CN116832152A - Immune checkpoint inhibitor composition and application thereof - Google Patents
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Abstract
The invention provides an immune checkpoint inhibitor composition and application thereof, belongs to the technical field of biological medicines, and can solve the technical problem that the tumor effect of the existing immune checkpoint inhibitor is not ideal. Wherein the immune checkpoint inhibitor composition comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is a cytokine for improving tumor response rate, and the second active ingredient is two immune checkpoint inhibitors; the cytokines that increase tumor response rate are human interleukin 12, and the two immune checkpoint inhibitors are PD-1 antibody and CTLA4 antibody. The immune checkpoint inhibitor composition can be applied to the preparation of a preparation or a medicament for treating tumors.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an immune checkpoint inhibitor composition and application thereof.
Background
The immune checkpoint inhibitor is a novel immune treatment mode, and the aim of resisting tumor is fulfilled mainly by improving the immune microenvironment around the tumor so as to activate the in-vivo immune cell activity. Since 2014, 9 th FDA has accelerated approval of the first PD-1 immune checkpoint inhibitor for the second line treatment of melanoma, various immune checkpoint inhibitors have been approved worldwide so far for the second/third and even first line treatment of various solid tumors such as non-small cell lung cancer, urothelial cancer, and all microsatellite high instability (MSI-H) solid tumors.
However, while immune checkpoint inhibitors demonstrate great potential for the human immune system in combating cancer, they have limited efficacy in some so-called "cold" tumors, and many cancer patients do not respond to this innovative therapy. For single administration, the response rate of immune checkpoint inhibitor is 10-35%, for example, the effective rate of classical hodgkin lymphoma and melanoma can reach more than 80%, and the average effective rate is less than 30%, and 70% of people cannot benefit. Therefore, the combination of immune checkpoint inhibitors at different targets or the combination of immune checkpoint inhibitors with other therapeutic approaches is currently being studied clinically.
Interleukin 12 (hereinafter referred to as "IL-12") is a multifunctional cytokine bridging specific immunity and nonspecific immunity, and can activate NK cells and CD8+ T lymphocytes simultaneously, regulate tumor antigen presentation, and stimulate CD4+ T cells to differentiate into Th1, and the proliferation and differentiation of Th1 cells can generate effector Th1 cells and memory T cells with specific immunity memory, thus being ideal regulatory factors capable of breaking tumor microenvironment immunosuppression and starting anti-tumor "distal effect" in multiple layers. Currently, IL-12 has been tested in human clinical trials as an immunotherapeutic agent for the treatment of a wide variety of cancers, including renal cancer, colon cancer, ovarian cancer, melanoma, and T-cell lymphoma, as well as an adjunct for cancer vaccines. However, in previous clinical studies, systemic administration of IL-12 resulted in severe toxicity due to frequent and excessive doses, and generally lower response rates to recombinant human IL-12, resulting in a resumption of clinical development.
Therefore, how to achieve low dose use of IL-12, reduce systemic toxicity, while combining with other immune checkpoint inhibitors to achieve a significant enhancement of tumor therapeutic effect is critical to solve the above-described problems.
Disclosure of Invention
Aiming at the technical problem that the tumor effect of the existing immune checkpoint inhibitor is not ideal, the invention provides a novel immune checkpoint inhibitor composition, and the cytokine IL-12 for improving the tumor response rate is combined with two immune checkpoint inhibitors, so that the treatment effect of tumors can be obviously improved.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an immune checkpoint inhibitor composition comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is a cytokine that increases tumor response rate and the second active ingredient is two immune checkpoint inhibitors;
the cytokine for improving the tumor response rate is human interleukin 12, and the two immune checkpoint inhibitors are PD-1 antibody and CTLA4 antibody.
In one embodiment, the immune checkpoint inhibitor composition is in unit dosage form, each unit dosage form having a content of the human interleukin 12 of 2-9 μg/dose, each unit dosage form having a content of the PD-1 antibody of 0.2-0.4 mg/kg/dose, and a content of CTLA4 antibody of 0.2-0.4 mg/kg/dose.
In one embodiment, the immune checkpoint inhibitor composition is in unit dosage form, each unit dosage form having a content of the human interleukin 12 of 9 μg/dose, each unit dosage form having a content of the PD-1 antibody of 0.3 mg/kg/dose, and each unit dosage form having a content of CTLA4 antibody of 0.3 mg/kg/dose.
In one embodiment, the unit dosage form is a dosage form comprising a unit dose of the active ingredient, and the unit dose refers to a single administration dose of the active ingredient.
In one embodiment, the first active ingredient and the second active ingredient are present separately.
In one embodiment, the immune checkpoint inhibitor composition is in the form of an injectable or oral formulation.
The invention also provides an application of the immune checkpoint inhibitor composition in preparing a preparation or a medicament for treating tumors.
In one embodiment, the tumor treating agent is an agent or drug that restores T cell activity, enhances T cell immune responses;
or agents or drugs that inhibit tumor cell proliferation and/or induce tumor cell apoptosis;
or agents or drugs that inhibit the tumorigenicity of tumor cells.
In one embodiment, the tumor is a solid tumor including, but not limited to, lung cancer, stomach cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous carcinoma, nasopharyngeal carcinoma, brain glioma, lymphoma.
Compared with the prior art, the invention has the advantages and positive effects that:
1. according to the immune checkpoint inhibitor composition, the cytokine human IL-12 for improving the tumor response rate is combined with two immune checkpoint inhibitors (PD-1 antibody and CTLA4 antibody), so that the tumor treatment effect is improved, the effective activity can be generated by using the IL-12 at a low dose, and the systemic toxicity is reduced;
2. the immune checkpoint inhibitor composition provided by the invention can improve the tumor treatment effect, especially has better effect on tumors insensitive to immune checkpoint inhibitors, and simultaneously, the dosage of the immune checkpoint inhibitor can be reduced, the toxic and side effects can be reduced, and the administration burden of patients can be reduced by combining the human IL-12 with the immune checkpoint inhibitor.
Drawings
FIG. 1 is a graph showing the average volume change of tumor tissues of mice in different experimental groups according to the embodiment of the invention;
fig. 2 is a graph showing the weight change results of mice in different experimental groups according to the embodiment of the present invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The embodiment of the invention provides an immune checkpoint inhibitor composition, which comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is a cytokine for improving tumor response rate, and the second active ingredient is two immune checkpoint inhibitors;
the cytokine for improving the tumor response rate is human interleukin 12, and the two immune checkpoint inhibitors are PD-1 antibody and CTLA4 antibody.
In the technical scheme, a novel immune checkpoint inhibitor composition is provided, and the novel immune checkpoint inhibitor composition not only improves the tumor treatment effect, particularly has better effect on tumors insensitive to immune checkpoint inhibitors, but also ensures that the IL-12 can generate effective activity after being used at a low dose by combining cytokines for improving tumor response rate with two immune checkpoint inhibitors (PD-1 antibody and CTLA4 antibody), thereby reducing systemic toxicity. It should be noted that, since no new human interleukin-12 is currently marketed, the human interleukin-12 used in the present invention is recombinant human interleukin-12, and the preparation methods thereof are disclosed in the patent publications CN102876684B and CN 103555734B.
Further, the reason why the present invention selects human interleukin-12 as a cytokine and immune checkpoint inhibitor for increasing tumor response rate is that:
IL-12 is a multifunctional cytokine bridging specific immunity and nonspecific immunity, can activate NK cells and CD8+ T lymphocytes at the same time, can regulate the presentation effect of tumor antigens, and can stimulate CD4+ T cells to differentiate towards Th1, and Th1 cell proliferation and differentiation can generate effector Th1 cells and memory T cells with specific immunity memory, thus being an ideal regulating factor capable of breaking tumor microenvironment immunosuppression and starting anti-tumor 'far-end effect' in multiple layers. Currently, IL-12 has been tested in human clinical trials as an immunotherapeutic agent for the treatment of a wide variety of cancers, including renal cancer, colon cancer, ovarian cancer, melanoma, and T-cell lymphoma, as well as an adjunct for cancer vaccines. However, in previous clinical studies, since frequent administration and excessive administration of IL-12 produced serious toxicity and generally low response rate to recombinant human IL-12, clinical development was re-established, and therefore, in order to avoid excessive administration of IL-12 to the whole body, it was first necessary to ensure low dose administration, but to sufficiently exert the effect of improving the therapeutic effect of the immune checkpoint inhibitor while low dose administration, and it was found that controlling the dose of human interleukin-12 within a proper range was one of the difficulties to be overcome by the present invention.
Furthermore, according to the invention, based on the principle, a large number of screening experiments are carried out, so that when the content of the human interleukin 12 in each unit dosage form is 2-9 mug/dose, preferably 9 mug/dose, the effect of improving the treatment effect of the immune checkpoint inhibitor can be achieved, and systemic toxic reaction caused by overdose is avoided.
Furthermore, the invention also provides a limitation on the administration mode (comprising administration time, administration sequence and the like) of the immune checkpoint inhibitor composition, namely, the anti-PD-1 monoclonal antibody and the anti-CTLA-4 monoclonal antibody are sequentially injected after 18-30 hours, preferably 24 hours, of the human interleukin 12 administration. This mode of administration defines the time point of administration of human interleukin 12, and is capable of eliciting T cell activity in advance, 24 hours earlier than administration of anti-PD-1 mab and anti-CTLA-4 mab.
It should be further noted that, as an adjuvant drug for tumor treatment, IL-2, IL-12, IL-15, IL-21 and the like have been used in the subsequent research and development, the invention tries to combine various cytokines with anti-PD-1 monoclonal antibody and anti-CTLA 4 monoclonal antibody, and experimental results show that the IL-12 has the best effect, and can excite proliferation and activity of T cells with lower dosage, thus achieving better therapeutic effect.
In a specific embodiment, the immune checkpoint inhibitor composition is in unit dosage form, the content of human interleukin 12 in each unit dosage form is 2-9 μg/dose, the content of PD-1 antibody in each unit dosage form is 0.2-0.4 mg/kg/dose, and the content of CTLA4 antibody is 0.2-0.4 mg/kg/dose.
In a specific embodiment, the immune checkpoint inhibitor composition is in unit dosage form, each unit dosage form having a content of the human interleukin 12 of 9 μg/dose, each unit dosage form having a content of the PD-1 antibody of 0.3 mg/kg/dose, and each unit dosage form having a content of CTLA4 antibody of 0.3 mg/kg/dose.
In a specific embodiment, the unit dosage form is a dosage form comprising a unit dose of the active ingredient, and the unit dose refers to a single administration dose of the active ingredient.
In a specific embodiment, the first active ingredient and the second active ingredient are present separately.
In a specific embodiment, the immune checkpoint inhibitor composition is in the form of an injectable or oral formulation.
The invention also provides an application of the immune checkpoint inhibitor composition in preparing a preparation or a medicament for treating tumors.
In one embodiment, the tumor treating agent is an agent or drug that restores T cell activity, enhances T cell immune responses;
or agents or drugs that inhibit tumor cell proliferation and/or induce tumor cell apoptosis;
or agents or drugs that inhibit the tumorigenicity of tumor cells.
In a specific embodiment, the tumor is a solid tumor including, but not limited to, lung cancer, stomach cancer, liver cancer, pancreatic cancer, esophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous carcinoma, nasopharyngeal carcinoma, glioma, lymphoma.
In order to more clearly describe the immune checkpoint inhibitor compositions and their uses provided by the embodiments of the present invention in detail, the following description will be made with reference to specific embodiments.
Example 1
In this example, the antitumor activity of the immune checkpoint inhibitor composition was evaluated using a375 cell line mouse subcutaneous tumor transplantation model (PBMC added), specifically:
experimental grouping, see table below:
TABLE 1 anti-tumor Activity Experimental grouping cases
Remarks: except that hIL-12 (i.e. human interleukin 12) D0 is singly administrated subcutaneously on the same day, the other doses are administrated twice a week and are injected intraperitoneally, and are prepared and used at present, and stored at 2-8 ℃ in a dark place, and the first dose is defined as D0 on the same day; i.p. is intraperitoneal injection, i.h. is subcutaneous injection, and BIW is 2 times per week.
The experimental method comprises the following steps:
(1) Cell culture
The culture medium of the A375 cell strain is DMEM (Gibco, cat# C11995500 BT); 10% fetal bovine serum (Gibco, cat# 10099-141C); 2mM L-Glutamine (Gibco, cat# 25030-081); 100U/ml penicillin and 100. Mu.g/ml streptomycin (Hyclone, cat# SV 30010). Cells were digested with 0.25% pancreatin (Gibco, cat# 25200-056) and passaged 1:3 days apart. After the cells are amplified to the required cell number and the cells are in the logarithmic growth phase, collecting the cell count, adjusting the concentration and then mixing with matrigel uniformly; cell suspension with matrigel (Corning, cat# 356235) according to 1:1 are evenly mixed on ice and then are placed on ice for standby.
(2) Tumor cell inoculation and grouping
The mice were randomly divided into 6 groups of 10 mice each based on body weight. Right back subcutaneous inoculation of each mouse 4X 10 6 0.05mL of A375 tumor cells and 1X 10 6 0.05mL of PBMC cell mixture (cell suspension: matrigel=1:1). 60 mice were vaccinated with a mixture volume of 0.1 mL/mouse, and dosed about 4 hours after vaccination.
(3) Animal administration
The administration mode is as follows: the other doses were given twice weekly, i.e. by intraperitoneal injection, 9 times in total, except for a single subcutaneous dose of hIL-12D0 on the day.
(4) Tumor volume measurement
Tumor volumes were measured 2 times per week, and the long and short diameters of the tumors were measured using vernier calipers. Tumor volume was reduced by 50% and above, denoted PR (Partial Response); the tumor completely disappeared to CR (Complete Response).
(5) Sample collection after the end of the experiment
The following day after the last administration, animals are sacrificed and tumor tissues are collected; each tumor tissue was weighed after being peeled off, and photographed as a whole.
(6) Observation index
The Tumor Volume (TV), tumor growth inhibition ratio (TGI), body Weight (BW), tumor Weight (TW), relative tumor proliferation ratio T/C (%), tumor weight inhibition ratio IRTW (%) were calculated, respectively, as follows:
tumor Volume (TV) =0.5×a×b 2 (wherein a and b represent the major and minor diameters of the tumor, respectively)
Tumor growth inhibition rate (TGI%) = (1- (V) Dt (treatment group) -VD0 (treatment group))/(V Dt (control group) -V D0 (control group)) ×100%
Tumor weight tumor inhibition rate (IRTW%) = (1-TW (treatment group)/TW (control group)) ×100%
In the above formula, TV D0 Representing tumor volume obtained by first measurement of packet, TV Dt Rtv=tv, representing tumor volume at each subsequent measurement Dt /TV D0 。
Experimental results:
the experiment randomly divides tumor-bearing mice into 6 groups, which are respectively: vehicle (PBS, biw×9), hIL-12 (20 ng/mouse, single dose), anti-PD-L1 mab (0.3 mpk, biw×9), anti-CTLA-4 mab (0.3 mpk, biw×9), anti-PD-L1 mab+ctla4 mab+hil-12 (0.3 mpk &20ng/mouse, biw×9& Single dose), anti-PD-L1 mab+anti-CTLA 4 mab (0.3 mpk &3mpk & biw×9), the experiments were completed after 9 doses, tumor tissues were harvested from the animals and tumor-related data were calculated for each group, as shown in fig. 1 (note: mpk mg/kg; biw twice a week).
As can be seen from the results shown in fig. 1: tumor volume of Vehicle group mice continuously increased, and tumor average volume reached 2480.7 + -178.1 mm at day 31 of administration 3 The method comprises the steps of carrying out a first treatment on the surface of the The tumor volumes of the anti-PD-L1 monoclonal antibody group, the anti-CTLA-4 monoclonal antibody group, the anti-PD-L1 monoclonal antibody+anti-CTLA 4 monoclonal antibody group and the hIL-12 group mice continuously and slowly increase, wherein the average tumor volumes respectively reach 1692.3 +/-263.2 (TGI: 290.2, P < 0.01), 2107.9 +/-162.5 (TGI: 386.0, P < 0.01), 943.1 +/-201.9 (TGI: 117.5, P > 0.05) and 443.7 +/-231.4 mm at the 31 st day of administration 3 (TGI: 72.0, P < 0.01); however, the anti-PD-L1 monoclonal antibody, the anti-CTLA 4 monoclonal antibody and the hIL-12 have an inhibition effect on tumors, and the average tumor volume reaches 49.0+/-28.6 mm at the 31 st day of administration 3 (TGI：88.7，＞0.05)。
Further, as can be seen from the above results, compared with the immune checkpoint inhibitor which requires high expression of tumor PD-L1 and can have good effect, the present invention adopts the combination mode of human interleukin 12 and PD-L1 and CTLA4, the tumor inhibition rate is significantly enhanced, and compared with the negative control group (i.e., PBS group), the tumor volume can be reduced by about 50 times; compared with the combination of anti-PD-L1 monoclonal antibody, anti-CTLA-4 monoclonal antibody, anti-PD-L1 monoclonal antibody and anti-CTLA 4 monoclonal antibody and the independent administration of IL-12, the combined administration of human IL-12, PD-L1 and CTLA4 can reduce the tumor volume by 35, 43, 19 and 10 times.
In addition, the weight changes of animals are counted in the embodiment of the invention (as shown in figure 2), and the average weight of animals in the Vehicle group, the hIL-12 group, the PD-L1 group, the CTLA-4 group and the IL-12+PD-L1+CTLA-4 group is reduced from the 24 th day of administration but still greater than the initial weight along with the increase of tumors during the experimental administration period; the body weight of animals in the PD-L1+CTLA-4 group has no influence. Experimental results show that IL-12+PD-L1+CTLA-4 has good safety in combination.
Claims (9)
1. An immune checkpoint inhibitor composition, characterized in that the immune checkpoint inhibitor composition comprises a first active ingredient and a second active ingredient, wherein the first active ingredient is a cytokine that increases the tumor response rate, and the second active ingredient is two immune checkpoint inhibitors;
the cytokine for improving the tumor response rate is human interleukin 12, and the two immune checkpoint inhibitors are PD-1 antibody and CTLA4 antibody.
2. The immune checkpoint inhibitor composition according to claim 1, wherein the immune checkpoint inhibitor composition is in unit dosage form, wherein the human interleukin 12 content in each unit dosage form is 2-9 μg/dose, wherein the PD-1 antibody content in each unit dosage form is 0.2-0.4 mg/kg/dose, and wherein CTLA4 antibody content is 0.2-0.4 mg/kg/dose.
3. The immune checkpoint inhibitor composition according to claim 2, wherein the immune checkpoint inhibitor composition is in unit dosage forms, wherein the human interleukin 12 content in each unit dosage form is 9 μg/dose, wherein the PD-1 antibody content in each unit dosage form is 0.3 mg/kg/dose, and wherein CTLA4 antibody content is 0.3 mg/kg/dose.
4. The immune checkpoint inhibitor composition according to claim 2, characterized in that the unit dosage form is a dosage form comprising a unit dose of active ingredient, and the unit dose refers to a single administration dose of active ingredient.
5. The immune checkpoint inhibitor composition according to claim 1, characterized in that the first and second active ingredient are present separately.
6. The immune checkpoint inhibitor composition according to claim 1, wherein the immune checkpoint inhibitor composition is in the form of an injectable or oral formulation.
7. Use of the immune checkpoint inhibitor composition as defined in any one of claims 1-6 in the manufacture of a medicament for the treatment of a tumor.
8. The use of an immune checkpoint inhibitor composition according to claim 7 in the manufacture of a formulation or medicament for the treatment of a tumor, wherein the therapeutic tumor medicament is a formulation or medicament that restores T cell activity, enhances T cell immune responses;
or agents or drugs that inhibit tumor cell proliferation and/or induce tumor cell apoptosis;
or agents or drugs that inhibit the tumorigenicity of tumor cells.
9. The use of an immune checkpoint inhibitor composition as claimed in claim 7 in the manufacture of a formulation or medicament for the treatment of a tumour, wherein the tumour is a solid tumour including but not limited to lung cancer, stomach cancer, liver cancer, pancreatic cancer, oesophageal cancer, colorectal cancer, renal cancer, urothelial cancer, ovarian cancer, breast cancer, malignant melanoma, head and neck squamous carcinoma, nasopharyngeal cancer, brain glioma, lymphoma.
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