Methods for treating netosis and neutrophil activation

A technology of neutrophils and cells, applied in chemical instruments and methods, biochemical equipment and methods, extracellular fluid diseases, etc., can solve problems such as tissue damage

Pending Publication Date: 2020-06-30
TRUSTEES OF BOSTON UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] To date, no therapy exists to avert or halt activated PMN-driven tissue damage or sy

Method used

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  • Methods for treating netosis and neutrophil activation
  • Methods for treating netosis and neutrophil activation
  • Methods for treating netosis and neutrophil activation

Examples

Experimental program
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preparation example Construction

[0423] The preparation of such modified nucleic acids, backbones and nucleobases is well known in the art.

[0424] Another modification of the inhibitory nucleic acid featured in the invention involves chemically linking to the inhibitory nucleic acid one or more ligands, moieties or conjugates that enhance the cellular uptake, activity of the iRNA , cellular distribution or pharmacokinetic properties. Such moieties include, but are not limited to: lipid moieties, such as cholesterol moieties (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86:6553-6556); Let., 1994, 4:1053-1060); thioethers, such as beryl-S-trityl mercaptan (Manoharan et al., Ann.N.Y.Acad.Sci., 1992, 660:306-309; Manoharan et al., Biorg Med.Chem.Let., 1993, 3:2765-2770); Thiocholesterol (Oberhauser et al., Nucl.Acids Res., 1992, 20:533-538); Fatty chains, such as dodecanediol or deca -Alkyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svi...

Embodiment 1

[0581] Example 1: Anti-DEspR therapy in maladaptive neutrophil hyperactivity-mediated pathology

[0582] The present invention relates to anti-DEspR technology that inhibits or abrogates (abrogate) the prolonged survival mechanism in activated neutrophils (IC 50 <8nM), thereby inhibiting all activated neutrophil activity that drives and interacts with other cellular players towards maladaptive pathogenic cascades. The actPMN-driven pathogenicity cascade results in a rapid feed-forward interaction that tends toward disease progression and subsequent debilitating sequelae or death.

[0583] The present invention further relates to compositions comprising DEspR inhibitory compounds and methods of using these DEspR inhibitory compounds for the treatment of disorders or diseases involving induction by activated neutrophils (actPMN) and / or by NETosis , driven and / or propagated pathogenicity cascade.

[0584] Neutrophils are polymorphonuclear cells (PMCs) with 2-5 lobes in their nu...

Embodiment 2

[0659] Example 2: Anti-DEspR mAb Therapy [hu-6g8]: Efficacy-Safety Advantages

[0660] Stabilized S228P IgG4 backbone: efficacy based on receptor blockade rather than ADCC or CDC

[0661] Overview of the rationale and mode of action of anti-DEspR in combination with immunotherapy:

[0662] Complementary mode of action: Inhibition of CSC survival / self-renewal, tumor cell invasiveness, and angiogenesis by anti-DEspR (hu-6g8 or ABT-468) collectively causes a decrease in metastatic dissemination and progression cycles, which complements Immunotherapy immunosurveillance to eliminate tumor cells. This can be seen in the fact that anti-DEspR was more effective in tumor regression in spontaneous mammary tumors in immunocompetent rats than in xenografted pancreatic tumors and glioblastomas in which tumor growth rate was suppressed without regression. Strong ( Figure 16 ) 74 .

[0663] Depletion of activated neutrophils (tumor-associated neutrophils or TAN and circulating neutroph...

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Abstract

Described herein are methods and compositions relating to methods of inhibiting neutrophils, e.g., inhibiting NET release or NETosis, by means of a DEspR inhibitor, e.g., an anti-DEspR antibody reagent. In some embodiments, the methods can relate to the treatment of a disease, e.g., cancer or a disease wherein neutrophils; NETs; or NETosing or NETting neutrophils contribute to pathogenesis, chronicity, or worsening of disease. In some embodiments, the DEspR inhibitor can be a bi-specific reagent or an antibody-drug conjugate.

Description

[0001] Cross References to Related Applications [0002] Pursuant to 35 U.S.C. §119(e), this application claims priority to U.S. Provisional Application No. 62 / 559,874, filed September 18, 2017, and U.S. Provisional Application No. 62 / 685,377, filed June 15, 2018, Their contents are hereby incorporated by reference in their entirety. [0003] governmental support [0004] This invention was made with Government support under Grant No. T32EB006359 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] The technology described herein relates to methods of treating NETosis and neutrophil-related pathologies. Background technique [0006] The most common type of blood cell, the polynuclear morphogenic neutrophil (PMN), is short-lived, usually only lasting a few hours in the bloodstream. During the response to injury and / or infection, these PMNs are activated to kill bacterial cells, and their lifespan is...

Claims

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Application Information

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IPC IPC(8): A61K39/00A61P7/00A61P29/00A61P37/06C07K16/18C07K16/28
CPCC07K16/2863C07K2317/24C07K2317/73C07K2317/76A61P11/00A61P9/12A61P35/00C12N9/78C12N9/50C12N9/0065C12Y304/24007A61K2039/505C12Y305/03001C12Y305/04004C12Y304/21037C12Y111/02002C12Y301/21001C12N9/16A61K47/6801A61K39/001109A61K9/51
Inventor 纳尔逊·鲁伊斯-奥帕索维多利亚·L.M.·埃雷拉
Owner TRUSTEES OF BOSTON UNIV
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