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Compositions and uses for preventing or reversing t-cell failure by inhibition of extracellular nucleotidase and antibody-mediated targeted phagocytosis

An antibody and antigen technology, applied in the direction of anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, antibody, drug combination, etc., can solve the problems of toxic side effects, inability to completely inhibit ectonucleotidase activity, etc.

Pending Publication Date: 2021-09-10
BEIJING EIRENE BIOTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And the problem is not only the toxic side effects they cause, but also that these anti-CD39 and anti-CD73 antibodies do not actually completely inhibit the ectonucleotidase activity of cells, especially in tumor infiltrated lymphocytes (TILs) T When lymphocytes are depleted (this is also the reason why many patients are resistant to tumor immunotherapy such as PD-1 antibody)

Method used

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  • Compositions and uses for preventing or reversing t-cell failure by inhibition of extracellular nucleotidase and antibody-mediated targeted phagocytosis
  • Compositions and uses for preventing or reversing t-cell failure by inhibition of extracellular nucleotidase and antibody-mediated targeted phagocytosis
  • Compositions and uses for preventing or reversing t-cell failure by inhibition of extracellular nucleotidase and antibody-mediated targeted phagocytosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1: Antigen production

[0112] A plasmid expressing human ENTPD1 (CD39) was purchased from Genscript. The clone number of this plasmid in Genscript is OHu15001. The name of the plasmid is pcDNA3.1+ / c-(K)DYK. Its coding region sequence corresponds to NM_001776.5 in the National Center for Biotechnology Information (NCBI) database. The specific nucleotide sequence of the coding region is SEQ ID NO 11 and the amino acid sequence SEQ ID NO 12. Raji (ATCC) cells were seeded and cultured in 10 cm dishes. When the cell concentration reaches 1x 10 6 / ml for transfection. For transfection, 14 μg of pcDNA3.1+ / c-(K)DYK and 15 μL of Lipofectamine 2000 (Thermofisher Scientific) were dissolved in Opti-MEM medium. Then mix the two well and let it stand at room temperature for 5 minutes. During this time Raji cells were resuspended in Opti-MEM medium and placed in 6-well plates. At the end of five minutes, the Opti-MEM medium containing the plasmid and Lipofectamine 200...

Embodiment 2

[0118] Example 2: Using Raji cells overexpressing human CD39 to immunize rabbits and detect whether anti-human CD39 antibodies are produced in the serum of rabbits

[0119] Collect 1x 10 7 Raji cells overexpressing human CD39. And these cells were injected into the blood vessels of rabbits through the rabbit's ear vein. One week later, blood was collected from the rabbit's ear vein to extract serum. And use ELISA method to detect whether the serum contains anti-human CD39 antibody. The specific ELISA method is as follows: first coat the ELISA plate with recombinant human ENTPD1 / CD39 (R&D Systems), and incubate overnight at 4°C. The next day, ELISA plates were blocked with PBS containing bovine serum. Then the serum to be tested was added and placed on a shaker at room temperature for 2 hours, and then the ELISA plate was washed with PBST. After washing, goatanti-Rabbit IgG carrying HRP was added to the ELISA plate. Place on a shaker at room temperature for 1 hour. Then ...

Embodiment 3

[0120] Example 3: Isolation, extraction and expansion of single B cells in the spleen of rabbits, and screening of positive clones capable of secreting anti-human CD39 antibodies

[0121]The spleens of rabbits that received cellular immunization were surgically removed. The spleen was gently crushed on a 70 μm sieve. Wash the sieve with cell culture medium and collect the filtered cell suspension. Use red blood cell lysate to remove red blood cells from the cell suspension. Subsequently, the cell concentration was counted, and the cells in the spleen cell suspension were placed in a 384-well plate for culture at an amount of 0.8 cells per well. Then add cytokine-containing medium to the 384-well plate to promote B cell proliferation. After 48 hours, the supernatant of the cells in the 384-well plate was collected, and ELISA was used to detect whether the supernatant contained anti-human CD39 antibody. The specific ELISA method is as follows: first coat the ELISA plate with...

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Abstract

The invention relates to a method for reducing T cell depletion and a medicine which has the function and can be used for clinical treatment. The medicament specifically comprises an anti-CD39 antibody medicament. According to the therapeutic dose level, the anti-CD39 antibody drug can reduce the expression quantity of CD39 on the surfaces of CD45 positive immune cells. And the CD39 structural domain recognized by the anti-CD39 antibody drug is included in the CD39 structural domain combined with the group of antibodies PB1, PB2, PB3, PB4 and PB5. The anti-CD39 antibody drug can also be effectively combined to Fc gamma RIIIa of cells.

Description

technical field [0001] The invention relates to a method capable of reducing T cell exhaustion and a drug with this function that can be used for clinical treatment. Such drugs specifically include an anti-CD39 antibody drug and its use in the field of pharmacy. Background technique [0002] Extracellular adenosine is a suppressor of immune function. Although intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and methionine cycle, extracellular adenosine mainly plays a role in signal transduction. It affects various physiological functions including the nervous, cardiovascular and immune systems through G protein-coupled adenosine receptors on the cell surface (Fredholm et al., Pharmacol Rev (2001) 53:527). Extracellular adenosine concentrations respond to changes in cellular metabolism. Insufficient adenosine triphosphate (ATP) biosynthesis reduces the ratio of ATP to adenosine when cells are starved of nutrients or oxygen. To reduce ATP ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K16/28A61K39/395A61P35/00A61P35/02
CPCC07K16/2896A61P35/00A61P35/02C07K2317/56C07K2317/565C07K2317/92C07K2317/77
Inventor 赵海涛胡少勇
Owner BEIJING EIRENE BIOTECH INC
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