Methods for treating disseminated intravascular coagulation by inhibiting MASP-2 dependent complement activation

A MASP-2, complement activation technology, applied in chemical instruments and methods, biochemical equipment and methods, allergic diseases, etc., can solve problems such as the complexity and diversity of carbohydrate structures that are difficult to identify and share molecular determinants

Active Publication Date: 2012-11-14
OMEROS CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The only feature shared by these activators is the presence of carbohydrates, but the complexity and diversity of carbohydrate structures make it difficult to identify shared molecular determinants, which are well recognized

Method used

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  • Methods for treating disseminated intravascular coagulation by inhibiting MASP-2 dependent complement activation
  • Methods for treating disseminated intravascular coagulation by inhibiting MASP-2 dependent complement activation
  • Methods for treating disseminated intravascular coagulation by inhibiting MASP-2 dependent complement activation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0497] This example describes the generation of a mouse strain deficient in MASP-2 (MASP-2- / -) but sufficient in MAp19 (MAp19+ / +).

[0498] Materials and methods: The targeting vector pKO-NTKV 1901 was designed to disrupt the three exons encoding the C-terminus of murine MASP-2, including the exon encoding the serine protease domain, see Figure 4 . The murine ES cell line E14.1a (SV129 Ola) was transfected with PKO-NTKV 1901. Neomycin-resistant and thymidine kinase-sensitive clones were selected. 600 ES clones were screened, of which 4 different clones were identified, confirmed by Southern blotting to contain the expected selection of targeting events and recombination events, see Figure 4 . Chimeras were generated from these 4 positive clones by embryo transfer. The chimeras were then backcrossed against the genetic background C57 / BL6 to generate transgenic male mice. When transgenic males were crossed with females to produce F1, 50% of the offspring showed MASP 2 H...

Embodiment 2

[0502] This example demonstrates that MASP-2 is required for complement activation through the alternative and lectin pathways.

[0503] Methods and Materials:

[0504] Lectin pathway-specific C4 cleavage assay: The C4 cleavage assay is described in Petersen et al., J. Immunol. Methods 257 : 107 (2001), an assay that measures the activation of the lectin pathway produced by lipoteichoic acid (LTA) from Staphylococcus aureus that binds L-ficolin. A modification of the assay described in Example 11 was used to measure agglutination by MBL by adding serum from MASP-2 - / - mice after coating plates with LPS and mannan or zymosan Activation of the protein pathway, as described below. The assay was also modified to eliminate the possibility of C4 cleavage by the classical pathway. This is achieved by using a sample dilution buffer containing 1 M NaCl, which allows the lectin pathway recognition components to bind their ligands with high affinity, yet prevents the activation of en...

Embodiment 3

[0531] This example describes the generation of a transgenic mouse line expressing a murine MASP-2- / -, MApl9+ / + human MASP-2 transgene (mouse MASP-2 knockout, human MASP-2 knockin).

[0532] Materials and methods: Construct including human MASP 2 The small gene (SEQ ID NO:49) of gene promoter region and encoding human MASP-2, is called " mini hMASP-2 ", see Figure 5 , which includes the first 3 exons (exon 1 to exon 3), followed by a cDNA sequence representing the coding sequence of the next 8 exons, thus encoding full-length MASP driven by its endogenous promoter -2 protein. Injection of mini hMASP-2 constructs into MASP-2- / - zygotes to transgenically express human MASP-2 in place of deletion mice MASP 2 Gene.

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Abstract

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. In one embodiment, the invention provides methods of treating a subject suffering from a complement mediated coagulation disorder, such as disseminated intravascular coagulation. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (Clq-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of Provisional Application No. 61 / 279279, filed October 16, 2009, and Provisional Application No. 61 / 322722, filed April 9, 2010, both of which are hereby incorporated by reference in their entirety. [0003] Statement Regarding Sequence Listing [0004] The Sequence Listing associated with this application is provided in text format instead of a hard copy and is hereby incorporated by reference into this specification. The name of the text file containing the sequence listing is 35668_Seq_Final.txt. This text file is 109 KB; created on October 15, 2010; and is being submitted via EFS-Web with the submission of this specification. Background of the invention [0005] The complement system provides an early mechanism of action for initiating and enhancing inflammatory responses to microbial infections and other acute insults (M.K. Liszewski and J.P. Atkinson, 1993, in Fundamental Imm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395
CPCC07K2317/92C07K2317/54C07K16/40A61K2039/505C07K2317/55C07K2316/96C07K2317/24C07K2317/76C12Y304/21104A61P1/16A61P15/00A61P17/02A61P25/00A61P31/00A61P31/04A61P35/00A61P37/00A61P37/06A61P39/00A61P39/02A61P43/00A61P7/00A61P7/02A61P7/04A61P9/00A61P9/10A61P9/14A61K39/395C07K2317/21
Inventor H.施维布尔T.A.杜德勒C.E.特德福德J.B.帕伦特G.A.德莫普罗斯
Owner OMEROS CORP
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