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Novel VISTA-Ig constructs and the use of VISTA-Ig for Treatment of Autoimmune, Allergic and Inflammatory Disorders

a technology of vistaig and constructs, which is applied in the direction of peptide/protein ingredients, dna/rna fragmentation, fusion polypeptides, etc., can solve the problems of immune system that cannot distinguish between self and non-self, response that destroys normal body tissues, and cannot adequately control inflammation in ctla-4 ko mi

Inactive Publication Date: 2018-02-22
TRUSTEES OF DARTMOUTH COLLEGE THE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent relates to the use of soluble forms of a protein called VISTA, which can be administered to treat autoimmune, allergic, and inflammatory conditions in humans. The patent describes optimized versions of VISTA that can be fused with other proteins, such as immunoglobulins, to create more potent and effective treatments. The patent also provides a method for creating fusion proteins using VISTA and other proteins. Overall, this patent provides new ways to use VISTA to treat various medical conditions.

Problems solved by technology

(1993) Science 262, 907-909), whereas CTLA-4 KO mice can not adequately control inflammation and develop systemic autoimmune diseases.
However, in patients with an autoimmune disorder, the immune system can not distinguish between self and non-self (e.g., healthy tissue and foreign antigens).
The result is an immune response that destroys normal body tissues.
Side effects of medications used to suppress the immune system can be severe, such as infections that can be hard to control.
Similarly, progressive destruction of the tissue would compromise the survival of the organism.

Method used

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  • Novel VISTA-Ig constructs and the use of VISTA-Ig for Treatment of Autoimmune, Allergic and Inflammatory Disorders
  • Novel VISTA-Ig constructs and the use of VISTA-Ig for Treatment of Autoimmune, Allergic and Inflammatory Disorders
  • Novel VISTA-Ig constructs and the use of VISTA-Ig for Treatment of Autoimmune, Allergic and Inflammatory Disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Cloning and Sequence Analysis of VISTA (PD-L3)

[0668]VISTA (PD-L3) and Treg-sTNF were identified by global transcriptional profiling of resting Treg, Treg activated with αCD3, and Treg activated with αCD3 / αGITR. αGITR was selected for this analysis as triggering of GITR on Treg has been shown to extinguish their contact-dependent suppressive activity (Shimizu, et al. (2002) supra). VISTA (PD-L3) and Treg-sTNF were identified on AFFIMETRIX® DNA arrays based on their unique expression patterns (Table 2). VISTA (PD-L3) exhibited an increase in expression in αCD3 activated Treg and reduced expression in the presence of αGITR; and Treg-sTNF exhibited a αCD3 / αGITR-dependent increase in expression.

[0669]Purified CD4+CD25+ T cells were stimulated in culture overnight with none, αCD3, or αCD3 / αGITR, and RNA isolated for real-time PCR analysis. Expression listed is relative to actin.

TABLE 2Relative ExpressionmRNANoneαCD3αCD3 / αGITRVISTA (PD-L3)6107Treg-sTNF0.20.31.5

[0670]AFFIMETRIX® analysis of...

example 2

Expression Studies of VISTA (PD-L3) by RT-PCR Analysis and Flow Cytometry

[0675]RT-PCR analysis was used to determine the mRNA expression pattern of VISTA (PD-L3) in mouse tissues (FIG. 3A). VISTA (PD-L3) is mostly expressed on hematopoietic tissues (spleen, thymus, bone marrow), or tissues with ample infiltration of leukocytes (i.e. lung). Weak expression was also detected in non-hematopoietic tissues (i.e. heart, kidney, brain, and ovary). Analysis of several hematopoietic cell types reveals expression of VISTA (PD-L3) on peritoneal macrophages, splenic CD11b+ monocytes, CD11c+ DCs, CD4+ T cells and CD8+ T cells, but lower expression level on B cells (FIG. 3B). This expression pattern is also largely consistent with the GNF (Genomics Institute of Novartis Research Foundation) gene array database, as well as NCBI GEO (gene expression omnibus) database (FIG. 3A-3D). See Su, et al. (2002) Proc Natl Acad Sci USA 99: 4465-4470.

[0676]In order to study the protein expression, VISTA (PD-L3...

example 3

Functional Impact of VISTA (PD-L3) Signaling on CD4+ and CD8+ T Cell Responses

[0683]A VISTA (PD-L3)-Ig fusion proteins were was produced to examine the regulatory roles of VISTA (PD-L3) on CD4+ T cell responses. The VISTA (PD-L3)-Ig fusion protein contains the extracellular domain of VISTA (PD-L3) fused to the human IgG1 Fc region. When immobilized on the microplate, VISTA (PD-L3)-Ig but not control Ig suppressed the proliferation of bulk purified CD4+ and CD8+ T cells in response to plate-bound anti-CD3 stimulation, as determined by arrested cell division (FIG. 9A-9B). The VISTA (PD-L3) Ig fusion protein did not affect the absorption of anti-CD3 antibody to the plastic wells, as determined by ELISA, thus excluding the possibility of non-specific inhibitory effects. PD-1 KO CD4+ T cells were also suppressed (FIGS. 9C, 9D), indicating that PD-1 is not the receptor for VISTA (PD-L3). The inhibitory effect of PD-L1-Ig and VISTA (PD-L3)-Ig was also directly compared (FIG. 10). When titr...

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Abstract

The present invention relates to a fusion proteins comprising regulatory T cell protein, VISTA (V-domain Immunoglobulin Suppressor of T cell Activation (PD-L3) and an immunoglobulin protein (Ig), preferably also containing a flexible linker intervening the VISTA and Ig Fc polypeptide. The invention also provides the use of VISTA polypeptides, multimeric VISTA polypeptides, VISTA-conjugates (e.g., VISTA-Ig), and VISTA antagonists for the treatment of autoimmune disease, allergy, and inflammatory conditions, especially lupus, multiple sclerosis, psoriasis, psoriatic arthritis, multiple sclerosis, Crohn's disease, inflammatory bowel disease and type 1 or type 2 diabetes.

Description

RELATED APPLICATIONS[0001]This application is a continuation of U.S. patent application Ser. No. 13 / 925,034, filed Jun. 24, 2013, which is a continuation of PCT Application No. PCT / US13 / 47009 filed on Jun. 21, 2013, entitled “Novel VISTA-Ig constructs and the use of VISTA-Ig for Treatment of Autoimmune, Allergic and Inflammatory Disorders”, which claims priority to U.S. Provisional Application No. 61 / 663,431 filed on Jun. 22, 2012, entitled “VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders”, U.S. Provisional Application No. 61 / 663,969 filed on Jun. 25, 2012, entitled “VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders”, U.S. Provisional Application No. 61 / 735,799 filed on Dec. 11, 2012, entitled “VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders”, U.S. Provisional Application No. 61 / 776,234 filed on Mar. 11, 2013, entitled “VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders”, and U.S. Provisional Application No. 61 / 807,135 filed...

Claims

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Application Information

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IPC IPC(8): C07K16/18C07K14/705
CPCC07K14/70532C07K16/18A01K2267/0387A01K2267/0368A01K2267/0325C12N2310/14C07K2319/735A01K67/0276A01K2227/105A01K2217/075A61K39/39C07K2319/32C07K2319/30C07K2317/76C07K16/2827A61K39/395C12N15/1138A61K45/06A61K39/3955A61K38/00A61K2039/505C07K14/70503A61K39/00C07K2319/60A61P1/00A61P1/02A61P1/04A61P1/14A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P11/16A61P13/02A61P13/08A61P13/10A61P13/12A61P15/00A61P15/02A61P15/06A61P15/08A61P15/10A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P17/14A61P19/02A61P19/04A61P19/06A61P19/10A61P21/00A61P21/02A61P21/04A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/04A61P27/12A61P27/16A61P29/00A61P3/00A61P3/04A61P31/04A61P31/06A61P31/10A61P31/12A61P31/14A61P31/18A61P31/20A61P33/06A61P33/10A61P33/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P39/02A61P43/00A61P5/00A61P5/08A61P5/14A61P5/36A61P5/38A61P5/50A61P7/00A61P7/04A61P7/06A61P7/10A61P9/00A61P9/06A61P9/08A61P9/10A61P9/12A61P3/10Y02A50/30A61K31/00
Inventor NOELLE, RANDOLPH J.CEERAZ, SABRINALEMERCIER, ISABELLENOWAK, ELIZABETHLINES, JANET
Owner TRUSTEES OF DARTMOUTH COLLEGE THE
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