Background VISTA (V-domain Ig suppressor of T-cell activation) is a negative checkpoint regulator (NCR), highly expressed on myeloid cells.1 PSGL-1 on T-cells has been identified as a novel NCR that limits survival and promotes T-cell exhaustion.2 Recently, VISTA was reported to bind PSGL-1 and suppress T-cell activity exclusively under acidic conditions (~pH 6 in lymph nodes or the tumor microenvironment).3, 4 Although VISTA inhibition demonstrated excellent therapeutic combinability with other modalities targeting NCRs (e.g. CTLA-4, PD-1/PD-L1),5 clinical development of anti-VISTA antibodies has been challenging due to: 1) high clearance via target-mediated drug disposition (TMDD) by VISTA+ neutrophils and monocytes at physiologic pH; and 2) cellular activation and cytokine release syndrome (CRS) at sub-therapeutic doses by engagement of VISTA in the blood.6
We developed SNS-101, a human monoclonal IgG1 antibody specific for the protonated, active form of VISTA, which is designed to disrupt the immunosuppressive VISTA:PSGL-1 interaction, avoid TMDD and mitigate potential CRS.
Methods The binding potential of SNS-101 to VISTA+ cells was determined in human and non-human primate (NHP) whole-blood by flow cytometry. The effect of SNS-101 on human monocytes and T-cells was evaluated in vivo in human CD34+ cord blood cell reconstituted BRGSF mice, which develop both human lymphoid and myeloid compartments. The pharmacokinetic (PK) profile was assessed in NHPs. Anti-tumor efficacy was assessed in VISTA-KI mice implanted with the syngeneic tumor model, MC38, and tumor-infiltrating T-cells were analyzed by flow cytometry.
Results SNS-101 did not bind to human or NHP VISTA+ monocytes, neutrophils and natural killer cells. In humanized BRGSF mice, SNS-101 induced significant expansion of CD4 and CD8 central memory (CCR7+CD45RA-), and naïve (CCR7+CD45RA+) CD8 T-cells, respectively, but had no significant impact on monocyte activation. PK studies in NHPs showed linear elimination kinetics. Conversely, a non-pH-sensitive antibody bound VISTA+immune cells, induced monocyte activation followed by a decrease in cell numbers and was rapidly cleared in NHPs. Anti-tumor efficacy studies in MC-38 demonstrate that SNS-101 enhanced anti-PD-1 response and dose-dependently increased tumor-infiltrating CD8 T-cells.
Conclusions Our results demonstrate that SNS-101 exhibits linear elimination kinetics in NHPs, overcoming TMDD-induced PK limitations observed with other anti-VISTA antibodies. Importantly, SNS-101 induced expansion of naïve and memory T-cell phenotypes in vivo without activation or depletion of monocytes, differentiating it from non-pH-selective VISTA antibodies. In the MC-38 syngeneic tumor model, SNS-101 demonstrated significant enhancement of anti-tumor effects in combination with anti-PD-1 antibodies through an increase in CD8+ T-cells.
Yuan L, Tatineni J, Mahoney KM, et al. VISTA: a mediator of quiescence and a promising target in cancer immunotherapy. Trends Immunol. 2021; 42:209–227.
Tinoco R, Carrette F, Barraza ML, et al. PSGL-1 is an immune checkpoint regulator that promotes T cell exhaustion. Immunity. 2016; 44:1190–1203.
Johnston RJ, Su LJ, Pinckney J, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature 2019; 574:565–570.
Wu H, Estrella V, Beatty M, et al. T-cells produce acidic niches in lymph nodes to suppress their own effector functions. Nat Commun. 2020; 11:4113.
Gao J, Ward JF, Pettaway CA, et al. VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat. Med. 2017; 23:551–555.
Curis Corporate Presentation Jan 2022 [http://investors.curis.com/events-and-presentations?item=100]
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.