Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation

Mehta, Nishant; Maddineni, Sainiteesh; Mathews, I.I.; Sperberg, R Andres Parra; Huang, Po-Ssu; Cochran, Jennifer R.

doi:10.1016/j.celrep.2019.07.073

Cited by 68 publications

(89 citation statements)

References 42 publications

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“…Earlier studies by our group demonstrated the www.nature.com/scientificreports/ importance of the R54, F62, and Q63 residues for binding to VSTB112 (Fig. 3c, cyan bars) 12 . We also expanded the panel to include five residues adjacent in 3D space to the mapped SG7 region to probe for locations potentially missed by the yeast screen ( Fig.…”

Section: Sg7 Binds To a Distinct Epitope On Vistamentioning

confidence: 77%

“…In sort 2, remaining mutants that had lost binding to SG7 were screened against 5 nM SG7 for increased stringency. VSTB112 binds a conformational epitope 12 and could therefore be used as a positive control for structural integrity. Thus, to select against mutations that caused protein misfolding, the library was screened with VSTB112 in sort 3 and only clones that retained binding to 100 nM VSTB112 were collected.…”

Section: Sg7 Binds To a Distinct Epitope On Vistamentioning

confidence: 99%

“…The DNA library was electroporated into the EBY100 strain of S. cerevisiae yeast for a resulting library size of ~ 2*10 8 mutants. Yeast displaying hVISTA mutants that lost binding to SG7 but retained binding to VSTB112 were isolated from the library using an alternating positive and negative FACS screening strategy, as described previously 12 . Yeast were incubated with the following concentrations of antibody: Sort 1, 500 pM SG7; Sort 2, 5 nM SG7; Sort 3, 100 nM VSTB112; Sort 4, 25 nM SG7.…”

Section: Creation Of Biased Scfv Library For Affinity Maturationmentioning

confidence: 99%

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An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

Mehta

Maddineni

Kelly

et al. 2020

Sci Rep

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V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint that maintains peripheral T cell quiescence and inhibits anti-tumor immune responses. VISTA functions by dampening the interaction between myeloid cells and T cells, orthogonal to PD-1 and other checkpoints of the tumor-T cell signaling axis. Here, we report the use of yeast surface display to engineer an anti-VISTA antibody that binds with high affinity to mouse, human, and cynomolgus monkey VISTA. Our anti-VISTA antibody (SG7) inhibits VISTA function and blocks purported interactions with both PSGL-1 and VSIG3 proteins. SG7 binds a unique epitope on the surface of VISTA, which partially overlaps with other clinically relevant antibodies. As a monotherapy, and to a greater extent as a combination with anti-PD1, SG7 slows tumor growth in multiple syngeneic mouse models. SG7 is a promising clinical candidate that can be tested in fully immunocompetent mouse models and its binding epitope can be used for future campaigns to develop species cross-reactive inhibitors of VISTA.

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Section: Sg7 Binds To a Distinct Epitope On Vistamentioning

confidence: 77%

Section: Sg7 Binds To a Distinct Epitope On Vistamentioning

confidence: 99%

Section: Creation Of Biased Scfv Library For Affinity Maturationmentioning

confidence: 99%

See 1 more Smart Citation

An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

Mehta

Maddineni

Kelly

et al. 2020

Sci Rep

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“…VISTA is a transmembrane protein that contains an immunoglobulin variable (IgV)-like fold and shares similarities with B7 family members PD1, PDL1, CD28 and CTLA4 [17]. The extracellular domain of VISTA contains four conserved cysteines that are not present in other B7 family members [17].…”

Section: Vista Structure and Binding Partnersmentioning

confidence: 99%

Exploring the VISTA of microglia: immune checkpoints in CNS inflammation

et al. 2020

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Negative checkpoint regulators (NCR) are intensely pursued as targets to modulate the immune response in cancer and autoimmunity. A large variety of NCR is expressed by central nervous system (CNS)-resident cell types and is associated with CNS homeostasis, interactions with peripheral immunity and CNS inflammation and disease. Immunotherapy blocking NCR affects the CNS as patients can develop neurological issues including encephalitis and multiple sclerosis (MS). How these treatments affect the CNS is incompletely understood, since expression and function of NCR in the CNS are only beginning to be unravelled. V-type immunoglobulin-like suppressor of T cell activation (VISTA) is an NCR that is expressed primarily in the haematopoietic system by myeloid and T cells. VISTA regulates T cell quiescence and activation and has a variety of functions in myeloid cells including efferocytosis, cytokine response and chemotaxis. In the CNS, VISTA is predominantly expressed by microglia and macrophages of the CNS. In this review, we summarize the role of NCR in the CNS during health and disease. We highlight expression of VISTA across cell types and CNS diseases and discuss the function of VISTA in microglia and during CNS ageing, inflammation and neurodegeneration. Understanding the role of VISTA and other NCR in the CNS is important considering the adverse effects of immunotherapy on the CNS, and in view of their therapeutic potential in CNS disease.

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“…The closest homolog within the B7 family is PD-L1,which shares a modest 23% sequence identity with VISTA. VISTA regulates a broad spectrum of immune responses [10][11][12][13][14][15][16], and is highly expressed on myeloid cells and tumor-infiltrating lymphocytes (i.e., macrophages and myeloid-derived suppressor cells (MDSCs)). It is also expressed on naïve CD4 + and CD8 + T cells, where it negatively regulates Tcell responses.…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Qie³

et al. 2020

Preprint

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Background: Cancer immunotherapy has gained increasing popularity as a novel approach to treat cancer. A member of the B7 family, V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel immune checkpoint that regulates a broad spectrum of immune responses. VISTA is an acidic pH-selective ligand for P-selectin glycoprotein ligand-1(PSGL-1). CA-170, a first-in-class small-molecule dual antagonist of VISTA/PD-L1, was collaboratively developed by Aurigene Discovery Technologies Limited and Curis, Inc. It is currently in Phase I clinical trial.Results: In this study, we develop homology modeling for the VISTA 3D structure and subsequent virtual screening for VISTA small-molecule hit ligands. Visualization of the binding postures of docked ligands with the VISTA protein indicates that some small molecular compounds target VISTA. The ability of antagonist to disrupt immune checkpoint VISTA pathways was investigated though functional studies in vitro.Conclusions: Affinity active molecule for VISTA was obtained through virtual screening, and the antagonist compound activity to VISTA was assayed in cellular level. We reported a small molecule with high VISTA affinity as antagonist , providing ideas for development VISTA-targeted small molecule compound in cancer immunotherapy.

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Structure and Functional Binding Epitope of V-domain Ig Suppressor of T Cell Activation

Cited by 68 publications

References 42 publications

An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA

Exploring the VISTA of microglia: immune checkpoints in CNS inflammation

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

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