Attenuated virus vector system, application of attenuated virus vector system in preparation of anti-malignant tumor drugs and drug use method

A technology of attenuated virus and carrier system, which is applied in the field of biomedicine and can solve problems such as drug resistance

Inactive Publication Date: 2019-12-13
董春升
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] While cure rates for several malignancies have now been dramatically improved through decades of research into the development of new technologies and therapies in cancer treatment, outcomes for patients with advanced solid tumors have remained brutally unchanged over the past few decades , which emphasizes the need for new therapies. Antibodies against tumor immune checkpoints, such as PD-1 / PD-L1 and CTLA4, have been put into clinical use in solid tumors. These monoclonal antibodies that effectively antagonize immune checkpoint molecules The key point is the effective production capacity per unit volume. In addition, the problem of drug resistance of immune checkpoint antibodies needs to be solved urgently. The current research progress of tumor immunotherapy has attracted the attention of various countries

Method used

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  • Attenuated virus vector system, application of attenuated virus vector system in preparation of anti-malignant tumor drugs and drug use method
  • Attenuated virus vector system, application of attenuated virus vector system in preparation of anti-malignant tumor drugs and drug use method
  • Attenuated virus vector system, application of attenuated virus vector system in preparation of anti-malignant tumor drugs and drug use method

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Effect test

Embodiment 1

[0048] This embodiment provides an attenuated virus vector system, the virus is an RNA virus, the genetic material of the virus does not have the ability to integrate in mammalian cells, the virus is Rhabdoviridae, vesicular stomatitis virus, the virus Molecules encoded by chimeric structural genes of the carrier system include at least one specific inhibitor for immune checkpoint molecules.

[0049] Preferably, the vesicular stomatitis virus is an attenuated mutant strain, wherein the 51st amino acid of the M gene undergoes a M->R mutation, and the point mutation includes at least one or more point mutations in the M gene of the virus.

[0050] Preferably, antibodies and antibody analogs of immune checkpoint molecules on the cell surface are one or more of single-chain antibodies, single-domain antibodies, bifunctional single-chain antibodies or multifunctional single-domain antibodies, and the antibodies and antibody analogs The immune checkpoint molecules are abnormally exp...

Embodiment 2

[0061] This embodiment provides an application of an attenuated virus vector system in the preparation of anti-cancer drugs, which includes the above-mentioned attenuated virus vector system.

[0062] Preferably, the active substance in the medicine also includes one or more of clofibrate, choline, methionine, nicotinic acid or ursodeoxycholic acid.

[0063] Preferably, the drug also includes one or more oncolytic viruses or corresponding attenuated strains of vaccinia virus, herpes virus, measles virus, Newcastle disease virus, alphavirus, parvovirus and enterovirus strains.

[0064] In yet another aspect, this embodiment also provides an application of an attenuated virus vector system in drugs for killing abnormally proliferative cells, inducing and promoting anti-tumor immune responses, or eliminating immunosuppression in tumor tissue microenvironments, and the drugs are at least Said attenuated viral vector system is included.

[0065] Preferably, the abnormal proliferat...

Embodiment example 3

[0082] Example 3: In this example, the treatment of rectal cancer in mice by oncolytic virus VSV-scFv-PD-L1 is described in detail.

[0083] The first is the establishment of a mouse colorectal cancer model, such as Figure 7 As shown in A, each CB7BL / 6 was subcutaneously inoculated with 2.0*10^5 (200uL) MC38 colon cancer cells. The tumor size was measured every other day and calculated according to the following formula: M12*M2 / 2 (M1: short diameter, M2: long diameter). After the tumor volume of mice in each group grew more than 50mm3, 107PFU (20ul) intratumoral injection of virus was given on day7, day9 and day11 respectively, and the changes in tumor volume were continuously observed and recorded.

[0084] Pharmacodynamic performance testing of VSV-scFV-PDL1 immunotherapy, such as Figure 7 As shown in B, similar to non-small cell lung cancer in mice, oncolytic virus-loaded PD-L1 single-chain antibody treatment, compared with control virus VSV-M51R treatment, can effectiv...

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Abstract

The invention discloses an attenuated virus vector system, an application of the attenuated virus vector system in preparation of anti-malignant tumor drugs and a drug use method. The virus is RNA virus, its genetic material does not have integration capability in the mammalian cells, and the virus belongs to the field of rhabdoviridae and vesicular stomatitis viruses. The virus vector system structure gene chimeric coding molecule at least comprises an inhibitor specific to an immune checkpoint molecule, the attenuated virus vector system is a novel recombinant expression vector system for chimeric expression of a single-chain antibody aiming at an immune checkpoint, the replication can be specifically completed in tumor cells, and meanwhile, specific antibodies secreting molecules binding to the surfaces of the tumor cells can be expressed, the tumor antigen is released, the anti-tumor specific immune response of immune cells is activated at the same time, meanwhile, the secreted single-chain antibody breaks the immunosuppressive effect of the tumor microenvironment, the removal of CTL cells to tumor cells is promoted, a systematic specific anti-tumor immune memory reaction of anorganism is promoted, and the recurrence of tumors is controlled.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to an attenuated virus vector system and its application in the preparation of anti-malignant medicaments and a method for using the medicaments. Background technique [0002] The range of treatment options available to cancer patients has changed dramatically over the past decade. With the understanding of driver mutations related to tumor growth and development, coupled with the development of these specific mutation-targeted molecular inhibitors, a new field of tumor treatment, namely precision oncology, has emerged. Tumor immunotherapy The theoretical basis is that the immune system has the ability to recognize tumor-associated antigens and regulate the body's ability to attack tumor cells (highly specific cytolysis). This biological process is very complex and is still under a lot of basic research. [0003] In the 1990s, several scientific research groups have discovered tumor ant...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/86A61K39/395A61K35/766A61K45/06A61P35/00A61P35/02A61P35/04
CPCA61K35/766A61K39/39558A61K45/06A61K2039/5254A61K2039/5256A61P35/00A61P35/02A61P35/04C12N15/86C12N2760/20243C12N2800/107A61K2300/00
Inventor 董春升
Owner 董春升
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