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Liquid preparation comprising anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody

A technology for monoclonal antibodies and liquid preparations, which can be used in medical preparations with non-active ingredients, anti-animal/human immunoglobulins, antibodies, etc., and can solve problems such as process failure, reduced recovery rate, and reduced tangential flow rate. , to achieve good clinical results

Active Publication Date: 2022-02-11
QYUNS THERAPEUTICS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In some extreme cases, a gel-like substance may even form, which brings great challenges to the ultrafiltration membrane and the ultrafiltration equipment itself, such as the decrease in the tangential flow rate caused by the rapid increase in the pressure difference during the final concentration, and the concentration difference Polarization gets out of control until protein precipitation clogs the membrane, which inevitably leads to reduced recovery or process failure
On the other hand, even if the final high-concentration protein solution is obtained by improving the equipment or membrane type, it is difficult to put it into actual clinical application, because it needs to be sucked by disposable sterile syringe or prefilled needle for subcutaneous administration The final packaging form, and too high viscosity will reduce the sliding performance of the filled syringe, so that it cannot be manually pushed into the subcutaneous
Another difficulty in concentrating high-concentration monoclonal antibody solutions by ultrafiltration is that protein samples tend to aggregate to form soluble aggregates when highly concentrated, and further aggregate to form protein precipitates

Method used

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  • Liquid preparation comprising anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody
  • Liquid preparation comprising anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody
  • Liquid preparation comprising anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody

Examples

Experimental program
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Effect test

Embodiment 1

[0127] Embodiment 1 Preparation of anti-human TSLP monoclonal antibody QX008N

[0128] Purchasing human thymic stromal lymphopoietin (hTSLP) from Shanghai Nearshore Technology Co., Ltd. for immunization of New Zealand rabbits, using B cell cloning technology to obtain antigen-binding specific antibody clones, and then screening for binding to human TSLP and having human TSLP inhibitory activity of monoclonal antibodies. The cell supernatant was detected by Binding ELISA and Blocking ELISA, and the target clone was selected. The above immunization and screening processes are entrusted to commercial companies.

[0129] Seven clones were selected for recombinant expression and sequenced. It has been determined that 8G2 has the best cell neutralizing activity. Therefore, the 8G2 clone was humanized. Use NCBI IgBlast to carry out homology comparison of human IgG germline sequence (Germline), select IGHV3-66*01 as the heavy chain CDR transplantation template, and clone the CDR r...

Embodiment 2

[0134] The mensuration of embodiment 2 equilibrium dissociation constant (KD)

[0135] The affinity between QX008N(HZD8G2-57) and human TSLP was detected by Biacore T200, and all processes were carried out at 25°C. Using a commercial Protein A chip, an appropriate amount of antibody was immobilized by the capture method, so that the Rmax was around 50RU, and the capture flow rate was 10 μl / min. The antigen was serially diluted, the flow rate of the instrument was switched to 30 μl / min, and the concentration flowed through the reference channel and the channel of the immobilized antibody in order of concentration from low to high, and the buffer was used as a negative control. After each association and dissociation, the chip was regenerated with pH 1.5 glycine. Use the instrument's own analysis software to select the 1:1 binding model in the Kinetics option for fitting, and calculate the antibody's association rate constant ka, dissociation rate constant kd, and dissociation ...

Embodiment 3

[0140] Example 3 QX008N and Tezepelumab neutralize the STAT5 phosphorylation activity of human TSLP-induced SW756-STAT5-Luciferase reporter cells The SW756-STAT5-Luciferase reporter cell line was used to measure QX008N antagonizing the intracellular activity of human TSLP mediated by TSLPR-IL-7R Phosphorylation activity of signal molecule STAT5: Cells in the culture medium were divided into 4×10 per well 4 Cells were added to 96 wells and then incubated at 37°C and 5% CO 2 conditions overnight. Add the pre-incubated antibody and human TSLP mixture to the cells, where the final concentration of QX008N ranges from 0 to 50 ng / ml, the final concentration of Tezepelumab ranges from 0 to 400 ng / ml, and the final concentration of TSLP is 0.5 ng / ml. Then at 37 °C and 5% CO 2 Cultivate under conditions for 24 hours, discard the cell culture supernatant, add 120 μl ONE-Glo-Luciferase Reagent detection reagent to each well, and act for 30 minutes, take 100 μl from each well to a white ...

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Abstract

The invention discloses a liquid preparation of an anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody. The liquid preparation comprises an anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody and an amino acid protection agent, wherein the protein concentration of the anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody is 100-300mg / ml, the amino acid concentration of the amino acid protection agent is 10-500mM, the monoclonal antibody comprises three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and three light chain complementarity determining regions (CDR-L1, CDR-L2 and CDR-L3), the amino acid sequence of the CDR-H1 is as shown in SEQ ID NO: 1, the amino acid sequence of the CDR-H2 is as shown in SEQ ID NO: 2, the amino acid sequence of the CDR-H3 is as shown in SEQ ID NO: 3, the amino acid sequence of the CDR-L1 is as shown in SEQ ID NO: 4, the amino acid sequence of the CDR-L2 is as shown in SEQ ID NO: 5, and the amino acid sequence of the CDR-L3 is as shown in SEQ ID NO: 6. The liquid preparation disclosed by the invention is relatively low in viscosity and can be easily injected by a syringe, so that the liquid preparation can be used as an injection, especially a hypodermic injection.

Description

technical field [0001] The present application relates to the field of biotechnology, in particular to a liquid preparation containing anti-human thymus stromal lymphopoietin (TSLP) monoclonal antibody. Background technique [0002] Therapeutic biological products are a fast-growing market with numerous R&D pipelines, and at the same time bring more innovative therapies to patients. For some autoimmune-related diseases that are difficult to treat with traditional small molecule drugs, biological drug targeted drugs provide more choices. On the other hand, in order to reduce the cost of clinical use of biological agents and improve patient compliance, the dosage form of biological agents has gradually changed from freeze-dried dosage form to aqueous injection dosage form, and the route of administration has also changed from intravenous administration to subcutaneous injection dosage form. Since the dosage of monoclonal antibody injection is usually in the range of 100mg to ...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K9/00A61K47/18A61K47/22A61K47/20A61P11/06
CPCC07K16/18A61K9/0019A61K47/183A61K47/22A61K47/20A61P11/06C07K2317/565C07K2317/56
Inventor 薛刚朱华杰戴长松李帅许芹郭彩明陈卫吴亦亮
Owner QYUNS THERAPEUTICS CO LTD
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