Modified hinge and its application in constructing car skeleton

Abstract

The invention belongs to the field of immunotherapy, and in particular relates to a modified hinge region and its application in constructing a CAR framework. The hinge region provided by the present invention can prolong the persistence of CAR-T cells in vivo and / or improve the ability of CAR-T cells to infiltrate tumors, and the amino acid sequences of the hinge region are shown in SEQ ID NO.1 and SEQ ID NO.2. The hinge region structure provided by the present invention can prolong the duration of CAR-T cells in vivo, and the chimeric antigen receptor combined with the hinge region structure can be more stably expressed in T lymphocytes, and the CAR-T containing the hinge region of the present invention can survive in vivo The survival time is longer, the ability of cells to infiltrate the tumor is significantly enhanced, and the killing effect is better.

Description

technical field [0001] The invention belongs to the field of immunotherapy, and relates to a modified hinge region and its application in constructing a CAR framework, in particular to a hinge region capable of prolonging the persistence of CAR-T cells in vivo and / or improving the ability of CAR-T cells to infiltrate tumors And its application in constructing CAR skeleton. Background technique [0002] Chimeric antigen receptor (CAR) is an artificial receptor that mimics the function of TCR, including antigen recognition domain, hinge region, transmembrane region and intracellular signaling domain. The intracellular signaling domain is usually CD3ζ chain or FcRγ, or linked to one or more co-stimulatory molecules, such as 4-1BB (CD137), CD28, ICOS (CD278). When the antigen (receptor) on the surface of the tumor cell binds to the antibody (ligand) of the chimeric antigen receptor, the signal is transmitted into the cell through the hinge region and the transmembrane region, a...

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Problems solved by technology

However, even for acute lymphoblastic leukemia (ALL) with significant treatment effect, the median time of complete remission after treatment is generally about 8 months, and a large number of patients still relapse, which may be related to the short duration of CAR-T cells in patients. , Improving the duration of CAR-T in vivo is of great significance for the efficacy of CAR-T therapy

[0004] Although the use of CAR-T in the study of solid tumors has also been paid more and more attention, the effect of most CAR-T in the treatment of solid tumors is not satisfactory. Death soon affects the effectiveness of killing; on the other hand, most solid tumors will limit the control and killing of the immune system in many aspects due to their pluripotency in metabolism, immune escape, and tissue formation, resulting in CAR-T cells It is difficult to infiltrate into the tumor tissue of solid tumors, so CAR-T therapy for large solid tumors has little effect

Prolonging the persistence of CAR-T in vivo, promoting the infiltration of CAR-T cells in solid tumor tissues, can effectively kill tumors and inhibit the recurrence of tumor cells, but there is no effective way to prolong the persistence of CAR-T in vivo and promote the tumor infiltration of CAR-T cells Methods

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