Human VISTA Antibody Family

Blockade of VISTA with Anti-hVISTA mAbs

The Anti-hVISTA isotype family is a collection of recombinant monoclonal antibodies (mAbs) featuring:

• A Variable region that specifically targets human VISTA
• A Constant region that is either a natural (IgG1) or engineered (IgG1NQ and IgG1fut) human IgG1 isotype

The different isotypes in this collection provide various effector functions (e.g. decreased ADCC). The Anti-hVISTA isotype family has been generated by recombinant DNA technology, produced in CHO cells, and purified by protein G affinity chromatography.

VISTA: the target

V-domain Ig-containing suppressor of T-cell activation (VISTA), also known as programmed death-1 homolog (PD-1H), is a distant member of the CD28/B7 protein superfamily, sharing homology with another important immune checkpoint, PD-L1 (programmed death receptor 1) [1]. VISTA is predominantly expressed on antigen-presenting cells (APCs), and directly suppresses T cell proliferation and cytokine production [2]. Additionally, VISTA is expressed on a number of subsets of T cells (i.e. CD4+ and CD8+ cells) [3]. Thus, VISTA can be considered both a ligand and a receptor, whereby it transmits both extrinsic and intrinsic inhibitory signals to T cells. However, due to the lack of knowledge of its receptor, the underlying molecular mechanisms of effector T cell activation through VISTA remains poorly elucidated [4].

VISTA in the context of cancer immunotherapy

VISTA expression is heightened on cells that infiltrate the tumor microenvironment (TME) supporting a growing interest in the development of VISTA blocking mAbs [3]. Anti-hVISTA mAbs inhibit the engagement of VISTA with its receptor on T cells preventing VISTA from providing negative signaling. Unlike PD-L1, VISTA is not found to be expressed on tumor cells and is, therefore, a promising target for immune checkpoint blockade therapy to boost the anti-tumor T cell response.  Of note, the IL-23/IL-17 inflammatory axis has been shown to regulate the inflammatory response within the TME [5]. Interestingly, VISTA has also been shown to play a key role in the suppression of the IL-23/IL-17-mediated inflammatory axis by inhibiting the activation of dendritic cells and the production of IL-23 following TLR7 stimulation, as well as controlling IL-17 production by T cell subsets [5].  Altogether, current knowledge points to VISTA as a highly unique immune checkpoint that regulates both innate and adaptive immune responses. Therefore, targeting VISTA could benefit the treatment of not only autoimmune and inflammatory diseases but also boost the response to cancer therapy.

References:

1. Lines, J.L. et al. 2014. VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res 2, 510-517.
2. Lines, J.L. et al. 2014. VISTA is an immune checkpoint molecule for human T cells. Cancer Res 74, 1924-1932.
3. Nowak, E.C. et al. 2017. Immunoregulatory functions of VISTA. Immunol Rev 276, 66-79.
4. Xu, W. et al. 2018. The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 15, 438-446.
5. Li, N. et al. 2017. Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 7, 148.