CN111840541A - Application of polyinosinic acid cytidylic acid and anti-CD 47 antibody in tumor treatment - Google Patents
Application of polyinosinic acid cytidylic acid and anti-CD 47 antibody in tumor treatment Download PDFInfo
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- CN111840541A CN111840541A CN202010635908.5A CN202010635908A CN111840541A CN 111840541 A CN111840541 A CN 111840541A CN 202010635908 A CN202010635908 A CN 202010635908A CN 111840541 A CN111840541 A CN 111840541A
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
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- A—HUMAN NECESSITIES
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
- A61K2039/55583—Polysaccharides
Abstract
The invention discloses an application of poly-sarcosine combined with an anti-CD 47 antibody in tumor treatment, which can promote the innate immune function of macrophages, thereby improving the activation performance of the anti-CD 47 antibody, promoting the macrophages to kill tumor cells and improving the response rate of a tumor patient to the anti-CD 47 antibody. Meanwhile, the poly-sarcosine combined with the anti-CD 47 antibody for treating the tumor can obviously reduce adverse reactions such as anemia and the like caused in the treatment process, and improve the life quality of patients and the compliance in the treatment process; more importantly, the Poly I/C immunoadjuvant combined with the anti-CD 47 antibody for immunotherapy can treat solid tumors including colon cancer, and breaks through the restriction that the anti-CD 47 antibody in the prior art is difficult to realize effective treatment effect on the solid tumors; provides a new research direction for immunotherapy and colon cancer therapy in the prior art and promotes the development of the field of tumor therapy.
Description
Technical Field
The invention relates to the field of medical treatment, in particular to application of polyinosinic acid cytidylic acid and an anti-CD 47 antibody in tumor treatment.
Background
CD47 is also called integrin-associated protein, and its ligand is the signal regulatory protein alpha chain (SIRP alpha) on the surface of macrophage, and when CD47 binds with SIRP alpha, it can transmit inhibition signal to inhibit phagocytic activity of macrophage. Tumor cells reduce the effect of macrophages on tumor development by expressing CD47 and binding to macrophage sirpa to promote immune escape, so that a large number of macrophages cannot fully exert their phagocytic effect. On the basis, aiming at achieving the purpose of treating tumors, the prior art researches have the medicines for blocking a CD 47-SIRPa pathway, such as an anti-CD 47 antibody, but the treatment effect is limited, the medicine has certain effect on cancers of a hematopoietic system, but the treatment effect on the effect on solid tumors is not obvious, and the response rate of treating the cancers including the solid tumors is low. Meanwhile, in the prior art, although the CD47 antagonist such as an anti-CD 47 antibody has a certain curative effect on part of cancers, the CD47 antagonist also causes more adverse reactions, because normal cells such as erythrocytes and the like express CD47 besides tumor cells, and the CD47 antagonist also acts on the normal cells to cause more strong adverse reactions. Therefore, considering the advantages of immunotherapy based on the body's autoimmune system against tumors, there is a need for a drug or a combination of drugs that combines the features of immunotherapy to improve the effect of immunotherapy and reduce the adverse effects caused by the therapy.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides the application of the polyinosinic acid combined with the anti-CD 47 antibody in tumor treatment, and the polyinosinic acid (Poly I: C) is used as an immunologic adjuvant, so that the effect of the immunotherapy mainly comprising the anti-CD 47 antibody can be improved, the adverse reaction caused by the therapy is reduced, the response rate of the tumor is improved, the survival period of a tumor patient is prolonged, and the survival quality of the tumor patient is improved.
The technical scheme adopted by the invention is as follows:
the invention provides an application of a polyinosinic acid (Poly I: C) immunological adjuvant and an anti-CD 47 antibody in preparation of an anti-tumor medicament.
When the Poly-inosinic acid (Poly I: C) and the anti-CD 47 antibody are jointly applied, the Poly I: C not only can be used as a TLR3 agonist to further activate T cell immune response, but also can promote reprogramming of part of tumor-related macrophages, and can also promote innate immune functions of non-tumor macrophages, so that the activation performance of the anti-CD 47 antibody is improved, the macrophages are promoted to kill tumor cells, and the response rate of a tumor patient to the anti-CD 47 antibody is improved. More importantly, the Poly I: C can remarkably improve the effect of killing tumor cells by macrophages with the same dosage, and the application of the anti-CD 47 antibody and the Poly I: C is helpful for maintaining the treatment effect of the anti-CD 47 antibody which is singly used and reducing the dosage of the anti-CD 47 antibody, so that the anti-CD 47 antibody which acts on normal cells is at least quantitatively reduced, the adverse reactions such as anemia and the like caused in the immune treatment process can be remarkably reduced, and the survival quality of patients and the compliance in the treatment process are improved. In one embodiment of the present invention, even though the amount of anti-CD 47 antibody is not reduced, the combination of Poly I: C can significantly reduce the side effects, i.e., Poly I: C itself has the effect of reducing the side effects caused by anti-CD 47 antibody. The invention takes Poly-I: C as immune adjuvant, improves the effect of anti-CD 47 antibody immunotherapy, thereby prolonging the survival period of tumor patients, improving the survival rate and the survival quality of the tumor patients and reducing the adverse reaction brought by the immunotherapy.
Furthermore, the polyinosinic acid (Poly I: C) immunological adjuvant and the anti-CD 47 antibody are used as active ingredients, and pharmaceutically acceptable preparations are prepared by using acceptable pharmaceutical carriers. The polyinosinic acid (Poly I: C) immune adjuvant and the anti-CD 47 antibody can be supplemented with acceptable medicinal carriers or respectively supplemented with acceptable medicinal carriers, so that a pharmaceutically acceptable preparation is prepared, the practical use of the polyinosinic acid (Poly I: C) immune adjuvant and the anti-CD 47 antibody is facilitated, and the combined application of the polyinosinic acid (Poly I: C) immune adjuvant and the anti-CD 47 antibody on clinical treatment is facilitated.
Further, the preparation is selected from oral liquid, solid dispersion, capsule, granule, tablet, injection, ointment, patch, and implant. Various preparation forms contribute to the wide use of polyinosinic acid (Poly I: C) immunological adjuvants and anti-CD 47 antibodies as active ingredients, contributing to the expansion of the range of use thereof.
Further, the pharmaceutically acceptable carrier includes a carrier that targets a tumor or tumor microenvironment. The carrier targeting tumor or tumor microenvironment is helpful for targeting the anti-CD 47 antibody to the tumor, so that the adverse reaction of the anti-CD 47 antibody treatment is further obviously reduced.
Further, the medicament is administered in combination with at least one anti-cancer treatment selected from the group consisting of immunotherapy, chemotherapy, radiotherapy, angiogenesis inhibitor therapy, biologic therapy, bone marrow transplantation, peripheral blood stem cell transplantation, thermotherapy, laser therapy, photodynamic therapy, cancer-targeted therapy. Polysarcosine (Poly I: C) and anti-CD 47 antibodies can be used in combination with other therapies or drugs to further improve the therapeutic effect of tumors, in addition to immunotherapy.
Furthermore, the dosage of the Poly I: C immune adjuvant in the medicine is less than that of the anti-CD 47 antibody. Because Poly I: C belongs to TLR3 agonist, it can activate certain immune cells to promote immune response and promote anti-tumor process. However, TLR3 is also expressed in non-immune cells, and when the amount of Poly I: C is too large during immunotherapy, the Poly I: C is likely to act on non-immune cells more, thereby causing variability in the therapeutic process. Therefore, the use of less Poly I: C immunoadjuvant than the anti-CD 47 antibody helps to maintain the dominating effect of the anti-CD 47 antibody and maintain a stable therapeutic effect.
Further, the tumor is a solid tumor. In one embodiment of the invention, Poly I: C + anti-CD 47 antibody combination therapy enables treatment of the solid tumors colon cancer. Compared with the prior art that only blood tumors can be effectively treated by using the anti-CD 47 antibody alone, the invention improves the treatment effect of the anti-CD 47 antibody and enables the anti-CD 47 antibody to effectively act on solid tumors by using Poly I: C as an immunologic adjuvant, breaks through the restriction of the anti-CD 47 antibody in the treatment process of the solid tumors in the prior art, is beneficial to providing a new research direction for the treatment of the solid tumors, is expected to research and obtain the medicines for immunotherapy aiming at the solid tumors, treats the solid tumors by using an immune system of which the body does not mutually reject, and reduces the side effect brought by the medicines with the self-heterogeneity of the body.
Further, the tumor is colon cancer. In one embodiment of the invention, the colon cancer can be effectively treated by the combination treatment of the Poly I: C + anti-CD 47 antibody, the response rate of treatment is improved, and the adverse reaction of immunotherapy is obviously reduced. Colon cancer is the most common malignancy of the digestive tract, with the third in global tumor incidence and the second in mortality. At present, the incidence rate of the Chinese medicine is always in an increasing trend in China. In the prior art, the treatment means for colon cancer mainly comprises three traditional treatment methods of operation, radiotherapy and chemotherapy, but the recurrence and metastasis after treatment are still obvious, and the toxic and side effects are not negligible. The immunotherapy utilizes the body autoimmune system to treat colon cancer, and substances which may cause side reactions only comprise immunotherapy drugs, but the invention can obviously reduce the side reactions of immunotherapy by combined administration of the Poly I C + anti-CD-47 antibodies, so that the treatment effect of the Poly I C + anti-CD-47 antibodies on colon cancer is beneficial to subsequent research to obtain anti-cancer drugs even without side reactions, and a basis is provided for the subsequent research to be applied to clinical drugs. And provide a direction for treatment of colon cancer.
It is another object of the invention to provide a kit comprising Poly I: C immunoadjuvant and an anti-CD 47 antibody. Further, the kit also comprises a carrier for combining the Poly I: C immunoadjuvant and the anti-CD 47 antibody. The kit is applied to tumor treatment, and further applied to colon cancer treatment.
Further, the Poly I: C immune adjuvant is administered concomitantly with or separately from the anti-CD 47 antibody. Only need to use Poly I, C immune adjuvant and anti-CD 47 antibody; the Poly I: C immune adjuvant and the anti-CD 47 antibody are used together, so that the Poly I: C immune adjuvant and the anti-CD 47 antibody can be injected simultaneously, the same treatment environment can be reached at the same time, immunotherapy can be started, and the situation that the optimal effect of the dosage cannot be fully exerted due to the fact that part of the anti-CD 47 antibody or the Poly I: C immune adjuvant acts on the tumor environment independently can be avoided. The separate administration is beneficial to selectively and separately administering according to the body condition of a patient, is beneficial to improving the compliance of the patient and promotes the smooth progress of the combined medication process.
Compared with the prior art, the invention has the beneficial effects that: the application of Poly I: C as an immunologic adjuvant in combination with an anti-CD 47 antibody for resisting tumors can promote the innate immune function of macrophages, thereby improving the activation performance of the anti-CD 47 antibody, promoting the macrophages to kill tumor cells and improving the response rate of tumor patients to the anti-CD 47 antibody. More importantly, the Poly I: C can obviously improve the effect of killing tumor cells by macrophages with the same dosage, so that the dosage of the anti-CD 47 antibody and the Poly I: C can reduce the dosage of the anti-CD 47 antibody under the condition of achieving the same treatment effect, thereby at least reducing the anti-CD 47 antibody acting on normal cells quantitatively, obviously reducing adverse reactions such as anemia and the like caused in the immune treatment process, and improving the survival quality of patients and the compliance in the treatment process; and the treatment effect can be further improved and the side effect can be reduced by utilizing the carrier targeting the tumor microenvironment based on the treatment effect. Meanwhile, the C immunoadjuvant combined with the anti-CD 47 antibody for immunotherapy can treat solid tumors including colon cancer, and breaks through the restriction that the anti-CD 47 antibody in the prior art is difficult to realize effective treatment effect on the solid tumors; provides a new research direction for the immunotherapy and the colon cancer treatment in the prior art, is beneficial to the follow-up research of clinical treatment to obviously improve the tumor treatment effect and has a medicament or treatment scheme with small side effect, and promotes the development of the tumor treatment field.
Drawings
FIG. 1 is a schematic diagram of the mouse model modeling process of the auto-induced tumor of the present invention.
Detailed Description
The drawings are only for purposes of illustration and are not to be construed as limiting the invention. For a better understanding of the following embodiments, certain features of the drawings may be omitted, enlarged or reduced, and do not represent the size of an actual product; it will be understood by those skilled in the art that certain well-known structures in the drawings and descriptions thereof may be omitted.
Example 1
Polysarcosine (Poly I: C) and anti-CD 47 antibodies in combination for treating colon cancer in a transplant tumor model
S1, culturing to obtain a colon cancer cell line to be inoculated; in the embodiment, a colorectal cancer cell line MC38 is cultured, and when the density is 80% -90%, 106/50 mu L of cell suspension is prepared;
s2, modeling and grouping the transplanted tumor models; in the embodiment, 18 healthy and age-matched male C57BL/6 mice are selected, and the mice are divided into three groups with the age of 8-10 weeks, wherein the three groups comprise a control group, an anti-CD 47 antibody treatment group and a Poly I, C + anti-CD 47 antibody combined treatment group. The cell suspension obtained in step S1 was inoculated subcutaneously in the right side of all three groups of mice, and each mouse was inoculated with 50 μ l (106 MC38 colorectal cancer cells). Specifically, the inoculation in this example was performed by intraperitoneal injection.
S3, detecting the development condition of subcutaneous tumors at certain time intervals after inoculation for specific time; in this example, the length, width and height of the subcutaneous tumor were measured with a vernier caliper starting 7 days after the mice were inoculated, and the subcutaneous tumor volume was calculated from the obtained length, width and height (subcutaneous tumor volume: length × width × height/2), and then measured every three days.
S4, when the subcutaneous tumor reaches a specific volume, corresponding administration is carried out according to the group; in this example, the volume of the subcutaneous tumor to be treated reached 100mm3The administration was started, injecting isotype to each mouse of the control group, injecting 200. mu.g of anti-CD 47 antibody to each mouse of the anti-CD 47 antibody treatment group, injecting 50ug of Poly I: C and 200. mu.g of anti-CD 47 antibody to each mouse of the Poly I: C + anti-CD 47 antibody combination treatment group, and injecting once every 4 days for 4 times in total.
S5, continuously recording the subcutaneous tumor development condition of each group of mice after administration and counting; in this example, the subcutaneous tumor volume in mice reached 1000mm3The time-stamp corresponds to the death of the mice, and the survival rate of each group of mice within a specific time is calculated.
As a result: the control mice developed a sustained growth trend of tumors, with a survival rate of only about 33.3% 30 days after injection and an average subcutaneous tumor volume of 1621mm at day 30 3(ii) a After administration, the mice in the anti-CD 47 antibody-treated group entered a plateau phase after a transient decrease in tumor growth, and had a survival rate of about 50% 30 days after injection and an average tumor volume of about 1089mm at day 303(ii) a C + anti-CD 47 antibody combination treatment group mice showed a sustained downward trend in tumor growth after administration, a survival rate of about 83.3% 30 days after injection, and an average tumor volume of about 466mm at day 303. Compared with the treatment by using the anti-CD 47 antibody alone, the combined treatment of the Poly I, C and anti-CD 47 antibody obviously improves the treatment effect, not only obviously increases the survival rate, but also obviously inhibits the growth of tumors, and the subcutaneous tumor size of the mice in the combined treatment group of the Poly I, C and anti-CD 47 antibody is more than one time smaller than that of the mice in the treatment group of the anti-CD 47 antibody alone.
Example 2
Polyinosinic acid (Poly I: C) and anti-CD 47 antibody for the treatment of AOM/DSS auto-induced colon cancer
S1, culturing to obtain a colon cancer cell line to be inoculated; in the embodiment, a colorectal cancer cell line MC38 is cultured, and when the density is 80% -90%, 106/50 mu L of cell suspension is prepared;
s2, modeling and grouping the mouse model of the self-induced tumor; in the example, 18 healthy and age-matched male C57BL/6 mice were selected, and the mice were divided into three groups with the age of 8-10 weeks, including a control group, an anti-CD 47 antibody treatment group, and a combination treatment group of Poly I, C + anti-CD 47 antibody. The process of figure 1 is adopted for molding, the AOM is firstly injected into all three groups of mice at the dosage of 8mg/kg, then the mice are cultured, 2.5 percent DSFWter is injected every day in the second week, the fifth week and the eighth week, and only water is injected in the rest of the culturing time. The mouse font-induced tumor model was completed at week 10.
S3, administration is carried out based on the constructed self-induced tumor mouse model; isotype was injected into each mouse of the control group, 200. mu.g of anti-CD 47 antibody was injected into each mouse of the anti-CD 47 antibody treatment group, and 50ug of Poly I: C and 200. mu.g of anti-CD 47 antibody were injected into each mouse of the Poly I: C + anti-CD 47 antibody combination treatment group, and were injected once every 4 days for 4 times in total.
S4, killing the mice and counting; 1 week after the administration, three groups of mice were sacrificed, and colorectal segments of the three groups of mice were taken out and washed to count the colon tumor development, which includes calculating the tumor burden. And also statistics on the physiological characteristics of the mice during the course of the drug administration treatment.
As a result: the average tumor load of the control group of mice is about 46, and symptoms such as anemia, hematochezia, emaciation, paleness and the like are very serious in the treatment process; after the anti-CD 47 antibody treatment group mice are administrated, the average tumor load is about 35, and symptoms such as anemia, hematochezia, emaciation, pallor and the like are serious; after administration, the mice in the Poly I: C + anti-CD 47 antibody combination group exhibited an average tumor burden of about 11, with less colon cancer-related symptoms. As can be seen from the experimental results, the combination treatment of the Poly I, C and anti-CD 47 antibody obviously improves the treatment effect compared with the treatment without treatment and the treatment with the anti-CD 47 antibody alone, and obviously reduces the adverse reaction of the treatment under the condition of the same dosage of the anti-CD 47 antibody.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the technical solutions of the present invention, and are not intended to limit the specific embodiments of the present invention. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention claims should be included in the protection scope of the present invention claims.
Claims (10)
- Use of a Poly I: C immunoadjuvant in combination with an anti-CD 47 antibody in the preparation of an anti-tumor medicament.
- 2. The use of claim 1, wherein the Poly I: C immunoadjuvant and the anti-CD 47 antibody are used as active ingredients, and are formulated with pharmaceutically acceptable carriers to form a pharmaceutically acceptable formulation.
- 3. Use according to claim 2, wherein the formulation is selected from the group consisting of oral liquids, solid dispersions, capsules, granules, tablets, injections, ointments, patches, implants.
- 4. The use of claim 2, wherein the pharmaceutically acceptable carrier comprises a carrier that targets a tumor or tumor microenvironment.
- 5. The use according to claim 1, wherein the medicament is administered in combination with at least one anti-cancer treatment selected from the group consisting of immunotherapy, chemotherapy, radiotherapy, angiogenesis inhibitor therapy, biologic therapy, bone marrow transplantation, peripheral blood stem cell transplantation, thermotherapy, laser therapy, photodynamic therapy, cancer-targeted therapy.
- 6. The use according to claim 1, wherein the amount of Poly I: C immunoadjuvant in the medicament is less than the amount of anti-CD 47 antibody.
- 7. The use according to claim 1, wherein the tumor is a solid tumor.
- 8. Use according to any one of claims 1 to 7, wherein the tumour is colon cancer.
- 9. A kit comprising Poly I: C immunoadjuvant and an anti-CD 47 antibody.
- 10. The kit of claim 9, wherein said Poly I: C immunoadjuvant is administered concomitantly with or separately from said CD 47.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103566377A (en) * | 2012-07-18 | 2014-02-12 | 上海博笛生物科技有限公司 | Targeted immunotherapy for cancer |
| WO2016118754A1 (en) * | 2015-01-21 | 2016-07-28 | The Board Of Trustees Of The Leland Stanford Junior University | Macrophages eat cancer cells using their own calreticulin as a guide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103566377A (en) * | 2012-07-18 | 2014-02-12 | 上海博笛生物科技有限公司 | Targeted immunotherapy for cancer |
| WO2016118754A1 (en) * | 2015-01-21 | 2016-07-28 | The Board Of Trustees Of The Leland Stanford Junior University | Macrophages eat cancer cells using their own calreticulin as a guide |
Non-Patent Citations (1)
| Title |
|---|
| XIN LIU 等: "IL-6 expression promoted by Poly(I:C) in cervical cancer cells regulates cytokine expression and recruitment of macrophages", 《J CELL MOL MED.》 * |
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