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Chimeric antigen receptors targeting msln

A chimeric antigen receptor and antigen technology, applied in the field of biomedicine, to achieve high activity, enhanced therapeutic effect, and small side effects.

Active Publication Date: 2021-06-22
北京百替生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

So far, there are still few CAR-T technologies for detecting MSLN targets in the existing technology, and CAR still has a lot to do in improving the sensitivity and specificity of binding to MSLN targets, and better activating T cells technology space

Method used

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  • Chimeric antigen receptors targeting msln
  • Chimeric antigen receptors targeting msln
  • Chimeric antigen receptors targeting msln

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1 Preparation of sc-Fv

[0040] 1. Animal immunization and preparation of monoclonal antibodies

[0041] The extracellular domain part of human MSLN protein was used as immunogen, mixed with complete Freund's adjuvant, and immunized 6-week-old female Balb / c mice (the dosage of immunogen was 100 μg / mouse), and the immunization method was subcutaneous multiple Spot immunization; two weeks later, the immunogen was mixed with incomplete Freund's adjuvant, and the mice were boosted (the dosage of immunogen was 50 μg / mouse), and the immunization method was subcutaneous multi-point immunization; every two weeks Booster immunization was carried out in the same way, a total of 3 booster immunizations. On the 7th day after the last booster immunization, the eyeballs of the mice were removed, blood was collected from the orbital venous plexus of the mice, and the serum was separated by centrifugation, and the antibody titer of the serum was detected by ELISA. If P / N≥2.1 ...

Embodiment 2

[0061] Example 2 Construction of Chimeric Antigen Receptor

[0062] Signal peptide, MSLN antigen-binding domain (sc-Fv prepared in Example 1), CD28 transmembrane co-stimulatory domain, 4-1BB transmembrane co-stimulatory domain, CD3ζT cell signaling region, co-expression through whole gene synthesis Runx3 agonist domain:

[0063] MSLN-CAR: signal peptide-MSLN scFv-CD28-4-1BB-CD3ζ-Runx3;

[0064] Wherein the signal peptide sequence is shown in SEQ ID NO: 16;

[0065] The gene sequence number of CD28 is XM_006712862.1; the gene sequence number of 4-1BB is U03397.1; the gene sequence number of CD3ζ is AF228312.1; the sequence selection refers to Sadelain M, Nature biotechnology, 2013,31(1):71 -5 Structures of designed chimeric antigen receptors.

[0066] At the same time, the comparison sequence MSLN-CAR-control is set. Compared with MSLN-CAR, the only difference is that the Runx3 segment is missing.

Embodiment 3

[0067] Example 3 Construction of MSLN-CAR-T lentivirus

[0068] Cloning of MSLN-CAR fragment and MSLN-CAR-control into lentiviral vector pc DNA TM For 3.1(+), the selected insertion site is Nhe I / Bam HI. The sequence was provided by the applicant, and the assembly procedure was completed by Suzhou Gemma Gene Co., Ltd.

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PUM

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Abstract

The invention relates to the field of biomedicine, in particular to a chimeric antigen receptor targeting MSLN. The chimeric antigen receptor includes an antigen binding region, a transmembrane co-stimulatory domain, a T cell signal transduction domain and a co-expressed Runx3 agonist in sequence from the N-terminus to the C-terminus. The co-expressed Runx3 agonist can significantly enhance the therapeutic effect of CAR‑T.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a chimeric antigen receptor targeting MSLN. Background technique [0002] CAR-T (Chimeric Antigen Receptor T-Cell Immunotherapy), that is, Chimeric Antigen Receptor T-Cell Immunotherapy. This therapy is a new type of cell therapy that has been around for many years but has only been improved and used clinically in recent years. It has remarkable efficacy in the treatment of acute leukemia and non-Hodgkin's lymphoma, and is considered to be one of the most promising tumor treatment methods. Like all technologies, CAR-T technology has also undergone a long evolutionary process. It is during this series of evolutionary processes that CAR-T technology has gradually matured. [0003] The key to this new therapeutic strategy is artificial receptors known as chimeric antigen receptors (CARs) that recognize target cells and, when genetically modified, express the CARs on the patient's T cell...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C12N15/62C12N15/867C12N5/10A61K35/17A61P35/00
CPCA61K35/17A61P35/00C07K14/7051C07K14/70521C07K14/70578C07K16/30C07K2317/24C07K2317/565C07K2319/02C07K2319/03C12N15/86C12N2740/15043
Inventor 郭磊
Owner 北京百替生物技术有限公司
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