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Antimalarial dimer immunoadhesin, pharmaceutical composition and application

A technology of immunoadhesin and dimer, which is applied in the direction of drug combination, antibody mimic/stent, anti-infective drug, etc., can solve the problems of unknown biological activity and anti-disease effect of immunoadhesin, and achieve in vivo stability Excellent, broad clinical application prospects, the effect of prevention and treatment of malaria

Inactive Publication Date: 2020-04-07
PHARCHOICE THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Plasmodium invasion of erythrocytes requires the participation of erythrocyte surface receptor proteins. However, there is no report on the preparation of immunoadhesins using erythrocyte surface receptor proteins. Whether the preparation can be realized and whether the biological activity of the prepared immunoadhesins is still Existence, whether the preparation of immunoadhesin has anti-disease effect, which receptor protein to choose for engineering, and which engineering method to choose are all unknown, and further confirmation is needed

Method used

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  • Antimalarial dimer immunoadhesin, pharmaceutical composition and application
  • Antimalarial dimer immunoadhesin, pharmaceutical composition and application
  • Antimalarial dimer immunoadhesin, pharmaceutical composition and application

Examples

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Effect test

Embodiment 1

[0037] Example 1. Construction and expression of soluble dimeric immunoadhesin

[0038] Such as figure 1 As shown, the soluble antimalarial dimer immunoadhesin is a dimer with antibody IgGFc, and the method of constructing and expressing the dimer immunoadhesin itself is a routine experimental technique in the field, and is briefly described as follows :

[0039] (1) Whole gene synthesis of soluble dimeric immunoadhesin BSG-Fc (comprising two polypeptide chains, the amino acid sequence and nucleotide sequence of each polypeptide chain are shown in SEQ ID NO.2 and SEQ ID NO.12) BSG / GYPA-Fc (comprising two polypeptide chains, the amino acid sequence and nucleotide sequence of the first polypeptide chain are shown in SEQ ID NO.4 and SEQ ID NO.13, the amino acid sequence of the second polypeptide chain and The nucleotide sequence is shown in SEQ ID NO.5 and SEQ ID NO.14); BSG / GYPB-Fc (comprising two polypeptide chains, the amino acid sequence and nucleotide sequence of the first...

Embodiment 2

[0042] Example 2. In vivo stability test of soluble dimeric immunoadhesin

[0043] The half-life of antimalarial dimeric immunoadhesin was evaluated in NOG mice using the literature (Hu S, et al. Science translational medicine, 2017, 9(380): eaag0339.) method. The results showed that the in vivo half-lives of BSG-Fc, BSG / GYPA-Fc, BSG / GYPB-Fc, and BSG / GYPC-Fc were 8.9 days, 8.1 days, 7.5 days, and 8.4 days, respectively; the positive control cetuximab was 8.6 days; while the half-lives of the three BSG antigen peptides (amino acid sequence TNINTLENSDHTCFAR; SNPYFIVGSR; ENYYNSDIAGPAR) were too short to be detected, and the half-life of the BSG extracellular protein half-life was too short to be detected.

Embodiment 3

[0044] Example 3. In vitro invasion experiment of soluble dimeric immunoadhesin

[0045] Type O human erythrocytes were used to conduct the Plasmodium invasion experiment, and the test method was the same as the literature (Zhang M Y, etal.blood, 2018, 131(10):1111-1121.). Four kinds of Plasmodium beads Dd2, 3D7, FCC1, and Nf54 were used to carry out this experiment, and healthy human IgG was used as the control group, and BSG-Fc, BSG / GYPA-Fc, BSG / GYPB-Fc, BSG / GYPC-Fc and control were administered respectively IgG, the dosage is 10 μg / ml. The calculation method of the invasion suppression rate is also the same as the literature, and the results are as follows figure 2 Shown: It shows that BSG-Fc, BSG / GYPA-Fc, BSG / GYPB-Fc, BSG / GYPC-Fc have a strong ability to inhibit invasion, and the invasion inhibition rate is close to 100%.

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Abstract

The invention provides an antimalarial dimer immunoadhesin, a pharmaceutical composition and an application. The dimer immunoadhesin comprises two dimerized polypeptide chains. The structural generalformula of the first polypeptide chain is Z1 to Z2, and the structural general formula of the second polypeptide chain is Y1 to Y2. Z1 is an extracellular domain or a functional variant or fragment thereof of a first cell surface receptor. Z2 is a dimerization domain or a functional variant or fragment thereof. Y1 is an extracellular domain or a functional variant or fragment thereof of a second cell surface receptor. Y2 is a dimerized domain or a functional variant or fragment thereof. The first cell surface receptor and the second cell surface receptor are selected from any one of GYPA, GYPB, GYPC, CR1 and BSG respectively. The dimer immunoadhesin provided by the invention can effectively block plasmodium strains from invading red blood cells, and the invasion inhibition rate is close to100%. The antimalarial effect of immune cells is improved. In addition, the antimalarial dimer immunoadhesin disclosed by the invention is excellent in in-vivo stability and has a wide clinical application prospect.

Description

technical field [0001] The invention relates to the technical field of biomedical engineering, in particular to a dimer immunoadhesin, a pharmaceutical composition using it as an active component and its medical application, especially the application for preventing and treating malaria. Background technique [0002] Malaria is a vector-borne disease caused by infection with Plasmodium parasites through mosquito bites or blood transfusion of people with Plasmodium parasites. There are four types of Plasmodium parasites in the human body, namely Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum and Plasmodium ovale. In my country, mainly Plasmodium vivax and Plasmodium falciparum; the other two are rare, and some cases imported from abroad have occasionally been seen in recent years. Different Plasmodium species cause Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum and Plasmodium ovale. The main manifestations of this disease are periodic attacks, ch...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/17A61K47/55A61P33/06
CPCA61K38/00A61P33/06C07K14/705C07K14/70525C07K14/70596C07K2319/00C07K2319/30Y02A50/30
Inventor 傅文燕丁敏凌月娥胡适
Owner PHARCHOICE THERAPEUTICS INC
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