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Tumor inhibitory peptide capable of being specifically bound with PD-1 and application thereof

A technology of tumor suppression and peptide inhibition, which is applied in the field of disease treatment to achieve good biological activity

Active Publication Date: 2017-11-24
生工生物工程(上海)股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, I did not expect Merck to come from behind, and Keytruda was the first to be approved in September

Method used

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  • Tumor inhibitory peptide capable of being specifically bound with PD-1 and application thereof

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Experimental program
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Effect test

Embodiment 1

[0027] Embodiment one: the acquisition of inhibitory peptide

[0028] The inventor designed the corresponding inhibitory peptides according to the computer-aided design method peptide designer of the inhibitory peptides designed by himself. The design method is to set random short peptides with a length of 25-150 amino acids to make them wander on the surface of PD-1 protein molecules , and change the relative position of the peptide and PD-1 through the charge, quickly calculate the force of each atom on the peptide and the adjacent atoms on the protein surface, as well as the energy change caused by moving and twisting the peptide; and repeatedly optimize and compare various Among the possible binding modes, choose the lowest energy and most fixed conformation. According to the distance and spatial relationship of the interacting atoms, the binding site of the polypeptide to the PD-1 molecule, the participating atomic groups and the mode of action were obtained, and finally ...

Embodiment 2

[0030] Example 2 Determination of the affinity of inhibitory peptides to PD-1

[0031] (1) Prepare the polypeptide with 1×PBS to a solution with a concentration of 1 mg / mL, and prepare the anti-PD-1 polypeptide to a solution with a concentration of 100 μg / mL, take 2.5 μL and drop it on a carboxylated SPR chip (purchased from Plexera company, Kx5 type SPR standard substrate), and the polypeptide was immobilized on the SPR chip through the specific reaction of streptavidin and biotin. Then, the PD-1 solution (diluted in 1×PBS) with concentrations of 0.1 μg / mL, 1 μg / mL, 10 μg / mL, and 50 μg / mL was passed through the chip surface as the mobile phase. The binding time was 150 s, the dissociation time was 130 s, and the regeneration time 200s. 1×PBS was used as the dissociation solution, and 0.5% phosphoric acid was used as the reconstitution solution. The binding-dissociation curves of polypeptides and TNF-α were recorded on a K×5 SPR instrument (Plexera).

[0032](2) Fitting the...

Embodiment 3

[0033] The biological activity detection of embodiment 3 polypeptide inhibitors

[0034] (1) Select JurKat / PD-1 / NFAT cells preserved in the General Microorganism Center of China Microbiological Culture Collection Management Committee with the registration number 10298 as target cells, and use DMEM / F12+10% FBS medium to illuminate 2.5×10 4 cells / well, spread evenly in a 96-well plate at a density of 100 μl / well (corning), 37°C, 5% CO 2 Incubate overnight in the incubator;

[0035] (2) Use 1640+10% fetal bovine serum medium to prepare different concentrations of polypeptide solutions and dilute to 1 μg / mL, then dilute 10 times down to 7 concentration points, and suck off the DMEM / F12+10 in the above 96-well plate %FBS medium, add the prepared peptide inhibitor solution to the 96-well plate according to 50 μl / well;

[0036] (3) Use 1640+10% fetal bovine serum medium to prepare target cell suspension, and follow the 5×10 4 per well, 50 μl / well density evenly spread to the above...

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Abstract

The invention relates to a tumor inhibitory peptide capable of being specifically bound with PD-1 and an application thereof. The inhibitory peptide can be bound with an extracellular region of a PD-1 protein receptor and can effectively close a PD-1 protein at protein level and cellular level and prevent the PD-1 protein from being bound with a ligand PD-L1. The polypeptide has good biological activity. The polypeptide can be used in tumor immunotherapy alone or combined with an anti-PD-1 monoclonal antibody or other anti-tumor drugs as well as diagnosis and screening of a PD-1 positive tumor patient, namely the polypeptide can be applied to preparation of drugs used for treating tumor and autoimmune diseases.

Description

technical field [0001] The invention relates to the technical field of disease treatment, in particular to a tumor suppressor peptide capable of specifically binding to PD-1 and its use. Background technique [0002] The body's T cell immunity plays an important role in controlling the occurrence and development of tumors. Among them, tumor-infiltrating CD 8+ T lymphocytes play a key role in the body's anti-tumor immune response. In recent years, it has been found that there is an immunosuppressive mechanism in tumor patients, which hinders the body from clearing the tumor and leads to long-term colonization of the tumor, which is manifested by T lymphocyte dysfunction and weakened proliferation ability. PD-1 has been recognized as a surface marker of exhausted T lymphocytes. Blocking the PD-1 / PD-L1 pathway can partially restore the function of exhausted T cells. It is known that PD-1 (programmed death 1) programmed death receptor 1 is an important immunosuppressive molec...

Claims

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Application Information

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IPC IPC(8): C07K14/00A61K38/16A61K47/69A61P35/00
CPCA61K38/00C07K14/001
Inventor 王振张成
Owner 生工生物工程(上海)股份有限公司
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