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Vista regulatory t cell mediator protein, vista binding agents and uses thereof

A technology of uses and cells, applied in the fields of peptide/protein components, anti-inflammatory agents, fusion polypeptides, etc., can solve problems such as damage and inability to fully control inflammation

Active Publication Date: 2017-01-18
TRUSTEES OF DARTMOUTH COLLEGE THE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

B7.1 and B7.2 knockout (KO) mice are impaired in the adaptive immune response, whereas CTLA-4 knockout mice fail to adequately control inflammation and develop systemic autoimmune disease

Method used

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  • Vista regulatory t cell mediator protein, vista binding agents and uses thereof
  • Vista regulatory t cell mediator protein, vista binding agents and uses thereof
  • Vista regulatory t cell mediator protein, vista binding agents and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0367] Example 1: Cloning and sequence analysis of PD-L3OR VISTA.

[0368] PD-L3OR VISTA and Treg-sTNF were identified by global transcriptional profiling of resting Tregs, αCD3-activated Tregs, and αCD3 / αGITR-activated Tregs. αGITR was chosen for this analysis because triggering of GITR on Tregs has been shown to suppress their contact-dependent inhibitory activity (Shimizu, et al. (2002) supra). exist PD-L3OR VISTA and Treg-sTNF were identified based on their unique expression patterns on DNA arrays (Table 1). PD-L3ORVISTA showed enhanced expression in αCD3-activated Tregs and decreased expression in the presence of αGITR; and Treg-sTNF showed αCD3 / αGITR-dependent enhancement of expression.

[0369] Purified CD4+CD25+ T cells were stimulated in overnight culture with none, αCD3 or αCD3 / αGITR, and RNA was isolated for real-time PCR analysis. Expression listed is compared to actin.

[0370] Table 1

[0371]

[0372] Affymetrix analysis of activated versus resting CD25...

Embodiment 2

[0377] Example 2: PD-L3 ORVISTA Expression Study by RT-PCR Analysis and Flow Cytometry

[0378] As shown in the experiments in Figure 3, RT-PCR analysis was used to determine the mRNA expression pattern of PD-L3OR VISTA in mouse tissues ( Figure 3A ). PD-L3OR VISTA is mainly expressed on hematopoietic tissues (spleen, thymus, bone marrow) or tissues with abundant lymphocyte infiltration (ie, lung). Weak expression was also detected in non-hematopoietic tissues (ie, heart, kidney, brain and ovary). Analysis of several hematopoietic cell types revealed that PD-L3OR VISTA was expressed on peritoneal macrophages, splenic CD11b+ monocytes, CD11c+ DCs, CD4+ T cells, and CD8+ T cells, but to a lesser extent on B cells ( Figure 3B ). This expression pattern is also highly consistent with the GNF (Genomics Institute of Novartis Research Foundation) gene array database (Su et al., (2002), Proc Natl Acad Sci USA 99, 4465-4470) and the NCBIGEO (gene expression omnibus) database (Fig....

Embodiment 3

[0386] Example 3: Functional impact of PD-L3OR VISTA signaling on CD4+ and CD8+ T cell responses

[0387] A PD-L3OR VISTA-Ig fusion protein was generated to study the modulatory effect of PD-L3OR VISTA on CD4+ T cell responses. The PD-L3OR VISTA-Ig fusion protein comprises the extracellular domain of PD-L3OR VISTA fused to the human IgG1 Fc region. When immobilized on microplates, PD-L3OR VISTA-Ig, but not control Ig, inhibited the proliferation of crudely purified CD4+ and CD8+ T cells in response to plate-bound anti-CD3 stimulation, as determined by inhibited cell division ( Figure 9A -B). The PD-L3ORVISTA Ig fusion protein did not affect the uptake of anti-CD3 antibodies into plastic wells, as determined by ELISA (data not shown), thus ruling out the possibility of non-specific inhibitory effects. PD-1KO CD4+ T cells were also suppressed ( Figure 9C ), thus indicating that PD-1 is not a receptor for PD-L3OR VISTA. The inhibitory effects of PD-L1-Ig and PD-L3OR VISTA-I...

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Abstract

The present invention relates to a novel regulatory T cell protein. The protein, named PD‑L3ORVISTA, resembles members of the PD‑L1 family and represents a novel and structurally distinct Ig superfamily inhibitory ligand whose ectodomain has the same identity as the B7 family ligand PD‑L1. source. This molecule is called PD‑L3OR VISTA or V-domain immunoglobulin inhibitor of T-cell activation (VISTA). The expression of VISTA is mainly localized in the hematopoietic compartment and is highly regulated on bone marrow APCs and T cells. Therapeutic intervention of the VISTA inhibitory pathway suggests a new approach to modulate T cell-mediated immunity for the treatment of various cancers such as ovarian, bladder and melanoma. Additionally, VISTA proteins, particularly multimeric VISTA proteins and antibodies are useful for suppressing T cell immunity in autoimmune diseases, allergies, infections and inflammatory disorders such as multiple sclerosis and joint disorders such as RA.

Description

[0001] Introduction [0002] This patent application claims U.S. Patent Serial No. 12 / 732,371 filed March 26, 2010, U.S. Provisional Application No. 61 / 390,434 filed October 6, 2010, U.S. Provisional Application No. .61 / 436,379 and priority to US Provisional Application No. 61 / 449,882 filed March 7, 2011. All of these patent applications are incorporated herein by application in their entirety. [0003] This patent application relates to our discovery, characterization and determined function of a novel, hematopoietic-restricted, structurally distinct Ig superfamily inhibitory ligand, known as the V domain-containing immunoglobulin inhibitor of T-cell activation (VISTA) or PD -L3. Its ectodomain shares homology with the B7 family ligand PD-L1, and like PD-L1, VISTA has profound effects on immunity. However, unlike PD-L1, the expression of VISTA is only localized in the hematopoietic compartment. Expression is most common on myeloid antigen-presenting cells (APCs), but expres...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/47C07K19/00C07K16/18A61K38/17A61K39/395A61P37/00A61P19/02A61K39/00
CPCC07K14/70503C07K16/28C07K16/2803A61K2039/505C07K2317/76C07K2319/30A61P1/02A61P1/04A61P1/14A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P11/16A61P13/02A61P13/12A61P15/08A61P15/10A61P17/00A61P17/02A61P17/04A61P17/06A61P17/14A61P19/02A61P19/06A61P21/00A61P21/02A61P21/04A61P25/00A61P25/06A61P25/08A61P25/28A61P27/02A61P27/16A61P29/00A61P31/00A61P31/04A61P31/06A61P31/10A61P31/12A61P31/14A61P31/18A61P31/20A61P33/06A61P33/10A61P33/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P39/02A61P43/00A61P5/00A61P5/14A61P5/38A61P7/00A61P7/04A61P7/06A61P9/00A61P9/06A61P9/08A61P9/10A61P3/10Y02A50/30A61K39/395C07K14/47C07K19/00C07K16/18A61K38/17
Inventor R·J·诺雷L·王
Owner TRUSTEES OF DARTMOUTH COLLEGE THE
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