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Monocytes and macrophages with solid tumor-directed chemotaxis ability expressing chemokine receptors, and preparation and application thereof

A chemokine receptor, monocyte-macrophage technology, applied in the field of monocytes and macrophages, can solve the problem of difficult delivery of immune cells, improve specific killing efficiency and utilization, reduce non-specific Immunity to attack effects

Active Publication Date: 2022-07-12
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example, glioblastoma (GBM) is located inside the brain of the body and is hindered by the blood-brain barrier and extracellular dense matrix. Traditional adoptive transplantation of immune cells is often difficult to deliver to the tumor lesion

Method used

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  • Monocytes and macrophages with solid tumor-directed chemotaxis ability expressing chemokine receptors, and preparation and application thereof
  • Monocytes and macrophages with solid tumor-directed chemotaxis ability expressing chemokine receptors, and preparation and application thereof
  • Monocytes and macrophages with solid tumor-directed chemotaxis ability expressing chemokine receptors, and preparation and application thereof

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preparation example Construction

[0053] In a second aspect, the present invention provides a method for preparing macrophages, comprising the steps of: constructing a lentiviral expression system containing a chemokine receptor gene, and using the lentiviral expression system to integrate the chemokine receptor gene into multiple From stem cells or monocyte-macrophages, macrophages are prepared after induction and differentiation;

[0054] Preferably, the pluripotent stem cells are first induced to differentiate into monocytes, and then differentiated into macrophages.

[0055] The strategy of stably expressing the receptor CCR2B, which recognizes the chemokine CCL2 secreted by solid tumor cells, in the adoptive transplant iMAC / Macrophage through the lentiviral expression system can endow the immune cells with three abilities in clinical treatment: 1. Significantly improve their ability to The ability of chemotaxis and migration to solid tumors that can secrete chemokines such as GBM, thereby enhancing the sp...

Embodiment 1

[0067] Example 1 Secretion of chemokine CCL2 in different solid tumor cells

[0068] Analysis of data from the cancer cell database CCLE (Cancer Cell Line Encyclopedia) revealed that solid tumors, including GBM, mesothelioma, and renal cancer, secrete higher levels of the chemokine CCL2.

[0069] Further data mining and comparison of the database are carried out, and the results are as follows figure 1 As shown in A, it was found that the level of CCL2 secreted by GBM was significantly higher than that in normal brain tissue.

[0070] GBM cell lines (U87MG, U251 and LN229), ovarian cancer cell lines (OVCAR8 and HO-8910) and blood mononuclear macrophages (THP1) were cultured in vitro, and ELISA experiments were performed on the above cells respectively. The results are as follows figure 1 As shown in B, it can be seen that GBM cell lines (U87MG, U251 and LN229) highly express the chemokine CCL2, and its expression level is significantly higher than that of ovarian cancer cell ...

Embodiment 2

[0082] Inject 1 x 10 subcutaneously in the ventral side of immunodeficient NSG mice 6 A U87MG cell with the luciferase gene. After tumor formation, 1 × 10 were injected through the tail vein. 6 iMAC and T lymphocytes with fluorescent dyes. Five days later, in vivo imaging of mice showed that both iMAC and T lymphocytes that did not express the chemokine receptor CCR2B were concentrated in the liver of mice, and neither had the ability to migrate to the GBM site ( figure 2 ).

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Abstract

The present invention provides monocytes and macrophages expressing chemokine receptors and having solid tumor-directed chemotaxis ability, as well as preparation and application thereof, and relates to the field of biotechnology. The present invention provides a macrophage, which overexpresses chemokine receptors, has the ability to chemotactically migrate to solid tumors, and has significant chemotactic migration and infiltration effects to tumors, and can improve adoptive transplantation macrophages. The specific killing efficiency and utilization rate of cells reduce the non-specific immune attack on normal tissues. The present invention provides a method for preparing macrophages, including constructing a lentivirus expression system containing chemokine receptor genes, and using the lentivirus expression system to integrate the chemokine receptor genes into pluripotent stem cells or mononuclear macrophages In the cells, macrophages are prepared after induced differentiation, and the macrophages can stably overexpress chemokine receptors for a long time.

Description

technical field [0001] The present invention relates to the field of biotechnology, in particular to a monocyte and macrophage expressing chemokine receptors and having solid tumor-directed chemotaxis ability, and preparation and application thereof. Background technique [0002] CAR-T is a new type of precise targeted therapy for the treatment of tumors. It has a good therapeutic effect in hematological tumors. However, due to the influence of off-target effects and tumor microenvironment inhibitory factors, it is widely used in the treatment of various solid tumors. Still not ideal. Therefore, there is an urgent need to find more effective and safe alternatives for immunotherapy against solid tumors. Due to its central role in the interaction between the adoptive immune system and the innate immune system, and its strong plasticity and long-term persistence in tumor tissues, Macrophage is becoming a new option for solid tumor immune cell therapy. choose. In addition, st...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12N5/10C12N15/12C12N15/867A61K39/00A61P35/00
CPCC07K14/7158C12N15/86C12N5/0645A61K39/0011A61P35/00C12N2506/115C12N2510/00C12N2740/15043A61K2039/80A61K2039/884A61K2039/812A61K2039/82A61K2039/86
Inventor 张进雷安华朱萌濛
Owner ZHEJIANG UNIV
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