Composition of il-15 prodrug and immune checkpoint inhibitor

Abstract

The present application relates to a composition of an IL-15 prodrug and an immune checkpoint inhibitor, and a use thereof in preparation of a drug for treating or preventing a tumor disease; a method for treating or preventing the tumor disease in a patient, comprising administering to a patient the composition of the IL-15 prodrug and the immune checkpoint inhibitor; and a pharmaceutical composition or a pharmaceutical composition package for treating or preventing the tumor disease, comprising the IL-15 prodrug and the immune checkpoint inhibitor.

Description

Combination of IL-15 prodrugs and immune checkpoint inhibitors

[0001] Cross-references

[0002] This application is based on the Chinese patent application with application number 202410219883.9 and application date of February 27, 2024, and claims the priority of the Chinese patent application. The entire content of the Chinese patent application is hereby introduced into this application as a reference. Technical Field

[0003] The present invention relates to the use of a combination of an IL-15 prodrug and an immune checkpoint inhibitor in the preparation of a drug for treating or preventing tumor diseases. Background Art

[0004] Interleukin-15 (IL-15) is a cytokine that can induce the proliferation of natural killer cells (NK) and other cells of the immune system, and can participate in killing virus-infected cells or tumor cells. However, the obvious side effects of IL-15 limit the dosage of such drugs. For example, WO2020 / 252264A discloses a prodrug of IL-15 code-named JR2.145.2; the prodrug is a recombinant human IL-15 prodrug-Fc fusion protein, which mainly exists in the form of a complete prodrug in the normal systemic circulation and is activated at a specific point in the tumor microenvironment, thereby stimulating the expansion and activation of NK cells and Teff cells, thereby improving the efficacy of the drug and significantly reducing systemic toxicity.

[0005] Immune checkpoint inhibitors have become powerful cancer treatments. These agents block inhibitory immune checkpoint signaling that limits immune system function. Consequently, immune checkpoint inhibitors can lead to enhanced T cell activation, proliferation, and / or signaling. Currently marketed immune checkpoint inhibitors primarily include CTLA-4 inhibitors, PD-1 antibodies, and PD-L1 antibodies.

[0006] We surprisingly found that the combined administration of IL-15 prodrug and immune checkpoint inhibitors resulted in improved effects. Summary of the Invention

[0007] The present invention provides a combination of an IL-15 prodrug and an immune checkpoint inhibitor and applications thereof. The drug combination has a better additive therapeutic effect than the single active ingredient alone and is highly safe.

[0008] In a first aspect of the present invention, a combination of an IL-15 prodrug and an immune checkpoint inhibitor is provided, and their use in the preparation of a medicament for treating or preventing a tumor disease; the constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, wherein the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof.

[0009] The second aspect of the present invention provides a method for treating or preventing tumor diseases in patients, characterized in that a combination of an IL-15 prodrug and an immune checkpoint inhibitor is administered to the patient; the constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, and the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof.

[0010] The third aspect of the present invention provides a pharmaceutical composition or drug combination package for treating or preventing tumor diseases, characterized in that it comprises an IL-15 prodrug and an immune checkpoint inhibitor; the constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, and the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof.

[0011] In one embodiment of the present invention, the IL-15 prodrug has a sequence with a similarity of not less than 90% (e.g., not less than 95%, not less than 98%, not less than 99%) to SEQ ID No: 1 and a similarity of not less than 90% (e.g., not less than 95%, not less than 98%, not less than 99%) to SEQ ID No: 2. In one embodiment of the present invention, the IL-15 prodrug has the sequences shown in SEQ ID No: 1 and SEQ ID No: 2; SEQ ID No: 1 and SEQ ID No: 2 are bound by a knob-into-hole (KiH) structure; the IL-15 prodrug is named "215β" in the present invention. The fusion protein composed of SEQ ID No: 1 and SEQ ID No: 2 is JR2.145.2 in WO2020 / 252264A (the two peptide chains of JR2.145.2 in WO2020 / 252264A need to remove the N-terminal 17aa signal peptide respectively).

[0012] SEQ ID No:1 Mask chain

[0013] SEQ ID No:2 Cytokine chain

[0014] In a specific embodiment of the present invention, the immune checkpoint inhibitor is selected from one or more of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, a dual-targeting antibody comprising an anti-PD-1 antibody, a dual-targeting antibody comprising an anti-PD-L1 antibody, and a dual-targeting antibody comprising an anti-CTLA-4 antibody. Exemplary, the anti-PD-1 antibodies include, but are not limited to, Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Penpulimab, Zimberelimab, Serplulimab, Pucotenlimab, Dostarlimab, Cemiplimab, and Prolgolimab. Exemplarily, the PD-L1 antibodies include, but are not limited to, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab, Adebrelimab, and Avelumab.

[0015] In a specific embodiment of the present invention, the immune checkpoint inhibitor is selected from Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Penpulimab, Zimberelimab, Serplulimab, limab), Pucotenlimab, Dostarlimab, Cemiplimab, Prolgolimab, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab, Adebrelimab, and Avelumab.

[0016] In one embodiment of the present invention, the dosage of the IL-15 prodrug is a fixed dose for each patient that does not vary with body weight; the dosage is approximately 15 mg to 120 mg administered once every two weeks, every three weeks, every four weeks, every six weeks, every month or every two months, by intravenous (IV) or subcutaneous injection (SubQ).

[0017] In one embodiment of the present invention, the dosage of the IL-15 prodrug is a fixed dose for each patient that does not vary with body weight; the dosage is approximately 3 mg to 20 mg administered once every two weeks, every three weeks, every four weeks, every six weeks, every month or every two months, by intravenous (IV) or subcutaneous injection (SubQ).

[0018] In a specific embodiment of the present invention, the dosage of the IL-15 prodrug is about 3 mg once every two weeks, about 6 mg once every two weeks, about 10 mg once every two weeks, about 15 mg once every two weeks, about 20 mg once every two weeks, about 25 mg once every two weeks, about 30 mg once every two weeks, about 45 mg once every two weeks, or about 60 mg once every two weeks, intravenously (IV) or subcutaneously (SubQ).

[0019] In a specific embodiment of the present invention, the dosage of the IL-15 prodrug is about 3 mg once every three weeks, about 6 mg once every three weeks, about 10 mg once every three weeks, about 15 mg once every three weeks, about 20 mg once every three weeks, about 25 mg once every three weeks, about 30 mg once every three weeks, about 45 mg once every three weeks, or about 60 mg once every three weeks, administered intravenously (IV) or subcutaneously (SubQ).

[0020] In a specific embodiment of the invention, the dosage of the IL-15 prodrug is about 3 mg once every four weeks, about 6 mg once every four weeks, about 10 mg once every four weeks, about 15 mg once every four weeks, about 20 mg once every four weeks, about 30 mg once every four weeks, about 45 mg once every four weeks, or about 60 mg once every four weeks, administered intravenously (IV) or subcutaneously (SubQ).

[0021] In a specific embodiment of the present invention, the dosage of the IL-15 prodrug is about 3 mg once every six weeks, about 6 mg once every six weeks, about 10 mg once every six weeks, about 15 mg once every six weeks, about 20 mg once every six weeks, about 30 mg once every six weeks, about 45 mg once every six weeks, or about 60 mg once every six weeks, intravenously (IV) or subcutaneously (SubQ).

[0022] In a specific embodiment of the present invention, the dosage of the IL-15 prodrug is about 6 mg or 10 mg or 15 mg or 20 mg once in the (n) cycle and about 6 mg or 10 mg or 15 mg or 20 mg once in the (n+m) cycle; intravenous injection (IV) or subcutaneous injection (SubQ); the length of the (n) cycle is 3 weeks, and the length of the (n+m) cycle is 6 weeks; n is 1, 2, 3, 4, 5, 6, 7, or 8, and m is a natural number and is not zero.

[0023] In a specific embodiment of the present invention, the tumor disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer or choriocarcinoma.

[0024] In a specific embodiment of the present invention, in the combination, the IL-15 prodrug and the immune checkpoint inhibitor are administered simultaneously or at different times.

[0025] In one embodiment of the present invention, the IL-15 prodrug is in a therapeutically effective amount; the administered dose may be one or more dosage specifications of the formulation. In one embodiment of the present invention, the immune checkpoint inhibitor is in a therapeutically effective amount; the administered dose may be one or more dosage specifications of the formulation. The dosage of the immune checkpoint inhibitor can be determined by a person skilled in the art based on the product instructions of the corresponding immune checkpoint inhibitor or other existing knowledge in the art.

[0026] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and nivolumab; the recommended dose of nivolumab is 3 mg / kg, administered by intravenous infusion once every 2 weeks.

[0027] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and pembrolizumab; the recommended dose of pembrolizumab is 2 mg / kg, intravenous infusion once every 3 weeks; the recommended dose of pembrolizumab is 200 mg, intravenous infusion once every 3 weeks.

[0028] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Toripalimab; the recommended dose of Toripalimab is 3 mg / kg, intravenous infusion once every 2 weeks; the recommended dose of Toripalimab is 240 mg, intravenous infusion once every 3 weeks.

[0029] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and sintilimab; the recommended dose of sintilimab is 200 mg, administered by intravenous infusion once every 3 weeks.

[0030] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Camrelizumab; the recommended dose of Camrelizumab is 3 mg / kg, intravenous infusion once every 3 weeks; the recommended dose of Camrelizumab is 200 mg, intravenous infusion once every 2 weeks; the recommended dose of Camrelizumab is 200 mg, intravenous infusion once every 3 weeks.

[0031] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and tislelizumab; the recommended dose of tislelizumab is 200 mg, administered by intravenous infusion once every 2 weeks.

[0032] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and penpulimab; the recommended dose of penpulimab is 200 mg / kg, intravenous infusion once every 2 weeks; the recommended dose of penpulimab is alternatively 200 mg / kg, intravenous infusion once every 3 weeks.

[0033] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and zimberelimab; the recommended dose of zimberelimab is 240 mg, administered by intravenous infusion once every 2 weeks.

[0034] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and serplulimab; the recommended dose of serplulimab is 3 mg / kg, intravenous infusion once every 2 weeks; the recommended dose of serplulimab is 4.5 mg / kg, intravenous infusion once every 3 weeks.

[0035] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Pucotenlimab; the recommended dose of Pucotenlimab is 200 mg, administered by intravenous infusion once every 3 weeks.

[0036] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and dostarlimab; the recommended dose of dostarlimab is 500 mg, intravenous infusion once every 3 weeks; the recommended dose of dostarlimab is 1000 mg, intravenous infusion once every 6 weeks.

[0037] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Cemiplimab; the recommended dose of Cemiplimab is 350 mg, administered by intravenous infusion once every 3 weeks.

[0038] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and durvalumab; the recommended dose of durvalumab is 10 mg / kg, administered by intravenous infusion once every 2 weeks.

[0039] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and atezolizumab; the recommended dose of atezolizumab is 1200 mg, administered by intravenous infusion once every 3 weeks.

[0040] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Envafolimab; the recommended dose of Envafolimab is 150 mg, administered subcutaneously once a week.

[0041] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Sugemalimab; the recommended dose of Sugemalimab is 1200 mg, administered by intravenous infusion once every 3 weeks.

[0042] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Adebrelimab; the recommended dose of Adebrelimab is 20 mg / kg, administered by intravenous infusion once every 3 weeks.

[0043] In a specific embodiment of the present invention, the combination of IL-15 prodrug and immune checkpoint inhibitor is a combination of 215β and Avelumab; the recommended dose of Avelumab is 10 mg / kg, administered by intravenous infusion once every 2 weeks.

[0044] In one embodiment of the present invention, the IL-15 prodrug is administered parenterally. In one embodiment of the present invention, the immune checkpoint inhibitor is administered parenterally.

[0045] Those skilled in the art can easily determine the CDR sequence based on the sequence of the antibody heavy or light chain variable region. To annotate the CDRs of an antibody variable region, one must select an antibody numbering scheme and a definition scheme. Numbering schemes include, but are not limited to, IMGT, Chothia, Kabat, and Martin (extended Chothia); definition schemes include, but are not limited to, Chothia, Kabat, IMGT, and Contact.

[0046] Sequence alignment typically uses a reference sequence as a comparison sequence for comparison. In this application, the term "similarity" refers to the proportion of identical amino acids between the test and target sequences (a relatively macroscopic description). In amino acid sequence alignments, similarity also includes, in addition to identical residues, whether the two residues at corresponding positions have similar properties, such as side chain size, charge, and hydrophilicity. Methods for sequence alignment are common knowledge in the art.

[0047] As used herein, the term "drug combination" includes fixed-dose combinations (in a single dosage form), drug combination packages for combined administration, and combination therapies. In the case of drug combination packages or combination therapies, the drugs may be administered simultaneously or separately at intervals. As used herein, the term "fixed-dose combination" refers to a single dosage form formulated to deliver a fixed amount of two or more drugs to a patient; exemplary examples include combination preparations and compound preparations. As used herein, the terms "combination preparation" or "combination preparation" refer to a drug product composed of several drug components; a "combination preparation" refers to a preparation composed of several drugs of different classes; a "combination preparation" refers to a preparation composed of several drugs of the same class, although other classes of drugs are also permitted. As used herein, the term "drug combination package" refers to a package consisting of two or more drug preparations with independent indications, usage, and dosages. As used herein, the term "combination therapy" refers to the administration of two or more drugs with independent indications, usage, and dosages to a patient to treat related diseases.

[0048] In the present invention, the term "pharmaceutically acceptable" refers to those substances, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0049] In the present invention, the term "comprising" or "including" may be open, semi-closed or closed. In other words, the term also includes "essentially consisting of" or "consisting of."

[0050] As used herein, "mass volume percentage" or "% (w / v)" or "% w / v" is a way of expressing mass volume concentration, which represents the grams of solute contained in every 100 ml of solution. For example, 20% (w / v) means that every 100 ml of solution contains 20 g of solute.

[0051] Sequence Listing

[0052] The sequence information involved in the present invention is provided in the table below. DETAILED DESCRIPTION

[0053] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.

[0054] Unless otherwise specified, the abbreviations in this invention have the following meanings:

[0055] BW Body weight

[0056] TV Tumor volume

[0057] QW quaque week once a week

[0058] NSG NOD SCID Gamma

[0059] Example 1

[0060] Negative control PBS buffer

[0061] PD-1 antibody nivolumab

[0062] IL15ref is a generic version of a drug currently under clinical investigation, a fusion protein consisting of IL-15, IL-15Rα (sushi), and Fc.

[0063] 1.1 Animal husbandry and care

[0064] NSG / MHCDKD / female (Cat. No. 025216) mice (6-8 weeks) were purchased from Jackson. The animals were housed in a pre-filled corncob litter. The mice were placed in disposable cages and given free access to food (rodent chow and sterile drinking water). On independently ventilated racks, HEPA-filtered air is provided at a rate of 55 air changes per hour. The room temperature is controlled at 72°F ± 5°F (approximately 22.2°C ± 2.8°C) and the humidity is ambient. The indoor lighting is timed to a 12-hour light / dark cycle. Animals are acclimated for at least 72 hours and up to one week after arrival. When grouping, they are individually identified by ear tags and grouped with cage cards. All personnel entering the animal area wear appropriate personal protective equipment; all work surfaces must be disinfected before and after use.

[0065] 1.2 Cell culture and inoculation

[0066] The human malignant melanoma cell line A375 (CRL-1619) was purchased from ATCC and cultured in a monolayer in DMEM supplemented with 10% heat-inactivated fetal bovine serum (FBS) at 37°C and 5% CO2 according to the culture information of ATCC. Depending on the growth rate of the tumor cells, routine passages were performed 2-3 times a week. The cells used for inoculation were cultured for no more than 5 generations after recovery. Cells in the logarithmic growth phase (80% confluence) were collected and centrifuged at 335g in a refrigerated centrifuge to discard the supernatant. When inoculating cells, the cells were resuspended in 10 volumes of serum-free DMEM, filtered through a 70μm nylon mesh cell strainer, and counted using an automated cell counter. The cell suspension was centrifuged again and resuspended in serum-free DMEM and cold Matrigel (1:1 volume configuration).

[0067] A375 cells were at passage 6 when they were recovered and at passage 8 when they were harvested and inoculated. The cell viability was 90% at inoculation and 89% after inoculation.

[0068] After a week of adaptation, the mice were given 5*10 6 A single-cell suspension of 0.2 ml of A375 tumor cells (50% serum-free DMEM medium + 50% Matrigel) was inoculated subcutaneously in the right lower abdomen (near the dorsal thigh) of mice. The mice were lightly anesthetized. The skin fold was lifted with one hand, and the injection was performed with the other hand, ensuring subcutaneous injection. Any droplets on the skin were carefully wiped after injection to further minimize the possibility of tumor ulceration.

[0069] 1.3 PBMC (HLA-A2) transplantation and animal grouping

[0070] Human PBMC were purchased from Stem Express Company with a cell viability of 95%. 7 PBMC (100 μl RPMI-1640 serum-free medium) were injected into the tail vein of the rats with an average tumor size of approximately 100 mm. 3 The mice were then randomly divided into groups.

[0071] When the tumor volume of mice reached 100±15mm 3 At the time of the experiment, the animals were randomly divided into groups. Mice with tumors or partial tumors extending into the muscle or skin, or with irregular tumor growth, were not included in the experimental group. A total of 60 mice were enrolled, with 10 mice in each group.

[0072] 1.4

[0073] Dosing began on the day of randomization and was designated as Day 0. The administration of the test article to each group of animals was as follows:

[0074] G1 group, PBS buffer intraperitoneal injection, QW*4 times;

[0075] Groups G2, G3, G4, G5, and G6 received intraperitoneal injection of PD-1 antibody, 3 mg / kg, QW*4 times;

[0076] G3 group, intraperitoneal injection of 215β, 0.1 mg / kg, QW*4 times;

[0077] G4 group, intraperitoneal injection of 215β, 0.3 mg / kg, QW*4 times;

[0078] Group G5, intraperitoneal injection of 215β, 1 mg / kg, QW*4 times;

[0079] Group G6 received intraperitoneal injection of IL15ref, 0.5 mg / kg, QW*4 times.

[0080] All animals were observed daily for food and water intake, tumor size, physical condition, activity, etc. Clinical signs were recorded twice a week, and activity, fur condition, physical condition, environment, hydration, and tumor ulceration were scored based on the observations, with scores ranging from 0 (no abnormal observation) to 3 (significant abnormality). Animals with a daily cumulative score of 5-6 points were given supplementary care (such as supplementary drinking water, dietary gel), and animals with a daily cumulative score of ≥8 points were euthanized. Animals that reached the euthanasia criteria (termination of the study) were euthanized. At the end of the study, all animals were euthanized by CO2 asphyxiation followed by cervical dislocation.

[0081] Body weights were recorded twice weekly; 2D dimensions of tumors were measured with calipers twice weekly.

[0082] Tumor volume (mm 3 )Calculation formula: a and b are the long diameter (in mm) and short diameter (in mm) of the tumor, respectively.

[0083] The tumor growth inhibition rate (%) was calculated as follows: [1-(Td-T0) / (Cd-C0)]*100%, where Td and Cd were the average tumor volumes of the treatment group and the control group on the measurement day, respectively, and T0 and C0 were the average tumor volumes of the treatment group and the control group on day 0, respectively.

[0084] The body weight change (%) was calculated as follows: [(BWday-BWD0) / BWD0]*100%, where BWday is the average body weight on the measurement day and BWD0 is the average body weight on day 0.

[0085] (1) Changes in tumor volume

[0086] The mean tumor volumes (TV) of different treatment groups at different days are shown in Table 1 .

[0087] Table 1

[0088] *Days: Days after treatment

[0089] Data are expressed as mean ± standard deviation

[0090] On day 18, the tumor growth inhibition rates of groups G2, G3, G4, G5, and G6 were 16.3%, 9.8%, 40.5%, 73.6%, and 38.0%, respectively. Group G5 had the best treatment effect, with a tumor growth inhibition rate of 73.6% on day 18.

[0091] (2) Survival curve

[0092] On day 25, the survival rate of mice in group G1 was 0%, while that in groups G2, G3, G4, G5, and G6 was 10%, 20%, 70%, 80%, and 20%, respectively. The overall survival rate in groups G4 and G5 was significantly prolonged on day 25 compared with group G1. Survival curves are shown in Table 2.

[0093] Table 2

[0094] *Days: Days after treatment

[0095] Data represent overall survival rate in corresponding days after treatment

[0096] Example 2

[0097] PD-1 antibody Tislelizumab

[0098] PD-L1 antibody Sugemalimab

[0099] 215β and PD-1 antibody (or PD-L1 antibody) can be infused on the same day or on different days.

[0100] 2.1 215β monotherapy

[0101] A single-dose study of IL-15 prodrug (215β) was conducted in subjects with locally advanced or metastatic solid tumors to observe the safety, pharmacokinetic characteristics and efficacy of 215β in subjects with locally advanced or metastatic solid tumors.

[0102] Eight dose groups (3mg, 6mg, 10mg, 20mg, 30mg, 45mg, 60mg, 90mg) were selected for implementation, and two alternative dose groups (75mg, 120mg) were set up; the drug was administered once every three weeks; the administration method was intravenous infusion.

[0103] During the trial, the dosage group will be adjusted if necessary based on the clinical trial data such as human safety and PK obtained. The dosing frequency or dosing interval may also be adjusted (such as once every 28 days or 42 days) if necessary.

[0104] 2.2 215β combined with PD-1 antibody

[0105] Patients with locally advanced or metastatic solid tumors were treated with IL-15 prodrug (215β) combined with tislelizumab.

[0106] 215β is divided into four dosage groups: 6mg, 10mg, 15mg, and 20mg, and is administered once every 3 weeks; the dosage of tislelizumab is 200mg, and is administered once every 3 weeks; the administration method is intravenous infusion.

[0107] 2.3 215β combined with PD-1 antibody

[0108] Patients with locally advanced or metastatic solid tumors were treated with IL-15 prodrug (215β) combined with tislelizumab.

[0109] The dose of 215β in the first cycle is 10 mg, and the recommended dose (6 mg, 10 mg, 15 mg, or 20 mg) is used in the second and subsequent cycles. The first cycle is Q3W (administered once every 3 weeks), and the second and subsequent cycles are Q6W (administered once every 6 weeks). The dose of tislelizumab is 200 mg, administered once every 3 weeks. The administration route is intravenous infusion.

[0110] 2.4 215β combined with PD-L1 antibody

[0111] Patients with locally advanced or metastatic solid tumors were treated with IL-15 prodrug (215β) combined with sugemalimab.

[0112] The recommended dose of 215β (6 mg, 10 mg, 15 mg, or 20 mg) is administered once every 3 weeks; the dose of sugemalimab is 1200 mg, administered once every 3 weeks; both are administered by intravenous infusion.

[0113] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above disclosure, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. The use of a combination of an IL-15 prodrug and an immune checkpoint inhibitor in the preparation of a drug for treating or preventing tumor diseases; The constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, wherein the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof; the IL-15 prodrug has a sequence that is not less than 90% similar to SEQ ID No: 1 and not less than 90% similar to SEQ ID No:

2.

2. A method for treating or preventing a tumor disease in a patient, characterized in that administering to the patient a combination of an IL-15 prodrug and an immune checkpoint inhibitor; The constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, wherein the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof; the IL-15 prodrug has a sequence that is not less than 90% similar to SEQ ID No: 1 and not less than 90% similar to SEQ ID No:

2.

3. A pharmaceutical composition or pharmaceutical combination package for treating or preventing tumor diseases, characterized in that: Contains IL-15 prodrug and immune checkpoint inhibitors; The constituent units of the IL-15 prodrug include the Sushi domain of the IL-15 receptor α subunit, IL-15 or a mutant thereof, and an anti-IL-15 scFv, wherein the anti-IL-15 scFv has the function of masking IL-15 or a mutant thereof; the IL-15 prodrug has a sequence that is not less than 90% similar to SEQ ID No: 1 and not less than 90% similar to SEQ ID No:

2.

4. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The IL-15 prodrug has the sequences shown in SEQ ID No: 1 and SEQ ID No: 2, and SEQ ID No: 1 and SEQ ID No: 2 are combined via a knob-into-hole (KiH) structure.

5. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The immune checkpoint inhibitor is selected from one or more of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, dual-targeting antibodies comprising anti-PD-1 antibodies, dual-targeting antibodies comprising anti-PD-L1 antibodies, and dual-targeting antibodies comprising anti-CTLA-4 antibodies.

6. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The immune checkpoint inhibitor is an anti-PD-1 antibody and / or an anti-PD-L1 antibody.

7. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The immune checkpoint inhibitor is selected from Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Penpulimab, Zimberelimab, Serplulimab, Pucotenlimab, Dostarlimab, Cemiplimab, Prolgolimab, Durvalumab, Atezolizumab, Envafolimab, Sugemalimab, Adebrelimab, Avelumab.

8. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The IL-15 prodrug is dosed at a fixed dose for each patient that does not vary with body weight; the dose is approximately 15 mg to 120 mg administered once every two weeks, three weeks, four weeks, six weeks, monthly, or every two months, intravenously (IV) or subcutaneously (SubQ).

9. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The IL-15 prodrug is dosed at a fixed dose for each patient that does not vary with body weight; the dose is approximately 3 mg to 20 mg administered once every two weeks, three weeks, four weeks, six weeks, monthly, or every two months, intravenously (IV) or subcutaneously (SubQ).

10. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The dosage of the IL-15 prodrug is about 3 mg once every two weeks, about 6 mg once every two weeks, about 10 mg once every two weeks, about 15 mg once every two weeks, about 20 mg once every two weeks, about 25 mg once every two weeks, about 30 mg once every two weeks, about 45 mg once every two weeks, or about 60 mg once every two weeks, intravenously (IV) or subcutaneously (SubQ); or, The IL-15 prodrug is administered at a dose of about 3 mg once every three weeks, about 6 mg once every three weeks, about 10 mg once every three weeks, about 15 mg once every three weeks, about 20 mg once every three weeks, about 25 mg once every three weeks, about 30 mg once every three weeks, about 45 mg once every three weeks, or about 60 mg once every three weeks, intravenously (IV) or subcutaneously (SubQ); or, The IL-15 prodrug is administered at a dose of about 3 mg once every four weeks, about 6 mg once every four weeks, about 10 mg once every four weeks, about 15 mg once every four weeks, about 20 mg once every four weeks, about 30 mg once every four weeks, about 45 mg once every four weeks, or about 60 mg once every four weeks, intravenously (IV) or subcutaneously (SubQ); or, The dosage of the IL-15 prodrug is about 3 mg once every six weeks, about 6 mg once every six weeks, about 10 mg once every six weeks, about 15 mg once every six weeks, about 20 mg once every six weeks, about 30 mg once every six weeks, about 45 mg once every six weeks, or about 60 mg once every six weeks, administered intravenously (IV) or subcutaneously (SubQ).

11. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The dosage of the IL-15 prodrug is approximately 6 mg, 10 mg, 15 mg, or 20 mg once in the (n) cycle and approximately 6 mg, 10 mg, 15 mg, or 20 mg once in the (n+m) cycle; intravenous injection (IV) or subcutaneous injection (SubQ); the length of the (n) cycle is 3 weeks, and the length of the (n+m) cycle is 6 weeks; n is 1, 2, 3, 4, 5, 6, 7, or 8, and m is a natural number and is not zero.

12. The use according to claim 1, or the method according to claim 2, or the pharmaceutical composition or pharmaceutical combination package according to claim 3, characterized in that: The tumor disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck cancer, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder tumor, gallbladder cancer, bile duct cancer or choriocarcinoma.

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