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Application of AMHR2 recombinant protein or fused protein in preparation of drugs for treating AMH signal axis abnormal activation related diseases

A technology of recombinant protein and fusion protein, which is applied in diseases, drug combinations, peptide/protein components, etc. It can solve the problems of unknown, undisclosed or prompted biological effects, and achieve excellent in vivo stability, long half-life, and binding force. strong effect

Inactive Publication Date: 2020-04-14
PHARCHOICE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it does not disclose or suggest its antagonism / neutralization of AMH. In fact, the signal transduction mediated by AMH and AMHR2 is participated by multiple receptors (such as multiple ALK receptors) and multiple adapter proteins. Recombinant AMHR2 and AMHR2 It is unknown whether the AMHR2 fusion protein can exert an antagonistic effect, that is, whether the recombinant protein and the fusion protein can block the AMH signaling axis, and whether it can antagonize / neutralize the biological effects mediated by AMH is unknown

Method used

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  • Application of AMHR2 recombinant protein or fused protein in preparation of drugs for treating AMH signal axis abnormal activation related diseases
  • Application of AMHR2 recombinant protein or fused protein in preparation of drugs for treating AMH signal axis abnormal activation related diseases
  • Application of AMHR2 recombinant protein or fused protein in preparation of drugs for treating AMH signal axis abnormal activation related diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Construction and expression of embodiment 1.AMHR2 recombinant protein and AMHR2 fusion protein

[0031] The construction and expression of AMHR2 recombinant protein and AMHR2 fusion protein are briefly described as follows:

[0032] (1) AMHR2 (the amino acid sequence and nucleotide sequence of the polypeptide chain are shown in SEQ ID NO.1 and SEQ ID NO.4) and AMHR2-Fc (the amino acid sequence and nucleotide sequence of the polypeptide chain are shown in SEQ ID NO.4) synthesized from the whole gene shown in ID NO.2 and SEQ IDNO.5), AMHR2-Fc-LALAPG (the amino acid sequence and nucleotide sequence of the polypeptide chain are shown in SEQ ID NO.3 and SEQ IDNO.6), obtain AMHR2 recombinant protein and Two forms of AMHR2 fusion proteins.

[0033] (2) Expression and purification of recombinant proteins and fusion proteins

[0034] According to the literature (Hu S, et al.Science translational medicine, 2017,9(380):eaag0339; Finck B K.Science,265.; Mihara M et al..Journal of...

Embodiment 2

[0035] In vivo stability test of embodiment 2.AMHR2 recombinant protein and AMHR2 fusion protein

[0036] The half-life of AMHR2 recombinant protein and AMHR2 fusion protein was evaluated in NSG mice using the literature (Hu S, et al. Science translational medicine, 2017, 9(380): eaag0339.). The results showed that the in vivo half-lives of AMHR2, AMHR2-Fc, and AMHR2-Fc-LALAPG were 2.1 days, 9.6 days, and 9.1 days, respectively; the positive control cetuximab was 9.7 days; the negative control AMHR2 antigenic peptide (amino acid sequence PPNRRTCV) The half-life is too short to be measured. The results show that AMHR2 has certain druggability and can be used for in vivo research, and the fusion proteins AMHR2-Fc and AMHR2-Fc-LALAPG have better in vivo stability.

Embodiment 3

[0037] Embodiment 3.AMHR2 recombinant protein and / or AMHR2 fusion protein binding test

[0038] This example was carried out using the ELISA binding assay protocol described in the literature (Hu S, et al. Science translational medicine, 2017, 9(380): eaag0339.). The plating concentration of AMH protein (purchased from R&D Systems) was 10 μg / ml, and the concentration range of AMHR2, AMHR2-Fc, AMHR2-Fc-LALAPG protein pre-labeled with biotin was 0.01-100 ng / μL. After incubating AMH and then detecting and developing the color, the results are as follows: figure 1 shown. The three proteins have strong binding ability, and the control antigen peptide and cetuximab have no binding ability.

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Abstract

The invention relates to application of an AMHR2 recombinant protein or fused protein in the preparation of drugs for treating AMH signal axis abnormal activation related diseases, and especially application in the preparation of AMH neutralizers or antagonists. Stability experiments show that the AMHR2 fused protein is long in half-life period, excellent in in-vivo stability and strong in AMH binding force, and has certain druggability. Cell experiments and animal model experiments show that the AMHR2 recombinant protein or the AMHR2 fused protein can effectively antagonize or neutralize AMHin vitro and vivo, can further block an AMH signal axis, and can effectively prevent and treat diseases caused by abnormal activation of the AMH signal axis.

Description

technical field [0001] The invention relates to the technical field of biomedical engineering, in particular to recombinant AMHR2 and AMHR2 fusion protein, a pharmaceutical composition using it as an active component and its medical application, especially the application for diseases related to abnormal activation of AMH signaling axis. Background technique [0002] Anti-Müllerian hormone (AMH), also known as Müllerian Inhibiting Substance (MIS), is a TGF-β family glycoprotein. AMH receptors include receptor complexes of type I receptors and type II receptors, wherein the type II receptor is AMHR2, and multiple type I receptors participate in signal transduction. AMH induces Müllerian regression in human male embryos but is expressed in females of reproductive age, does not fluctuate with cycle or pregnancy, and gradually decreases with both oocyte quantity and quality, suggesting that AMH can be used as a marker of ovarian physiology. Mark. See literature eg [Zec et al, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61K47/68A61P5/00A61P15/08A61P35/00
CPCA61K38/179A61K47/6811A61P15/08A61P5/00A61P35/00
Inventor 傅文燕胡适丁敏
Owner PHARCHOICE THERAPEUTICS INC
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