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Chimeric antigen receptor comprising cd28 and 4-1bb and its application

A chimeric antigen receptor and tumor antigen technology, which is applied in the field of anti-tumor drug preparation, can solve the problems of insufficient patient remission rate, many transplant complications, recurrence of leukemia and lymphoma, etc., so as to improve the therapeutic effect and prolong the survival time. , the effect of strong proliferation ability

Active Publication Date: 2021-09-17
杭州普科亭生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They have achieved a certain therapeutic effect clinically, but leukemia and lymphoma still recur after treatment; and there are side effects such as cytokine storm and neurotoxicity
And the patient's remission rate is not high enough, and other treatments such as bridging bone marrow transplantation are needed
[0003] Bridging bone marrow transplantation also has major defects, such as difficulty in obtaining bone marrow that meets the matching requirements, more complications of transplantation, and higher recurrence rate after transplantation, etc.

Method used

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  • Chimeric antigen receptor comprising cd28 and 4-1bb and its application
  • Chimeric antigen receptor comprising cd28 and 4-1bb and its application
  • Chimeric antigen receptor comprising cd28 and 4-1bb and its application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] This embodiment provides a chimeric antigen receptor, including a tumor antigen binding domain, an extracellular hinge and a transmembrane domain, an intracellular co-stimulatory signal domain, and a signal transduction domain.

[0042] In this embodiment, the tumor antigen binding domain can be a CD19-targeting single-chain antibody (single-chainantibody fragment / single-chain variable fragment, scFv), and the sequence of the CD19-targeting single-chain antibody is shown in SEQ NO: 1所示,具体为MALPVTALLLPLALLLHAARPDIQMTQTTSSLSASLGDRVTISCRASQDISKYLNWYQQKPDGTVKLLIYHTSRLHSGVPSRFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPYTFGGGTKLEITGGGGSGGGGSGGGGSEVKLQESGPGLVAPSQSLSVTCTVSGVSLPDYGVSWIRQPPRKGLEWLGVIWGSETTYYNSALKSRLTIIKDNSKSQVFLKMNSLQTDDTAIYYCAKHYYYGGSYAMDYWGQGTSVTVSS。

[0043] In this embodiment, the sequence of the intracellular signal transduction domain CD3zeta is shown in SEQ NO: 3, specifically RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQG...

Embodiment 2

[0054] This embodiment provides a chimeric antigen receptor, including a tumor antigen binding domain, an extracellular hinge and a transmembrane domain, an intracellular co-stimulatory signal domain, and a signal transduction domain.

[0055] In this example, the tumor antigen binding domain, extracellular hinge, transmembrane domain, and signal transduction domain are the same as those in Example 1.

[0056] In this embodiment, the co-stimulatory signal domain is a combination of CD28 sequence and 4-1BB functional region sequence. The structure of this combination can be found in Figure 1b , where the 4-1BB functional area includes QEED and EEEE.

[0057] For the convenience of expression, the CAR provided in this embodiment is called 28fBB.

[0058] The nucleotide preparation of the tumor antigen binding domain, extracellular hinge, transmembrane domain and CD28 co-stimulatory signal domain of the CAR provided in this example is the same as that in Example 1.

[0059] U...

Embodiment 3

[0063] This embodiment provides a chimeric antigen receptor, including a tumor antigen binding domain, an extracellular hinge and a transmembrane domain, an intracellular co-stimulatory signal domain, and a signal transduction domain.

[0064] In this example, the tumor antigen binding domain, extracellular hinge, transmembrane domain, and signal transduction domain are the same as those in Example 1.

[0065] In this embodiment, the co-stimulatory signal domain is a combination of CD28 mutant sequence and 4-1BB functional region sequence. The structure of this combination can be found in Figure 1c , wherein, the 4-1BB functional region includes QEED and EEEE, and the CD28 mutation sequence is specifically the mutation of YMNM in CD28 to AAAA.

[0066] For the convenience of expression, the CAR provided in this embodiment is called 28fMutBB.

[0067] In this example, the nucleotide sequence corresponding to the YMNM of CD28 in FMC28Z can be mutated into the AAAA nucleotide ...

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Abstract

The present application relates to a chimeric antigen receptor and its application. The chimeric antigen receptor includes a tumor antigen binding domain, an extracellular hinge and a transmembrane domain, an intracellular costimulatory signal domain, and a signal transduction domain; wherein the costimulatory signal domain includes CD28 and 4‑1BB functional area, which includes QEED and EEEE. The CAR provided by this application contains two co-stimulatory signal sequence mutants. The CAR has a stronger proliferation ability in vitro, provides a new tumor cell drug for the clinical treatment of leukemia, and also provides clinical treatment for solid tumors with chimeric antigen therapy. Provide new design ideas.

Description

technical field [0001] The application relates to the field of preparation of antitumor drugs, in particular to a chimeric antigen receptor and its application. Background technique [0002] Malignant tumors are one of the diseases that seriously threaten human health, especially the incidence of hematological tumors such as leukemia and lymphoma remains high. Drugs that have been used in the clinical treatment of leukemia and lymphoma include KymriahTM and Yescart. They have achieved a certain therapeutic effect clinically, but leukemia and lymphoma still recur after treatment; and there are side effects such as cytokine storm and neurotoxicity. Moreover, the patient's remission rate is not high enough, and other treatments such as bridging bone marrow transplantation are needed. [0003] Bridging bone marrow transplantation also has major drawbacks, such as difficulty in obtaining bone marrow that meets the matching requirements, many complications of transplantation, an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00C12N15/63C12N5/10A61K39/00A61P35/00A61P35/02
CPCA61K39/0011A61P35/00A61P35/02C07K14/7051C07K16/2803C07K2319/03C07K2319/33
Inventor 王甜
Owner 杭州普科亭生物医药有限公司