Multifunctional immune liposome, preparation method and application thereof

An immunoliposome, multi-functional technology, applied in liposome delivery, antibody, pharmaceutical formulation, etc., to achieve the effect of promoting infiltration, promoting tumor cell apoptosis, and enhancing anti-tumor effect

Active Publication Date: 2022-02-11
PEKING UNIV SCHOOL OF STOMATOLOGY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, how to reshape the immunosuppressive TME is still a huge challenge for immunotherapy to achieve the desired effect, and how to reshape the TME and promote the infiltration of CTLs is still a huge challenge for ICBs to achieve the maximum benefit

Method used

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  • Multifunctional immune liposome, preparation method and application thereof
  • Multifunctional immune liposome, preparation method and application thereof
  • Multifunctional immune liposome, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1 Preparation and Characterization of CAR@aCD47 / aPDL1-SSL

[0047] Materials: Lecithin (soybean) (SPC), cholesterol, 2,2'-[propane-2,2-diylbis-(thio)]diacetic acid, pimelic acid, 1-ethyl-3-(3 -(Dimethylamino)propyl)-carbodiimide (EDC) and N-hydroxy-succinimide (NHS) were both purchased from SigmaAldrich (St. Louis, USA). Coumarin (C6) was purchased from Aladdin Biochemical Technology Co., Ltd. (Shanghai, China). DSPE-PEG2000 (distearoylphosphatidylethanolamine-methoxy-polyethylene glycol) and DSPE-PEG2000-NHS (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[succinate Imide (polyethylene glycol)] was purchased from Corden Pharm (Eichenweg, Switzerland). CD47 (aCD47) antibody (clone: ​​miap301) and PDL1 (aPDL1) antibody (clone: ​​10F.9G2) were purchased from Bio XCell (West Belgium, NH, USA).

[0048] Cell lines and animals: The mouse melanoma cell line (B16F10) was purchased from the Cell Resource Center of the Chinese Academy of Medical Sciences. B16F10 c...

Embodiment 2

[0068] Example 2 The immune response induced by aCD47

[0069] The CD47 / SIRP-α pathway ("don't eat me" pathway) is considered to be an important mechanism for tumor cells to evade innate immune surveillance. However, innate immune cells including macrophages and dendritic cells (DCs) play important roles in antigen presentation and T lymphocyte activation. To verify whether aCD47 can effectively block the "don't eat me" pathway, and whether it can promote the infiltration of macrophages, DCs into tumor tissue, and activate T lymphocytes. We prepared aCD47-SSL and injected it intravenously into tumor-bearing mice.

[0070] Compared with IgG-SSL, aCD47-SSL can significantly promote the infiltration of phagocytic cells such as macrophages and DCs into tumor tissues ( Figure 4 a). Mature dendritic cells play an important role in antigen presentation and T lymphocyte activation.

[0071] Therefore, in order to further evaluate the effect of aCD47-SSL action, we further inves...

Embodiment 3

[0073] Example 3 aCD47 / aPDL1-SSL removes excess ROS in TME

[0074] ROS levels in TME:

[0075] To detect the ROS level in TME after aCD47 / aPDL1-SSL treatment, we first established a tumor-bearing animal model. C57BL / 6 (6-8 weeks old, 20g / b) mice were subcutaneously injected with B16F10 cells in the right anterior armpit at a density of 1×10 6 . When the tumor volume reaches 100mm 3 When the tumor-bearing mice were divided into two groups, aCD47 / aPDL1-SSL and aCD47-aPDL1-SSL (control group) were intravenously injected respectively (molaCD47:molaPDL1=1:1, aPDL1:1mg / kg. Flow cytometry (FACSCalibur; BD Biosciences, USA)) Detection of ROS levels in tumor tissues collected from mice treated with aCD47 / aPDL1-SSL or aCD47-aPDL1-SSL by CellROX Deep Red kit (Invitrogen, USA) and confocal laser scanning Microscopy (CLSM) (A1Rsi; Nikon, Tokyo, Japan).

[0076] Infiltration of immune cells in tumor tissue:

[0077]In order to study the infiltration of different immune cells in tum...

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Abstract

The invention discloses a multifunctional immune liposome (CAR@aCD47/aPDL1-SSL) which wraps an adrenergic receptor blocker-carvedilol (CAR) and is connected in series with an aCD47 antibody and an aPDL1 antibody on the surface of the liposome through an ROS sensitive joint. The invention also discloses a preparation method and application of the multifunctional immune liposome. According to the invention, the ROS sensitive joint not only can control the sequential release of antibodies aCD47 and aPDL1 on the surface of the liposome, but also can remove ROS in TME; the CAR can block tumor adrenergic nerve fibers, so that angiogenesis in tumor tissues is inhibited, immunosuppressive TME is remodeled, infiltration of T lymphocytes to the tumor tissues is promoted, and the anti-tumor effect is enhanced; and the adrenergic nerve blocker is innovatively applied to immunotherapy, and the effects of inhibiting in-situ tumors and metastatic tumors at the same time and inhibiting tumor metastasis can be achieved.

Description

technical field [0001] The invention relates to a multifunctional immune liposome and its preparation method and application, belonging to the field of multifunctional immune liposome delivery system, in particular to a kind of encapsulated adrenergic receptor blocker-carvedilol (CAR ), and a multifunctional immune liposome in series with aCD47 and aPDL1 antibodies on the surface of the liposome through a ROS sensitive linker and its preparation method and application. Background technique [0002] Immunosuppressive tumor microenvironment (TME) is an important factor affecting the efficacy of drug antitumor therapy. Immunosuppressive TME can suppress the effects of immune checkpoint inhibitors (ICBs) such as anti-PD-L1 (aPDL1) and anti-PD-1 (aPD1) by inhibiting the infiltration of T lymphocytes into tumor tissues. Immunosuppressive TME contains excess reactive oxygen species (ROS), and ROS is closely related to immunosuppressive response and tumor development. In addition,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/69A61K47/54A61K39/395A61K31/403A61P35/00A61P35/04A61K47/68
CPCA61K31/403A61K47/6913A61P35/00A61P35/04A61K39/39558A61K47/542A61K47/6851A61K2039/507A61K2300/00Y02P20/55
Inventor 魏世成黑玉熊春阳苏晓东
Owner PEKING UNIV SCHOOL OF STOMATOLOGY
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