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Tumor treatment drug

An anti-tumor drug and drug technology, applied in anti-tumor drugs, drug combinations, microorganisms, etc., can solve the problems of low cure rate, inability to successfully package, and inability to prepare recombinant viruses, and achieve the effect of strong adaptability

Active Publication Date: 2020-07-31
JOINT BIOSCIENCES (SH) LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when using VSV in combination with PD-1 or PD-L1 antibodies for tumor immunotherapy, there are still at least the following problems: (1) Directly combining wild or attenuated VSV strains with PD-1 or PD-L1 antibodies, The cure rate is not high, and compared with using one therapy alone, the effect is not significantly improved; (2) Wild-type VSV still has certain safety risks, and it is currently known to have strong neurotoxicity to rodents, so it is considered for clinical use , it needs to be genetically modified to further reduce the risk of pathogenicity and improve the efficiency of treatment; (3) If genetic modification is carried out randomly, it may lead to poor oncolytic effect, or it may not be successfully packaged, and recombinant virus cannot be prepared at all

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: Construction and effect display of attenuated strains with site-directed mutation

[0079] 1. According to the manner in Table 1, the M matrix protein of the Indiana strain of vesicular stomatitis virus was subjected to site-directed mutation to obtain three groups of mutated attenuated strains. The group number without gene mutation is: JBS000, as a control.

[0080] Table 1 The mutation status of each group

[0081]

[0082] The specific construction method of the attenuated strain is a conventional technique in the art, which is briefly described as follows:

[0083] (1) Construct the plasmid. Using the pVSV-XN2 plasmid as a template, the PCR method was used to introduce different mutation sites as described in Table 1. PCR was performed on the plasmid and primers for each mutation site, and then the PCR product was subjected to 1% agarose gel electrophoresis, and then the gel recovery kit was used for gel recovery to obtain plasmids with different m...

Embodiment 2

[0104] Example 2: Construction and effect display of oncolytic virus vaccine

[0105] 1. On the basis of each attenuated strain and wild-type virus prepared in Example 1, insert the NY-ESO-1 gene to construct an oncolytic virus vaccine. The construction schematic diagram is as follows Figure 5 shown. The insert fragments of each group are shown in Table 2.

[0106] Table 2 Display table of insert fragments in each group

[0107]

[0108] The specific preparation methods of JBS004-JBS007 are conventional techniques in the field, and are briefly described as follows. It should be noted that the following description does not limit JBS004 to JBS007 to be carried out according to the following method, but gives an example.

[0109] (1) Construction of attenuated strain plasmid. Artificially synthesized linking sequences with restriction enzyme sites Xho I and Mlu I, using biological technology and gene recombination technology, insert it into the non-coding between the G p...

Embodiment 3

[0126] Example 3: The pharmacokinetics and acute toxicity test results of JBS004

[0127] 1. Pharmacokinetic experiment. Select C57BL / 6 mice and subcutaneously inoculate 2×10 5 LLC cells, about 9 days after inoculation, the transplanted tumor grows to 100mm 3 Left and right, the LLC xenograft tumor model was established. Single intratumoral injection of 10 8 pfu / only JBS004, tumor tissue samples were taken at 0min (+15min), 6h, 12h, 48h, 96h, 120h and 14 days (repeat 3 times), the tissue was crushed with an automatic grinder, and the tumor tissue was extracted by Trizol The total RNA was finally analyzed by quantitative PCR (fluorescent probe method) for viral nucleic acid copy number. The result is as Figure 19 , 20 shown.

[0128] The results showed that the amount of virus in the tumor reached its peak at 6 hours after infection, which was about 500 times more than the initial dose; 48 hours after infection, the amount of virus began to be lower than the initial in...

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Abstract

The invention belongs to the field of biotechnology, and particularly relates to an oncolytic virus vaccine and a tumor treatment drug combing oncolytic virus vaccine with an immune checkpoint inhibitor. A brand-new oncolytic virus attenuated strain is provided by site-directed mutagenesis of wild-type virus matrix protein M of VSV (vesicular stomatitis virus). The attenuated strain can be used asa drug alone to treat tumors, and has safety and cure rate higher than those of wild-type viruses and other known attenuated strains. On the basis of the oncolytic virus attenuated strain, a vaccinethat can be used in tumor treatment is also provided by inserting NY-ESO-1 into the attenuated strain. The vaccine has high cure rate and high biological safety. On the basis of the vaccine, the invention also combines the vaccine with the immune checkpoint inhibitor to provide the drug capable of efficiently treating various tumors. In mouse lung cancer models, the cure rate can be astonishing, up to 87.5%, and the treatment effect on large tumors is also good.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to a medicine for treating tumors. Background technique [0002] According to the national cancer statistics released by the National Cancer Center in January 2019, there were about 3.929 million cancer cases and 2.338 million deaths in 2015. On average, more than 10,000 people are diagnosed with cancer every day, and 7.5 people are diagnosed with cancer every minute. Solid tumors such as liver cancer, colorectal cancer, and female breast cancer are still the main malignant tumors in my country. Malignant tumors (cancers) have become one of the major public health problems that seriously threaten the health of the Chinese population. Although the current cancer treatment has made great progress in multidisciplinary comprehensive treatment such as surgery, chemotherapy, radiotherapy and molecular targeted therapy, there is still no effective treatment for tumor recurrence a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61K35/766A61K39/00A61P35/00C12N15/47
CPCA61K35/766A61K39/3955A61K39/395A61K39/0011A61K39/001188A61P35/00C07K14/005C12N2760/20222A61K2039/505A61K2039/585A61K2039/876A61K2039/86A61K2300/00Y02A50/30C07K16/2818A61K39/39541A61K2039/545C12N2760/20243C12N2760/20232A61K45/06A61K2039/5254A61K2039/5256A61P17/00A61P11/00C12N2760/20234C12N2760/20262
Inventor 周国庆张译文张凡
Owner JOINT BIOSCIENCES (SH) LTD
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