in lead compounds targeting both VISTA and VSIG8 signaling pathways with desirable drug-like properties including good oral bioavailability. Potent functional activity comparable to that obtained with an anti-VISTA or anti-VSIG8 antibody in rescuing effector functions was observed with the lead compound along with selectivity against other immune checkpoint proteins. An advanced lead compound exhibited sustained immune PD in tumor-bearing animals including desirable impact on myeloid and T cells in both circulation and tumor. The advanced lead compound also exhibited significant efficacy in syngeneic preclinical tumor models of melanoma and colon cancers upon once-a-day oral dosing with excellent tolerability. Further development of the oral VISTA antagonist is under way towards advancing it to the clinic. Citation Format: Pottayil G. Sasikumar, Sudarshan S. Naremaddepalli, Raghuveer K. Ramachandra, Nagesh Gowda, Manikyala Rao Yerramsetti, Srinivasa Rao Bandireddy, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit A. Dhudashia, Samiulla S. Dodheri, Nagaraj M. Gowda, Murali Ramachandra. Functional antagonism of VSIG8-mediated immune suppression by oral VISTA agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B006.

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

“…It was hypothesized that a substantially reduced native pharmacophore derived from protein–protein interacting interfaces of one of the B7 family protein (such as PD-1) also has the potential to interact with other proteins belonging to IgSF (such as VISTA and TIM3) with structurally similar grooves induced by pockets of sequence similarity ( 71 ). A focused library was designed and synthesized using amino acids in the hotspot region including conserved residues in the hotspot regions to identify selective or spectrum-selective inhibitors targeting one or more non-redundant checkpoint signaling pathways such as PD-L1 and VISTA ( 72 ), PD-L1 and TIM3 ( 73 , 74 ), VISTA ( 75 ), TIM-3 ( 76 ), PD-L1 and T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) ( 77 ), TIGIT ( 78 ), and cluster of differentiation 47 (CD-47) ( 79 ) pathways with desirable physicochemical properties and exposure upon oral administration. It is worth noting that small molecules with dual immune checkpoint inhibition have only been reported from the amino-acids-inspired interface mimic approach.…”

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA

“…The peptide antagonist enhanced T cell proliferation in vitro and significantly enhanced antitumor immunity [ 30 ]. A small-molecule inhibitor of VISTA/PD-L1 (CA-170, the compound structure has not yet been disclosed)-collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc-can restore the IFN-γ production inhibited by soluble VISTA upon induction of human peripheral blood mononuclear cells (PBMCs) with anti-CD3 and anti-CD28 antibodies [ 31 , 32 ]. Currently, compound CA-170 is undergoing Phase I clinical trial for advanced tumors and lymphoma (NCT02812875) [ 33 ].…”

Identification of active small-molecule modulators targeting the novel immune checkpoint VISTA

“…The peptide antagonist enhanced T cell proliferation in vitro and significantly enhanced antitumor immunity [26]. A small-molecule inhibitor of VISTA/PD-L1 (CA-170, the compound structure has not yet been disclosed)-collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc-can restore the IFN-γ production inhibited by soluble VISTA upon induction of human peripheral blood mononuclear cells (PBMCs) with anti-CD3 and anti-CD28 antibodies [27,28]. Currently, compound CA-170 is undergoing Phase I clinical trial for advanced tumors and lymphoma (NCT02812875) [29].…”