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Novel VISTA-IG constructs and the use of VISTA-IG for treatment of autoimmune, allergic and inflammatory disorders

An immunosuppression and variant technology, applied in allergic diseases, DNA/RNA fragments, metabolic diseases, etc., can solve the problem that the immune system cannot distinguish between self and non-self

Active Publication Date: 2015-05-13
TRUSTEES OF DARTMOUTH COLLEGE THE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in patients with autoimmune diseases, the immune system cannot distinguish between self and non-self (for example, healthy tissue and foreign antigens)

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

Embodiment 1

[0740] Sequence Analysis of VISTA(PD-L3) Clones

[0741] VISTA (PD-L3) 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 it has been shown that triggering of GITR on Tregs suppresses their contact-dependent inhibitory activity (Shimizu, et al. (2002) supra). exist VISTA (PD-L3) and Treg-sTNF were identified based on their unique expression patterns on DNA arrays (Table 2). VISTA(PD-L3) 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.

[0742] 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.

[0743] Table 2

[0744]

[0745] Activated versus resting CD25+CD4+nTreg Analysis revealed exp...

Embodiment 2

[0751] VISTA (PD-L3) Expression Study by RT-PCR Analysis and Flow Cytometry

[0752] RT-PCR analysis was used to determine the mRNA expression pattern of VISTA (PD-L3) in mouse tissues ( image 3 A). VISTA (PD-L3) 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 VISTA (PD-L3) was expressed on peritoneal macrophages, splenic CD11b+ monocytes, CD11c+ DCs, CD4+ T cells, and CD8+ T cells, but less so on B cells. Low( image 3 B). This expression pattern is also highly consistent with the GNF (Genomics Institute of Novartis Research Foundation) gene array database and the NCBI GEO (gene expression comprehensive database) database ( image 3 A-D). See Su, et al. (2002) Proc Natl Acad Sci USA 99:4465–4470.

[0753]To study protei...

Embodiment 3

[0761] Functional impact of VISTA (PD-L3) signaling on CD4+ and CD8+ T cell responses

[0762] A VISTA(PD-L3)-Ig fusion protein was generated to study the regulatory effect of VISTA(PD-L3) on CD4+ T cell responses. The VISTA(PD-L3)-Ig fusion protein comprises the extracellular domain of VISTA(PD-L3) fused to the human IgG1 Fc region. When immobilized on microtiter plates, VISTA(PD-L3)-Ig, but not control Ig, inhibited the proliferation of crudely purified CD4+ and CD8+ T cells in response to plate-bound anti-CD3 stimulation, such as by inhibited cell division And measured ( Figure 9A -B). The VISTA(PD-L3) Ig fusion protein did not affect the uptake of anti-CD3 antibodies into plastic wells, as determined by ELISA, thereby ruling out the possibility of non-specific inhibitory effects. PD-1 KO CD4+ T cells were also suppressed (Fig. 9C,D), thus suggesting that PD-1 is not a receptor for VISTA (PD-L3). The inhibitory effects of PD-L1-Ig and VISTA(PD-L3)-Ig were also directly...

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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

[0001] related application [0002] This application requires U.S. Provisional Application No. 61 / 663,431 entitled "VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders" filed on June 22, 2012, U.S. Provisional Application No. 61 / 663,969, titled "VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders," filed June 25, 2012, December 2012 U.S. Provisional Application No. 61 / 735,799, titled "VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders," filed March 11, 2013 U.S. Provisional Application No. 61 / 776,234 entitled "VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders" and filed April 1, 2013 Priority to U.S. Provisional Application No. 61 / 807,135, also titled "VISTA-Ig for Treatment of Autoimmune and Inflammatory Disorders," the contents of all said provisional applications Incorporated by reference in its entirety. field of invention [0003] VISTA[T cell activation containing V Region immunoglobulin inhibitor (VISTA) or PD-L3] i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/47C07K19/00A61K39/00A61P35/00A61P37/00
CPCC07K14/70503C07K16/2827C12N15/1138A61K39/00C07K2319/32C07K2319/30A61K39/39A61K39/395C07K2317/76A01K67/0276A01K2217/075A01K2227/105A01K2267/0325A01K2267/0368A01K2267/0387A61K2039/505C07K2319/735A61K38/00C07K14/70532C12N2310/14A61K39/3955C07K2319/60A61P1/00A61P1/02A61P1/04A61P1/14A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/08A61P11/16A61P13/02A61P13/08A61P13/10A61P13/12A61P15/00A61P15/02A61P15/06A61P15/08A61P15/10A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P17/14A61P19/02A61P19/04A61P19/06A61P19/10A61P21/00A61P21/02A61P21/04A61P25/00A61P25/04A61P25/06A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/04A61P27/12A61P27/16A61P29/00A61P3/00A61P3/04A61P31/04A61P31/06A61P31/10A61P31/12A61P31/14A61P31/18A61P31/20A61P33/06A61P33/10A61P33/12A61P35/00A61P35/02A61P37/00A61P37/02A61P37/06A61P37/08A61P39/02A61P43/00A61P5/00A61P5/08A61P5/14A61P5/36A61P5/38A61P5/50A61P7/00A61P7/04A61P7/06A61P7/10A61P9/00A61P9/06A61P9/08A61P9/10A61P9/12A61P3/10Y02A50/30A61K31/00A61K45/06C07K16/18
Inventor R·J·诺埃尔S·赛拉兹I·勒梅西埃E·诺瓦克J·L·莱恩斯
Owner TRUSTEES OF DARTMOUTH COLLEGE THE
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