Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Methods for treating conditions associated with MASP-2 dependent complement activation

a technology of masp-2 dependent complement activation and inhibitory action, which is applied in the direction of antibacterial agents, peptide/protein ingredients, antibacterial agents, etc., can solve the problems of host cell lysis, no drugs have been approved for human use, organ damage, etc., to inhibit masp-2-dependent complement activation, and reduce side effects of chemotherapeutics

Inactive Publication Date: 2010-03-25
OMEROS CORP +1
View PDF50 Cites 12 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a method for inhibiting the adverse effects of MASP-2-dependent complement activation in living subjects. This is achieved by administering to the subject an MASP-2 inhibitory agent that can inhibit complement activation through the lectin-dependent MASP-2 system without substantially inhibiting complement activation through the classical or C1q-dependent system. The MASP-2 inhibitory agent can be an anti-MASP-2 antibody or a non-peptide MASP-2 inhibitor. The methods, compositions, and medications described in this patent can be used to treat various conditions associated with MASP-2-dependent complement activation, including but not limited to ischemic reperfusion injuries, atherosclerosis, and inflammatory gastrointestinal disorders.

Problems solved by technology

These activated cells are indiscriminate in their release of destructive enzymes and may cause organ damage.
In addition, complement activation may cause the deposition of lytic complement components on nearby host cells as well as on microbial targets, resulting in host cell lysis.
No drugs have been approved for human use that specifically target and inhibit complement activation.
This syndrome often results from mutations at several sites in the collagenous portion of MBL, which interfere with proper formation of MBL oligomers.
However, since MBL can function as an opsonin independent of complement, it is not known to what extent the increased susceptibility to infection is due to impaired complement activation.
Since the alternative pathway C3 convertase (C3bBb) contains C3b as an essential subunit, the question regarding the origin of the first C3b via the alternative pathway has presented a puzzling problem and has stimulated considerable research.
This bond is unstable and the electrophilic carbonyl group of glutamine can form a covalent bond with other molecules via hydroxyl or amino groups.
The only feature common to these activators is the presence of carbohydrate, but the complexity and variety of carbohydrate structures has made it difficult to establish the shared molecular determinants, which are recognized.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Methods for treating conditions associated with MASP-2 dependent complement activation
  • Methods for treating conditions associated with MASP-2 dependent complement activation
  • Methods for treating conditions associated with MASP-2 dependent complement activation

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0451]This example describes the generation of a mouse strain deficient in MASP-2 (MASP-2− / −) but sufficient of MAp19 (MAp19+ / +).

[0452]Materials and Methods: The targeting vector pKO-NTKV 1901 was designed to disrupt the three exons coding for the C-terminal end of murine MASP-2, including the exon that encodes the serine protease domain, as shown in FIG. 4. PKO-NTKV 1901 was used to transfect the murine ES cell line E14.1a (SV129 Ola). Neomycin-resistant and Thymidine Kinase-sensitive clones were selected. 600 ES clones were screened and, of these, four different clones were identified and verified by southern blot to contain the expected selective targeting and recombination event as shown in FIG. 4. Chimeras were generated from these four positive clones by embryo transfer. The chimeras were then backcrossed in the genetic background C57 / BL6 to create transgenic males. The transgenic males were crossed with females to generate F1s with 50% of the offspring showing heterozygosity ...

example 2

[0455]This example demonstrates that MASP-2 is required for complement activation via the alternative and the lectin pathway.

[0456]Methods and Materials:

[0457]Lectin pathway specific C4 Cleavage Assay: A C4 cleavage assay has been described by Petersen, et al., J. Immunol. Methods 257:107 (2001) that measures lectin pathway activation resulting from lipoteichoic acid (LTA) from S. aureus, which binds L-ficolin. The assay described in Example 11 was adapted to measure lectin pathway activation via MBL by coating the plate with LPS and mannan or zymosan prior to adding serum from MASP-2− / − mice as described below. The assay was also modified to remove the possibility of C4 cleavage due to the classical pathway. This was achieved by using a sample dilution buffer containing 1 M NaCl, which permits high affinity binding of lectin pathway recognition components to their ligands but prevents activation of endogenous C4, thereby excluding the participation of the classical pathway by disso...

example 3

[0483]This example describes the generation of a transgenic mouse strain that is murine MASP-2− / −, MAp19+ / + and that expresses a human MASP-2 transgene (a murine MASP-2 knock-out and a human MASP-2 knock-in).

[0484]Materials and Methods: A minigene encoding human MASP-2 called “mini hMASP-2” (SEQ ID NO:49) as shown in FIG. 5 was constructed which includes the promoter region of the human MASP 2 gene, including the first 3 exons (exon 1 to exon 3) followed by the cDNA sequence that represents the coding sequence of the following 8 exons, thereby encoding the full-length MASP-2 protein driven by its endogenous promoter. The mini hMASP-2 construct was injected into fertilized eggs of MASP-2− / − in order to replace the deficient murine MASP 2 gene by transgenically expressed human MASP-2.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
affinityaaaaaaaaaa
Login to View More

Abstract

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. 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 (C1q-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

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a division of application Ser. No. 11 / 645,359, filed Dec. 22, 2006, which claims the benefit of Provisional Application No. 60 / 788,876, filed Apr. 3, 2006, under 35 U.S.C. §119(e), and which is a continuation-in-part of application Ser. No. 11 / 150,883, filed Jun. 9, 2005, priority from which is claimed under 35 U.S.C. §120, which claims the benefit of Provisional Application No. 60 / 578,847, filed Jun. 10, 2004, under 35 U.S.C. §119(e).FIELD OF THE INVENTION[0002]The present invention relates to methods of inhibiting the adverse effects of MASP-2-dependent complement activation.BACKGROUND OF THE INVENTION[0003]The complement system provides an early acting mechanism to initiate and amplify the inflammatory response to microbial infection and other acute insults (M. K. Liszewski and J. P. Atkinson, 1993, in Fundamental Immunology, Third Edition, edited by W. E. Paul, Raven Press, Ltd., New York). While complement activa...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K38/02A61P9/00A61P25/00
CPCA01K67/0276Y10S514/912A01K2217/00A01K2217/075A01K2227/105A01K2267/03A01K2267/0375A61K39/395A61K49/0008A61K2039/505C07K16/40C07K2316/96C07K2317/24C07K2317/54C07K2317/55C12N9/6408C12N9/6424A01K2207/15C07K2317/76C12Y304/21104A61P1/00A61P1/06A61P1/18A61P11/00A61P13/00A61P13/10A61P13/12A61P15/00A61P17/00A61P17/02A61P19/00A61P19/02A61P19/06A61P21/00A61P21/04A61P25/00A61P25/14A61P27/02A61P29/00A61P3/00A61P35/00A61P37/00A61P37/02A61P37/06A61P5/00A61P7/00A61P7/06A61P9/00A61P9/10A61P3/10A61K38/16C07K2317/21C07K2317/71C07K2317/92
Inventor SCHWAEBLE, HANS-WILHELMSTOVER, CORDULA MARGARETTEDFORD, CLARK E.PARENT, JAMES B.FUJITA, TEIZO
Owner OMEROS CORP
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com