Combination of fusion molecule of Anti-PD-1 antibody-il-15 prodrug and chemotherapeutic drug, and use thereof

Abstract

Provided are a combination of a fusion molecule of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapeutic drug, and use thereof. Specifically, provided is use of a combination of an IL-15 prodrug and a chemotherapeutic drug in the preparation of a medicament for treating a tumor disease.

Description

Combination of anti-PD-1 antibody-IL-15 prodrug with chemotherapy drugs and its application

[0001] Cross-references

[0002] This disclosure is based on and claims priority to Chinese Patent Application No. CN202510114625.9, filed on January 24, 2025, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the use of a combination of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapeutic agent in the preparation of a medicament for treating tumor diseases. Background Technology

[0004] Interleukin-15 (IL-15) is a cytokine that can induce the proliferation of natural killer (NK) cells and other cells of the immune system, and can participate in killing virus-infected cells or tumor cells. However, the significant side effects of IL-15 limit the dosage of this type of drug.

[0005] WO2021 / 142471A discloses an IL-15 prodrug designated 215γ. 215γ is a fusion molecule of an anti-PD-1 fully human monoclonal antibody and an IL-15 prodrug. It can target PD-1-expressing immune cells, specifically activate IL-15 activity in the tumor microenvironment, prolong its half-life, and improve tolerability, thereby expanding the therapeutic window of IL-15. Before activation, the active site of IL-15 in 215γ is masked by a masking group. In the tumor microenvironment, the masking group is recognized and enzymatically cleaved, thereby activating IL-15 in 215γ. In the circulatory system, 215γ exists in prodrug form. After activation in the tumor microenvironment, the 215γ molecule can simultaneously bind to PD-1 and IL-15 receptors on the surface of T cells, exerting a synergistic activation effect, inducing immune cell activation and proliferation, and thus exerting a tumor-killing effect. The prodrug design of 215γ is intended to prevent IL-15 from binding nonspecifically to NK or T cells in the system, thereby increasing tolerability and reducing systemic toxicity.

[0006] Chemotherapy is a treatment method that uses chemical drugs to kill tumor cells and inhibit their growth. Summary of the Invention

[0007] We were pleasantly surprised to find that the combined administration of 215γ with chemotherapy drugs led to improved effects.

[0008] In a first aspect, the present invention provides the use of a combination of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapeutic agent in the preparation of a medicament for treating tumor diseases;

[0009] The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv.

[0010] The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents.

[0011] The combination may optionally further include targeted therapeutic agents.

[0012] A second aspect of the present invention provides a method for treating a tumor disease in a patient, characterized in that the patient is given a combination of a fusion molecule of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapy drug.

[0013] The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv.

[0014] The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents.

[0015] The combination may optionally further include targeted therapeutic agents.

[0016] A third aspect of the present invention provides a pharmaceutical combination for treating tumor diseases, characterized in that it comprises a fusion molecule of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapeutic agent;

[0017] The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv.

[0018] The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents.

[0019] The drug combination may optionally further include targeted therapeutic agents.

[0020] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two identical heavy chains fusion polypeptides. The amino acid sequence of the light chain has at least 90% similarity to SEQ ID NO:1 (e.g., at least 95%, at least 98%, or at least 99%), the amino acid sequence of the first heavy chain fusion polypeptide chain has at least 90% similarity to SEQ ID NO:2 (e.g., at least 95%, at least 98%, or at least 99%), and the amino acid sequence of the second heavy chain fusion polypeptide chain has at least 90% similarity to SEQ ID NO:3 (e.g., at least 95%, at least 98%, or at least 99%).

[0021] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is "215γ"; 215γ comprises two identical light chains and two heavy chains fusion polypeptides, the amino acid sequence of the light chain is SEQ ID NO:1, the amino acid sequence of the first heavy chain fusion polypeptide chain is SEQ ID NO:2, and the amino acid sequence of the second heavy chain fusion polypeptide chain is SEQ ID NO:3.

[0022] SEQ ID NO:1

[0023] SEQ ID NO:2

[0024] SEQ ID NO:3

[0025] In one embodiment of the present invention, the chemotherapeutic agent includes a pyrimidine analog chemotherapeutic agent.

[0026] In one embodiment of the present invention, the chemotherapeutic agent includes a platinum-based chemotherapeutic agent.

[0027] In one embodiment of the present invention, the chemotherapeutic agent includes a paclitaxel-based chemotherapeutic agent.

[0028] In one embodiment of the present invention, the chemotherapeutic agent includes camptothecin-based chemotherapeutic agents.

[0029] In one embodiment of the present invention, the chemotherapeutic agent includes anthracycline antibiotics.

[0030] In one embodiment of the present invention, the chemotherapeutic agent includes pyrimidine analog chemotherapeutic agents and camptothecin-based chemotherapeutic agents.

[0031] In one embodiment of the present invention, the chemotherapeutic agent includes pyrimidine analog chemotherapeutic agents and platinum-based chemotherapeutic agents.

[0032] Chemotherapy is a treatment method that uses chemical drugs to kill tumor cells and inhibit their growth.

[0033] In one embodiment of the present invention, the pyrimidine analog chemotherapeutic agent is selected from cytarabine, 5-fluorouracil (also known as fluorouracil, abbreviated as 5-Fu), decitabine, gemcitabine, carmofur, capecitabine, doxifluridine, tegafur, or azacitidine.

[0034] In one embodiment of the present invention, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, nedaplatin, oxaliplatin, or lobaplatin.

[0035] In one embodiment of the present invention, the paclitaxel-based chemotherapeutic agent is selected from paclitaxel, nab-paclitaxel, paclitaxel liposome, or docetaxel.

[0036] In one embodiment of the present invention, the camptothecin-based chemotherapeutic drug is selected from camptothecin, hydroxycamptothecin, topotecan, or irinotecan.

[0037] In one embodiment of the present invention, the anthracycline antibiotic chemotherapy drug is selected from doxorubicin or epirubicin.

[0038] In one embodiment of the present invention, the chemotherapeutic agent includes a pyrimidine analog chemotherapeutic agent and a camptothecin chemotherapeutic agent; the pyrimidine analog chemotherapeutic agent is selected from 5-fluorouracil, capecitabine or tegafur; the camptothecin chemotherapeutic agent is selected from topotecan or irinotecan.

[0039] In one embodiment of the present invention, the chemotherapeutic agent includes a pyrimidine analog chemotherapeutic agent and a platinum-based chemotherapeutic agent; the pyrimidine analog chemotherapeutic agent is selected from 5-fluorouracil, capecitabine or tegafur; the platinum-based chemotherapeutic agent is selected from oxaliplatin or cisplatin.

[0040] In one embodiment of the present invention, the chemotherapeutic drug may optionally be used in conjunction with adjuvant chemotherapeutic drugs.

[0041] In one embodiment of the present invention, the adjuvant chemotherapy drug is selected from calcium folinate, folinic acid, mesna, bisphosphonates, amifostine, granulocyte colony-stimulating factor (G-CSF), ondansetron, dexamethasone, prednisone, methylprednisolone, or omeprazole.

[0042] In one embodiment of the present invention, the adjuvant chemotherapy drug is selected from calcium folinate, folinic acid, or amifostine.

[0043] In one exemplary embodiment of the present invention, the chemotherapeutic drug is administered in combination with a chemotherapeutic adjuvant drug; the chemotherapeutic drug is 5-fluorouracil and irinotecan, and the chemotherapeutic adjuvant drug is leucovorin calcium.

[0044] In one exemplary embodiment of the present invention, the chemotherapeutic drug is administered in combination with a chemotherapeutic adjuvant drug; the chemotherapeutic drug is 5-fluorouracil and oxaliplatin, and the chemotherapeutic adjuvant drug is leucovorin calcium.

[0045] In one embodiment of the present invention, the targeted therapeutic drug is a drug that targets EGFR, VEGF, or VEGFR.

[0046] In one embodiment of the present invention, the targeted therapeutic drug is a drug that targets EGFR; the drug that targets EGFR is selected from EGFR kinase inhibitors or anti-EGFR antibodies.

[0047] In one embodiment of the present invention, the EGFR kinase inhibitor is selected from gefitinib, erlotinib, icotinib, lapatinib, afatinib, dacomitinib, neratinib, osimertinib, almonertinib, furmonertinib, rociletinib, abivertinib, befotertinib, rezivertinib, rilertinib, limertinib, lazertinib, or nazartinib.

[0048] In one embodiment of the present invention, the anti-EGFR antibody is selected from cetuximab, panitumumab, necitumumab, matuzumab, or nimotuzumab.

[0049] In one embodiment of the present invention, the targeted therapeutic drug is a drug that targets VEGF; the drug that targets VEGF is selected from anti-VEGF fusion protein or anti-VEGF antibody.

[0050] In one embodiment of the present invention, the anti-VEGF fusion protein is selected from aflibercept or conbercept.

[0051] In one embodiment of the present invention, the anti-VEGF antibody is selected from bevacizumab, ranibizumab, faricimab, ivonescimab, brolucizumab, or sevacizumab.

[0052] In one embodiment of the present invention, the targeted therapeutic drug is a drug that targets VEGFR; the drug that targets VEGFR is selected from VEGFR kinase inhibitors or anti-VEGFR antibodies.

[0053] In one embodiment of the present invention, the VEGFR kinase inhibitor is selected from fruguintinib, cabozantinib, sorafenib, donafenib, sunitinib, axitinib, anlotinib, apatinib, lenvatinib, famitinib, surufatinib, tivozanib, ponatinib, nintedanib, vorolanib, or regorafenib.

[0054] In one embodiment of the present invention, the anti-VEGFR antibody is selected from ramucirumab, plosixamab, gentuximab, olivaximab, JY025, or MSB0254.

[0055] In one embodiment of the present invention, the targeted therapeutic drug is selected from gefitinib, erlotinib, icotinib, lapatinib, afatinib, dacomitinib, neratinib, osimertinib, amitinib, vormetinib, roxitinib, avitinib, befotinib, retizinib, riertinib, liertinib, lazatinib, nazatinib, cetuximab, panitumumab, nexituzumab, mateuzumab, nimotuzumab, aflibercept, conbercept, and bevacizumab. Ranibizumab, ranibizumab, faraxicillinab, evokinemab, buxicillinab, suvisitabine, fruquintinib, cabozantinib, sorafenib, donafenib, sunitinib, axitinib, anlotinib, apatinib, lenvatinib, famitinib, surufatinib, tevozanib, ponatinib, nintedanib, voronibub, regorafenib, ramoximumab, proximab, gentuximab, ovaxicillinab, JY025, or MSB0254.

[0056] In one embodiment of the present invention, the targeted therapeutic drug is selected from fruquintinib, cetuximab, or bevacizumab.

[0057] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is a therapeutically effective amount; the dosage may be one or more formulation dosage specifications.

[0058] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered at a frequency of approximately once weekly, approximately once every two weeks, approximately once every three weeks, approximately once every four weeks, approximately once monthly, approximately once every six weeks, approximately once every eight weeks, approximately once every two months, approximately once every ten weeks, approximately once every twelve weeks, approximately once every three months, or approximately twice every three weeks. In a specific embodiment of the present invention, the dosage of the IL-15 prodrug is such that a dose X is given in cycle (n) and a dose Y is given in cycle (n+m); the length of cycle (n) is approximately 3 weeks, and the length of cycle (n+m) is approximately 6 weeks; n is independently 1, 2, 3, 4, 5, 6, 7, or 8, and m is a natural number and not zero.

[0059] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered via a non-gastrointestinal route. In another embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered intravenously (IV) or subcutaneously (SubQ).

[0060] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered at a dose of 0.1–10 mg / kg. In another embodiment of the present invention, the anti-PD-1 antibody-IL-15 prodrug is administered at a dose of 0.15–4.5 mg / kg. In yet another embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered at doses of 0.15 mg / kg, 0.3 mg / kg, 0.75 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg, or 4.5 mg / kg. The dosing frequency is approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, or approximately once every 6 weeks, or approximately once every 8 weeks, or approximately once every 10 weeks, or approximately once every 12 weeks.

[0061] In one embodiment of the present invention, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is at a concentration of 5–500 mg / m³. 2 Dosage administration. The frequency of administration is approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, or approximately once every 6 weeks, or approximately once every 8 weeks, or approximately once every 10 weeks, or approximately once every 12 weeks.

[0062] In one embodiment of the present invention, the dosage of the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is a fixed dose for each patient that does not vary with body weight (or body surface area); the dose is 10 mg to 1000 mg. The dosing frequency is approximately once every 2 weeks, approximately once every 3 weeks, approximately once every 4 weeks, or approximately once every 6 weeks, or approximately once every 8 weeks, or approximately once every 10 weeks, or approximately once every 12 weeks.

[0063] In one embodiment of the invention, the dosage of the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is a fixed dose for each patient that does not vary with body weight (or body surface area); the dose is about 10 mg, about 20 mg, about 30 mg, about 45 mg, about 60 mg, about 90 mg, about 120 mg, about 150 mg, about 180 mg, about 200 mg, about 300 mg, about 450 mg, or about 600 mg. The dosing frequency is about once every 2 weeks, about once every 3 weeks, about once every 4 weeks, or about once every 6 weeks, or about once every 8 weeks, or about once every 10 weeks, or about once every 12 weeks.

[0064] In one embodiment of the present invention, the chemotherapeutic drug is a therapeutically effective amount.

[0065] In one embodiment of the present invention, the chemotherapeutic agent is paclitaxel. An exemplary dosing regimen: paclitaxel 80 mg / m² 2Intravenous injection on days 1, 8, and 15; repeated every 21 days. Another exemplary dosing regimen: paclitaxel 60 mg / m² 2 Intravenous injection on days 1, 8, and 15; repeated every 21 days. Another exemplary dosing regimen: Paclitaxel 40 mg / m² 2 Intravenous injection, on days 1, 8, and 15; repeated every 21 days.

[0066] In one embodiment of the present invention, the chemotherapeutic agent is topotecan. An exemplary dosing regimen: Topotecan 1.25 mg / m² 2 Intravenous injection, days 1-5; repeat every 21 days.

[0067] In one embodiment of the present invention, the chemotherapeutic agent is irinotecan. An exemplary dosing regimen: irinotecan 350 mg / m² 2 Intravenous injection, day 1; repeated every 21 days. Another exemplary dosing regimen: Irinotecan 180 mg / m² 2 Intravenous injection, day 1; repeat every 14 days.

[0068] In one embodiment of the present invention, the chemotherapeutic agent is doxorubicin. An exemplary dosing regimen: doxorubicin 20 mg / m². 2 Intravenous injection, day 1; repeat every 14 or 21 days.

[0069] In one embodiment of the present invention, the chemotherapeutic agent is gemcitabine. An exemplary dosing regimen: gemcitabine 1000 mg / m² 2 Intravenous injection, on days 1 and 8; repeated every 21 days. Another exemplary dosing regimen: gemcitabine 1000–1250 mg / m². 2 Intravenous injection, on days 1, 8, and 15; repeated every 28 days.

[0070] In one embodiment of the present invention, the chemotherapy drug is docetaxel. An exemplary dosing regimen: docetaxel 75 mg / m² 2 Intravenous injection, day 1; repeated every 21 days. Another exemplary dosing regimen: Docetaxel 55 mg / m² 2 Intravenous injection, day 1; repeated every 21 days. Another exemplary dosing regimen: Docetaxel 37.5 mg / m² 2 Intravenous injection, day 1; repeat every 21 days.

[0071] In one embodiment of the present invention, the chemotherapeutic agent includes 5-fluorouracil, irinotecan, and the adjuvant chemotherapeutic agent calcium leucovorin. An exemplary dosing regimen: Irinotecan 180 mg / m² 2 Intravenous injection, day 1; leucovorin calcium 400mg / m²2 Intravenous injection, day 1; 5-fluorouracil 400 mg / m² 2 Intravenous injection, day 1; 5-fluorouracil, 1200 mg / m² 2 / day × 2 days of continuous intravenous infusion (total dose 2400 mg / m²) 2 Infusion over 46–48 hours, repeated every 14 days. Another exemplary dosing regimen: Irinotecan 180 mg / m² 2 Intravenous injection, days 1 and 15; leucovorin calcium 400 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil 400 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil, 1200 mg / m² 2 / day × 2 days of continuous intravenous infusion (total dose 2400 mg / m²) 2 Infusion over 46–48 hours, repeated every 28 days. Another exemplary dosing regimen: Irinotecan 150 mg / m². 2 Intravenous injection, days 1 and 15; leucovorin calcium 400 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil 320 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil, 960 mg / m² 2 / day × 2 days of continuous intravenous infusion (total dose 1920mg / m²) 2 Infusion over 46–48 hours, repeated every 28 days. Another exemplary dosing regimen: Irinotecan 120 mg / m². 2 Intravenous injection, days 1 and 15; leucovorin calcium 400 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil 240 mg / m² 2 Intravenous injection, days 1 and 15; 5-fluorouracil, 720 mg / m² 2 / day × 2 days of continuous intravenous infusion (total dose 1440mg / m²) 2 (Infusion for 46-48 hours), repeated every 28 days.

[0072] In one embodiment of the present invention, the chemotherapeutic agent includes 5-fluorouracil, oxaliplatin, and the adjuvant chemotherapeutic agent calcium leucovorin. An exemplary dosing regimen: Oxaliplatin 85 mg / m² 2 Intravenous injection, day 1; leucovorin calcium 400mg / m² 2 Intravenous injection, day 1; 5-fluorouracil 400 mg / m² 2 Intravenous injection, day 1; 5-fluorouracil, 1200 mg / m² 2 / day × 2 days of continuous intravenous infusion (total dose 2400 mg / m²)2 (Infusion for 46-48 hours), repeated every 14 days.

[0073] In one embodiment of the present invention, the targeted therapeutic drug is administered in a therapeutically effective amount; the dosage may be one or more formulation dosage strengths. In another embodiment of the present invention, the targeted therapeutic drug is administered at a frequency of approximately once a week, approximately once every two weeks, approximately once every three weeks, approximately once every four weeks, approximately once a month, approximately once every six weeks, approximately once every eight weeks, approximately once every two months, approximately once every ten weeks, approximately once every twelve weeks, approximately once every three months, or approximately twice every three weeks.

[0074] In one embodiment of the present invention, the targeted therapeutic agent is fruquintinib. An exemplary dosing regimen is: fruquintinib 5 mg, orally administered, from day 1 to day 21; repeated every 28 days.

[0075] In one embodiment of the present invention, the targeted therapeutic agent is cetuximab. An exemplary dosing regimen: an initial dose of cetuximab of 400 mg / m². 2 Maintenance dose 250 mg / m 2 Administer intravenously; repeat every 7 days.

[0076] In one embodiment of the present invention, the targeted therapeutic agent is bevacizumab. An exemplary dosing regimen: bevacizumab 5 mg / kg, intravenously, on days 1 and 15; repeated every 28 days. Another exemplary dosing regimen: bevacizumab 7.5 mg / kg, intravenously, on day 1; repeated every 21 days. Another exemplary dosing regimen: bevacizumab 15 mg / kg, intravenously, on day 1; repeated every 21 days.

[0077] In one 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.

[0078] In one specific embodiment of the present invention, the combination is wherein the anti-PD-1 antibody-IL-15 prodrug is administered simultaneously with or at different times with the chemotherapy drug.

[0079] In one specific embodiment of the present invention, the combination involves the anti-PD-1 antibody-IL-15 prodrug being administered simultaneously with chemotherapy drugs and targeted therapy drugs, or administered at different times.

[0080] In one specific embodiment of the present invention, the anti-PD-1 antibody-IL-15 prodrug, chemotherapy drug, and targeted therapy drug can be formulated, administered preventively, and their dosages adjusted according to clinical practice and drug instructions.

[0081] In addition, this application also relates to the following implementation schemes:

[0082] Implementation Scheme 1: Application of a combination of an anti-PD-1 antibody-IL-15 prodrug fusion molecule and a chemotherapeutic agent in the preparation of a drug for treating tumor diseases; the anti-PD-1 antibody-IL-15 prodrug fusion molecule comprises two identical light chains and two heavy chains of fusion polypeptide, wherein the light chain is an anti-PD-1 antibody light chain, the first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof, and the second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv; the chemotherapeutic agent is selected from one or more of pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, paclitaxel-based chemotherapeutic agents, and camptothecin-based chemotherapeutic agents.

[0083] Implementation Scheme 2: A method for treating tumor disease in a patient, characterized in that the patient is given a combination of a fusion molecule of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapy drug; the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of a fusion polypeptide, the light chain being an anti-PD-1 antibody light chain, the first heavy chain fusion polypeptide comprising an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof, the second heavy chain fusion polypeptide comprising an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv; the chemotherapy drug is selected from one or more of pyrimidine analog chemotherapy drugs, platinum-based chemotherapy drugs, paclitaxel-based chemotherapy drugs, and camptothecin-based chemotherapy drugs.

[0084] Implementation Scheme 3: A drug combination for treating tumor diseases, characterized in that it comprises a fusion molecule of an anti-PD-1 antibody-IL-15 prodrug and a chemotherapeutic agent; the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide, wherein the light chain is an anti-PD-1 antibody light chain, the constituent units of the first heavy chain fusion polypeptide include an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof, the constituent units of the second heavy chain fusion polypeptide include an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv; the chemotherapeutic agent is selected from one or more of pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, paclitaxel-based chemotherapeutic agents, and camptothecin-based chemotherapeutic agents.

[0085] Implementation Scheme 4: The application described in Implementation Scheme 1, or the method described in Implementation Scheme 2, or the drug combination described in Implementation Scheme 3, characterized in that the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises a fusion polypeptide consisting of two identical light chains and two heavy chains.

[0086] The light chain amino acid sequence has at least 90% similarity to SEQ ID NO:1, the first heavy chain fusion polypeptide chain amino acid sequence has at least 90% similarity to SEQ ID NO:2, and the second heavy chain fusion polypeptide chain amino acid sequence has at least 90% similarity to SEQ ID NO:3.

[0087] Implementation Scheme 5: The application according to Implementation Scheme 1, or the method according to Implementation Scheme 2, or the drug combination according to Implementation Scheme 3, characterized in that the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains fusion polypeptides, wherein the amino acid sequence of the light chain is SEQ ID NO:1, the amino acid sequence of the first heavy chain fusion polypeptide chain is SEQ ID NO:2, and the amino acid sequence of the second heavy chain fusion polypeptide chain is SEQ ID NO:3.

[0088] Implementation Scheme 6: The application described in Implementation Scheme 1, the method described in Implementation Scheme 2, or the drug combination described in Implementation Scheme 3, characterized in that the pyrimidine analog chemotherapeutic drug is selected from cytarabine, 5-fluorouracil, decitabine, gemcitabine, carmoflu, capecitabine, deoxyfluorouridine, tegafur, or azacitidine; the platinum-based chemotherapeutic drug is selected from cisplatin, carboplatin, nedaplatin, oxaliplatin, or lobaplatin; the paclitaxel-based chemotherapeutic drug is selected from paclitaxel or docetaxel; and the camptothecin-based chemotherapeutic drug is selected from camptothecin, hydroxycamptothecin, topotecan, or irinotecan.

[0089] Implementation Scheme 7: The application according to Implementation Scheme 1, or the method according to Implementation Scheme 2, or the drug combination according to Implementation Scheme 3, characterized in that the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered at a frequency of approximately once a week, approximately once every two weeks, approximately once every three weeks, approximately once every four weeks, approximately once a month, approximately once every six weeks, approximately once every two months, or twice every three weeks.

[0090] Implementation Scheme 8: The application according to Implementation Scheme 1, or the method according to Implementation Scheme 2, or the drug combination according to Implementation Scheme 3, characterized in that the dosage of the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is given as dose X in cycle (n) and dose Y in cycle (n+m); the length of cycle (n) is approximately 3 weeks, and the length of cycle (n+m) is approximately 6 weeks; n is independently 1, 2, 3, 4, 5, 6, 7, or 8, and m is a natural number and not zero.

[0091] Implementation Scheme 9: The application described in Implementation Scheme 1, or the method described in Implementation Scheme 2, or the drug combination described in Implementation Scheme 3, characterized in that the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered via a non-gastrointestinal route.

[0092] Implementation Scheme 10: The application described in Implementation Scheme 1, or the method described in Implementation Scheme 2, or the drug combination described in Implementation Scheme 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.

[0093] The term "combination" of drugs includes fixed-dose combinations of drugs (in a single dosage form), drug combination packages for combined administration, and combination therapies of drugs; when it is a drug combination package or a combination therapy of drugs, the drugs may be administered simultaneously or separately at time intervals. In this invention, the term "fixed-dose combination" refers to a single dosage form formulated to deliver a certain amount of two or more drugs to a patient; exemplary examples include compound preparations and complex preparations. In this invention, the terms "compound preparation" or "complex preparation" both refer to a drug product composed of several drug components; wherein "compound preparation" refers to a preparation composed of several different classes of drugs; wherein "complex preparation" refers to a preparation composed of several drugs of the same class, and other classes of drugs are also permitted. In this invention, the term "drug combination package" refers to a package consisting of two or more drug preparations having independent indications and dosages. In this invention, the term "combination therapy" of drugs refers to administering two or more drugs with independent indications and dosages to a patient to treat a related disease.

[0094] The term "pharmaceutically acceptable" refers to substances, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0095] The term "therapeutic effective amount" refers to the amount provided that is effective in treating or inhibiting a corresponding disease or symptom, thereby producing the desired therapeutic, ameliorative, inhibitory, or preventative effect. In this invention, the dosage of active ingredients (including but not limited to IL-15 prodrugs, chemotherapeutic agents, and targeted therapeutic agents) is specified unless otherwise stated. "mg / kg" indicates the amount of active ingredient administered per kilogram of body weight in mg (milligrams). 2 "This indicates that the corresponding mg of active ingredient is applied per square meter of body surface area. Those skilled in the art are familiar with methods for calculating body surface area, such as the Stevenson formula, the DuBois formula, the Mosteller formula, the Haycock formula, etc."

[0096] The term "intravenous injection" refers to the injection of liquid substances (including but not limited to blood, medications, and nutrient solutions) into a vein. Intravenous injections can be divided into transient and continuous types; transient intravenous injections are usually administered by direct injection into a vein using a syringe; continuous intravenous injections are usually carried out by intravenous infusion, including cases using an infusion pump.

[0097] The terms “containing” or “including (comprise)” can be open-ended, semi-closed, or closed. In other words, the terms also include “consistently made of” or “made of”.

[0098] "Percentage by volume" or "% (w / v)" or "% w / v" is a way of expressing mass-volume concentration, indicating the number of grams of solute contained in 100 ml of solution. For example, 20% (w / v) means that 100 ml of solution contains 20 g of solute.

[0099] "Optional" or "optionally" means that the event or condition described below may occur but is not required to occur, and the description includes both the scenario in which said event or condition occurs and the scenario in which said event or condition does not occur.

[0100] Sequence alignment typically involves using a control sequence to compare the test sequence. In this invention, 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 alignment, similarity also includes whether two residues at corresponding positions possess similar characteristics, such as the size, charge, and hydrophilicity / hydrophobicity of side chain groups, in addition to being completely identical. Methods for sequence alignment are common knowledge in the art.

[0101] The beneficial effects of the present invention are as follows: The present invention provides a combination of IL-15 prodrug and chemotherapy drugs and its application. The combination of drugs has a better therapeutic effect and higher safety than the sum of the therapeutic effects of the single active ingredients in the combination. Attached Figure Description

[0102] Figure 1 shows the effect of 215γ, oxaliplatin alone or in combination on the growth of MC38 / hPD-L1 subcutaneous xenografts of colon cancer in mice in Example 1. The horizontal axis of Figure 1 represents the time after drug administration (in days), and the vertical axis represents the mean tumor volume ± SEM (in cubic millimeters). Detailed Implementation

[0103] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0104] FOLFIRI: A chemotherapy regimen that includes irinotecan, leucovorin, and 5-fluorouracil.

[0105] mFOLFOX6: A chemotherapy regimen containing oxaliplatin, leucovorin, and 5-fluorouracil.

[0106] MSS: Microsatellite stabilization.

[0107] pMMR: Proficient mismatch repair, the mismatch repair function is working properly.

[0108] TBD: To be determined.

[0109] Q3W: Quaque 3Weeks, held every 3 weeks.

[0110] Q4W: Quaque 4Weeks, held every 4 weeks.

[0111] Unless otherwise specified, the following examples involve mouse efficacy studies:

[0112] The formula for calculating tumor volume (V) is V = 1 / 2 × a × b 2 Where a and b represent the length (long axis) and width (short axis) of the tumor, respectively.

[0113] T / C (%) = (T - T0) / (C - C0) × 100%. Where T and C are the tumor volumes on a specific day of the experiment; T0 and C0 are the tumor volumes at the beginning of the experiment. T and T0 are the treatment groups, and C and C0 are the negative control groups.

[0114] Tumor inhibition rate (TGI) (%) = 100% - T / C (%)

[0115] Example 1: Antitumor effect of 215γ combined with oxaliplatin on a PD-1 humanized mouse MC38 / hPD-L1 cell subcutaneous xenograft model

[0116] The study used a PD-1 humanized mouse colon cancer MC38 / hPD-L1 subcutaneous xenograft model. Mice were intraperitoneally injected with 215γ 3 mg / kg once a week for a total of 4 times; oxaliplatin was administered at 5 mg / kg once every 5 days for a total of 5 times; when the two were used in combination, the dosage and frequency were the same as above.

[0117] As shown in Figure 1, the results indicate that 215γ and oxaliplatin monotherapy inhibited the growth of MC38 / hPD-L1 subcutaneous xenografts, with inhibition rates of 30% and 45%, respectively. The combined use of these two drugs increased the inhibition rate of subcutaneous xenografts in mice to 59%, with 2 / 8 (25%) of the mice exhibiting stable tumor growth. The tumor-bearing mice showed good tolerance to all the drugs, with no significant weight loss or other symptoms. The data suggest that the combination of 215γ and oxaliplatin has a synergistic effect in inhibiting the growth of MC38 / hPD-L1 subcutaneous xenografts of colon cancer in mice.

[0118] In Figure 1, G-1A is the blank solvent group, G-1B is the 215γ monotherapy group, G-1C is the oxaliplatin monotherapy group, and G-1D is the 215γ and oxaliplatin combination group.

[0119] Example 2: Clinical Trial Study

[0120] A Phase I clinical trial, in its dose-finding phase, evaluated the safety, tolerability, pharmacokinetic (PK), and preliminary efficacy of 215γ in combination with different chemotherapy regimens for patients with advanced malignancies. The study included the following cohorts:

[0121] Cohort 1: Ovarian Cancer

[0122] Cohort 1 included patients with epithelial ovarian cancer who had relapsed or progressed during or within 6 months of their last platinum-based chemotherapy treatment. They received 215γ in combination with paclitaxel and bevacizumab until disease progression or unacceptable toxicity (whichever occurs first).

[0123] Cohort 2B: Colorectal Cancer

[0124] Cohort 2B enrolled patients with unresectable metastatic colorectal cancer who had failed treatment-naïve or first-line oxaliplatin-based chemotherapy and received 215γ in combination with FOLFIRI and bevacizumab until disease progression or unacceptable toxicity (whichever occurs first).

[0125] Cohort 3: Non-small cell lung cancer

[0126] Cohort 3 included patients with locally advanced or metastatic non-small cell lung cancer who had failed standard therapy and received 215γ in combination with docetaxel until disease progression or unacceptable toxicity (whichever occurs first).

[0127] The specific treatment plan is shown in Table 1.

[0128] Table 1

[0129] Example 3: Clinical Trial Study

[0130] This phase Ib / II, multicenter, open-label, safe introduction and dose expansion study aimed to evaluate the safety, tolerability, antitumor activity, PK / PD characteristics, and immunogenicity of 215γ in combination with different chemotherapy regimens in patients with metastatic colorectal cancer (mCRC). The study was conducted in two phases: a phase Ib safe introduction phase and a phase II dose expansion phase.

[0131] During the safety introduction phase, patients with MSS / pMMR metastatic colorectal cancer who had failed ≤1 line of standard therapy were included. The aim was to explore the safety and tolerability of 215γ in combination with mFOLFOX6 and bevacizumab in patients with metastatic colorectal cancer and to determine the recommended extended dose.

[0132] The dose-extension phase was a multicenter, randomized, open-label, positive-controlled phase II clinical trial designed to evaluate the safety and efficacy of two different doses of 215γ in combination with mFOLFOX6 / FOLFIRI + bevacizumab compared with physician-selected regimen (mFOLFOX6 / FOLFIRI + bevacizumab) in patients with MSS / pMMR metastatic colorectal cancer who had failed ≤1 line of standard therapy.

[0133] The specific treatment plan is shown in Table 2.

[0134] Table 2

[0135] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. The application of a combination of an anti-PD-1 antibody-IL-15 prodrug fusion molecule and a chemotherapeutic drug in the preparation of a drug for treating tumor diseases; The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv. The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents. The combination may optionally further include targeted therapeutic agents.

2. A method of treating a neoplastic disease in a patient, comprising administering to said patient a therapeutically effective amount of a compound of claim 1. The patient was given a combination of an anti-PD-1 antibody-IL-15 prodrug fusion molecule and a chemotherapy drug. The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv. The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents. The combination may optionally further include targeted therapeutic agents.

3. A pharmaceutical combination for treating a neoplastic disease, characterized in that, A fusion molecule containing an anti-PD-1 antibody-IL-15 prodrug and a chemotherapy drug; The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises two identical light chains and two heavy chains of fusion polypeptide. The light chains are anti-PD-1 antibody light chains. The first heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain, a Sushi domain of the α subunit of the IL-15 receptor, IL-15 or a mutant thereof. The second heavy chain fusion polypeptide comprises an anti-PD-1 antibody heavy chain and an anti-IL-15 scFv. The chemotherapeutic agent is selected from one or more of the following: pyrimidine analog chemotherapeutic agents, platinum-based chemotherapeutic agents, taxane-based chemotherapeutic agents, camptothecin-based chemotherapeutic agents, and anthracycline antibiotic chemotherapeutic agents. The drug combination may optionally further include targeted therapeutic agents.

4. The application according to claim 1, the method according to claim 2, or the drug combination according to claim 3, characterized in that, The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises a fusion polypeptide consisting of two identical light chains and two heavy chains. The light chain amino acid sequence has at least 90% similarity to SEQ ID NO:

1. The amino acid sequence of the first heavy chain fusion polypeptide chain has at least 90% similarity to SEQ ID NO:

2. The amino acid sequence of the second heavy chain fusion polypeptide chain has at least 90% similarity to SEQ ID NO:

3.

5. The application according to claim 1, the method according to claim 2, or the drug combination according to claim 3, characterized in that, The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug comprises a fusion polypeptide consisting of two identical light chains and two heavy chains. The light chain amino acid sequence is SEQ ID NO:

1. The amino acid sequence of the first heavy chain fusion polypeptide chain is SEQ ID NO:

2. The amino acid sequence of the second heavy chain fusion polypeptide chain is SEQ ID NO:

3.

6. The application according to claim 1, the method according to claim 2, or the drug combination according to claim 3, characterized in that, The pyrimidine analog chemotherapy drugs are selected from cytarabine, 5-fluorouracil, decitabine, gemcitabine, carmoflu, capecitabine, desoxyfluorouracil, tegafur, or azacitidine; The platinum-based chemotherapy drugs are selected from cisplatin, carboplatin, nedaplatin, oxaliplatin, or lobaplatin; The paclitaxel-based chemotherapeutic agents are selected from paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, or docetaxel; The camptothecin-based chemotherapeutic drugs are selected from camptothecin, hydroxycamptothecin, topotecan, or irinotecan; The anthracycline antibiotic chemotherapy drug is selected from doxorubicin or epirubicin.

7. The use according to claim 1, or the method according to claim 2, or the pharmaceutical combination according to claim 3, wherein, The targeted therapy drug is a drug that targets EGFR, VEGF, or VEGFR.

8. The use according to claim 1, or the method according to claim 2, or the pharmaceutical combination according to claim 3, wherein, The targeted therapy drugs are selected from gefitinib, erlotinib, icotinib, lapatinib, afatinib, dacomitinib, neratinib, osimertinib, amitinib, vormetinib, roxitinib, avitinib, befotinib, retizinib, riertinib, liertinib, lazatinib, nazatinib, cetuximab, panitumumab, nexituzumab, mateuzumab, nimotuzumab, aflibercept, conbercept, bevacizumab, and ranibizumab. Monoclonal antibodies, fareximab, ewasizumab, buxizumab, suvecitab, fruquintinib, cabozantinib, sorafenib, donafenib, sunitinib, axitinib, anlotinib, apatinib, lenvatinib, famitinib, surufatinib, tevozanib, ponatinib, nintedanib, voronibub, regorafenib, ramoximumab, proximab, gentuximab, ovasimab, JY025, or MSB0254.

9. The application according to claim 1, the method according to claim 2, or the drug combination according to claim 3, characterized in that, The fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered at a frequency of approximately once a week, approximately once every two weeks, approximately once every three weeks, approximately once every four weeks, approximately once a month, approximately once every six weeks, approximately once every eight weeks, approximately once every two months, approximately once every ten weeks, approximately once every twelve weeks, approximately once every three months, or approximately twice every three weeks.

10. The use of claim 1, or the method of claim 2, or the pharmaceutical combination of claim 3, wherein, the dosage of the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is X dosage at cycle (n) and Y dosage at cycle (n+m); the length of cycle (n) is about 3 weeks and the length of cycle (n+m) is about 6 weeks; n is independently 1, 2, 3, 4, 5, 6, 7, or 8, and m is a natural number and not zero.

11. The use of claim 1, or the method of claim 2, or the pharmaceutical combination of claim 3, wherein, the fusion molecule of the anti-PD-1 antibody-IL-15 prodrug is administered parenterally.

12. The use of claim 1, or the method of claim 2, or the pharmaceutical combination of claim 3, wherein, 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, ureter tumor, bladder tumor, gallbladder cancer, bile duct cancer, or choriocarcinoma.

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