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Trail receptor-binding agents and uses of same

A technology of use and antibody, applied in the direction of antibody, drug combination, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve the limited clinical application value of TNF-α and Fas ligand, toxic and side effects, etc. question

Active Publication Date: 2018-08-31
BEIJING SINOTAU INT PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TNF-α and Fas ligands have limited clinical value due to their toxic side effects

Method used

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  • Trail receptor-binding agents and uses of same
  • Trail receptor-binding agents and uses of same
  • Trail receptor-binding agents and uses of same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0327] Characterization of the Binding Specificity and Affinity of Example 1 HUCTB006

[0328] 1.1 Binding specificity

[0329] The binding specificity of HuCTB006 was assessed by chemiluminescent enzyme immunoassay (CLEIA). DR4-His–EC (batch number: 090222-P, 0.72mg / mL, Escherichia coli), DcR1-His (recombinant human TRAIL R3 / TNFRSF10C, Novoprotein Science, batch number: 0328670), DcR2-His (recombinant human TRAIL R4 / TNFRSF10d , Sino Biological, batch number LC06JU1502) and OPG-His (recombinant human osteoprotegerin (recombinant human osteoprotegerin) / TNFRSF11B, Wuxi Pharmatech Co.Ltd, batch number: 20120717) were coated on the microplate, and then it was blocked (Blocked).

[0330] HuCTB006 was diluted to 200, 40 and 8 ng / mL and added to the wells. After incubation for 1 hour at 37°C, the plates were washed. The binding of HuCTB006 to the immobilized antigen was detected with HRP-labeled secondary antibody and substrate solution. The result shows, as figure 1 As shown, t...

Embodiment 2

[0333] In vitro effectiveness of embodiment 2 HuCTB006 treatment

[0334] 2.1 Cytotoxicity of HuCTB006 in human normal tissue cell lines

[0335] Several human normal tissue cell lines, including human lung epithelial fibroblast WI-38, human embryonic lung fibroblast HFL-1, human umbilical vein epithelial cell HUV-EC-C, and human hepatic differentiated cells derived from liver-induced cells (Acquired from Peking University Third Hospital). Cells at 37 °C and 5% CO 2 and culture medium containing 10% FBS. The medium of WI-38 was MEM, and the medium of HFL-1 and HUV-EC-C was F-12K. Cells were treated with oxaliplatin for 24 hours, and then different concentrations of CTB006 were added to the combination group. Results were determined 24 hours after treatment, as image 3 and Figure 4 shown. The examined human normal tissue cells were not sensitive to CTB006, indicating that HuCTB006 had no cytotoxicity to human normal tissue cells.

[0336] 2.2 Cytotoxicity of CTB006 in...

Embodiment 3

[0343] Example 3. In Vivo Efficacy - Human Tumor Cells

[0344] The efficacy of HuCTB006 was tested in a subcutaneous model of nude mice using four human tumor cell lines (ie, two colon, one lung and one pancreatic cancer). The results showed that even at low or micro-dose, HuCTB006 inhibited the tumor growth of colon cancer cells, lung cancer cells and pancreatic cancer cells, while HuCTB006 alone showed the same therapeutic effect as chemotherapy drugs. Results are reproducible.

[0345] 3.1 Efficacy of HuCTB006 in the subcutaneous model of human tumor cells

[0346] 3.1.1 Drugs

[0347] HuCTB006 (batch number H61042F-P01) was obtained from Beijing Cotimes Biotech Co., Ltd.; irinotecan and gemcitabine were obtained from Jiangsu Hengrui Medicine Co., Ltd. ); Paclitaxel was obtained from Beijing Union Pharmaceutical Factory. The drug powder was first dissolved in NS to reach a concentration of 5 mg / ml, and then passed through a 0.2 μm filter membrane (PALL, Syringe Filte...

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Abstract

TRAIL receptor-binding agents exert therapeutic effects on tumor inhibition in vitro and in vivo, alone or in combination with an anti-cancer biologic. In particular, methods for the treatment of cancer comprise administering a TRAIL receptor binding agent, alone or in combination with TRAIL and / or interferon alpha-2b.

Description

field of invention [0001] The present disclosure generally relates to therapeutic uses of TRAIL receptor binding agents. In particular, the disclosure relates to methods and compositions comprising CTB006, an anti-TRAIL-R2 (DR5) antibody, and the therapeutic effects of CTB006 alone or in combination with TRAIL and interferon alpha-2b in tumor suppression in vitro and in vivo. Background of the invention [0002] TRAIL is known to play an important role in the immune surveillance of tumor cells. Activated T lymphocytes and NK cells express high levels of TRAIL, which endows these immunocompetent cells with the ability to kill tumor cells. Animal studies have shown that knockout of TRAIL leads to increased tumor incidence with age. Therefore, TRAIL deficiency or underexpression may be a factor in tumorigenesis. [0003] TRAIL is a member of the TNF protein family. Some proteins of this family are characterized by their ability to induce apoptosis, such as TNF-α and Fas lig...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61P35/00C07K16/28A61K38/21
CPCA61K38/177A61K38/212C07K2317/73C07K2317/75C07K2317/92G01N2800/52A61P35/00A61K2039/505C07K16/2878C07K2317/24A61K2300/00A61K39/39558G01N33/57492
Inventor 沈恩允曹峰琦李哲
Owner BEIJING SINOTAU INT PHARMA TECH CO LTD
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