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Compositions for inhibiting checkpoint gene expression and uses thereof

a technology of expression inhibition and compound, which is applied in the direction of dna/rna fragmentation, biochemistry apparatus and processes, organic active ingredients, etc., can solve the problems that many previous cancer immunotherapies have likely been limited by these suppressive mechanisms, and achieve enhanced antitumor immunotherapy applications, suppress the immune response, and effectively inhibit or decrease pd1.

Inactive Publication Date: 2018-02-15
IDERA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about compounds and methods for reducing the expression of genes involved in immune checkpoints, such as PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and OX40L, to enhance the effectiveness of cancer immunotherapy. The compounds are gene silencing compounds that can reduce the levels of these genes and proteins, which can be used to treat hyperproliferative diseases like cancer. The method involves administering the compound directly to the tumor cells.

Problems solved by technology

Many previous cancer immunotherapies have likely been limited by these suppressive mechanisms.

Method used

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  • Compositions for inhibiting checkpoint gene expression and uses thereof
  • Compositions for inhibiting checkpoint gene expression and uses thereof
  • Compositions for inhibiting checkpoint gene expression and uses thereof

Examples

Experimental program
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Effect test

example 1

Preparation of Oligonucleotide-Based Compounds

[0180]The oligonucleotide-based compounds of the invention were chemically synthesized using phosphoramidite chemistry on automated DNA / RNA synthesizer. TAC protected (Except U) 2′-O-TBDMS RNA monomers, A, G, C and U, were purchased from Sigma-Aldrich. 7-deaza-G, inosine and loxoribine monomers were purchased from ChemGenes Corporation. 0.25M 5-ethylthio-1H-tetrazole, PAC-anhydride Cap A and Cap B were purchased from Glen Research. 3% trichloroacetic acid (TCA) in dichloromethane (DCM) and 5% 3H-1,2-Benzodithiole-3-one-1,1-dioxide (Beaucage reagent) were made in house.

[0181]Oligonucleotide-based compounds of the invention were synthesized at 1-2 μM scale using a standard RNA synthesis protocol.

Cleavage and Base Deprotection

[0182]Oligonucleotide-based compounds of the invention were cleaved from solid support and the solution was further heated at 65° C. to removing protecting groups of exo cyclic-amines. The resulting solution was dried ...

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Abstract

The present invention is directed to compounds, compositions, and methods useful for modulating PD1, PDL1, IDO1, LAG3, TIM3, CTLA4, IDO2, CEACAM1, OX40, and / or OX40L mRNA or protein expression using gene silencing compounds comprising two or more single stranded antisense oligonucleotides that are linked through their 5′-ends to allow the presence of two or more accessible 3′-ends.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional patent application Ser. No. 62 / 126,368, filed on Feb. 27, 2015, the contents of which are incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTIONField of the Invention[0002]The present invention relates to compounds, compositions, and methods of use for the inhibition of checkpoint gene expression or for diagnosing, treating and / or preventing diseases and / or conditions that respond to the inhibition of checkpoint gene expression.Summary of the Related Art[0003]The immune system is a hosts defense against foreign antigens; however, in order to function properly a variety of checks and balances are required to protect against self-antigens (i.e., autoimmunity) and, at the same time, provide an appropriate response against foreign. Immune-activating and immune-suppressive receptors and ligands provide these regulatory checks and balances (see Pardoll et al., The blockade of immune che...

Claims

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Application Information

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IPC IPC(8): C12N15/11A61K31/7105C12N15/113A61K45/06
CPCC12N2310/51C12N15/1138A61K45/06C12N15/11C12N2310/11C12N2310/314A61K31/7105
Inventor AGRAWAL, SUDHIRJIANG, WAYNEWANG, DAQINGSEITZER, JESSICAZHU, FU-GANGMAO, XIANZHI
Owner IDERA PHARMA INC