Antagonist of the btla/hvem interaction for use in therapy

a technology of hvem and hvem, which is applied in the field of anti-hvem interaction of btla/hvem interaction for use in therapy, can solve the problems of t cells having a substantial disadvantage compared with v9v2 cells, and the homeostasis of v9v2 cells remains poorly understood, and achieves the effect of increasing the proliferation of v9v2 t cells

Inactive Publication Date: 2016-05-05
INST JEAN PAOLI & IRENE CALMETTES +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014]A first object of the invention thus relates to an antagonist of the BTLA / HVEM interaction for use in therapy, wherein said antagonist increases the proliferation of Vγ9Vδ2 T cells.
[0131]The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.

Problems solved by technology

However, the homeostasis of Vγ9Vδ2 cells remain poorly understood.
Thus, γδ T cells have a substantial disadvantage compared to αβ T cells during their expansion.

Method used

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  • Antagonist of the btla/hvem interaction for use in therapy
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  • Antagonist of the btla/hvem interaction for use in therapy

Examples

Experimental program
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Effect test

example 1

The Co-Receptor BTLA Negatively Regulates Human Vγ9Vδ2T Cell Proliferation

MATERIAL & METHODS

[0163]Patients

[0164]Eleven lymph nodes from lymphoma patients were evaluated including 9 NHLs and 3 Hodgkin lymphoma (HL), NHLs samples were classified as B-cell follicular lymphoma (FL, n=7) and diffuse large B-cell lymphoma (DLBCL, n=1). HLs samples belonged to the classical form. Informed consent was obtained from all participants in accordance with the Declaration of Helsinki. The study was approved by the institutional review boards of the Institut Paoli Calmettes. The control group consisted of seven healthy volunteers (HV) provided by Marseille Blood Bank. Mononuclear cells from lymph nodes were isolated after mechanical disruption. Peripheral blood mononuclear cells from HV were isolated by density gradient centrifugation (Lymphoprep, Abcys). Isolated cells were viably frozen in fetal bovine serum (PAN Biotech) containing 10% dimethyl sulfoxide (Sigma-Aldrich) until use.

[0165]Reagents...

example 2

HVEM is Expressed on Solid Tumors

[0209]1. A. HVEM Expression by QRT-PCR on Prostate, Melanoma and Breast Cancer Cell Lines

[0210]The inventors tested various and different lines of solid tumors, illustrating a large scope of different solid tumors.

[0211]More specifically, they used various cell lines from:[0212]prostate cancer,[0213]breast cancer,[0214]melanoma, and

[0215]By using QRT-PCR, they observed that HVEM transcript is expressed heterogeneously on solid tumors (various cell lines from prostate cancer, melanoma and breast cancer were tested).

[0216]The gene expression is higher when delta Ct is lower. FIG. 7, left panel show HVEM delta Ct vs housekeeping gene GAPDH for each cell line. FIG. 7, right panel shows mean expression by pathology.

[0217]In conclusion, HVEM transcript is expressed heterogeneously on tumor cell lines, as illustrated on melanoma, then prostate cancer and breast cancer.

[0218]2. HVEM Expression by Immunohistochemistry

[0219]The inventors further evaluate HVEM ...

example 3

Effect of HVEM / BTLA Blockade on γδT Cell Proliferation

[0225]1. HVEM / BTLA Blockade Enhance the Proliferation of γδ T Cells

[0226]The inventors isolated and purified_γδ T cells from healthy donors, stained with Cell Trace Violet and cultured with 200 UI / ml IL2, with or without low dose BrHPP (50 nM), + / −20 μg / m1 anti-BTLA 8.2, HVEM 18.10 or isotypic control for 5 days. At day 5, γδ T cells proliferation was quantified by Cell Trace Violet dilution (flow cytometry) and represented as the percentage of divided cells among the γδ T cells. (n=10).

[0227]The inventors observed that the blockade of HVEM / BTLA interaction with anti-BTLA 8.2 or HVEM 18.10 antibody significantly increased the proliferation of γδ T cells (FIG. 9).

[0228]This indicates that HVEM / BTLA pathway is involved in the regulation of γδ T lymphocytes by inhibiting their proliferation and that the use of blocking mAbs could restore or enhance γδ T proliferation.

[0229]2. HVEM / BTLA Blockade is Efficient on Different Prostate Tum...

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Abstract

The present invention relates to an antagonist of the BTLA / HVEM interaction for use in therapy, wherein said antagonist increases the proliferation of Vγ9Vδ2 T cells.

Description

FIELD OF THE INVENTION[0001]The present invention relates to an antagonist of the BTLA / HVEM interaction for use in therapy.BACKGROUND OF THE INVENTION[0002]Vγ9Vδ2 cells represent a major peripheral blood T cell subset in humans displaying a broad reactivity against microbial agents and tumors. They have the ability to simultaneously recognize and respond to phosphorylated non-peptide antigens (phosphoantigens, PAg), molecules found on a wide variety of pathogenic organisms and tumor cells in a HLA unrestricted fashion. Accordingly, Vγ9Vδ2 T cells are involved in tumor immune surveillance notably against carcinomas and hematologic malignancies.[0003]Maintenance of lymphocyte population size is usually achieved by balancing the generation of new cells and clonal expansion with cell death. However, the homeostasis of Vγ9Vδ2 cells remain poorly understood. The size of the Vγ9Vδ2 cell pool is regulated by the availability of IL-15 and IL-7, and their homeostasis is maintained in competit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28
CPCC07K16/2866C07K2317/515C07K2317/51A61K39/00C07K16/2818C07K2317/55C07K2317/74C07K2317/76C07K16/2875A61P1/04A61P1/16A61P15/00A61P17/00A61P19/02A61P21/04A61P25/00A61P29/00A61P35/00A61P35/02A61P37/06A61P5/14A61P7/00A61P7/04A61P7/06A61P3/10
Inventor OLIVEGERTNER-DARDENNE, JULIEPASERO, CHRISTINE
Owner INST JEAN PAOLI & IRENE CALMETTES
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