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TRAIL receptor agonists for treatment of fibrotic diseases

A fibrosis and agonist technology, which can be used in skin diseases, bone diseases, respiratory diseases, etc., and can solve problems such as targeting multiple molecules at the same time

Pending Publication Date: 2017-04-19
B&L DELIPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Inhibition of one fibrosis-associated molecule would provide some anti-fibrotic efficacy; however, because fibrogenesis is a complex process involving multiple pathways involving many fibrogenesis molecules, this approach would not be efficient in arresting or reversing fibrosis
Simultaneous inhibition or downregulation of multiple fibrosis-associated molecules would exhibit strong anti-fibrotic efficacy, however, it is difficult to simultaneously target multiple molecules under physiological conditions, especially by utilizing a single drug molecule

Method used

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  • TRAIL receptor agonists for treatment of fibrotic diseases
  • TRAIL receptor agonists for treatment of fibrotic diseases
  • TRAIL receptor agonists for treatment of fibrotic diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0244] Example 1: Expression of TRAIL-R1 / DR4 and TRAIL-R2 / DR5 by Activated Primary Human Hepatic Stellate Cells (HSC) and Pancreatic Stellate Cells (PSC)

[0245] Materials and methods

[0246] Human primary hepatic stellate cells

[0247] Human primary HSC, PSC and stellate cell medium (SteCM) were obtained from ScienCell Research Laboratories (Carlsbad, CA). On polylysine-coated plates, culture in SteCM medium supplemented with 2% FBS, 1% stellate cell growth supplement and 1% penicillin / streptomycin solution cell. Then, in order to activate primary stellate cells, the cells were cultured in 6-well plastic culture plates for 1, 4, 7 and 14 days, and the cells were harvested. Expression of DR-4, DR-5 and α-SMA in cultured astrocytes was determined by Western blot analysis and real-time PCR.

[0248] Comparative quantitative real-time RT-PCR

[0249] Total RNA of cultured cells was extracted with TRIzol reagent (Life Technologies, Grand Island, NY), and reverse transcri...

Embodiment 2

[0254] Example 2: Activated human primary HSCs and PSCs show enhanced sensitivity to TRAIL agonist-induced apoptosis.

[0255] Materials and methods

[0256] Immunofluorescent staining of apoptosis

[0257] Cells were plated on glass coverslips in 35mm dishes (MatTek Corporation, Ashland, MA) and grown for 1, 4, 7 and 14 days. They were then treated with or without TRAIL agonist containing 1 microgram / ml ([mu]g / ml) TRAIL, PEGTRAIL, or DR5 antibody (R&D systems, Minneapolis, MN) at 50 ng / ml for 3 hours on these days. Cells were washed twice with cold PBS and fixed in 4% paraformaldehyde in PBS for 10 min. For detection of apoptosis, TdTIn Situ Apoptosis Detection Kit (TUNEL)-Fluorescein (R&D systems, Gaithersburg, MD) was used according to the manufacturer's instructions. Briefly, cells were incubated with proteinase K for 15 min at room temperature, then washed twice with DW, submerged with TdT labeling buffer, and then incubated with TdT labeling reaction mixture for 1 h...

Embodiment 3

[0265] Example 3: TRAIL treatment prevents liver fibrosis.

[0266] Materials and methods

[0267] in rats via CC1 4 Induced liver fibrosis (group 1)

[0268] SD rats aged 6-8 weeks (Hanlim Experimental Animal Laboratory, Seoul, Korea) were divided into 3 groups (8-10 rats per group); i) vehicle (olive oil), ii) 20 %CCl 4 and iii) CCl in olive oil 4 and TRAIL (group 1, figure 2 ). CCl was administered to rats by intraperitoneal injection three times a week 4 (20% CCl in olive oil 4 , 2ml / kg) or administration of olive oil as a control for 4 weeks, simultaneously treated with TRAIL administered intravenously at 4 mg / kg every 3 days or for the control group (Group 1, figure 2 ) were treated with the same amount of brine.

[0269] Liver histology and immunohistochemistry in liver fibrosis

[0270] After treatment, the animals were sacrificed, and the collected liver tissues were fixed in 10% buffered formaldehyde, embedded in paraffin, and cut into 4 μm thick sectio...

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Abstract

Pro-apoptotic agents such as ligands and agonists of agonistic TRAIL receptors can induce or increase apoptosis of cells that cause fibrosis and underlying diseases such as liver, pancreatic, lung and skin diseases characterized by fibrosis, cirrhosis, or complications thereof. The compositions and methods can be used to selectively remove activated hepatic stellate cells (HSCs), the originators of liver fibrosis and cirrhosis, and activated pancreatic stellate cells (PSCs), the originators of pancreas fibrosis and pancreatitis, and can be effective to reduce or prevent further chronic fibrosis by simultaneously reducing multiple fibrosis-associated molecules secreted or induced by such activated stellate cells. The compositions are typically effective to target agonistic TRAIL receptors such as TRAIL-R1 / DR4 and TRAIL-R2 / DR5 that are selectively expressed in activated HSCs and PSCs in physiological conditions. Ligands and agonists that can be used to target agonistic TRAIL receptors include, but are not limited to, TRAIL-R1 / DR4 and / or TRAIL-R2 / DR5 agonists.

Description

[0001] cross reference [0002] This application claims priority and benefit to U.S. Provisional Patent Application No. 61 / 982,207, filed April 21, 2014, U.S. Provisional Patent Application No. 61 / 990,530, filed May 8, 2014, and is a 2015 Continuation-in-Part of US Utility Model Application No. 14 / 645,276, filed March 11, the disclosure of which is expressly incorporated herein by reference. [0003] Reference to Sequence Listing [0004] This application contains a Sequence Listing submitted via EFS-Web in ASCII format, which is hereby incorporated by reference in its entirety. The ASCII copy, created on April 9, 2015, is named "THER_100_ST25.txt" and is 4,814 bytes in size. technical field [0005] The present invention relates generally to compositions and methods for treating fibrotic diseases, and in particular to TRAIL pro-apoptotic agents and methods for treating liver fibrosis and cirrhosis and complications thereof and fibrosis of other organs such as the pancreas, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K47/60A61P1/18A61P1/16A61P11/00A61P17/02
CPCA61K39/3955A61K39/39591A61K2039/505A61K38/1761A61K47/60A61P1/16A61P1/18A61P11/00A61P17/00A61P17/02A61P19/04A61P43/00C07K16/2878
Inventor 李康春
Owner B&L DELIPHARM CORP
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