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Antibodies to bone morphogenic proteins and receptors therefor and methods for their use

An antibody, antibody fragment technology, applied in the fields of immunology and molecular biology, can solve problems such as the inability to prevent bone formation and spinal fusion

Inactive Publication Date: 2010-01-13
MEDAREX LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0026] Overall, little progress has been made in developing treatments for ankylosing spondylitis and other spondylotic diseases, partly because these treatments do not prevent bone formation and fusion of the spine

Method used

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  • Antibodies to bone morphogenic proteins and receptors therefor and methods for their use
  • Antibodies to bone morphogenic proteins and receptors therefor and methods for their use
  • Antibodies to bone morphogenic proteins and receptors therefor and methods for their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0474] Human monoclonal anti-BMP2, BMP4, BMPR1A, BMPR1B, ACTR1 and BMPR2 Antibody production

[0475] This example discloses methodology for generating human monoclonal antibodies that specifically bind human BMP2, BMP4, BMPR1A, BMPR1B, ACTR1, and BMPR2.

[0476] antigen

[0477] Mice were immunized with recombinant human BMP2, BMP4, BMPR1A, BMPR1B, ACTR1 and / or BMPR2. Specifically, mice were immunized with commercially available recombinant human BMP2 or BMP4. Human recombinant BMP-2 was obtained from R&D Systems, Inc. (Catalog No. 355-BM / CF, Lot.-MSA10605H) or Medtronic, Inc. (Lot.-M115006AAJ). Human recombinant BMP4 was obtained from R&D Systems, Inc. (Catalog No. 31-BP / CF, Lots BEM186051 and BEM316071 and MSA10605H). Lyophilized antigen was reconstituted according to the manufacturer's instructions and stored at -20°C.

[0478] transgenic mouse HuMAb and KM

[0479] Fully human monoclonal antibodies against BMP2, BMP4, BMPR1A, BMPR1B, ACTR1 and BMPR2 can...

Embodiment 2

[0492] Structural Characterization of Human Monoclonal Antibodies

[0493] This example discloses the structural characteristics of human monoclonal antibodies that specifically bind to BMP2 and BMP4. Specifically, the structures of anti-BMP2 / 4 monoclonal antibodies 6H4, 11F2, 12E3, 1F6, 10F6, 10H6, 16b7, 7D6, 8B3, 33F7 and 15F3 are disclosed in this example.

[0494] The monoclonal antibodies obtained by the methodology of Example 1 can be obtained from anti-BMP2, anti-BMP4, anti-BMPR1A, anti-BMPR1B, anti-ACTR1 and / or anti-BMPR2 hybridomas, respectively, by standard PCR techniques The cDNA sequences encoding the heavy and light chain variable regions were obtained and sequenced by standard DNA sequencing techniques.

[0495] The cDNA sequences encoding the heavy and light chain variable regions of the 6H4, 11F2 and 12E3 monoclonal antibodies, respectively, were obtained from the 6H4, 11F2 and 12E3 hybridomas by standard PCR techniques and sequenced by standard DNA sequenci...

Embodiment 3

[0509] Anti-BMP2, Anti-BMP4, Anti-BMPR1A, Anti-BMPR1B, Anti-ACTR1 Characterization of Binding Specificity of Anti-BMPR2 Monoclonal Antibodies

[0510] This example discloses the methodology used to make the following comparisons: Anti-BMP2, anti-BMP4, anti-BMPR1A, anti-BMPR1B, anti-ACTR1 and / or anti-BMPR2 antibodies were compared by ELISA and Western blot assays with Antigen binding specificity was examined by immunopurified antigen binding, or by comparing the binding of the antibody to BMP2 / 4 in tissue using immunohistochemistry.

[0511] Recombinant His-tagged or myc-tagged antigens were coated overnight on plates and then tested for binding to human monoclonal antibodies generated by the methodology disclosed in Example 1. Perform standard ELISA procedures. Anti-BMP2, anti-BMP4, anti-BMPR1A, anti-BMPR1B, anti-ACTR1 and / or anti-BMPR2 human monoclonal antibodies were applied at a concentration of 1 μg / ml and titrated down in serial dilutions of 1:2. A goat anti-human I...

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Abstract

The present invention provides isolated monoclonal antibodies, particularly human monoclonal antibodies, which specifically bind to BMP2, BMP4, BMPRlA, BMPRlB, ACTRl, and / or BMPR2 with high affinity. Nucleic acid molecules encoding the antibodies of the invention, expression vectors, host cells and methods for expressing the antibodies of the invention are also provided. Also provided are immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies of the invention and, optionally, one or more additional therapeutic. The invention also provides methods for treating diseases associated with abnormal bone formation and ossification mediated by BMP2, -BMP4, BMPRlA, BMPRlB, ACTRl5 and / or BMPR2.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. 60 / 824,596, filed September 5, 2006, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates generally to the fields of immunology and molecular biology. More specifically, provided herein are antibodies against bone morphogenic protein (BMP) and its receptors and other therapeutic proteins, as well as nucleic acids encoding said antibodies and therapeutic proteins, for use in preparing the monoclonal Methods of Antibodies and Other Therapeutic Proteins, and Methods of Treating Diseases, such as Bone Diseases and Cancers Mediated by BMP Expression / Activity and / or Associated with Aberrant Expression / Activity of Their Receptors . Background technique [0004] The human skeleton consists of more than 200 bones connected by joints. During embryogenesis, the skeleton develops from undifferen...

Claims

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Application Information

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IPC IPC(8): C07K16/00C07K16/18C07K16/22C07K16/26C07K16/46C12N15/13C12N15/63C12N15/10C12N15/16C12N15/22C12N15/24C12N15/26C12N15/28C12N1/15C12N1/19C12N1/21
CPCC07K16/22C07K2317/92C07K16/2896C07K2317/21C07K2317/732A61K2039/505C07K2317/72C07K2317/41C07K2317/56C07K2316/96C07K2317/34C07K2317/76A61P19/00A61P19/02A61P19/04A61P19/08A61P35/00A61P9/00C07K16/18C12N15/11A61K39/395
Inventor 德博拉·L·齐默尔曼M·塞尔比M·斯里尼瓦桑A·贝尔S·辛格R·小西奥利斯H·N·勒布朗K·D·岑斯T·W·斯普劳尔
Owner MEDAREX LLC
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