WO2023063918A1 - Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy - Google Patents
Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy Download PDFInfo
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- WO2023063918A1 WO2023063918A1 PCT/TR2022/051136 TR2022051136W WO2023063918A1 WO 2023063918 A1 WO2023063918 A1 WO 2023063918A1 TR 2022051136 W TR2022051136 W TR 2022051136W WO 2023063918 A1 WO2023063918 A1 WO 2023063918A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
- C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
Definitions
- the invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccine developed as a biological and immunotherapeutic agent to be used in the treatment of pancreatic, ovarian, endometrial, uterus, kidney, lymphoma and leukaemia cancers as well as the most common cancer types such as lung, breast, colon, stomach, liver cancers.
- the invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine containing anti-idiotypic monoclonal ACP antibodies generated against said anticancer peptides (ACP) and used as immunizing and peptide antibiotics and immunotherapeutic anticancer peptides (iACP) of bacteriocin (antimicrobial peptide-AMP) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli as active substance.
- ACP anticancer peptides
- iACP immunotherapeutic anticancer peptides
- Immunotherapy is a type of cancer treatment that helps the immune system fight cancer.
- the immune system consists of white blood cells and organs and tissues of the lymphatic system, which help our body fight infections and other diseases.
- Immunotherapy is a type of biological therapy.
- Biological therapy is a type of therapy that uses substances made from living organisms to treat cancer.
- immune checkpoint inhibitors which are drugs that block immune checkpoints
- T cell transfer therapy which is a treatment that enhances the natural ability of T cells to fight cancer
- immune system modulators that increase the body's immune response to cancer
- monoclonal antibodies which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells
- treatment vaccines that work against cancer by enhancing your immune system's response to cancer cells.
- Immune checkpoint inhibitors which are drugs that block immune checkpoints: These checkpoints are a normal part of the immune system and prevent immune responses from being too strong. These drugs enable immune cells to respond more strongly to cancer by blocking them. Common side effects of immune checkpoint inhibitors may include rash, diarrhoea, burnout, and rarely widespread inflammation.
- T cell transfer therapy a treatment that enhances the natural ability of T cells to fight cancer:
- immune cells are taken from the tumour and those most active against cancer are selected or modified in the laboratory to better attack cancer cells, grown in large groups, and injected into the body with a needle through a vein, is given back.
- T-cell transfer therapy can also be called adoptive cell therapy, adoptive immunotherapy or immune cell therapy.
- This treatment has some disadvantages.
- the process of growing T cells in the laboratory can take 2 to 8 weeks, during which time chemotherapy and radiation therapy may be necessary to get rid of other immune cells. Reducing immune cells helps the transferred T cells to be more effective. After these treatments, T cells grown in the laboratory are returned with an intravenous needle.
- TIL therapy uses T cells found in the tumour, called tumourinfiltrating lymphocytes. Doctors test these lymphocytes in the lab to find out which ones recognize the tumour cells best. These selected lymphocytes are then treated with substances that allow them to multiply rapidly. The idea behind this approach is that lymphocytes in or near the tumour have already demonstrated the ability to recognize tumour cells. However, it may not be sufficient to kill the tumour or to overcome the signals that the tumour releases to suppress the immune system. Giving a large number of lymphocytes that respond best to the tumour can help overcome these barriers.
- CAR T-cell therapy is similar to TIL therapy but is modified in the laboratory to make a type of protein known as CAR before the T cells are grown and returned to the patient. CAR stands for chimeric antigen receptor. CARs are designed to enhance their ability to attack cancer cells by allowing T cells to bind to specific proteins on the surface of cancer cells.
- Immune system modulators that increase the body's immune response to cancer: Some of these agents affect specific parts of the immune system, while others affect the immune system in a more general way. Cytokines, which are proteins made by white blood cells, play important roles in the body's normal immune responses and the immune system's ability to respond to cancer. Cytokines sometimes used to treat cancer are interferons (INFs), interleukins (ILs), hematopoietic growth factors. Immunostimulating agents can cause flu-like symptoms such as fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, burnout, and headache.
- INFs interferons
- ILs interleukins
- Immunostimulating agents can cause flu-like symptoms such as fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, burnout, and headache.
- Cytokines can also cause many serious side effects: difficulty breathing, low or high blood pressure, severe allergic reactions, low blood counts, increased risk of infection and bleeding problems, blood clots, problems with mood, behaviour, thinking and memory, skin rash, injection site burning and ulcers, organ damage, etc.
- Monoclonal antibodies which are immune system proteins created in the laboratory that are designed to bind to specific targets on cancer cells: Some monoclonal antibodies mark cancer cells for better detection and destruction by the immune system. Such monoclonal antibodies are a type of immunotherapy. Monoclonal antibodies may also be referred to as therapeutic antibodies. Monoclonal antibodies are immune system proteins created in the laboratory. Antibodies are produced naturally by the body and help the immune system recognize and mark disease-causing microbes such as bacteria and viruses for destruction. Like the body's own antibodies, monoclonal antibodies recognize specific targets. Many monoclonal antibodies are used in cancer treatment. It is a type of targeted cancer therapy, meaning it is designed to interact with specific targets. Some monoclonal antibodies are also immunotherapy because they help turn the immune system against cancer.
- some monoclonal antibodies mark cancer cells so that the immune system can better recognize them and destroy them.
- rituximab which binds to a protein called CD20 on B cells and some cancer cells, causing the immune system to kill them.
- B cells are a type of white blood cell.
- Other monoclonal antibodies bring T cells closer to cancer cells and help immune cells kill cancer cells.
- An example is blinatumomab (Blincyto®), which binds both to CD19, a protein found on the surface of leukaemia cells, and to CD3, a protein found on the surface of T cells. This process helps T cells respond to leukaemia cells and get close enough to kill them.
- monoclonal antibodies can cause skin reactions at the needle site and flu-like symptoms.
- Treatment vaccines that work against cancer by enhancing the immune system's response to cancer cells Treatment vaccines are different from those that help prevent disease.
- Cancer treatment vaccines are a type of immunotherapy that treats cancer by boosting the body's natural defences against cancer. Unlike cancer prevention vaccines, cancer treatment vaccines are designed for use in people who already have cancer and work against cancer cells, not something that causes cancer. The idea behind treatment vaccines is that cancer cells contain substances called tumour-associated antigens that are not found in normal cells or are present at lower levels, if any. Treatment vaccines can help the immune system learn to recognize and respond to these antigens and destroy cancer cells that contain them. Cancer treatment vaccines can cause flu-like symptoms such as fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, burnout, headache, difficulty breathing, low or high blood pressure.
- tumour cell vaccines can be administered in six main ways.
- One of them is tumour cell vaccines. It can be made from the patient's own tumour cells. This means that they are specially produced to cause an immune response to the characteristics specific to the patient's cancer.
- Tumour-associated antigen found on cancer cells of many people with certain types of cancer can be made. Such a vaccine can induce an immune response in any patient whose cancer produces this antigen. This type of vaccine is still in the experimental stage.
- Dendritic cell vaccines another type of immune cell, can be made from the patient's own dendritic cells. Dendritic cell vaccines stimulate the immune system to respond to an antigen on tumour cells.
- a dendritic cell vaccine called sipuleucel-T used to treat some men with advanced prostate cancer, has been approved and is currently in use.
- Oncolytic virus vaccines are a different type of cancer treatment called oncolytic virus therapy and are sometimes described as a type of cancer treatment vaccine.
- An oncolytic virus is used, which is a virus that does not harm normal cells while infecting and destroying cancer cells.
- Antigen vaccines use proteins on the tumour surface as tumour-specific antigens to stimulate the immune system. By presenting these antigens to the cancerous area, the number of antibodies increases, causing it to fight the cancerous cell.
- DNA vaccines DNA samples taken from the patient's cells are used.
- the present invention relates to a method for providing a personalized cancer vaccine comprising the following steps: (a) identifying cancer-specific somatic mutations in a tumour sample of a cancer patient to provide a cancer mutation signature of the patient; and (b) providing a vaccine that exhibits the cancer mutation signature feature obtained in step a.
- the present invention relates to vaccines obtainable by said method.
- Patent document EP220100B1 presents new methods for increasing the T-cell stimulatory capacity of human dendritic cells (DCs) and their use in cancer vaccine.
- the method is applied to human DCs (CD40L, CD70) of different molecular adjuvants by transfection at least two mRNA or DNA molecules encoding markers selected from constitutively active TLR4 (caTLR4), IL-12p70, EL-selectin, CCR7 and/or the 4-1 BBL group or in combination with inhibition of SOCS, A20, PD-L1 and/or STAT3 expression, for example, by siRNA transfection.
- a clear increase in the immunostimulatory capacity of DCs thus obtained is shown, allowing them to elicit an unexpectedly high T-cell response in vitro.
- tumour-specific antigen allows for the eliciting of a pronounced host-mediated in vivo T-cell immune response against tumour antigen by DCs, thus making their use in anti-cancer vaccines very attractive.
- TR 2017 06714 is related to prove the possibility of using bacteriocin, a natural antimicrobial substance belonging to the lactic acid bacteria Lactobacillus acidophilus LA-S2 strain, as an antigen, that is, vaccine material, and then, developing anti-idiotypic vaccines by obtaining antibodies from these antigens again and its use in immunotherapy treatment method in cancer treatments and especially in colon cancer.
- the present invention relates to the development and production as cancer vaccine of anticancer peptides of bacteriocin origin as a biological and immunotherapeutic agent in cancer immunotherapy, and as peptide antibiotics in infection immunotherapy, which meet the above-mentioned requirements, eliminate all disadvantages and bring some additional advantages.
- the main purpose of the invention is to reveal a method for the development of cancer vaccines and new generation peptide antibiotics against different cancer types for cancer immunotherapy.
- the aim of the invention is to enable bacteriocins, which are antimicrobial peptides of microbial origin known as natural biological protective agents in peptide structure, to be defined as new generation peptide antibiotics and anticancer peptides, in addition to known natural antimicrobial peptide properties.
- the object of the invention is to provide a method for the production of peptide antibiotics, immunotherapeutic anticancer peptides (ACP) and anti-idiotypic monoclonal ACP antibodybased immunotherapeutic cancer vaccines in accordance with international pharmacopoeias.
- the invention is an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine developed for use in the treatment of the most common types of cancer such as lung, breast, colon, stomach, liver cancers, as well as pancreatic, ovarian, endometrial, uterus, kidney, lymphoma and leukemia cancers and its feature is to contains the following as an active ingredient:
- Peptide antibiotics of bacteriocin antiimicrobial peptide-AMP origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli,
- Immunotherapeutic anticancer peptides (iACP) of bacteriocin origin produced by these microorganism groups
- the invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccine developed as a biological and immunotherapeutic agent for use in the treatment of different types of cancer.
- the invention is particularly related to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine containing peptide antibiotics of bacteriocin origin developed for use in infectious immunotherapy treatment, immunotherapeutic anticancer peptides (ACP) of bacteriocin origin developed to be used as an active ingredient (pharmacophore) biomolecule in cancer treatment, and anti- idiotypic monoclonal anticancer peptide (ACP) antibodies formed and used as immunizers against the mentioned anticancer peptides (ACP).
- ACP immunotherapeutic anticancer peptides
- ACP anti- idiotypic monoclonal anticancer peptide
- Peptide antibiotics of bacteriocin origin used in the content of the anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine developed within the scope of the invention can also be used orally for infectious immunotherapy against infectious diseases and can be produced in tablet or capsule form.
- Anticancer peptides (ACP) can also be used orally in cancer treatment for cancer immunotherapy and can be produced in tablet or capsule form.
- bacteriocins which are antimicrobial peptides of microbial origin, were used as materials, but these bacteriocins were defined in 2 different ways as a new generation anticancer peptide and peptide antibiotic of bacteriocin origin instead of bacteriocin (antimicrobial peptide-AMP/substance) as a result of in vitro, in vivo studies, ex vivo, animal model studies and clinical studies performed on pathogens that cause infection in various cancer types and organs and tissues where these cancer types are seen.
- bacteriocin-producing microbial strains were also used in the same experiments within the scope of the invention, and the relationship between producer strain - bacteriocin (antimicrobial peptide), ACP and peptide antibiotics was examined on the basis of anticarcinogenic effects.
- peptides defined as anticancer peptides (ACP) were used as vaccine material (immunizer) by determining the cancer type in which each ACP was effective, and anti-idiotypic monoclonal ACP antibodies were developed against these cancer types and cancer vaccine formulations were prepared.
- ADME absorption, distribution, metabolism, and excretion
- toxicology studies pharmacokinetic and pharmacodynamic tests in accordance with Investigational New Drug-1 ND studies were carried out.
- data related to safety/tolerance, pharmacokinetics, bioavailability and concentration-effect data, efficacy in the therapeutic indication, optimal dose range, bioavailability and bioequivalence, side effect profile and safety data, drug-disease interaction, drug-drug interaction, dose intervals, risk-benefit information, efficacy in subgroups, and unexpected (adverse) side effects were obtained.
- cancer and microorganisms that cause infection on related cancerous tissue and/or organ were determined and compound sequences as peptide antibiotics and anticancer peptides of bacteriocins, which are antimicrobial peptides of microbial origin, against these cancer types and microorganisms were formed.
- step “e” were repeated with the obtained anti-idiotypic monoclonal ACP antibodies to determine their anticarcinogenic effects.
- preformulations were prepared and physical, chemical and microbiological analyses and compatibility tests were carried out in the pre-formulations.
- primary and secondary packaging materials were determined and the specifications of these materials were determined by physicochemical and microbiological methods and techniques, and quality controls were made.
- Phase 2 clinical studies were carried out in accordance with good clinical practices (GCP- Good Clinical Practice) by forming sampling groups consisting of volunteers with the target disease in which Phase 2 clinical studies will be conducted, and the effectiveness in the therapeutic indication, optimal dose range, bioavailability and bioequivalence, side effect profile and safety data as a result of Phase 2 clinical studies were obtained.
- the general production method of the vaccine subject to the invention is as follows;
- a normal vaccine production line is used in the production of the vaccine subject to the invention, and it may differ only in accordance with the material used as the vaccine material.
- microbial strains are first developed, then downstream processes and purification processes are performed to collect the anticancer peptides (ACP) of bacteriocin origin from the producer strain. During the process, necessary tests are completed and anti-idiotypic monoclonal ACP antibodies are obtained against purified ACPs.
- the formulation is completed by combining these anti-idiotypic monoclonal ACP antibodies with appropriate adjuvants and excipients suitable for pharmacopoeia, with the help of calculations made according to production capacity and dose amount. After the controls are made, it is filled and lyophilized, packaged and transferred by cold chain.
- IV intravenous
- oral Immunotherapy is administered as tablets or capsules.
- the vaccine (end product) to be obtained within the scope of the invention was produced in two forms.
- the first of these is in a vial containing sterile IV infusion solution produced in accordance with GMP rules.
- the pharmaceutical form is in the form of a clear or slightly opalescent solution, colourless to light yellow, in a concentrated form containing a solution for infusion.
- Packaging and packaging processes have been completed with the appropriate primary and secondary packaging materials that have been tested. Cold chain is required for transportation and storage.
- It is in lyophilized concentrated powder form in accordance with GMP rules and is in the form of edible vaccine prepared in vials suitable for solution form during use.
- Packaging and packaging processes have been completed with the appropriate primary and secondary packaging materials that have been tested. It is required with cold chain in transportation and storage.
- anti-idiotypic monoclonal AGP antibodies obtained by using anticancer peptides (AGP) of bacteriocin (AMP-antimicrobial peptide) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli, are used.
- AGP anticancer peptides
- AMP-antimicrobial peptide bacteriocin
- the vaccine subject to the invention was tried against the most common cancer types such as breast, colon, lung, liver, stomach cancers, as well as pancreatic, ovarian, endometrium, uterus, kidney, lymphoma and leukemia cancers, and as a result of the data obtained, the most appropriate ACP-cancer type was determined. Appropriate formulations for each type of cancer have been prepared and made available.
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Abstract
Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy The invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccines containing, especially as active ingredient, peptide antibiotics and immunotherapeutic anticancer peptides (iACP) of bacteriocin (AMP) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli, and anti-idiotypic monoclonal ACP antibodies formed against anticancer peptides (ACP) in quesiton and used as immunizers.
Description
Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy
TECHNICAL FIELD
The invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccine developed as a biological and immunotherapeutic agent to be used in the treatment of pancreatic, ovarian, endometrial, uterus, kidney, lymphoma and leukaemia cancers as well as the most common cancer types such as lung, breast, colon, stomach, liver cancers.
The invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine containing anti-idiotypic monoclonal ACP antibodies generated against said anticancer peptides (ACP) and used as immunizing and peptide antibiotics and immunotherapeutic anticancer peptides (iACP) of bacteriocin (antimicrobial peptide-AMP) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli as active substance.
TECHNICAL BACKGROUND
Immunotherapy is a type of cancer treatment that helps the immune system fight cancer. The immune system consists of white blood cells and organs and tissues of the lymphatic system, which help our body fight infections and other diseases. Immunotherapy is a type of biological therapy. Biological therapy is a type of therapy that uses substances made from living organisms to treat cancer.
To treat cancer in the prior art, various types of immunotherapy are used, such as immune checkpoint inhibitors, which are drugs that block immune checkpoints, T cell transfer therapy, which is a treatment that enhances the natural ability of T cells to fight cancer, immune system modulators that increase the body's immune response to cancer, monoclonal
antibodies, which are immune system proteins created in the lab that are designed to bind to specific targets on cancer cells, treatment vaccines that work against cancer by enhancing your immune system's response to cancer cells.
Immune checkpoint inhibitors, which are drugs that block immune checkpoints: These checkpoints are a normal part of the immune system and prevent immune responses from being too strong. These drugs enable immune cells to respond more strongly to cancer by blocking them. Common side effects of immune checkpoint inhibitors may include rash, diarrhoea, burnout, and rarely widespread inflammation. Problems depending on the affected organ of the body: changes in skin colour caused by inflammation skin inflammation, redness and itching sensation, cough and chest pains caused by inflammation in the lungs, abdominal pain and diarrhoea caused by inflammation in the colon, diabetes caused by pancreatitis, hepatitis (liver inflammation), hypophysitis (inflammation of the pituitary gland), myocarditis (inflammation of the heart muscle), nephritis (inflammation of the kidneys) and impaired kidney function, overactive or underactive thyroid, nervous system problems such as muscle weakness, lethargy and difficulty breathing.
T cell transfer therapy, a treatment that enhances the natural ability of T cells to fight cancer: In this treatment, immune cells are taken from the tumour and those most active against cancer are selected or modified in the laboratory to better attack cancer cells, grown in large groups, and injected into the body with a needle through a vein, is given back. T-cell transfer therapy can also be called adoptive cell therapy, adoptive immunotherapy or immune cell therapy. This treatment has some disadvantages. The process of growing T cells in the laboratory can take 2 to 8 weeks, during which time chemotherapy and radiation therapy may be necessary to get rid of other immune cells. Reducing immune cells helps the transferred T cells to be more effective. After these treatments, T cells grown in the laboratory are returned with an intravenous needle. TIL therapy uses T cells found in the tumour, called tumourinfiltrating lymphocytes. Doctors test these lymphocytes in the lab to find out which ones recognize the tumour cells best. These selected lymphocytes are then treated with substances that allow them to multiply rapidly. The idea behind this approach is that lymphocytes in or near the tumour have already demonstrated the ability to recognize tumour cells. However, it may not be sufficient to kill the tumour or to overcome the signals that the tumour releases to suppress the immune system. Giving a large number of lymphocytes that respond best to the tumour can help overcome these barriers. CAR T-cell therapy is similar to TIL therapy but is modified in the laboratory to make a type of protein known as CAR
before the T cells are grown and returned to the patient. CAR stands for chimeric antigen receptor. CARs are designed to enhance their ability to attack cancer cells by allowing T cells to bind to specific proteins on the surface of cancer cells.
Immune system modulators that increase the body's immune response to cancer: Some of these agents affect specific parts of the immune system, while others affect the immune system in a more general way. Cytokines, which are proteins made by white blood cells, play important roles in the body's normal immune responses and the immune system's ability to respond to cancer. Cytokines sometimes used to treat cancer are interferons (INFs), interleukins (ILs), hematopoietic growth factors. Immunostimulating agents can cause flu-like symptoms such as fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, burnout, and headache. Cytokines can also cause many serious side effects: difficulty breathing, low or high blood pressure, severe allergic reactions, low blood counts, increased risk of infection and bleeding problems, blood clots, problems with mood, behaviour, thinking and memory, skin rash, injection site burning and ulcers, organ damage, etc.
Monoclonal antibodies, which are immune system proteins created in the laboratory that are designed to bind to specific targets on cancer cells: Some monoclonal antibodies mark cancer cells for better detection and destruction by the immune system. Such monoclonal antibodies are a type of immunotherapy. Monoclonal antibodies may also be referred to as therapeutic antibodies. Monoclonal antibodies are immune system proteins created in the laboratory. Antibodies are produced naturally by the body and help the immune system recognize and mark disease-causing microbes such as bacteria and viruses for destruction. Like the body's own antibodies, monoclonal antibodies recognize specific targets. Many monoclonal antibodies are used in cancer treatment. It is a type of targeted cancer therapy, meaning it is designed to interact with specific targets. Some monoclonal antibodies are also immunotherapy because they help turn the immune system against cancer. For example, some monoclonal antibodies mark cancer cells so that the immune system can better recognize them and destroy them. One example is rituximab, which binds to a protein called CD20 on B cells and some cancer cells, causing the immune system to kill them. B cells are a type of white blood cell. Other monoclonal antibodies bring T cells closer to cancer cells and help immune cells kill cancer cells. An example is blinatumomab (Blincyto®), which binds both to CD19, a protein found on the surface of leukaemia cells, and to CD3, a protein found on the surface of T cells. This process helps T cells respond to leukaemia cells and get
close enough to kill them. Like most types of immunotherapy, monoclonal antibodies can cause skin reactions at the needle site and flu-like symptoms.
Treatment vaccines that work against cancer by enhancing the immune system's response to cancer cells: Treatment vaccines are different from those that help prevent disease. Cancer treatment vaccines are a type of immunotherapy that treats cancer by boosting the body's natural defences against cancer. Unlike cancer prevention vaccines, cancer treatment vaccines are designed for use in people who already have cancer and work against cancer cells, not something that causes cancer. The idea behind treatment vaccines is that cancer cells contain substances called tumour-associated antigens that are not found in normal cells or are present at lower levels, if any. Treatment vaccines can help the immune system learn to recognize and respond to these antigens and destroy cancer cells that contain them. Cancer treatment vaccines can cause flu-like symptoms such as fever, chills, weakness, dizziness, nausea or vomiting, muscle or joint pain, burnout, headache, difficulty breathing, low or high blood pressure.
Cancer treatment vaccines can be administered in six main ways. One of them is tumour cell vaccines. It can be made from the patient's own tumour cells. This means that they are specially produced to cause an immune response to the characteristics specific to the patient's cancer. Tumour-associated antigen found on cancer cells of many people with certain types of cancer can be made. Such a vaccine can induce an immune response in any patient whose cancer produces this antigen. This type of vaccine is still in the experimental stage. Dendritic cell vaccines, another type of immune cell, can be made from the patient's own dendritic cells. Dendritic cell vaccines stimulate the immune system to respond to an antigen on tumour cells. A dendritic cell vaccine called sipuleucel-T, used to treat some men with advanced prostate cancer, has been approved and is currently in use. Oncolytic virus vaccines are a different type of cancer treatment called oncolytic virus therapy and are sometimes described as a type of cancer treatment vaccine. An oncolytic virus is used, which is a virus that does not harm normal cells while infecting and destroying cancer cells. Antigen vaccines use proteins on the tumour surface as tumour-specific antigens to stimulate the immune system. By presenting these antigens to the cancerous area, the number of antibodies increases, causing it to fight the cancerous cell. In DNA vaccines, DNA samples taken from the patient's cells are used. In anti-idiotype vaccines, some antibodies known as idiotypical antibodies are used as immune response triggering antigens.
In the state of the art, there are some studies on the subject. One of these, patent document EP2714071 B1 relates to the provision of vaccines that are specific to a patient's tumour and potentially useful for immunotherapy of the primary tumour as well as tumour metastases. In one aspect, the present invention relates to a method for providing a personalized cancer vaccine comprising the following steps: (a) identifying cancer-specific somatic mutations in a tumour sample of a cancer patient to provide a cancer mutation signature of the patient; and (b) providing a vaccine that exhibits the cancer mutation signature feature obtained in step a. In an additional aspect, the present invention relates to vaccines obtainable by said method.
Patent document EP220100B1 presents new methods for increasing the T-cell stimulatory capacity of human dendritic cells (DCs) and their use in cancer vaccine. The method is applied to human DCs (CD40L, CD70) of different molecular adjuvants by transfection at least two mRNA or DNA molecules encoding markers selected from constitutively active TLR4 (caTLR4), IL-12p70, EL-selectin, CCR7 and/or the 4-1 BBL group or in combination with inhibition of SOCS, A20, PD-L1 and/or STAT3 expression, for example, by siRNA transfection. A clear increase in the immunostimulatory capacity of DCs thus obtained is shown, allowing them to elicit an unexpectedly high T-cell response in vitro. Coadministration of at least two of the above-mentioned molecules with tumour-specific antigen allows for the eliciting of a pronounced host-mediated in vivo T-cell immune response against tumour antigen by DCs, thus making their use in anti-cancer vaccines very attractive.
The patent application numbered TR 2017 06714, on the other hand, is related to prove the possibility of using bacteriocin, a natural antimicrobial substance belonging to the lactic acid bacteria Lactobacillus acidophilus LA-S2 strain, as an antigen, that is, vaccine material, and then, developing anti-idiotypic vaccines by obtaining antibodies from these antigens again and its use in immunotherapy treatment method in cancer treatments and especially in colon cancer.
Among the commercially available cancer vaccines for immunotherapy in current cancer treatment applications, the most widely used vaccines are monoclonal antibody and anti- idiotypic antibody vaccines, generally consisting of antibodies developed against tumour cells. DNA-based vaccines lost their scientific value with the use of mRNA technique in cancer studies. Both mRNA vaccines and peptide-protein-based cancer vaccines such as HER2 currently require standardization of procedures, internal and external quality control
assessment and competency assessment of existing methods, new development and accurate diagnostic tests to provide accurate, reliable and clinically relevant test results. In addition, large clinical trials are required to determine the technique that most reliably predicts a favourable response to anti-HER2 drugs.
As a result, due to the above-mentioned negativities and deficiencies, the need to make an innovation in the relevant technical field has emerged.
OBJECTIVE OF THE INVENTION
The present invention relates to the development and production as cancer vaccine of anticancer peptides of bacteriocin origin as a biological and immunotherapeutic agent in cancer immunotherapy, and as peptide antibiotics in infection immunotherapy, which meet the above-mentioned requirements, eliminate all disadvantages and bring some additional advantages.
The main purpose of the invention is to reveal a method for the development of cancer vaccines and new generation peptide antibiotics against different cancer types for cancer immunotherapy.
The aim of the invention is to enable bacteriocins, which are antimicrobial peptides of microbial origin known as natural biological protective agents in peptide structure, to be defined as new generation peptide antibiotics and anticancer peptides, in addition to known natural antimicrobial peptide properties.
The object of the invention is to provide a method for the production of peptide antibiotics, immunotherapeutic anticancer peptides (ACP) and anti-idiotypic monoclonal ACP antibodybased immunotherapeutic cancer vaccines in accordance with international pharmacopoeias.
To fulfill the above-described purposes, the invention is an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine developed for use in the treatment of the most common types of cancer such as lung, breast, colon, stomach, liver cancers, as well as
pancreatic, ovarian, endometrial, uterus, kidney, lymphoma and leukemia cancers and its feature is to contains the following as an active ingredient:
• Peptide antibiotics of bacteriocin (antimicrobial peptide-AMP) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli,
• Immunotherapeutic anticancer peptides (iACP) of bacteriocin origin produced by these microorganism groups
• anti-idiotypic monoclonal ACP antibodies formed against the aforementioned anticancer peptides (ACP) and used as an immunizes
The structural and characteristic features of the invention and all its advantages will be understood more clearly thanks to the detailed explanation given below, and therefore the evaluation should be made by taking this detailed explanation into consideration.
DETAILED DESCRIPTION OF THE INVENTION
In this detailed explanation, the development and production as a cancer vaccine of anticancer peptides of bacteriocin origin as a biological and immunotherapeutic agent in cancer immunotherapy and as peptide antibiotics in infection immunotherapy, which is the subject of the invention, is explained in a way that does not have any limiting effect only for a better understanding of the subject.
The invention relates to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccine developed as a biological and immunotherapeutic agent for use in the treatment of different types of cancer. The invention is particularly related to an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine containing peptide antibiotics of bacteriocin origin developed for use in infectious immunotherapy treatment, immunotherapeutic anticancer peptides (ACP) of bacteriocin origin developed to be used as an active ingredient (pharmacophore) biomolecule in cancer treatment, and anti-
idiotypic monoclonal anticancer peptide (ACP) antibodies formed and used as immunizers against the mentioned anticancer peptides (ACP).
Peptide antibiotics of bacteriocin origin used in the content of the anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine developed within the scope of the invention can also be used orally for infectious immunotherapy against infectious diseases and can be produced in tablet or capsule form. Anticancer peptides (ACP) can also be used orally in cancer treatment for cancer immunotherapy and can be produced in tablet or capsule form.
Within the scope of the invention, bacteriocins, which are antimicrobial peptides of microbial origin, were used as materials, but these bacteriocins were defined in 2 different ways as a new generation anticancer peptide and peptide antibiotic of bacteriocin origin instead of bacteriocin (antimicrobial peptide-AMP/substance) as a result of in vitro, in vivo studies, ex vivo, animal model studies and clinical studies performed on pathogens that cause infection in various cancer types and organs and tissues where these cancer types are seen. In addition, bacteriocin-producing microbial strains were also used in the same experiments within the scope of the invention, and the relationship between producer strain - bacteriocin (antimicrobial peptide), ACP and peptide antibiotics was examined on the basis of anticarcinogenic effects. Following this definition, peptides defined as anticancer peptides (ACP) were used as vaccine material (immunizer) by determining the cancer type in which each ACP was effective, and anti-idiotypic monoclonal ACP antibodies were developed against these cancer types and cancer vaccine formulations were prepared. Demonstration of ADME (absorption, distribution, metabolism, and excretion) and/or immune response, toxicology studies, pharmacokinetic and pharmacodynamic tests in accordance with Investigational New Drug-1 ND studies were carried out. As a result of clinical studies, data related to safety/tolerance, pharmacokinetics, bioavailability and concentration-effect data, efficacy in the therapeutic indication, optimal dose range, bioavailability and bioequivalence, side effect profile and safety data, drug-disease interaction, drug-drug interaction, dose intervals, risk-benefit information, efficacy in subgroups, and unexpected (adverse) side effects were obtained. By using a GMP compatible scalable and reproducible production system for peptide antibiotics, anticancer peptides and anti-idiotypic monoclonal ACP antibody cancer vaccines, whose technical, biochemical and clinical properties are determined by internationally valid methods and techniques, with trials carried out in accordance with standards (GLP and GCP), the vaccine in question was formulated and
applied for laboratory, pilot and commercial serial production, and finished product analysis and process validations were made for all 3 serial productions.
Within the scope of the invention, the following were applied for the production of peptide antibiotics, immunotherapeutic anticancer peptides (ACP) and anti-idiotypic monoclonal ACP antibody-based immunotherapeutic cancer vaccines in accordance with international pharmacopoeias:
1. For the first version of therapeutic compounds, within the scope of target/candidate identification and characterization, cancer and microorganisms that cause infection on related cancerous tissue and/or organ were determined and compound sequences as peptide antibiotics and anticancer peptides of bacteriocins, which are antimicrobial peptides of microbial origin, against these cancer types and microorganisms were formed.
2. Purification, characterization, molecular structure and mechanism of action were determined for pharmacophore properties.
3. Biological barrier resilience, stress tolerance, toxicology and safety evaluations, pharmacokinetic and pharmacodynamics, immune response tests for preclinical studies were performed by completing ex vivo and in vitro simulation trials at the GLP (Good Laboratory Practice) level and their activity and effectiveness were optimized.
4. Markers, assays and endpoints have been determined for use in clinical and non-clinical studies.
5. To determine the effectiveness of each ACP on different types of cancer and microorganisms that cause infection in the related cancerous tissue and/or organ, adhesion factors and adhesion to human cells, hydrophobicity degrees, coagulation and auto-aggregation tests, inhibitory effects against adhesion and invasion of infectious microorganisms to cancer cells, antiproliferative activities, their effects on the membrane integrity of cancer and normal cells, forms of cell death (apoptosis, primary and
secondary necrosis), changes in cancer cell membranes, membrane permeability of cancer cells were investigated and ACP-cancer and peptide antibiotic-pathogen spectrum match was made with the data obtained by examining their affinities with cancer cells , cytotoxicity grades, caspase activities, metastasis and angiogenesis status.
6. Immunomodulatory, immunostimulatory and immunoregulatory effects on the interaction with the immune system were examined through immunological tests.
7. Toxicology, pharmacodynamic and pharmacokinetic tests of ACP and peptide antibiotics (lead compounds) with the highest potential and tests for determining the immune response have been tested in appropriate in vivo animal models.
8. In order to determine of the potential for use of ACPs of bacteriocin origin, whose biological and immunotherapeutic properties and mechanism of action have been described in detail, as vaccine material-immunizer, first monoclonal and then anti- idiotypic monoclonal ACP antibodies were obtained by using immunization, hybridoma and monoclonal antibody techniques.
9. The tests in step “e” were repeated with the obtained anti-idiotypic monoclonal ACP antibodies to determine their anticarcinogenic effects.
10. In order to develop suitable formulations for the application routes of the treatment, preformulations were prepared and physical, chemical and microbiological analyses and compatibility tests were carried out in the pre-formulations. In addition, primary and secondary packaging materials were determined and the specifications of these materials were determined by physicochemical and microbiological methods and techniques, and quality controls were made.
11. By carrying out laboratory-scale formulation and process development studies, appropriate doses and concentrations were determined, and combinations were determined for the application way and dose. By making laboratory-scale trial
productions, parameters such as potency, purity, identity, sterility, toxicology, stability etc. in these productions were examined with physical, chemical and microbiological analyses and the finished product characterization and specifications were completed. For administration of anti-idiotypic monoclonal ACP antibodies as cancer vaccine;
• in vivo cancer animal model
• in vivo animal model of angiogenesis
• in vivo metastasis animal model
• in vivo anti-inflammatory and anti-infectious animal model
• animal model studies of the immunomodulatory effect in vivo have been conducted. Toxicology studies suitable for Investigational New Drug-IND studies and GLP compatible animal studies for demonstration of appropriate ADME (absorption, distribution, metabolism, and excretion) and/or immune response have been demonstrated in vivo. By performing scale-up studies for pilot scale production, pilot production trials were carried out and optimum production parameters were determined. In order to develop a scalable and reproducible production process in compliance with GMP (Good Manufacturing Practices), pilot scale productions were implemented in 3 series, and finished product analyses for each production and process validation of pilot scale productions were completed. Sampling groups (<100 individuals) consisting of "pilot lots" complying with GMP (Good Manufacturing Practice) and healthy volunteers where Phase 1 clinical trials will be conducted, and patient volunteers according to the nature of the investigational product (oncology) were formed. Clinical studies were carried out in accordance with good clinical practices (GCP- Good Clinical Practice) and as a result of Phase 1 clinical studies, safety/tolerance, pharmacokinetic, bioavailability and concentration-effect data were obtained. In order to investigate the safe therapeutic dose limits and effectiveness, Phase 2 clinical studies were carried out in accordance with good clinical practices (GCP- Good Clinical Practice) by forming sampling groups consisting of volunteers with the target disease in which Phase 2 clinical studies will be conducted, and the effectiveness in the therapeutic
indication, optimal dose range, bioavailability and bioequivalence, side effect profile and safety data as a result of Phase 2 clinical studies were obtained.
17. By verifying the Lot-to-Lot Consistency of the production process in compliance with GMP (Good Manufacturing Practice), sampling groups consisting of real patients in which Phase 3 clinical studies will be conducted were formed. Phase 3 clinical studies have been carried out in accordance with good clinical practice (GCP- Good Clinical Practice), and efficacy has been proven. As a result of phase 3 clinical studies, data on drug-disease interaction, drug-drug interaction, dose intervals, risk-benefit information, efficacy in subgroups and unexpected (adverse) side effects were obtained. All tests required for the registration application have been completed in accordance with the European Pharmacopoeia. After phase trials, anti-idiotypic monoclonal ACP antibodybased cancer vaccine was made ready for industrial production line.
The general production method of the vaccine subject to the invention is as follows;
A normal vaccine production line is used in the production of the vaccine subject to the invention, and it may differ only in accordance with the material used as the vaccine material. In order to obtain anti-idiotypic monoclonal ACP antibodies formed against anticancer peptides of bacteriocin origin, microbial strains are first developed, then downstream processes and purification processes are performed to collect the anticancer peptides (ACP) of bacteriocin origin from the producer strain. During the process, necessary tests are completed and anti-idiotypic monoclonal ACP antibodies are obtained against purified ACPs. The formulation is completed by combining these anti-idiotypic monoclonal ACP antibodies with appropriate adjuvants and excipients suitable for pharmacopoeia, with the help of calculations made according to production capacity and dose amount. After the controls are made, it is filled and lyophilized, packaged and transferred by cold chain.
As is known, different forms of immunotherapy can be administered in different ways. Said forms of administration are intravenous (IV) (Immunotherapy is administered directly intravenously, which is how cancer vaccines are) and oral (Immunotherapy is administered as tablets or capsules).
The vaccine (end product) to be obtained within the scope of the invention was produced in two forms. The first of these is in a vial containing sterile IV infusion solution produced in
accordance with GMP rules. The pharmaceutical form is in the form of a clear or slightly opalescent solution, colourless to light yellow, in a concentrated form containing a solution for infusion. Packaging and packaging processes have been completed with the appropriate primary and secondary packaging materials that have been tested. Cold chain is required for transportation and storage. Secondly, unlike other cancer vaccines; It is in lyophilized concentrated powder form in accordance with GMP rules and is in the form of edible vaccine prepared in vials suitable for solution form during use. Packaging and packaging processes have been completed with the appropriate primary and secondary packaging materials that have been tested. It is required with cold chain in transportation and storage.
All production process and control analyses are performed in clean room conditions with HVAC units.
In the production of the vaccine, which is the subject of the invention, anti-idiotypic monoclonal AGP antibodies obtained by using anticancer peptides (AGP) of bacteriocin (AMP-antimicrobial peptide) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli, are used.
The vaccine subject to the invention was tried against the most common cancer types such as breast, colon, lung, liver, stomach cancers, as well as pancreatic, ovarian, endometrium, uterus, kidney, lymphoma and leukemia cancers, and as a result of the data obtained, the most appropriate ACP-cancer type was determined. Appropriate formulations for each type of cancer have been prepared and made available.
Claims
CLAIMS The invention is an anti-idiotypic monoclonal ACP antibody-based immunotherapeutic vaccine developed to be used in the treatment of pancreatic, ovarian, endometrial, uterus, kidney, lymphoma and leukaemia cancers, as well as the most common cancer types such as lung, breast, colon, stomach and liver cancers; its feature is to contains the following as an active ingredient:
• Peptide antibiotics of bacteriocin (AMP) origin produced by Lactobacillus, Lactococcus, Leuconoctoc, Carnobacterium, Pediococcus, Entrococcus, Propionibacterium, Brevibacterium, Bacillus, Staphylococcus, Pseudomonas genus and Escherichia coli,
• Immunotherapeutic anticancer peptides (iACP) of bacteriocin origin produced by these groups of microorganisms,
• anti-idiotypic monoclonal ACP antibodies formed against the aforementioned anticancer peptides (ACP) and used as immunizers It is a vaccine according to claim 1 and its feature is; It is in concentrated form containing sterile intravenous (IV) infusion solution for intravenous administration. It is a vaccine according to claim 1 and its feature is; It is in the form of lyophilized concentrated powder for oral administration.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2021016155 | 2021-10-17 | ||
| TR2021/016155 TR2021016155A2 (en) | 2021-10-17 | Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy. |
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| WO2023063918A1 true WO2023063918A1 (en) | 2023-04-20 |
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| PCT/TR2022/051136 WO2023063918A1 (en) | 2021-10-17 | 2022-10-16 | Development and production of anticancer peptides of bacteriocin origin as biological and immunotherapeutic agents in cancer immunotherapy and as peptide antibiotics in infection immunotherapy |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR201706714A2 (en) * | 2017-05-08 | 2017-09-21 | Filiz Arslan | IMMUNOTHERAPIC CANCER VACCINE |
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- 2022-10-16 WO PCT/TR2022/051136 patent/WO2023063918A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TR201706714A2 (en) * | 2017-05-08 | 2017-09-21 | Filiz Arslan | IMMUNOTHERAPIC CANCER VACCINE |
Non-Patent Citations (1)
| Title |
|---|
| ARSLAN, F.: "Research on possible use aiming at immunotherapy in treatment of colon cancer of anti-idiotypic monoclonal antibodies formed against lactobacillus acidophilus and their bacteriocins", CONFERENCE, DRESDEN, GERMANY, 25 May 2008 (2008-05-25), pages 24, XP09546201 * |
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