Use of compositions modulating chromatin structure for graft versus host disease (GVHD)

A graft-versus-host, disease technology, used in drug combinations, allergic diseases, medical preparations containing active ingredients, etc., can solve problems such as resistance, patient infection or cancer recurrence

Inactive Publication Date: 2017-10-13
DANA FARBER CANCER INST INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, high doses of immunosuppressive steroids can pose a risk of infection or cancer recurrence in patients; patients may also be resistant to steroid regimens

Method used

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  • Use of compositions modulating chromatin structure for graft versus host disease (GVHD)
  • Use of compositions modulating chromatin structure for graft versus host disease (GVHD)
  • Use of compositions modulating chromatin structure for graft versus host disease (GVHD)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0521] method

[0522] On days -3 and -2 (120 mg / kg / day i.p.), B10.BR recipients were conditioned with cyclophosphamide. On Day -1, recipients received TBI (8.3 Gy) by X-ray. B6 donor BM were T cells depleted with anti-Thyl.2 mAb followed by rabbit complement. Purified from spleens by incubation with biotinylated anti-CD19, anti-CD11b, anti-CD11c, anti-NK1.1 and anti-γδTCR (eBioscience) followed by incubation with streptavidin beads and depletion with magnetic columns (StemCell Technologies) T cells. On day 0, purified T cells (0.075-0.1x10 6 ), the receiver accepts 10×10 6 T cell depleted BM cells. Body weights of individual mice were recorded weekly. When indicated, recipients in the BM and T cell groups were given an EZH2 inhibitor (10% hydroxypropyl-β-cyclodextrin and JQ-EZH2-5 in DMSO in a 9:1 ratio (75 μg / animal / week 3 times) or JQ1 (50 μg / animal / day)) or Bcl 79-6 in PBS (50 μg / animal / 3 times a week).

[0523] result

[0524] Bcl6 in T-cells is required for ...

Embodiment 2

[0560] EZH2 knockout bone marrow and Treg with or without JQ5 inhibition

[0561] Table 5 provides a schematic representation of the animal model protocol used for this experiment.

[0562] table 5

[0563]

[0564] Animals in this experiment were transplanted with wild-type or EZH2-knockout BM and wild-type or EZH2-knockout BM T-cells, then treated with vehicle or an EZH2 inhibitor (JQ5).

[0565] Specifically, B10.BR mice were conditioned with 120 mg / Kg cyclophosphamide on days -3 and -2 and subjected to whole body irradiation (830X) on day -1. On day 0, mice were transplanted with wild-type B6 bone marrow with or without splenocytes or purified splenic T cells. On day 28 after transplantation, mice were dosed with vehicle control or JQ5 (75 mg / Kg, 3x weekly) until day 56. On day 60, mice were subjected to the forced oscillatory technique on the Scireq Flexivent system. Tissues were collected and analyzed for collagen deposition by trichrome staining, Ig deposition, pre...

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PUM

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Abstract

In some aspects, the instant disclosure relates to methods of treating chronic graft versus host disease (cGVHD). In some embodiments, the method comprises administering to a subject in need thereof a EZH2 inhibitor, a Bcl6 inhibitor and / or BRD4 inhibitor. The present disclosure is based, at least in part, on the discovery that enhancer of zeste homolog 2 (EZH2) inhibitors, B-cell lymphoma 6 protein (Bcl6) inhibitors and / or bromodomain-containing protein 4 (BRD4) inhibitors can be used to treat chronic graft versus host disease (cGVHD).

Description

[0001] related application [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application U.S.S.N. 62 / 076,358, filed November 6, 2014, which is incorporated herein by reference. [0003] governmental support [0004] This invention was made with government support under Approval Numbers CA128972(K08), CA142106(P01), AI056299(P01), AU112613(R01) and AI007313(T32) issued by the National Institutes of Health. The government has certain rights in inventions. Background technique [0005] Graft versus host disease (GVHD) is a potentially serious complication of allogeneic tissue transplantation and blood transfusion. The underlying cause of GVHD is the presence of functional immune cells, such as white blood cells, in the transplanted tissue (graft). For example, T cells present in the graft can recognize the recipient (host) tissue as a "foreign" antigen and attack the host cells. Due to the immunocompromised state of the transplant recipient...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5517
CPCA61K45/06A61K31/427A61K31/4439A61K31/444A61K31/496A61P37/00A61K31/551A61K31/58A61K2300/00
Inventor J.E.布拉德纳B.布莱扎R.弗林J.齐
Owner DANA FARBER CANCER INST INC
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