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Pharmaceutical composition for treating or preventing heterotopic ossification

A composition and drug technology, applied in the field of anti-ALK2 antibody, can solve problems such as the fundamental treatment method has not yet been established

Pending Publication Date: 2020-10-27
SAITAMA MEDICAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, since the heterotopic bone tissue formed in FOP is formed by normal chondrocytes or osteoblasts, it is metabolized in the same way as normal bone tissue, so medical methods such as drugs cannot be used to remove only heterotopic bone tissue
[0004] The fundamental treatment for inhibiting FOP heterotopic ossification has not been established, only symptomatic treatment for pain

Method used

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  • Pharmaceutical composition for treating or preventing heterotopic ossification
  • Pharmaceutical composition for treating or preventing heterotopic ossification
  • Pharmaceutical composition for treating or preventing heterotopic ossification

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0294] Evaluation of BMP Signaling Activation by Anti-ALK2 Antibody (27D-H2L2_LALA) Using a Luciferase Reporter Assay

[0295] The anti-ALK2 antibody (27D-H2L2_LALA) used in the experiment was produced according to the method described in Example 12 of WO2016 / 121908.

[0296]Activation of BMP intracellular signaling mediated by raised anti-ALK2 antibodies was analyzed using a BMP-specific luciferase reporter gene. HEK293A cells were treated with 1×10 4 Cells / well were inoculated into a 96-well white microtiter plate (manufactured by CORNING) for luciferase detection, in DMEM medium containing 10% FBS, at 37°C, 5% CO 2 cultured overnight under conditions. On the next day, using Lipofectamine 2000 (manufactured by Invitrogen), the wild-type and R206H mutant expression plasmids of human or mouse ALK2 were respectively introduced together with pGL4.26 / Id1WT4F-luc (Genes Cells, 7, 949 (2002)). After 3 hours, the medium was replaced with fresh OPTI-MEM I (manufactured by Life Tec...

Embodiment 2

[0299] Fab (27D-H2L2_Fab) and F(ab') of anti-ALK2 antibody (27D-H2L2_LALA) 2 (27D-H2L2_F(ab') 2 ) preparation

[0300] 2)-1

[0301] Fabization of 27D-H2L2_LALA

[0302] Use papain from Papaya latex (SIGMA-ALDRICH) to restrict digestion of 27D-H2L2_LALA, then use HiLoad 26 / 600Superdex 200pg (GE Healthcare) to remove Fc fragments, etc., and then use HiTrap MabSelect SuRe, 1mL ( GE Healthcare) separated unreacted 27D-H2L2_LALA, and recovered Fab.

[0303] 2)-2

[0304] F(ab') of 27D-H2L2_LALA 2 change

[0305] Use endoproteinase (Endoproteinase) Glu-C (SIGMA-ALDRICH) to cut 27D-H2L2_LALA, then use HiTrap MabSelect SuRe, 10mL (GE Healthcare) to separate unreacted 27D-H2L2_LALA, and then use Bio-Scale CHT Type I ,5mL (BIO-RAD) recovered F(ab') 2 .

Embodiment 3

[0307] Evaluation of Fab(27D-H2L2_Fab) and F(ab') of Anti-ALK2 Antibody Using Luciferase Reporter Assay 2 (27D-H2L2_F(ab') 2 Activation of BMP signaling in )

[0308] 27D-H2L2_Fab and 27D-H2L2_F(ab') produced in Example 2 were analyzed using a BMP-specific luciferase reporter gene 2 Activation of BMP-mediated intracellular signal transduction. As a comparison control, 27D-H2L2_LALA, which is a full-length anti-ALK2 antibody, was used. The assay of the luciferase reporter gene was carried out in the same manner as in Example 1.

[0309] The result is as figure 2 mentioned. Similar to 27D-H2L2_LALA, 27D-H2L2_F(ab') was confirmed only in HEK293 cells expressing mouse R206H mutant ALK2 2 Increases BMP-specific luciferase activity in a concentration-dependent manner. On the other hand, in 27D-H2L2_Fab, no increase in the activity of the BMP reporter gene was found even under any of the conditions.

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Abstract

The present application relates to a pharmaceutical composition which can be used in a method for treating and / or preventing a patient having heterotopic ossification and / or brain tumor, the pharmaceutical composition being characterized in that the patient has an activated mutation in ALK2 protein that is a cause of heterotopic ossification or brain tumor, the amino acid residue at position-330 in ALK2 is proline, and an active ingredient of the composition is an anti-ALK2 antibody having a property to bind to ALK2, a property to crosslink with ALK2 and a property to inhibit BMP signal transfer or an antigen-binding fragment of the antibody.

Description

technical field [0001] The present invention relates to a pharmaceutical composition, which is used for the treatment and / or prevention of heterotopic ossification and / or brain tumors, characterized in that the activating mutation of ALK2 and the 330th amino acid of ALK2 Patients without mutations in residues were given anti-ALK2 antibodies with ALK2-binding and cross-linking capabilities. Background technique [0002] Fibrodysplasia ossificans progressiva (FOP) is a hereditary disease in which cartilage or bone tissue is formed ectopically in soft tissues such as skeletal muscles, tendons, ligaments, etc. Patent Documents 1-3). In this disease, heterotopic ossification occurs in the whole body including the face, and the heterotopic bone tissue fuses with the existing bone tissue to significantly reduce joint mobility and deform the body (Non-Patent Documents 1-3). [0003] It is known that heterotopic ossification in FOP develops not only chronically with growth, but als...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P25/00A61P35/00A61P43/00C12Q1/68
CPCA61P43/00A61P35/00A61P25/00C07K16/2863C07K2317/52C07K2317/70C07K2317/54C07K2317/55C07K2317/75C07K2317/76C07K2317/24A61P19/04C07K2317/565C07K2317/35C07K14/71A61K2039/55A61K39/3955G01N2800/52C12Q1/6883C12Q1/6886C12Q2600/106C12Q2600/156G01N33/6893A61K2039/505C07K16/2896
Inventor 片桐岳信塚本翔熊谷桂吾辻真之介
Owner SAITAMA MEDICAL UNIVERSITY
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