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Antibodies targeting bone morphogenetic protein 9 (BMP9) and methods therefor

a technology of bone morphogenetic protein and antibody, applied in the field of antibodies targeting bone morphogenetic protein 9 (bmp9) and methods therefor, can solve the problems of affecting tissue or organ function, so as to reduce the activity of bmp9

Inactive Publication Date: 2019-05-23
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The isolated antibody or antigen-binding fragment thereof of the present invention can reduce the activity of human BMP9 in vitro, as measured in a reporter gene assay. The antibody can also be combined with an additional therapeutic agent to further reduce the activity of BMP9. The term "chimeric antibody" refers to an antibody molecule where the constant region is altered to link to a different constant region or effector function, or a completely different molecule. The chimeric antibody has reduced antigenicity in human as compared to the original mouse antibody. The term "neutralization" refers to the ability of an antibody to reduce the activity, level, or stability of its target, such as BMP9, by at least partially reducing its signaling or its role in phosphorylation of Smad1 / 5 / 8 and fibrosis, e.g., liver fibrosis.

Problems solved by technology

Although processes related to fibrosis can occur as part of normal tissue formation or repair, dysregulation of these processes can lead to altered cellular composition and excess connective tissue deposition that progressively impairs tissue or organ function.
Existing therapies for liver diseases, including fibrotic liver disease, including cirrhosis, can have low efficacy and undesirable side effects.
Moreover, there are currently no wholly effective treatments or cures for liver disease, including fibrotic liver diseases, including cirrhosis.

Method used

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  • Antibodies targeting bone morphogenetic protein 9 (BMP9) and methods therefor
  • Antibodies targeting bone morphogenetic protein 9 (BMP9) and methods therefor
  • Antibodies targeting bone morphogenetic protein 9 (BMP9) and methods therefor

Examples

Experimental program
Comparison scheme
Effect test

example 1

n of Recombinant BMP9

[0516]DNA sequence encoding full length hBMP9 protein was cloned an expression vector and confirmed by DNA sequencing. hBMP9 construct was transiently transfected into 293F cell line and the cells were further optimized for hBMP9 protein production. The final production was carried out at 10 L scale and multiple runs. Final harvests were collected when cell viability was >80%. Cell debris in the final harvest were removed by centrifugation and filtration processes. The target hBMP9 protein was purified by using cation exchange chromatography and anion exchange chromatography. Ultrafiltration was used to concentrate hBMP9 protein and to exchange buffer. Quantitation of the protein was determined by Lowry method. Purified hBMP9 protein was analyzed by SDS-PAGE, Western blot and HPLC.

example 2

n of Anti-BMP9 Antibodies by Hybridoma Technology

Mice Immunization and Fusion

[0517]Ten BALB / c mice were immunized with recombinant protein human BMP9 (huBMP9) by a repetitive procedure involving 4 injections either subcutaneously or interperitoneally of 25-50 ug huBMP9. Spleens of immunized mice were harvested, and isolated splenocytes were fused to myeloma cells (P3Ag8.653 cell line) to create hybridoma clones. Supernatant from hybridoma clones was tested with binding ELISA as the primary screening assay to identify positive clones binding to BMP9. Supernatant of positive clones identified from primary screening binding assay was then tested in blocking ELISA to identify positive clones that can inhibit the interactions between BMP9 and its receptors. Four different recombinant BMP9 receptors were used: human Alk1-Fc (R&D system, 370-AL-100); human BMPRII-Fc (R&D system, 811-BR-100); human ActRIIA-Fc (R&D system, 340-R2-100); human ActRIIB-Fc (R&D system).

[0518]Two clones were sele...

example 3

n of Anti-BMP9 Antibodies by Phage Display Technology

[0536]In parallel with efforts to identify anti-BMP9 antibodies by mouse hybridoma and humanization procedures, described above, phage display was used to identify fully human anti-BMP9 antibodies. Briefly, for the selection of antibodies recognizing human BMP9, multiple panning strategies were employed. Therapeutic antibodies against human BMP9 protein were generated by selection of clones having high binding affinities, using as the source of antibody variant proteins a commercially available phage display library, the MorphoSys HuCAL PLATINUM® library. The phagemid library is based on the HuCAL® concept (Knappik et al., (2000) J Mol Biol 296:57-86) and employs the CysDisplay® technology for displaying the Fab on the phage surface (WO01 / 05950 to Lohning) In order to increase antibody binding affinity whilst maintaining library diversity the second round output of both solution and solid phase pannings were entered into the RapMA...

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Abstract

The present invention relates to isolated antibodies and antigen-binding fragments thereof which bind human BMP9 and compositions and methods of use thereof.

Description

RELATED APPLICATIONS[0001]This application is a divisional application of U.S. patent application Ser. No. 15 / 165,150, filed on May 26, 2016, now U.S. Pat. No. 10,047,155, which claims priority to PCT Application No. PCT / CN2015 / 080887, filed Jun. 5, 2015, the entire contents of each of these applications are incorporated herein by reference in their entireties.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 4, 2016, is named PAT056928-US—NP_SL.txt and is 163,925 bytes in size.INTRODUCTION[0003]The present invention relates to antibodies and antigen-binding fragments thereof which bind human BMP9, and compositions and methods of use thereof.BACKGROUND OF THE INVENTION[0004]Fibrosis is a pathological process that refers to the aberrant formation or development of excess fibrous connective tissue by cells in an organ ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/22C12N15/09A61K45/06C12N15/63A61K38/18A61K31/7072A61K31/675A61K31/575A61K31/522A61K31/513A61K31/497A61K31/4725A61K31/4439A61K31/355A61K31/155A61K39/395
CPCC07K16/22C12N15/09A61K45/06C12N15/63A61K38/1875A61K31/7072A61K31/675A61K31/575A61K31/522A61K31/513A61K31/497A61K31/4725A61K31/4439A61K31/355A61K31/155A61K39/3955C07K2317/92C07K2317/76C07K2317/73C07K2317/55C07K2317/515C07K2317/51C07K2317/94C07K2317/33C07K2317/24C07K2317/21A61K2039/505C07K2317/90C07K2317/34A61P1/16A61P31/12A61P37/06A61P43/00A61K2300/00C07K2317/52C07K2317/56C07K2317/565
Inventor CHEN, ZIJUNDENG, SUJUNHE, YUNHUANG, DAGANGKUGLER, MARKUSLI, QIANLU, CHRIS XIANGYANGLUO, XIAOSHAN, YONGQIANGTISSOT-DAGUETTE, KATHRIN ULRIKEWU, JING
Owner NOVARTIS AG
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