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Bone morphogenetic protein (bmp)-binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and use of same

A morphogenetic protein, binding domain technology, applied in animal/human protein, anti-growth factor immunoglobulin, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc.

Inactive Publication Date: 2010-07-14
ABBVIE DEUTSHLAND GMBH & CO KG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This same receptor is mediated through the binding of nerve growth factor-1, but also mediates the opposite effect of stimulating nerve fiber growth

Method used

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  • Bone morphogenetic protein (bmp)-binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and use of same
  • Bone morphogenetic protein (bmp)-binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and use of same
  • Bone morphogenetic protein (bmp)-binding domains of proteins of the repulsive guidance molecule (rgm) protein family and functional fragments thereof, and use of same

Examples

Experimental program
Comparison scheme
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specific example

[0085] SGSHAPASDDTPE

[0086] SHLNSAVDGFDSE

[0087] LSLRGGGSSGALRGGGGGGRGGGVGSGG

[0088] Examples of BMP-binding domains include amino acid sequences ranging from amino acid 30 to 180 of SEQ ID NO: 2, amino acid 80 to 230 of SEQ ID NO: 4, or amino acid 20 to 150 of SEQ ID NO: 6, or Its functional regenerative protein receptor-binding fragment. These binding domains (and fragments derived therefrom) are also referred to as high-affinity BMP-binding domains. In particular the high-affinity BMP-binding domain also has a high-affinity interaction with the regeneration protein and is therefore also referred to as a high-affinity regeneration protein-binding domain. On the other hand, an example of a low affinity regenerative protein-binding domain is the RGM A fragment 218-284 of SEQ ID NO: 2 described in WO 2007 / 039256 (the disclosure of which is expressly incorporated herein by reference). is not limited thereto, for example when K D (dissociation constant)>1 μM, such as 2...

Embodiment 1

[0636] Production Example 1: Production of RGMA Protein in Mammalian Cells

[0637] To characterize active RGM A, the following RGM A molecules were expressed as Fc fusion proteins in mammalian cells (HEK293):

[0638] -41-168 / Xa

[0639] -47-90

[0640] -47-168

[0641] -316-386

[0642] -1-450

[0643] For this purpose, the DNA encoding the specific molecule was cloned into the vector pcDNA3.1 (+) ZeoIgK / Xa / hIgG lambda hc 257-stop) x HindIII / EcoRI / phosphatase (Invitrogen). To this end, DNA encoding specific fragment regions was amplified by PCR from an RZPD clone (clone AL136826 (DKFZp434D0727); published RZPD sequence: BC015886, AL136826). For this purpose the oligonucleotide primers listed below derived from the published RGMA sequence (published sequence: NM_020211) were used.

[0644] PCR was performed in each case on the RZPD clone pSport-1 DKFZp434D0727 mentioned above using these primers and AccuPrime polymerase. After purifying the PCR product, it was digested...

Embodiment 2

[0699] Operation example 2: In vitro interaction assays employing BMP-4 and BMP-2;

[0700] Comparing RGMA Fragment 47-168 and RGMA

[0701] Fusion protein to be tested:

[0702] RGMA-Fc

[0703] 47-168-Fc ("Fragment 0")

[0704] Detection was performed according to detection method 4 variant B above with immobilization of the fusion protein (1 mg / mL). BMP-4 and -2 binding were detected using anti-BMP-4 and anti-BMP-2 biotin antibodies, respectively.

[0705] The results are plotted in Figure 4 . Significant binding of BMP-4 and -2 to RGMA and surprisingly more pronounced binding to the 47-168 fragment was observed. BMP-2 and 4 bind with approximately equal strength in each case.

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Abstract

The present invention relates to the identification and use of bone morphogenetic protein (BMP)-binding domains of members of the repulsive guidance molecule (RGM) protein family, and polypeptide fragments and fusion proteins derived therefrom. The domains, i.e., peptide fragments and fusion proteins, according to the invention are suitable as agents for the active or passive immunization of individuals, or as diagnostic and therapeutic agents for use for diseases or medical conditions in whose origin or progression a member of the RGM family and a cellular receptor associated with this molecule, such as neogenin and / or BMP in particular, is involved. The invention further relates to monoclonal and polyclonal antibodies directed against the binding domains according to the invention, and against the polypeptides derived therefrom, and to methods for producing the polypeptides, fusion proteins, and antibodies according to the invention.

Description

[0001] The present invention relates to the identification and use of bone morphogenetic protein (BMP)-binding domains of members of the Repulsion Guide Molecule (RGM) protein family and polypeptide fragments and fusion proteins derived therefrom. The domains of the invention, i.e. peptide fragments and fusion proteins, are suitable as medicaments for active or passive immunization of individuals, or as diagnosing and therapeutic medicaments for diseases or medical conditions whose origin or progression involves members of the RGM family and cellular receptors associated with this molecule, such as regenerative proteins and / or especially BMPs. The invention further relates to monoclonal and polyclonal antibodies directed against the binding domains of the invention and against polypeptides derived therefrom, as well as methods of producing polypeptides, fusion proteins and antibodies of the invention. Background of the invention [0002] The function of the RGM protein family ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/705C07K16/28
CPCC07K14/705C07K16/22A61P1/04A61P3/10A61P7/06A61P9/00A61P17/00A61P17/06A61P17/14A61P19/00A61P19/02A61P19/08A61P25/00A61P25/02A61P25/04A61P29/00A61P35/00A61P35/04A61P37/02A61P37/04A61P43/00
Inventor B·米勒G·沙法A·迈尔M·施米德特
Owner ABBVIE DEUTSHLAND GMBH & CO KG
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