CN118045167A - Anti-tumor composite vaccine - Google Patents
Anti-tumor composite vaccine Download PDFInfo
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- CN118045167A CN118045167A CN202410179247.8A CN202410179247A CN118045167A CN 118045167 A CN118045167 A CN 118045167A CN 202410179247 A CN202410179247 A CN 202410179247A CN 118045167 A CN118045167 A CN 118045167A
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention discloses application of more than three of the following microorganisms in preparation of an anti-tumor composite vaccine: pertussis, typhoid bacillus, paratyphoid bacillus a, paratyphoid bacillus b, staphylococcus aureus, listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, pertussis, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes. The anti-tumor composite vaccine has broad spectrum, safety and no toxicity, and has clinical application prospect.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a broad-spectrum anti-tumor composite vaccine.
Background
In recent years, with the rapid development of Tumor Microenvironments (TMEs) and tumor microbiome studies in the medical community, and the good anti-tumor prospects exhibited by Immune Checkpoint Inhibitors (ICI) and chimeric antigen receptor-T cells (CAR-T) in clinical applications, new strategies for treating tumors by bacteria and bacterial components have attracted increasing attention and research.
As early as the 80 s of the last century, our country began to explore the use of bacteria to treat tumors, and found that bacterial vaccines alone were not therapeutic. Therefore, the inventor Wang Zhenyi of the famous blood tumor specialist in China and the worldwide application of induced differentiation therapy for treating acute promyelocytic leukemia propose that the idea of resisting cancer must be changed, and the research subjects for treating tumors by combining bacterial vaccines are developed together with doctors such as Kong Runlian, xu Kecheng and the like by proposing to start from improving the whole immunity of the organism and to implement multi-target immune attack, namely 'multi-component multi-target effect'. Referring to patent documents CN101569746A, CN101628114B, CN106667907A and CN112618581A, the mechanism of treating tumors by combining microorganism vaccines (also called composite vaccines and combined bacterial vaccines) is summarized by organically combining the uniqueness and targeting of different microorganism vaccines, and the organism is stimulated by all directions and multiple targets to generate various nonspecific antibodies and comprehensive immunity, so that the development and even elimination of cancer cells with different types, complex physiological properties and various types are resisted flexibly, broad-spectrum immunity is generated, the extremely heterogeneous nature, dynamic nature and good denaturation of cancers are effectively resisted, and the overall treatment effect of nonspecific resisting tumors is achieved. Referring to literature Therapeutic bacteria to combat cancer;current advances,challenges,and opportunities.Sedighi,Mansour,et al.,[J].Cancer Medicine,2019,8(6):3167-3181.doi:10.1002/cam4.2148., literature Recent advances in bacteria-mediated cancer therapy.Frontiers in Bioengineering and Biotechnology 2022,10https://doi.org/10.3389/fbioe.2022.1026248. and the like, many clinical research results in the medical community have also demonstrated the scientific and clinical application prospects of the combined bacterial vaccine for treating tumors.
Disclosure of Invention
The inventor continuously continues the anti-tumor research of Wang Zhenyi subject group from 1990, is dedicated to the actual clinical application of broad-spectrum anti-tumor composite vaccine, continuously optimizes the composition scheme of composite vaccine preparation, and forms the composite microbial vaccine preparation which has obvious treatment effect on various malignant tumors and is safe and free from toxic and side effects through animal experiments by cooperating with Shanghai medical institute, shanghai Biochemical institute of China academy of sciences and Shanghai drug institute of China academy of sciences. Based on the research results, the invention comprises the following technical proposal.
The first aspect of the present invention is to provide the use of the following microorganisms in the preparation of an anti-tumor composite vaccine comprising a combination of three or more microorganisms: pertussis, typhoid bacillus, paratyphoid bacillus a, paratyphoid bacillus b, staphylococcus aureus, listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, pertussis, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes.
To emphasize the immune effects of these microorganisms and their role as pharmaceutically active ingredients (vaccine active ingredients) in composite vaccine formulations, these microorganisms are sometimes referred to herein as "bacterial vaccines" or "vaccine bacteria".
In a second aspect, the present invention provides an antitumor composite vaccine, wherein the pharmaceutically active ingredient (vaccine active ingredient) comprises, more preferably consists of, an inactivated preparation of the following three microorganisms: pertussis bacillus, typhoid bacillus and staphylococcus aureus; or alternatively
An antitumor compound vaccine, the pharmaceutical active ingredients (vaccine active ingredients) of which comprise, besides pertussis bacillus, typhoid bacillus and staphylococcus aureus, paratyphoid bacillus A and paratyphoid bacillus B, namely, the pharmaceutical active ingredients (vaccine active ingredients) of which comprise, more preferably consist of, the following five microbial inactivation preparations: pertussis bacillus, typhoid bacillus, paratyphoid bacillus a, paratyphoid bacillus b and staphylococcus aureus; or alternatively
An antitumor compound vaccine, the pharmaceutical active ingredients (vaccine active ingredients) of which comprise, more preferably consist of, the following nine microorganism inactivated preparations: listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, bai-sha, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes.
The inactivation reagent is an inactivation product of a microorganism suspension, for example, a physiological saline suspension or a PBS buffer solution (phosphate buffer solution) suspension for injection of a microorganism.
As is well known to those skilled in the art, the inactivation method of the microbial suspension is preferably a physical method inactivation, including heat inactivation, for example, at 121℃for about 15min to 20min, or UV inactivation, or a combination of heat inactivation and UV inactivation.
In one embodiment, the suspensions of different microorganisms are individually inactivated; or alternatively
Mixing the suspension of different microorganisms and inactivating the suspension; or alternatively
The suspension of different microorganisms is inactivated after mixing with the vaccine dressing/adjuvant.
Alternatively, the concentration of the suspension of each microorganism before inactivation is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL), respectively. Namely:
The concentration of the suspension of the bordetella pertussis is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The suspension concentration of the typhoid bacillus is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The suspension concentration of paratyphi A is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The concentration of the suspension of the paratyphoid bacillus B is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL);
The suspension concentration of staphylococcus aureus is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The concentration of the suspension of Listeria is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL);
The concentration of the suspension of Escherichia coli is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL);
The suspension concentration of Proteus is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The suspension concentration of the lactobacillus is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The suspension concentration of bifidobacterium longum is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The concentration of the suspension of the hectorite is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3×10 10/mL to 5×10 10/mL);
The concentration of the suspension of Clostridium acetobutylicum is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL);
The concentration of the suspension of Salmonella typhimurium is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL);
The concentration of the suspension of Streptococcus pyogenes is 10-100 hundred million cells/mL (10 10-11/mL), preferably 30-50 hundred million cells/mL (3X 10 10/mL to 5X 10 10/mL).
Preferably, the anti-tumor composite vaccine is in the form of injection selected from subcutaneous injection and intramuscular injection. Subcutaneous injections and intramuscular injections (intramuscular injections) are preferred because of simple use, convenient and rapid operation, and easy handling.
Further, the above-mentioned antitumor composite vaccine is a pharmaceutical composition comprising, in addition to a microbial inactivation formulation as a pharmaceutical active ingredient (vaccine active ingredient), a pharmaceutically acceptable dressing/adjuvant for injectable vaccine, which includes, but is not limited to, the following: poly inosinic acid (polyI: C), dextran, lecithin, oil for injection, vitamin A, aluminum stearate, CMC-Na (sodium carboxymethyl cellulose, medical grade, viscosity 800-1200), fat emulsion for injection, span-20, etc.
In a preferred embodiment, the above-mentioned antitumor composite vaccine is selected from the following formulations:
Formula I: 8-15v/v%, preferably 10-12v/v%, 5-15v/v%, preferably 8-10v/v% of an inactivated preparation of Bacillus typhi, 5-15v/v%, preferably 8-10v/v% of an inactivated preparation of Staphylococcus aureus, 0.05-0.5wt%, preferably 0.1-0.2wt%, 3-10wt%, preferably 5-8wt% of poly inosinic acid (polyI: C), the balance of physiological saline being used to make up 100 wt%;
And the formula II: the inactivated preparation of the pertussis is 6-15v/v%, preferably 8-10v/v%, the inactivated preparation of the typhoid bacillus is 8-15v/v%, preferably 10-12v/v%, the inactivated preparation of the paratyphoid bacillus A is 2-8v/v%, preferably 3-5v/v%, the inactivated preparation of the paratyphoid bacillus B is 2-8v/v%, preferably 3-5v/v%, the inactivated preparation of the staphylococcus aureus is 3-10v/v%, preferably 5-8v/v%, poly inosinic acid (polyI:C) is 0.05-0.5wt%, preferably 0.1-0.2wt%, glucan is 5-15wt%, preferably 8-10wt%, and the balance of physiological saline is used for supplementing 100% by weight;
And the formula III: the inactivated preparation of Listeria 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Escherichia coli 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Proteus 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Lactobacillus 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Bifidobacterium longum 3-10v/v%, preferably 5-7 v%, the inactivated preparation of Centipeda 4-10 v%, preferably 6-8v/v%, the inactivated preparation of Clostridium acetobutylicum 1-5v/v%, preferably 2-3v/v%, the inactivated preparation of Salmonella typhimurium 1-5v/v%, preferably 2-3v/v%, the inactivated preparation of Streptococcus pyogenes 0.5-5v/v%, preferably 1-2v/v%, vitamin A0.2-2wt%, preferably 0.5-1wt%, aluminum stearate 1-2wt%, preferably 1-2wt%, CMC-carboxymethyl cellulose sodium (Na-cellulose) and the balance of preferably 1-2-5 wt%, the balance being preferably 1-5.5-5% and the physiological saline for injection.
The percentages of microorganisms in the formulations mentioned herein refer to the weight percent wt% or the volume percent v/v% of the microorganism inactivating agent. For example, 10% of the pertussis in the formulation refers to 10% by weight or 10v/v% of the pertussis inactivated formulation, and so on.
Whereas the specific gravity of physiological saline and PBS buffer for injection is substantially identical to that of water, the specific gravity of fat emulsion for injection is not much different from that of water, and the volume percentage v/v% used herein can be replaced by weight percentage wt%.
It will be understood that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The formula one of the anti-tumor composite vaccine can be as follows: about 10v/v% of the inactivated preparation of bordetella pertussis, about 10v/v% of the inactivated preparation of typhoid bacillus, about 10v/v% of the inactivated preparation of staphylococcus aureus, about 0.1wt% of poly inosinic acid (polyI: C), about 8wt% of dextran, the balance of normal saline being used to make up 100 wt% of formula one, herein; or alternatively
About 11v/v% of the inactivated preparation of bordetella pertussis, about 9v/v% of the inactivated preparation of typhoid bacillus, about 9v/v% of the inactivated preparation of staphylococcus aureus, about 0.2wt% of poly inosinic acid (polyI: C), about 6wt% of dextran, the balance of normal saline being used to make up 100 wt% of formula one B; or alternatively
The inactivated preparation of bordetella pertussis is about 12v/v%, the inactivated preparation of typhoid bacillus about 8v/v%, the inactivated preparation of staphylococcus aureus about 8v/v%, poly inosinic acid (polyI: C) about 0.1wt%, dextran about 7wt%, and the balance of normal saline to make up 100 wt%, referred to herein as formula one C.
The formula II of the anti-tumor composite vaccine can be as follows: about 10v/v% of the inactivated preparation of bordetella pertussis, about 10v/v% of the inactivated preparation of typhoid bacillus, about 3v/v% of the inactivated preparation of paratyphoid bacillus a, about 5v/v% of the inactivated preparation of paratyphoid bacillus b, about 8v/v% of the inactivated preparation of staphylococcus aureus, about 0.1wt% of poly inosinic acid (polyI: C), about 8wt% of dextran, the balance of normal saline being used to make up 100 wt% of formula two a; or alternatively
About 8v/v% of the inactivated preparation of bordetella pertussis, about 12v/v% of the inactivated preparation of typhoid bacillus, about 5v/v% of the inactivated preparation of paratyphoid bacillus a, about 5v/v% of the inactivated preparation of paratyphoid bacillus B, about 5v/v% of the inactivated preparation of staphylococcus aureus, about 0.2wt% of poly inosinic acid (polyI: C), about 10wt% of dextran, the balance of normal saline being used to make up 100 wt% of formula B; or alternatively
About 9v/v% of the inactivated preparation of bordetella pertussis, about 11v/v% of the inactivated preparation of typhoid bacillus, about 4v/v% of the inactivated preparation of paratyphoid bacillus a, about 4v/v% of the inactivated preparation of paratyphoid bacillus b, about 7v/v% of the inactivated preparation of staphylococcus aureus, about 0.1wt% of poly inosinic acid (polyI: C), about 9wt% of dextran, the balance of normal saline being used to make up 100 wt% of formula two C; or alternatively
The inactivated preparation of bordetella pertussis is about 10v/v%, the inactivated preparation of typhoid bacillus about 11v/v%, the inactivated preparation of paratyphoid bacillus about 5v/v%, the inactivated preparation of paratyphoid bacillus about 3v/v%, the inactivated preparation of staphylococcus aureus about 6v/v%, poly inosinic acid (polyI: C) about 0.1wt%, dextran about 10wt%, and the balance of normal saline to make up 100% weight percent, referred to herein as formula two D.
Preferably, formulation one and formulation two are subcutaneous injection or intramuscular injection (intramuscular injection) formulations.
Surprisingly, although formulation one contained only three bacterial vaccines (bordetella pertussis, typhoid bacillus, staphylococcus aureus) and two adjuvants (poly inosinic acid, beta-glucan), it also had broad spectrum anti-tumor function. Compared with the multicomponent composite vaccine in the prior art, the reduction and the saving of the raw material types are beneficial to the standardization and the quality control of the production management of the product, and have economic significance.
The formula III of the anti-tumor composite vaccine can be as follows: about 7v/v% of the inactivated preparation of listeria, about 5v/v% of the inactivated preparation of escherichia coli, about 7v/v% of the inactivated preparation of proteus, about 5v/v% of the inactivated preparation of lactobacillus, about 5v/v% of the inactivated preparation of bifidobacterium longum, about 8v/v% of the inactivated preparation of bai-broken bacteria, about 2.5v/v% of the inactivated preparation of clostridium acetobutylicum, about 2v/v% of the inactivated preparation of salmonella typhimurium, about 1v/v% of the inactivated preparation of streptococcus suppurative, about 0.5wt% of vitamin a, about 1wt% of aluminum stearate, CMC-Na (sodium carboxymethyl cellulose, pharmaceutical grade, viscosity 800-1200), about 5v/v% of fat milk for injection, about 1wt% of span-20, the balance of physiological saline being used to complement 100% by weight, referred to herein as formulation three a; or alternatively
About 5v/v% of an inactivated preparation of listeria, about 7v/v% of an inactivated preparation of escherichia coli, about 5v/v% of an inactivated preparation of proteus, about 7v/v% of an inactivated preparation of lactobacillus, about 7v/v% of an inactivated preparation of bifidobacterium longum, about 6v/v% of an inactivated preparation of clostridium acetobutylicum, about 3v/v% of an inactivated preparation of salmonella typhimurium, about 2v/v% of an inactivated preparation of streptococcus pyogenes, about 0.8wt% of vitamin a, about 1.7wt% of aluminum stearate, CMC-Na (sodium carboxymethyl cellulose, pharmaceutical grade, viscosity 800-1200), about 7v/v% of fat milk for injection, about 2wt% of span-20, the balance of physiological saline being used to complement 100% by weight, referred to herein as formulation tri B; or alternatively
About 6v/v% of the inactivated preparation of listeria, about 6v/v% of the inactivated preparation of escherichia coli, about 6v/v% of the inactivated preparation of proteus, about 6v/v% of the inactivated preparation of lactobacillus, about 6v/v% of the inactivated preparation of bifidobacterium longum, about 7v/v% of the inactivated preparation of clostridium acetobutylicum, about 2v/v% of the inactivated preparation of clostridium acetobutylicum, about 3v/v% of the inactivated preparation of salmonella typhimurium, about 2v/v% of the inactivated preparation of streptococcus suppuration, about 0.9wt% of vitamin a, about 1.5wt% of aluminum stearate, CMC-Na (sodium carboxymethyl cellulose, pharmaceutical grade, viscosity 800-1200), about 6v/v% of fat milk for injection, about 1.5wt% of span-20, and the balance of physiological saline for supplementing 100% by weight, referred to herein as formulation tri-C.
Formulation three may be a subcutaneous injection dosage form or an intramuscular injection (intramuscular injection) dosage form.
In order to avoid possible infection such as septicemia, the anti-tumor composite vaccine of the invention comprises the formula I, the formula II and the formula III which are injection forms, and does not adopt intravenous injection forms reported in the prior art such as patent documents CN101569746A, CN101628114B, CN106667907A and CN112618581A, but adopts safe subcutaneous injection forms or intramuscular injection forms so as to prevent any medical accidents.
It should be understood that the terms "about," "approximately," or "about," when used herein in reference to a numerical feature, mean that the number represented may have an error range or float range of + -10%, + -9%, + -8%, + -6%, or + -5%.
In an alternative embodiment, the anti-tumor composite vaccine can be prepared into a freeze-dried agent, so that the anti-tumor composite vaccine is convenient to store and transport, and can be dissolved into a specified volume or concentration by using sterile double distilled water or physiological saline when in use.
In one embodiment, the tumor in the above-mentioned antitumor composite vaccine is one or a combination of two or more selected from the group consisting of cancers/tumors: malignant epithelial tumors, lymphomas, blastomas, sarcomas, leukemias, basal cell carcinomas, cholangiocarcinomas; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma (GBM); liver cancer; hepatoma; intraepithelial tumors; renal cancer; laryngeal carcinoma; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous carcinoma); lymphomas, including hodgkin's lymphomas and non-hodgkin's lymphomas; melanoma; a myeloma; neuroblastoma; oral cancers (e.g., lips, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancers of the respiratory system; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of urinary system; vulvar cancer; other carcinomas and sarcomas; and B-cell lymphomas (including low grade/follicular non-hodgkin's lymphoma (NHL), small Lymphocytic (SL) NHL, medium grade/follicular NHL, medium grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-dividing NHL, large tumor EHL (bulk DISEASE NHL), mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's s Macroglobulinemia); chronic Lymphocytic Leukemia (CLL); acute Lymphoblastic Leukemia (ALL); hairy cell leukemia; chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with mole-type hamartoma (phakomatoses), oedema (e.g., oedema associated with brain tumors) and migus syndrome.
In one exemplary embodiment, the cancer/tumor is one or a combination of two or more of the following: liver cancer, sarcoma, bladder cancer, prostate cancer, colon cancer, rectal cancer, ovarian cancer, renal cancer, breast cancer, glioblastoma, melanoma, malignant melanoma, or lung cancer.
The novel compound vaccine has high safety, and acute toxicity experiments performed on Wistar rats, SD young rats and Kunming mice show that the subcutaneous injection of the novel compound vaccine is 900-15000 times of the adult dosage, all animals survive, the kidney function is not affected, and no toxic or side effect is observed; in addition, the novel compound vaccine can effectively inhibit the growth and metastasis of tumors such as liver cancer, sarcoma, bladder cancer, melanoma and the like, obviously reduces the weight and volume of solid tumors, embodies the broad spectrum of anti-tumor and shows good clinical application prospect.
Drawings
FIG. 1 shows photographs of a study of the tumor-inhibiting effect of a composite vaccine formulation three A on C57 mice Lewis lung cancer.
FIG. 2 shows a photograph of a study of the tumor-inhibiting effect of compound vaccine formulation A on Lewis lung cancer in C57 mice.
FIG. 3 shows photographs of a study of the tumor-inhibiting effect of composite vaccine formulation two A on C57 mice Lewis lung carcinoma.
FIG. 4 shows photographs of tumor inhibition studies of 7 composite vaccine formulations on BL/6 mice B16 melanoma.
Detailed Description
The novel formula composite vaccine developed by the invention has broad spectrum anti-tumor property, and various mouse tumor models prove that the anti-tumor composite vaccine (comprising formula one and formula two) containing the pertussis bacillus, staphylococcus aureus, typhoid bacillus and/or paratyphoid bacillus A and/or paratyphoid bacillus B can be used for treating solid tumors such as liver cancer, sarcoma, bladder cancer and/or melanoma.
The term "or" as used herein sometimes means "and/or," and the term "or" sometimes means "and/or. The term "and/or" as used in phrases herein such as "a and/or B" is intended to include both a and B; a or B; a (alone); and B (alone).
The terms "anti-tumor composite vaccine", "anti-tumor vaccine", "composite bacterial vaccine", "composite microorganism" and "composite bacterial vaccine" and "composite vaccine" are used herein to mean the same meaning and are used with each other, in particular, to designate a first, a second and a third formulation. For convenience of description, the term "vaccine" may be abbreviated herein.
The composite vaccine of the present invention is preferably administered to a subject by injection, including but not limited to intravenous (iv), intramuscular (im), subcutaneous (ih/sc), intradermal (ic), intraperitoneal (ip), intravenous drip, or intra-tissue injection. Subcutaneous injections (ih/sc) and intramuscular injections (im) are preferred because of simplicity of use, ease of handling and ease of handling.
The term "subject" means a human or animal. Typically, the animal is a vertebrate, such as a primate, rodent, livestock or hunting animal. Primates include chimpanzees, cynomolgus monkeys, spider monkeys, and macaques, e.g., rhesus monkeys. Rodents include mice, rats, woodchuck, ferrets, rabbits, and hamsters. Domestic animals and hunting animals include cattle, horses, pigs, deer, wild cattle, buffalo, feline species (e.g., domestic cats), canine species (e.g., dogs, foxes, wolves). In some embodiments, the subject is a mammal, e.g., a primate such as a human. The terms "individual," "patient," and "subject" are used interchangeably herein. Preferably, the subject is a mammal. The mammal may be a human, non-human primate, mouse, rat, dog, cat, horse or cow, but is not limited to these examples. The subject may be male or female.
It will be readily appreciated by those skilled in the art that the above-described composite vaccines are generally pharmaceutical compositions which may comprise a pharmaceutically acceptable carrier in addition to the various bacterial inactivators of the principal component. Preferably, the carrier is provided with an effective amount of the active ingredient suitable for administration to a subject, suitable for pharmaceutical preservation and transportation, and the like, on the premise of having a freshness retaining effect, i.e., maintaining its biological activity.
For example, when the composite vaccine is a pharmaceutical composition in an injectable form, pharmaceutically acceptable injectable vaccine dressings/adjuvants include, but are not limited to, the following: poly inosinic acid (polyI: C), dextran, lecithin, oil for injection, vitamin A, aluminum stearate, CMC-Na (sodium carboxymethyl cellulose, medical grade, viscosity 800-1200), fat emulsion for injection, span-20, etc.
More preferably, the pharmaceutically acceptable carrier is a substance which can produce a synergistic effect with various bacterial deactivation substances as the main ingredient of the pharmaceutical active ingredient, thereby enhancing the antitumor effect. For example, for either formulation one or formulation two, comparative experiments showed that the combination of dressing poly inosinic acid (polyI: C) +dextran with bordetella pertussis, staphylococcus aureus, typhoid bacillus and/or paratyphoid bacillus A and/or paratyphoid bacillus B produced a synergistic effect.
Polyinosinic acid, collectively referred to as polyinosinic-polycytidylic acid, also known as polyinosinic, is an artificially synthesized double-stranded ribonucleic acid (double-stranded RNA), one strand is ploy (I) and the other strand is poly (C). Polyinosinic acid is an interferon inducer, produces interferon under in vivo cell induction, has antiviral and immunoregulatory functions similar to interferon, and is used for chronic hepatitis B, epidemic hemorrhagic fever, epidemic encephalitis B, viral keratitis, herpes zoster, various warts, respiratory tract infection and the like, so that the polyinosinic acid has broad-spectrum antiviral and immunoregulatory functions, and can be used for the auxiliary treatment of viral infectious diseases and tumors.
Beta-glucan, abbreviated as glucan, is a polysaccharide natural product found in a variety of plants and fungi such as mushrooms, yeasts, algae, and the like. Beta-glucan has many important biological activities and pharmacological actions, called "immune gold", playing an important role in the immune system. It can enhance the activity of immune cells, promote the proliferation and differentiation of immune cells, and improve the recognition and clearance of immune cells to pathogens. In addition, the beta-glucan has various functions of anti-inflammation, anti-tumor, antioxidation and the like, can regulate the function of an immune system and maintain the immune balance, and is widely applied to the fields of medicines, health-care products, food additives and the like.
In an alternative embodiment, the pharmaceutical composition may further comprise another type of anti-tumor drug such as certain nucleic acid molecule (RNA or DNA) drugs or polypeptide drugs without side effects, provided that the biological activity of the bacterial vaccine is not compromised. As used herein, the term "nucleic acid" or "nucleic acid molecule" refers to any molecule, preferably a polymeric molecule, including units of ribonucleic acid, deoxyribonucleic acid, or an analog thereof. The nucleic acid may be single-stranded or double-stranded. The single-stranded nucleic acid may be one strand of denatured double-stranded DNA. Or it may be a single stranded nucleic acid that is not derived from any double stranded DNA. In one aspect, the nucleic acid may be DNA. In another aspect, the nucleic acid may be RNA.
The phrase "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers are well known in the art and include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient, including for example, aqueous solutions (such as water or physiological buffered saline) or other solvents or vehicles (such as glycols, glycerol, oils (such as olive oil) or injectable organic esters). Excipients may be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The pharmaceutical compositions may be in the form of dosage units, such as tablets, capsules (including dispersible capsules and gelatin capsules), granules, powders, solutions, syrups, suppositories, injections and the like. The composition may also be present in a transdermal delivery system (e.g., a skin patch). The composition may also be present in a solution suitable for topical application (e.g. a lotion, cream or ointment).
For example, pharmaceutically acceptable carriers include protein stabilizers, which may be selected from stabilizers commonly used in protein drugs and/or living cell drugs for maintaining protein and/or cell activity, such as at least one of, or a combination of two or more of, including but not limited to, the following: ① buffer: such as sodium citrate-citric acid buffer; ② And (2) a surfactant: such as nonionic surfactants polysorbate; ③ Sugar and polyol: such as sucrose, glucose, trehalose, maltose, glycerol, mannitol, sorbitol, PEG, inositol, and the like; ④ salts: such as sodium chloride; ⑤ Polyethylene glycols; ⑥ Macromolecular compound: such as 2-hydroxypropyl-beta-cyclodextrin, albumin, serum protein (HAS), and the like; ⑦ Histidine, glycine, glutamic acid and lysine hydrochloride, and the like.
The term "effective amount" as used herein refers to the amount of treatment required to reduce the symptoms of cancer or tumor, and relates to a sufficient amount of the pharmaceutical composition to provide the desired effect. Thus, the term "therapeutically effective amount" refers to a therapeutic amount sufficient to cause a particular effect when administered to a typical subject. In various contexts, an effective amount as used herein also includes an amount sufficient to delay the progression of cancer, alter the course of a tumor condition (e.g., without limitation, slow the progression of a cancer condition), or reverse a tumor condition. It should be appreciated that there are many ways known in the art to determine an effective amount for a given application. For example, pharmacological methods for dose determination may be used in a therapeutic setting. In the context of therapeutic or prophylactic applications, the amount of composition administered to a subject will depend on the type and severity of the disease and the characteristics of the individual, such as general health, age, sex, weight and tolerance to drugs. It also depends on the extent, severity and type of the disease. One skilled in the art will be able to determine the appropriate dosage based on these and other factors.
A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the composite vaccine required. For example, a physician or veterinarian may initiate a dose of the composite vaccine at a level below that required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved. "therapeutically effective amount" means a concentration of a compound sufficient to cause a desired therapeutic effect. It is generally understood that the effective amount of the combination vaccine will vary depending on the weight, sex, age and medical history of the subject. Other factors affecting an effective amount may include, but are not limited to, the severity of the patient's cancer condition, the stability of the tumor volume, and, if desired, another type of therapeutic agent administered with the composite vaccine of the present invention. A larger total dose may be delivered by multiple administrations of the agent. Methods of determining efficacy and dosage are known to those skilled in the art.
Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion. "injection" includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intrahepatic, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracerebroventricular and intrasternal injection and infusion. Administration may be systemic or local.
In general, a suitable daily dose of the microbial vaccine used in the combination vaccine compositions and methods of the present invention will be the amount of the combination vaccine that is the lowest dose effective to produce a therapeutic effect on a particular tumor. Such an effective dose will generally depend on the factors described above.
If desired, the effective daily/weekly/monthly dose of the combination vaccine may be administered as one, two, three, four, five, six or more sub-doses administered separately, optionally in unit dosage form, at appropriate time intervals throughout the day. In certain embodiments of the invention, the composite vaccine may be administered twice or three times per day/week/month. In other embodiments, the composite vaccine will be administered once a week/month.
The patient receiving this treatment is any animal in need thereof, including primates (particularly humans); and other mammals (e.g., horses, cattle, pigs, sheep, cats, and dogs); poultry; and in general pets.
When the composite vaccine of the present invention is administered to a subject, a strong immune response is generated in the body, including humoral immune response to generate sufficient virus/bacteria neutralizing antibodies of various classes, and also including induction of cellular immune response to eliminate tumor cells.
The composite vaccine of the invention is not specific to specific cancers such as malignant tumors, but is nonspecific, has broad spectrum, and can be applied to subjects suffering from more than two cancers/tumors simultaneously, so as to reduce or even eliminate cancer cells, or inhibit the progress and metastasis of the cancers, reduce the tumor volume, at least lighten the condition of the cancers, and enable the cancer subjects to live with tumors.
As used herein, the term "cancer" generally refers to a class of diseases or disorders in which abnormal cells divide uncontrollably and can invade nearby tissues. Cancer cells can also spread to other parts of the body through the blood and lymphatic system. There are several major types of cancer. Cancers (malignant epithelial tumors) are cancers that originate from the lining (line) or the skin or tissue covering the internal organs. Sarcomas are cancers that originate in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue. Leukemia is a cancer that begins in hematopoietic tissues (e.g., bone marrow) and results in the production of large numbers of abnormal blood cells and into the blood. Lymphomas and multiple myelomas are derived from cells of the immune system. Central nervous system cancers are cancers that originate in brain and spinal cord tissue.
In some embodiments of any aspect, the cancer is a primary cancer. In some embodiments of any aspect, the cancer is a malignant cancer. As used herein, the term "malignant" refers to cancers in which a group of tumor cells exhibit one or more of uncontrolled growth (i.e., division beyond normal), invasion (i.e., invasion and destruction of adjacent tissues), and metastasis (i.e., spread to other locations of the body by lymph or blood). As used herein, the term "metastasis" refers to the spread of cancer from one part of the body to another. Tumors formed by cells that have spread are referred to as "metastatic tumors" or "metastasis". Metastatic tumors comprise cells similar to those in the primary (primary) tumor.
As used herein, the term "benign" or "non-malignant" refers to a tumor that may grow larger but does not spread to other parts of the body. Benign tumors are self-limiting and generally do not invade or metastasize.
"Cancer cell" or "tumor cell" refers to a single cell of cancerous growth or tissue. Tumors generally refer to tumors or lesions formed by abnormal growth of cells, which may be benign, precancerous, or malignant. Most cancer cells form tumors, but some (e.g., leukemia) do not necessarily form tumors. For those cells that form a tumor, the terms cancer (cell) and tumor (cell) are used interchangeably.
A subject with cancer or tumor is a subject having objectively measurable cancer cells present in the body of the subject. This definition includes malignant, actively proliferating cancers, as well as potentially dormant tumors or micrometastases. Cancers that migrate from their original location and implant other vital organs eventually lead to death of the subject through deterioration of the function of the affected organ. Hematopoietic cancers (e.g., leukemia) can compete with the normal hematopoietic compartment of the subject, resulting in hematopoietic failure (in the form of anemia, thrombocytopenia, and neutropenia), ultimately leading to death.
Examples of cancers include, but are not limited to: malignant epithelial tumors, lymphomas, blastomas, sarcomas, leukemias, basal cell carcinomas, cholangiocarcinomas; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma (GBM); liver cancer; hepatoma; intraepithelial tumors; renal cancer; laryngeal carcinoma; leukemia; liver cancer; lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous carcinoma); lymphomas, including hodgkin's lymphomas and non-hodgkin's lymphomas; melanoma; a myeloma; neuroblastoma; oral cancers (e.g., lips, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancers of the respiratory system; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of urinary system; vulvar cancer; other carcinomas and sarcomas; and B-cell lymphomas (including low grade/follicular non-hodgkin's lymphoma (NHL), small Lymphocytic (SL) NHL, medium grade/follicular NHL, medium grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-dividing NHL, large tumor EHL (bulk DISEASE NHL), mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's s Macroglobulinemia); chronic Lymphocytic Leukemia (CLL); acute Lymphoblastic Leukemia (ALL); hairy cell leukemia; chronic myelogenous leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with mole-type hamartoma (phakomatoses), oedema (e.g., oedema associated with brain tumors) and migus syndrome.
A "cancer cell" is a cancer cell, a pre-cancerous cell, or a transformed cell in vivo, ex vivo, or in tissue culture that has a spontaneous or induced phenotypic change that does not necessarily involve uptake of new genetic material. Although transformation may be caused by infection by the transforming virus and incorporation of new genomic nucleic acid, or uptake of exogenous nucleic acid, it may also occur spontaneously or after exposure to a carcinogen, thereby mutating the endogenous gene. Transformation/cancer involves, for example, morphological changes, cell immortalization, abnormal growth control, lesion formation, non-adherence dependence, malignancy, loss of contact inhibition and growth density limitation, growth factor or serum independence, tumor-specific markers, invasiveness or metastasis, and tumor growth in a suitable animal host (e.g., nude mice).
The subject may be a subject that has been previously diagnosed with or identified as having a disorder (e.g., cancer) or one or more complications associated with such a disorder, in need of treatment, and (optionally but not necessarily) has undergone treatment for a disorder or one or more complications associated with the disorder. Or the subject may be a subject who has not been previously diagnosed as having a condition in need of treatment or one or more complications associated with such a condition. For example, a subject may be a subject that exhibits one or more symptoms risk factors or one or more complications associated with the symptoms, or a subject that does not exhibit a risk factor. A "subject in need of treatment" for a particular disorder may be a subject suffering from, diagnosed with, or at risk of developing the disorder.
The terms "reduce", "decrease" or "inhibit" are used herein to mean a statistically significant amount of decrease. In some embodiments, "reducing," "reducing," or "reducing" or "inhibiting" generally refers to a reduction of at least 10% compared to a reference level (e.g., in the absence of a given treatment or agent), and may include, for example, a reduction of at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or more. As used herein, "reducing" or "inhibition" does not encompass complete inhibition or reduction compared to a reference level. "complete inhibition" is 100% inhibition compared to the reference level. For individuals without a given condition, the decrease may preferably be to an acceptable level within the normal range.
The new compound vaccine of the invention is adopted to carry out more than 60 groups of tumor inhibition experiments on mouse models including liver cancer, sarcoma, bladder cancer, melanoma and the like, the tumor inhibition rate is 25.9-73.7%, and the test tumor inhibition rate of 60% is more than 50%, thus the invention has the broad spectrum of anti-tumor.
As a typical illustration, one of the inventors has diagnosed with intrabiliary cell liver cancer (stage II) in 2006 and received lobe resection. The liver tumor is insensitive to radiotherapy and chemotherapy, and the median survival time of patients is not more than 2 years. The inventor does not receive radiotherapy and chemotherapy, and based on the concept of treating tumors by the composite vaccine constructed by the subject group, the inventor only receives the injection treatment of the composite vaccine as a reagent for up to 2 years. The compound vaccine is similar or identical to the formula in the invention, and the inventor has healthy survival without recrudescence for 18 years, and various physiological indexes are normal at present although the annual situation is high. The sister of the inventor suffers from the same biliary tract cell liver cancer in 2011, but multiple forms of hepatic lymph node metastasis are impossible to remove by surgery, the patient refuses to receive radiotherapy and chemotherapy, and only receives compound vaccine treatment, and in 5 years thereafter, the intrahepatic tumor is once 'disappeared' in imaging, and the patient 'does not live in progress' for 4 years. Moreover, the safety of the injected composite vaccine was also confirmed, and the inventors received the composite vaccine for 1000 times in total, except for local redness and swelling of the skin at the injection site and temporary mild fever (which is necessary for generating immune effect), without any toxic reaction.
Regarding the effectiveness and safety of the composite vaccine of the present invention, the inventors disclosed in document A New Tumor Therapeutic Vaccine:A Real-World Survey on Treatment of 68Patients with Advanced Cancer.Kecheng Xu,et al.,Clinics in Surgery.03Mar,2022,Volume 7,Article 3432. the following facts that the composite vaccine (including the formulation one, formulation two and formulation three of the present invention) was tested in volunteers suffering from tumors:
Tumor Therapeutic Vaccines (TTV) are complexes composed of a variety of bacterial or toxin vaccines plus adjuvants. One of the authors herein is a "volunteer" who received such a composite vaccine TTV. In 2008, the authors herein followed patients with middle and advanced cancer who had used the vaccine mainly 10 years ago. These patients were all advanced tumor patients that proved untreated. Through a visiting gate and telephone inquiry, 38 cases are visited together, and 28 cases still exist during the follow-up visit; survival time is 2-16 years, 23 cases survive for more than 10 years; 10 deaths, only 2 of which die from cancer recurrence. After 2010, the inventors have prospectively observed the efficacy of the composite vaccine for volunteers. The following conditions were met for 68 patients with advanced cancer: (1) Losing the opportunity for surgical treatment and/or losing the patients with radiation and chemotherapy; (2) those with pathological diagnosis; (3) those expected to survive for no more than 1 year. Results: survival time is 8-204 months, median 48 months, and 33 cases still exist at follow-up.
A total of 68 progressive substantial cancer patients received a "real world" investigation, who had failed to receive conventional therapy and had received only TTV injection therapy. Results: the TTV injection treatment is carried out for 3-96 months, and the median time is 24 months; tumor Complete Response (CR) was found in 44.1% of cases, partial Response (PR) 36.7%, stable (SD) 19.1%; from TTV treatment, the total survival of the patient is 8-204 months, median 48 months, and finally 48.5% of the fashionable survivors follow-up. The investigation shows that the simple and safe treatment method can effectively promote tumor recession or stabilize the tumor, prolong the life cycle of patients and treat some cases. TTV is a promising alternative treatment for advanced cancers.
In order to make the invention more comprehensible, preferred embodiments accompanied with figures are described in detail below. It will be appreciated by those skilled in the art that the following examples are provided for illustration of the invention and are not intended to be limiting thereof.
Examples
The amounts, amounts and concentrations of various substances are referred to herein, wherein the percentages refer to percentages by mass unless otherwise specified.
In the examples herein, if no specific explanation is made for the operating temperature, this temperature is generally referred to as room temperature (15-35 ℃).
The various composite vaccine formulations used in the examples were prepared by Shaoxing Yuan biomedical technology Co., ltd, which is available to any unit or individual for the verification of the present invention, but Shaoxing Yuan biomedical technology Co., ltd, which is not used for other purposes, including development and utilization, scientific research and teaching, is not used for the treatment of cancer patients or animals suffering from cancer.
Animal model construction and administration studies used in the examples were carried out by Shanghai medical industry institute Limited.
Statistical analysis: in the study, the numerical variables are all expressed by mean ± standard error, the comparison between two groups adopts a double-tail Student t test, and the comparison between three groups adopts an ANOVA test. Statistical differences were considered when P < 0.05.
Example 1: preparation of composite vaccine
1. Preparation of microorganism inactivating preparation
The suspension inactivating preparation of various microorganisms is prepared according to the technical means well known to the person skilled in the art. The microorganism comprises pertussis bacillus, typhoid bacillus, paratyphoid bacillus A, paratyphoid bacillus B, staphylococcus aureus, listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, pertussis bacteria, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes.
Taking the known escherichia coli, namely escherichia coli as an example, the preparation method of the suspension inactivating preparation can comprise the following steps:
Single colonies were selected from LB plates of E.coli (10 g/L tryptone, 5g/L yeast extract, 10g/L sodium chloride, pH7.2.LB solid medium plus 15g/L agar powder.) and inoculated into 5ml LB medium, and incubated at 37 ℃; inoculating 1% v/v ratio into 1000mL shake flask containing 100mL TB culture medium (24 g/L yeast extract, 12g/L tryptone, 16.43g/L K 2HPO4.3H2O、2.31g/L KH2PO4, 5g/L glycerol, pH 7.0-7.5), culturing at 37deg.C and 220rpm for 20-24 hr, centrifuging to collect bacteria, washing with physiological saline of equal culture medium volume for three times, centrifuging to collect bacteria, suspending with physiological saline, and regulating bacteria concentration to obtain suspension with concentration of 10-100 hundred million cells/mL (10 10-11/mL).
And (3) placing the suspension into a sterilizing pot, and heating at 121 ℃ for about 15min to obtain the inactivated preparation of the escherichia coli.
An inactivated preparation of all microorganisms was prepared in a similar manner.
2. And (3) carrying out heating, pressurizing and sterilizing treatment or bacteria filtering treatment on the solution of the various auxiliary material mixtures to obtain a sterile auxiliary material mixture solution.
According to the proportion content of each component in the formula, mixing the microorganism inactivation preparation and the sterile auxiliary material mixture solution in a preset proportion in a sterile environment such as a clean workbench to obtain the sterile composite vaccine.
The aforementioned formulation one A, formulation one B, formulation one C, formulation two A, formulation two B, formulation two C, formulation two D, formulation three A, formulation three B and formulation three C have been prepared by Shaoxing Yuan biological medicine technology Co. Placing in a refrigerator at 4 ℃ for standby.
Example 2: safety investigation of various composite vaccines
The toxicity studies of all composite vaccines by Shanghai pharmaceutical industry institute Limited were commissioned and demonstrated that all composite vaccines of the present invention, including the formulation prepared in example 1, were safe and non-toxic. The following is a brief description of formulation three A.
Maximum dose experiment (toxicity experiment) of tumor vaccine sample to ICR mice
1. Purpose of test
The tumor vaccine samples were observed for toxic response and mortality resulting from subcutaneous single administration of the shaoxing tumor vaccine samples to ICR mice.
2. Test drug
Sample name: shaoxing more natural tumor vaccine samples.
3. Experimental animal
20 ICR mice, male and female halves, 20+ -2 g, supplied by Shanghai Laek laboratory animal liability Co., ltd., production license number: SCXK (Shanghai) 2017-0005; use license number: SYXK (Shanghai) 2019-0027.
4. Administration method
4.1 Dose: 1 ml/mouse.
4.2 Accepted amount: 1ml.
4.3 Times of administration: 1 time.
5. Route of administration
Subcutaneous administration
6. Preparing a liquid medicine: sample stock solution
7. Test method
10 Female ICR mice were divided into normal groups (n=5), dosing groups (n=5), and were given once subcutaneously at a dose of 1 ml/mouse (maximum volume maximum concentration), and various manifestations of the poisoning symptoms of the animals were observed and dead animals were recorded immediately after the administration. The experiment was observed for 14 days.
10 Male ICR mice, divided into normal (n=5) and unsterilized (n=5) groups, were given subcutaneously once at a dose of 1 ml/mouse (maximum volume maximum concentration), and various manifestations of the poisoning symptoms of the animals were observed and the dead animals were recorded immediately after the administration. The experiment was observed for 14 days.
8. Observation index
Immediately after animal administration, animals were observed for various manifestations and poisoning symptoms, and twice daily (morning and afternoon) during the experiment.
Death: the number of mice dead during the observation period was recorded. The dead animals were immediately cadaverized, and changes in the major organs (heart, liver, spleen, lung, kidney, etc.) of the mice were visually observed, and pathological examination was performed if abnormality was visually observed.
Toxicity reaction: the behavior activity, skin, respiration, urination and defecation, appetite, abnormal secretion of nose, eyes and mouth and the like of female and male mice in the observation period are recorded.
9. Period of observation
All surviving mice were sacrificed at the end of the observation period (14 days), and the animals were tested for the presence of abnormal internal organs by dissection and macro examination.
10. Test results
The present study was designed to observe the toxic response and mortality of the surprise sample from a subcutaneous single administration to ICR mice. The SPF-class ICR mice used in the test were divided into a normal group and an administration group of 20 male and female mice, each group having 10 male and female mice. The sample was given subcutaneously once to ICR mice at a dose of 1 ml/mouse (maximum volume maximum concentration) and observed for 14 days. The test results show that mice are not dead, and adverse reactions such as diet and activity are not generated during the whole observation period. All mice were sacrificed after the end of the observation period and no abnormalities in the internal organs were found in the dissections and macroscopical examination.
TABLE 1 mortality of shaoxing Yuan tumor vaccine sterilized and unsterilized sample mice
11. Conclusion(s)
The tumor vaccine sample is once subcutaneously administered for 1 ml/mouse, no death of the mouse is seen, no obvious toxic reaction experiment is seen in the 14-day observation period, the main viscera of the dissected giant test of the mouse are killed, no abnormality is seen, and the vaccine is safe within the dosage range.
Example 3: research on tumor inhibiting effect of composite vaccine on lung cancer
The compound vaccine prepared in the example 1 has the tumor inhibiting effect on lung cancer proved by the research on lung cancer inhibition of compound vaccine by Shanghai medical industry institute Limited company. Taking formulation three a as an example, the experiment is reported below.
Tumor inhibition research of C57 mouse Lewis lung cancer by using more natural antitumor vaccine
1. Purpose(s)
Test for observing anti-tumor efficacy of Shaoxing Yuan tumor vaccine on Lewis lung cancer of mice
2 Test agent
3.1 Name
Antitumor vaccine
3.3 Preparation method
Subcutaneously injecting tumor vaccine stock solution into the dosage forms of 0.1 ml/dose and 0.2 ml/dose; 0.1 ml/intramuscular injection.
3 Experimental materials
3.1 Positive control
Cisplatin powder injection 10mg/bottle, manufactured by Qilu pharmaceutical Co., ltd., batch No. 0H0484B03.
3.2 Tumor Source
The Lewis lung cancer model is maintained by passage from the Shanghai pharmaceutical industry institute pharmacological research evaluation center.
4. Experimental animal
50C 57BL/6 mice, 20+ -2 g, were obtained from Zhejiang Vetolihua laboratory animal technology Co., ltd. Production license number: SCXK (Zhejiang) 2020-0002. Use license: SYXK (Shanghai) 2019-0027.
5. Dose setting
Subcutaneous stock solution injection 0.1 ml/dose, 0.2 ml/dose; 0.1 ml/intramuscular injection
6. Dosing regimen
1, 4, 7, 10 Days after inoculation, subcutaneously injected.
7. Experimental control
The negative control was given an equivalent volume of physiological saline to the test group of 10 mice each, and the positive control cisplatin DDP6mg/kg was administered once every other day, three times in succession.
8 Main steps of experiment
The growing Lewis cells are taken and inoculated to the axilla of a C57BL/6 mouse to be subcutaneously inoculated with 0.2 ml/mouse (about 1-2 multiplied by 10 6), the following day is dosed according to the experimental design scheme, the experiment is ended on the 15 th day, animals of each group are sacrificed, tumors are dissected and weighed, and the tumor inhibition rate is calculated according to the following formula:
tumor inhibition ratio% = [ (average tumor weight of control group-average tumor weight of administration group)/average tumor weight of control group ] ×100%
9. Experimental results
The experimental results are shown in table 1 and fig. 1. Compared with the negative control group, the tumor inhibition rate of the cisplatin (DDP) group is 80.5%, the tumor inhibition rate of the low dose (0.1 ml/only) is 54.9%, the tumor inhibition rate of the high dose (0.2 ml/only) is 75.2%, and the tumor inhibition rate of the myonote (0.1 ml/only) is 77.0%. The cisplatin group and the intramuscular injection group have higher anti-tumor activity, the weight of the mice in the intramuscular injection group is reduced after the cisplatin group and the intramuscular mice are dosed in the test process, the weight of the mice in the intramuscular injection group is obviously reduced, and the leg injection part affects the normal activity. No significant toxic response was observed in the high and low dose groups, and no death of the animals was seen with normal growth.
TABLE 1 anti-tumor vaccine anti-tumor efficacy experiment
* Vs negative control, p < 0.0001.
Example 4: study on tumor inhibition effect of composite vaccine on lung cancer
The compound vaccine formulation a prepared in example 1 was committed to the study of lung cancer inhibition by Shanghai pharmaceutical industry institute, inc., and differences in vaccine titers of live bacteria and dead bacteria were examined in comparison with live bacteria preparations that did not inactivate the microorganisms pertussis, typhoid bacillus, and staphylococcus aureus. The experiment is reported below.
1. Purpose(s)
Test for observing anti-tumor efficacy of more natural tumor vaccine on Lewis lung cancer of mice
2. Test agent
3.1 Name
Tumor vaccine: 1. non-sterilized, lot number N20230821-00M; 2. sterilizing, and adding lots N20230821-12N
3.3 Preparation method
The more unsterilized, sterilized tumor vaccine stock solutions were injected at 0.1 ml/dose and at 0.2 ml/dose.
3. Experimental materials
3.1 Positive control
Cisplatin powder injection 10mg/bottle, manufactured by Qilu pharmaceutical Co., ltd., batch No. 0H0484B03.
3.2 Tumor Source
The Lewis lung cancer model is maintained by passage from the Shanghai pharmaceutical industry institute pharmacodynamic research evaluation center.
4. Experimental animal
60C 57BL/6 mice, 20+ -2 g, were obtained from Zhejiang Vetolihua laboratory animal technology Co., ltd. Production license number: SCXK (Zhejiang) 2020-0002. Use license: SYXK (Shanghai) 2019-0027.
5. Dose setting
The non-sterilized and sterilized stock solutions were injected at 0.1 ml/dose or 0.2 ml/dose.
6. Dosing regimen
1, 4, 7, 10 Days after inoculation, subcutaneously injected.
7. Experimental control
The negative control was given physiological saline of the same volume and concentration as the high dose of the test group, 10 mice per group, and the positive control cisplatin DDP6mg/kg, once every other day, three times in succession.
8. The main steps of the experiment
The method comprises the steps of taking a tumor source with vigorous growth, subcutaneously inoculating 0.2 ml/dose (about 1-2×10 6) of armpit of a corresponding host, administering according to an experimental design scheme on the next day, killing animals in each group after the experiment is ended on the 13 th day, weighing the tumor by sectioning, and calculating the tumor inhibition rate according to the following formula:
tumor inhibition ratio% = [ (average tumor weight of control group-average tumor weight of administration group)/average tumor weight of control group ] ×100%
9. Experimental results
The experimental results are shown in table 2 and fig. 2. Compared with the negative control group, the tumor weight of the cisplatin group, the unsterilized sample low, high dose group, the sterilized sample low and high dose group is obviously reduced, the tumor inhibition rate of cisplatin is 74.6 percent, the tumor inhibition rate of unsterilized low dose (0.1 ml/only) is 49.0 percent, the tumor inhibition rate of high dose (0.2 ml/only) is 79.3 percent, the tumor inhibition rate of sterilized low dose (0.1 ml/only) is 79.0 percent, and the tumor inhibition rate of sterilized high dose (0.2 ml/only) is 82.8 percent. The antitumor effect of the sterilized group was observed to be superior to that of the unsterilized group from this experiment.
TABLE 1 test of the anti-tumor efficacy of the more natural anti-tumor vaccine
* Vs negative control, p < 0.0001.
Example 5: study on tumor inhibiting effect of composite vaccine on lung cancer
The compound vaccine formulation II A prepared in example 1 was committed to the study of lung cancer inhibition by Shanghai pharmaceutical industry Co., ltd, and the experimental report is as follows.
1. Summary: the tumor-bearing animals were subjected to in vivo experimental antitumor tests at a dose of 0.1 ml/mouse following 1, 4, 7, 10 days, subcutaneous injection dosing regimen of C57/BL/6 mice vaccinated with tumors, as a result: the tumor inhibition rate of the animals is 42.09%.
2. The purpose is as follows: test of anti-tumor efficacy of Lewis lung cancer of mice by using more natural samples
3 Test drug:
3.1 name: the more natural the sample.
3.2 Provides units: shaoxing Yuan biological medicine technology Co.Ltd
3.3 Preparation method: stock solution was injected at 0.1 ml/mouse.
4 Experimental materials:
4.1 solvents: physiological saline.
4.2 Positive control: Cisplatin powder injection 10mg/bottle, manufactured by Qilu pharmaceutical Co., ltd., batch No. 111024CF.
4.3 Tumor origin: the Lewis lung cancer model is maintained by passage from Shanghai pharmaceutical industry institute pharmaceutical evaluation research center.
5. Experimental animals:
5.1 sources: C57/BL/6 mice were supplied by Shanghai Srilk laboratory animal liability Co., ltd., eligibility number: SCXK 2012-0014. The laboratory animal allowed license number: SYXK (Shanghai) 2004-0015.
5.2 Body weight: 18-22 g.
5.3 Sex: and (3) female.
5.4 Animal count: test and positive control groups of 10 mice each, and negative controls were two groups.
6. Dose setting: stock solution was injected at 0.1 ml/mouse.
7. Dosing regimen: 1, 4, 7, 10 days after inoculation, subcutaneous injection
8. Test control: the negative control was given normal saline at the same concentration as the high dose equivalent volume of the test group, and the positive control cisplatin DDP7mg/kg was administered once every other day, twice consecutively.
9. The main test steps are as follows:
The animals of each group were sacrificed at the end of the experiment by taking the tumor source with vigorous growth, subcutaneously inoculating 0.2 ml/mouse (about 1-2×10 6) in the axilla of the corresponding host, and the tumor inhibition was calculated according to the following formula:
tumor inhibition ratio% = [ (average tumor weight of control group-average tumor weight of administration group)/average tumor weight of control group ] ×100%
10. Experimental results:
The tumor-bearing animals were subjected to in vivo experimental antitumor tests at a dose of 0.1 ml/mouse following 1, 4, 7, 10 days, subcutaneous injection dosing regimen of C57/BL/6 mice vaccinated with tumors, as a result: the tumor inhibition rate of the animals is 42.09%. See table 3 and fig. 3 for details.
TABLE 3 test of anti-tumor efficacy of the more natural samples against Lewis lung carcinoma in mice
* P values < 0.01 compared to negative control.
Example 6: study on tumor inhibition effect of composite vaccine on melanoma
The compound vaccines prepared in example 1, formulation one A, formulation one B, formulation one C, formulation two A, formulation three B, formulation three C, were commissioned to inhibit melanoma by Shanghai pharmaceutical industry institute Co., ltd. The 7 composite vaccines were numbered "surprise sample No. 1, no. 2, no. 3, no. 4, no. 5, no. 6, no. 7", respectively, and the experiments were reported below.
Test of anti-tumor efficacy of more natural samples on mouse B16 melanoma
1. Summary:
whereas samples (No. 1, no.2, no. 3, no. 4, no. 5, no. 6, no. 7) were subjected to in vivo experimental antitumor tests on B16 melanoma in mice at doses of 0.1 ml/mouse, 1,4, 7, 10 days after inoculation, subcutaneous injection dosing regimen, as a result of the tumor inhibition rates of B16 melanoma being respectively: 19.23% No. 1, 17.52% No.2, 25.21% No. 3, 6.41% No. 4, 35.04% No. 5, 44.02% No. 6, 48.72% No. 7.
2. The purpose is as follows:
test of anti-tumor efficacy of more natural samples on mouse B16 melanoma
3. Test drug:
3.1 name: samples (No. 1, no. 2, no. 3, no. 4, no. 5, no. 6, no. 7).
3.2 Provides units: shaoxing Yuan biological medicine technology Co.Ltd
3.3 Preparation method: stock solution was injected at 0.1 ml/mouse.
4. Experimental materials:
4.1 solvents: physiological saline.
4.2 Positive control: Cisplatin powder injection 10mg/bottle, manufactured by Qilu pharmaceutical Co., ltd., batch No. 111024CF.
4.3 Tumor origin: b16 melanoma model was maintained by passage from the Shanghai pharmaceutical industry institute pharmacological evaluation research center.
5. Experimental animals:
5.1 sources: BL/6 mice were supplied by Shanghai Style laboratory animal liability Co., ltd., eligibility number: SCXK 2012-0014. The laboratory animal allowed license number: SYXK (Shanghai) 2004-0015.
5.2 Body weight: 18-22 g.
5.3 Sex: and (3) female.
5.4 Animal count: test and positive control groups of 10 mice each, and negative controls were two groups.
6. Dose setting: stock solution was injected at 0.1 ml/mouse.
7. Dosing regimen: 1, 4, 7, 10 days after inoculation, subcutaneous injection
8. Test control: the negative control was given the corresponding solvent in the same volume and concentration as the high dose of the test group, and the positive control cisplatin DDP7mg/kg was administered once every other day, and twice consecutively.
9. The main test steps are as follows:
The animals of each group were sacrificed at the end of the experiment by taking the tumor source with vigorous growth, subcutaneously inoculating 0.2 ml/mouse (about 1-2×10 6) in the axilla of the corresponding host, and the tumor inhibition was calculated according to the following formula:
tumor inhibition ratio% = [ (average tumor weight of control group-average tumor weight of administration group)/average tumor weight of control group ] ×100%
10. Experimental results:
Whereas samples (No. 1, no. 2, no. 3, no. 4, no. 5, no. 6, no. 7) were subjected to in vivo experimental antitumor tests on B16 melanoma in mice at doses of 0.1 ml/mouse, 1, 4, 7, 10 days after inoculation, subcutaneous injection dosing regimen, as a result of the tumor inhibition rates of B16 melanoma being respectively: 19.23% No. 1, 17.52% No. 2, 25.21% No. 3, 6.41% No. 4, 35.04% No. 5, 44.02% No. 6, 48.72% No. 7. See table 4 and fig. 4 for details.
TABLE 4 test of anti-tumor efficacy of the surprise samples on mouse B16 melanoma
* P values < 0.01 compared to negative control.
Experimental results show that the compound vaccine formula I, the formula II and the formula III of the invention have obvious anti-tumor curative effects on the Lewis lung cancer of mice and the melanoma of the B16 of the mice, prove the broad spectrum of anti-tumor performance, are safe and nontoxic, and indicate that the compound vaccine can be used for clinical practice of cancer treatment.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the teachings of this invention, should consider improvements and modifications made without departing from the scope of this invention as still within the scope of this invention.
It should also be noted that the listing or discussion of a prior-published document in this specification should not be taken as an acknowledgement that the document is prior art or common general knowledge as equivalent or alternative to the invention.
Claims (10)
1. The application of the following microorganisms in preparing the anti-tumor composite vaccine is characterized by comprising the combination of more than three microorganisms: pertussis, typhoid bacillus, paratyphoid bacillus a, paratyphoid bacillus b, staphylococcus aureus, listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, pertussis, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes.
2. An anti-tumour composite vaccine, characterized in that the pharmaceutically active ingredient comprises, more preferably consists of, an inactivated preparation of the following three of the microorganisms as claimed in claim 1: pertussis bacillus, typhoid bacillus and staphylococcus aureus; or alternatively
The pharmaceutically active ingredient comprises, in addition to the pertussis, the typhoid bacillus and the staphylococcus aureus in the microorganisms as claimed in claim 1, the paratyphoid bacillus a and the paratyphoid bacillus b, namely the pharmaceutically active ingredient comprises, more preferably consists of, an inactivated preparation of the following five microorganisms among the microorganisms as claimed in claim 1: pertussis bacillus, typhoid bacillus, paratyphoid bacillus a, paratyphoid bacillus b and staphylococcus aureus; or alternatively
A pharmaceutical active ingredient comprising, more preferably consisting of, an inactivated preparation of nine of the following microorganisms as claimed in claim 1: listeria, escherichia coli, proteus, lactobacillus, bifidobacterium longum, bai-sha, clostridium acetobutylicum, salmonella typhimurium and streptococcus pyogenes.
3. The anti-tumor composite vaccine according to claim 2, wherein the inactivated preparation is an inactivated product of a microorganism suspension, for example, an inactivated product of a physiological saline suspension or a PBS buffer suspension for injection of a microorganism.
4. The anti-tumor composite vaccine according to claim 3, wherein the inactivation method of the microbial suspension is physical inactivation selected from heat inactivation, uv light inactivation, or a combination of heat inactivation and uv light inactivation.
5. The anti-tumor composite vaccine according to claim 4, wherein the suspensions of different microorganisms are inactivated separately; or mixing the suspension of different microorganisms and inactivating the mixture; or the suspension of different microorganisms is inactivated after being mixed with the vaccine dressing/adjuvant.
6. The anti-tumor composite vaccine according to claim 5, wherein the concentration of the suspension of each microorganism before inactivation is 10-100 hundred million cells/ml, preferably 30-50 hundred million cells/ml, respectively.
7. The anti-tumor composite vaccine according to any one of claims 2-4, wherein the dosage form is an injection selected from subcutaneous injection, intramuscular injection.
8. The anti-tumor composite vaccine according to claim 7, which is a pharmaceutical composition comprising, in addition to a microbial inactivation agent as a pharmaceutically active ingredient, a pharmaceutically acceptable injectable vaccine dressing/adjuvant including, but not limited to, the following: poly inosinic acid, dextran, lecithin, oil for injection, vitamin A, aluminum stearate, sodium carboxymethyl cellulose, fat emulsion for injection, span-20.
9. The anti-tumor composite vaccine according to claim 8, wherein the anti-tumor composite vaccine is selected from the following formulas:
Formula I: 8-15v/v%, preferably 10-12v/v%, 5-15v/v%, preferably 8-10v/v% of an inactivated preparation of Bacillus typhi, 5-15v/v%, preferably 8-10v/v% of an inactivated preparation of Staphylococcus aureus, 0.05-0.5wt%, preferably 0.1-0.2wt%, 3-10wt%, preferably 5-8wt% of poly inosinic acid (polyI: C), the balance of physiological saline being used to make up 100 wt%;
And the formula II: the inactivated preparation of the pertussis is 6-15v/v%, preferably 8-10v/v%, the inactivated preparation of the typhoid bacillus is 8-15v/v%, preferably 10-12v/v%, the inactivated preparation of the paratyphoid bacillus A is 2-8v/v%, preferably 3-5v/v%, the inactivated preparation of the paratyphoid bacillus B is 2-8v/v%, preferably 3-5v/v%, the inactivated preparation of the staphylococcus aureus is 3-10v/v%, preferably 5-8v/v%, poly inosinic acid (polyI:C) is 0.05-0.5wt%, preferably 0.1-0.2wt%, glucan is 5-15wt%, preferably 8-10wt%, and the balance of physiological saline is used for supplementing 100% by weight;
And the formula III: the inactivated preparation of Listeria 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Escherichia coli 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Proteus 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Lactobacillus 3-10v/v%, preferably 5-7v/v%, the inactivated preparation of Bifidobacterium longum 3-10v/v%, preferably 5-7 v%, the inactivated preparation of Centipeda 4-10 v%, preferably 6-8v/v%, the inactivated preparation of Clostridium acetobutylicum 1-5v/v%, preferably 2-3v/v%, the inactivated preparation of Salmonella typhimurium 1-5v/v%, preferably 2-3v/v%, the inactivated preparation of Streptococcus pyogenes 0.5-5v/v%, preferably 1-2v/v%, vitamin A0.2-2wt%, preferably 0.5-1wt%, aluminum stearate 1-2wt%, preferably 1-2wt%, CMC-carboxymethyl cellulose sodium (Na-cellulose) and the balance of preferably 1-2-5 wt%, the balance being preferably 1-5.5-5% and the physiological saline for injection.
10. The use of claim 1, wherein the tumor is one or a combination of two or more selected from the group consisting of: malignant epithelial tumors, lymphomas, blastomas, sarcomas, leukemias, basal cell carcinomas, cholangiocarcinomas; bladder cancer; bone cancer; brain and central nervous system cancers; breast cancer; peritoneal cancer; cervical cancer; choriocarcinoma; colorectal cancer; connective tissue cancer; digestive system cancer; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer, gastrointestinal cancer; glioblastoma; liver cancer; hepatoma; intraepithelial tumors; renal cancer; laryngeal carcinoma; leukemia; liver cancer; lung cancer; lymphomas, including hodgkin's lymphomas and non-hodgkin's lymphomas; melanoma; a myeloma; neuroblastoma; oral cancer; ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer;
Cancers of the respiratory system; salivary gland cancer; sarcoma; skin cancer; squamous cell carcinoma; stomach cancer; testicular cancer; thyroid cancer;
Uterine or endometrial cancer; cancer of urinary system; vulvar cancer; other carcinomas and sarcomas; b-cell lymphomas;
Chronic lymphocytic leukemia; acute lymphoblastic leukemia; hairy cell leukemia; chronic myelogenous leukemia; and post-transplant lymphoproliferative disorders, abnormal vascular proliferation associated with mole-type hamartoma, edema, and mergers syndrome.
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