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Compositions for inhibiting masp-2 dependent complement acitivation

A technology of MASP-2 and complement activation, which is applied in the direction of introducing foreign genetic material using carriers, drug combinations, and medical preparations containing active ingredients, etc. It can solve molecular determinants that are difficult to determine and share due to the complexity and diversity of carbohydrate structures And other issues

Active Publication Date: 2014-03-26
OMEROS CORP
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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 is acknowledged

Method used

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  • Compositions for inhibiting masp-2 dependent complement acitivation
  • Compositions for inhibiting masp-2 dependent complement acitivation
  • Compositions for inhibiting masp-2 dependent complement acitivation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0378] This example describes the recombinant expression and protein production of recombinant full-length human, rat, and mouse MASP-2, MASP-2-derived polypeptides, and catalytically inactive mutant forms of MASP-2.

[0379] Expression of full-length human and rat MASP-2:

[0380] The human MASP-2 full-length cDNA sequence (SEQ ID NO: 1) with the leader sequence (SEQ ID NO: 2) encoding the human MASP-2 polypeptide was subcloned into the mammalian expression vector pCI-Neo (Promega), which Eukaryotic expression is driven under the control of the CMV enhancer / promoter region (described in Kaufman R.J. et al., Nucleic Acids Research 19:4485-90, 1991; Kaufman, Methods in Enzymology, 185:537-66 (1991)). The rat MASP-2 full-length cDNA (SEQ ID NO: 4) encoding the rat MASP-2 polypeptide with a leader sequence (SEQ ID NO: 5) was subcloned into the pED expression vector. The MASP-2 expression vector was then transfected into the adherent Chinese hamster ovary cell line DXB1 using the...

Embodiment 2

[0393] This example describes the screening method used to identify high affinity fully human anti-MASP-2 scFv antibody candidates that block MASP-2 functional activity to progress to affinity maturation.

[0394] Background and rationale:

[0395] MASP-2 is a complex protein with many individual functional domains, including: one or more MBL and ficolin binding sites, serine protease catalytic site, proteolytic substrate C2 binding site, proteolytic substrate C4 binding site, MASP-2 cleavage site for MASP-2 zymogen self-activation and two Ca ++ binding site. scFv antibody fragments were identified as binding MASP-2 with high affinity, and the identified Fab2 fragments were tested in functional assays to determine whether they were able to block MASP-2 functional activity.

[0396] In order to block MASP-2 functional activity, an antibody or scFv or Fab2 antibody fragment must bind to and interfere with a structural epitope on MASP-2 that is required for MASP-2 functional ac...

Embodiment 3

[0453] This example describes the MASP-2 functional screening method used to analyze the ability of high affinity fully human anti-MASP-2 scFv antibody candidates to block MASP-2 activity in normal human serum.

[0454] Rationale / Background

[0455] Assay to Measure Inhibition of Lectin Pathway C3 Convertase Formation

[0456]A functional assay measuring inhibition of lectin pathway C3 convertase formation was used to evaluate the "blocking activity" of anti-MASP-2 scFv candidate clones. The lectin pathway C3 convertase is an enzyme complex (C4b2a) that proteolytically cleaves C3 into two potent pro-inflammatory fragments, anaphylatoxin C3a and opsonic C3b. The formation of C3 convertase appears to be a critical step in the lectin pathway in mediating inflammation. MASP-2 is not a structural component of the lectin pathway C3 convertase (C4b2a); therefore an anti-MASP-2 antibody (or Fab2) will not directly inhibit the activity of an already existing C3 convertase. However...

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Abstract

The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising such antibodies for use in inhibiting the adverse effects of MASP-2 dependent complement activation. In one aspect, the invention provides an isolated human monoclonal antibody, or antigen binding fragment thereof, that binds to human MASP-2, comprising:(i) a heavy chain variable region comprising CDR-HI, CDR-H2 and CDR-H3 sequences; and (ii) a light chain variable region comprising CDR-LI, CDR-L2 and CDR-L3, wherein the heavy chain variable region CDR-H3 sequence comprises an amino acid sequence set with factor B in forming additional alternative pathway C3 convertase (C3bBb). The alternative pathway C3 convertase is stabilized by the binding of properdin. Properdin extends the alternative pathway C3 convertase half-life six to ten fold. Addition of C3b to the alternative pathway C3 convertase leads to the formation of the alternative pathway C5 convertase.

Description

field of invention [0001] The present invention relates to anti-MASP-2 inhibitory antibodies and compositions comprising the same for inhibiting the adverse effects of MASP-2 dependent complement activation. [0002] Cross References to Related Applications [0003] This application claims the benefit of US Provisional Application No. 61 / 482,567, filed May 4, 2011, which is hereby incorporated by reference in its entirety. [0004] Statement Regarding Sequence Listing [0005] The Sequence Listing associated with this application is provided in text format in lieu of a paper copy and is hereby incorporated by reference into the specification. The name of the text file containing the sequence listing is MP_1_0115_PCT_SequenceListingasFiled_20120504_ST25. The text file is 158KB, was created on May 4, 2012, and is being submitted via EFS-Web together with the submission of the manual. Background of the invention [0006] The complement system provides an early mechanism of ...

Claims

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Application Information

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IPC IPC(8): A61K39/395C07K16/40C12N15/13C12N15/63C12P21/08C12N5/10C12N1/19
CPCC12N9/6424C07K16/40C07K2317/53C07K2317/565C07K2317/622C12Y304/21104C07K2317/76C07K2317/21A61K2039/505C07K2317/33C07K2317/92A61P9/00A61P37/06A61P43/00A61K39/3955C07K2317/54C07K2317/55C07K2317/56
Inventor T.杜德勒W.R.贡博茨J.B.帕伦特C.E.特德福德A.卡夫利U.B.黑格曼H.里尔森S.基普里贾诺夫
Owner OMEROS CORP
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