Molecular structure and application of tumor necrosis factor receptor 1 proligand assembly domain glycocluster

A tumor necrosis factor and conjugate technology, applied in the field of tumor necrosis factor receptor 1 pro-ligand assembly domain protein conjugates, can solve the problems of indistinguishability, increased incidence of lymphoma, inability to distinguish multiple TNFR pathways, etc.

Inactive Publication Date: 2011-10-05
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since this TNFα-targeted treatment method cannot distinguish between multiple TNFR pathways, such as the combination of TNFα and TNFR1 and TNFR2, it will also inhibit the physiological effects mediated by TNFR2 when inhibiting TNFR1-induced diseases, which may Causes side effects such as lupus-like disease, mycobacterial infection, and increased incidence of lymphoma

Method used

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  • Molecular structure and application of tumor necrosis factor receptor 1 proligand assembly domain glycocluster
  • Molecular structure and application of tumor necrosis factor receptor 1 proligand assembly domain glycocluster
  • Molecular structure and application of tumor necrosis factor receptor 1 proligand assembly domain glycocluster

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Coupling of mPEG-aldehyde to the N-terminal α-amino group of PLAD (SEQ ID NO: 1, Xaa=Leu)

[0031]Use 20mM acetic acid-sodium acetate buffer to configure PLAD into a protein solution of 10mg / ml, pH5.2, and add methoxypolyethylene glycol with a molecular weight of 20000Da using 20mM acetic acid-sodium acetate buffer Aldehyde (mPEG-ALD20000), so that the molar ratio of protein to PEG is 1:1, and sodium cyanoborocyanide at a final concentration of 20 mM is added to catalyze the reduction reaction. Leave to react at 4°C for 16 hours. After the reaction, dilute the reaction solution and adjust the pH value to neutral to stop the reaction. The reaction proceeds according to the following reaction formula:

[0032]

Embodiment 2

[0034] mPEG-maleimide coupled to Cys at the end of PLAD (SEQ ID NO: 2, Xaa=Cys)

[0035] Use 20mM Tris-HCl buffer to configure PLAD into a 6mg / ml, pH8.0 protein solution, add 2000Da methoxypolyethylene glycol maleyl with a molecular weight of 20mM Tris-HCl buffer imine (mPEG-MAL2000) such that the molar ratio of protein to PEG was 1:1. Leave to react at 4°C for more than 6 hours.

[0036] The reaction proceeds according to the following reaction formula:

[0037]

Embodiment 3

[0039] Coupling of mPEG-vinylsulfone to Cys at the end of PLAD (SEQ ID NO: 3, Xaa=Cys)

[0040] Use 20mM Tris-HCl buffer to configure PLAD into a 6mg / ml, pH 8.0 protein solution, add 5000Da methoxypolyethylene glycol vinyl sulfone with a molecular weight of 20mM Tris-HCl buffer (mPEG-VS5000) such that the molar ratio of protein to PEG was 1:2. Leave to react at 4°C for more than 6 hours. The reaction proceeds according to the following reaction formula:

[0041]

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Abstract

The invention belongs to the field of biotechnology and specially relates to a molecular structure, a preparation method and an application of a tumor necrosis factor receptor 1 proligand assembly domain glycocluster. A proligand assembly domain (PLAD) of a tumor necrosis factor receptor 1 and molecules of polyethylene glycol (PEG) and the like are connected through covalent bonds to form a tumor necrosis factor receptor 1 proligand assembly domain protein glycocluster molecule, wherein the PLAD part can be prepared through a technology of protein recombinant and expression. The invention aims at obtaining a PLAD molecule with a long serum half-life period and the PLAD molecule is utilized for treating human inflammatory diseases.

Description

technical field [0001] The invention belongs to the field of biotechnology and relates to a tumor necrosis factor receptor 1 pro-ligand assembly domain protein conjugate. Background technique [0002] The extracellular region of tumor necrosis factor receptor (TNFR) superfamily is mainly responsible for ligand recognition and binding, and their extracellular region usually contains 1 to 6 cysteine-rich domains (CRD). These receptors usually bind ligands as trimers to function as receptors. The above functions are mediated by at least one cysteine-rich proligand assembly domain. Members of the TNFR superfamily, including TRAIL receptor 1, CD40, TNFR1 and TNFR2, all have this association function. Other TNFR superfamily members such as Fas, LTβR, HVEM, RANK, CD40, CD30, CD27, OX40, and DR4 all contain pre-ligand assembly domains. [0003] It was found that PLAD is necessary and sufficient for the formation of receptor aggregates in the absence of ligands. Although PLAD is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/715A61K38/17A61K47/48A61P19/02A61P29/00
Inventor 姚文兵曹进孟芳田浤高向东
Owner CHINA PHARM UNIV
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