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WO2023072043A1 - 治疗肿瘤的联用药物 - Google Patents

治疗肿瘤的联用药物 Download PDF

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Publication number
WO2023072043A1
WO2023072043A1 PCT/CN2022/127280 CN2022127280W WO2023072043A1 WO 2023072043 A1 WO2023072043 A1 WO 2023072043A1 CN 2022127280 W CN2022127280 W CN 2022127280W WO 2023072043 A1 WO2023072043 A1 WO 2023072043A1
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WO
WIPO (PCT)
Prior art keywords
antibody
amino acid
seq
acid sequence
fusion protein
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PCT/CN2022/127280
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English (en)
French (fr)
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WO2023072043A8 (zh
Inventor
李许
张喜全
王训强
于鼎
梁洪铭
黄剑强
Original Assignee
正大天晴药业集团股份有限公司
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Priority to CN202280066732.3A priority Critical patent/CN118176017A/zh
Publication of WO2023072043A1 publication Critical patent/WO2023072043A1/zh
Publication of WO2023072043A8 publication Critical patent/WO2023072043A8/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the disclosure belongs to the field of biomedicine, and in particular relates to combined drugs for treating tumors.
  • Pancreatic cancer is the most aggressive form of cancer, and most patients have metastasized when first diagnosed. The prognosis of metastatic pancreatic cancer is extremely poor. Even with the development of science and technology, surgical techniques and drug treatments for pancreatic cancer have been continuously improved, but the improvement of survival rate of pancreatic cancer patients is still very limited. In the past 45 years (1975 -2020), the 5-year survival rate of pancreatic cancer patients has only increased from 3% to 9%.
  • pancreatic cancer that loses the value of surgery mainly relies on drug treatment.
  • pancreatic cancer treatment guidelines namely the AG program (Gemcitabine (Gemcitabine) and nab-paclitaxel (Abraxane/ nab-paclitaxel) combined) and FOLFIRINOX program (leucovorin, fluorouracil, irinotecan and oxaliplatin combined).
  • Programmed death-ligand 1 is a ligand of programmed death molecule 1 (Programmed death, PD-1), which is highly expressed in various solid malignant tumors, and its expression level and The clinical manifestations and prognosis of the patients are closely related.
  • PD-L1 on the surface of tumor cells binds to PD-1 or CD80 on the surface of T cells, inhibits the activation and proliferation of T cells, promotes effector T cells to enter a state of exhaustion or anergy, and induces T cell activation.
  • Apoptosis stimulates helper T cells to differentiate into regulatory T cells, thereby preventing T cells from killing tumor cells.
  • Anti-PD-L1 antibodies can prevent the activity of effector T cells in the tumor microenvironment from being inhibited by blocking the interaction of PD-L1 with PD-1 and CD80, and enhance the endogenous anti-tumor immune effect.
  • TGF- ⁇ Transforming growth factor ⁇
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can inhibit the TGF- ⁇ signaling pathway on the basis of inhibiting the PD-L1/PD-1 pathway, improve the immune microenvironment, and enhance the effect of immunotherapy.
  • Tyrosine kinase is a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. It plays an important role in signal transduction in cells. It is involved in the regulation, signal transmission and development of normal cells. It is closely related to the proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases (Receptor tyrosine kinase, RTK) are related to the formation of tumors, and can be divided into epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) according to their extracellular domain structure. , vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), etc.
  • EGFR epidermal growth factor receptor
  • PDGFR platelet-derived growth factor receptor
  • VEGFR vascular endothelial growth factor receptor
  • FGFR fibroblast growth factor receptor
  • Anlotinib is a quinoline derivative tyrosine kinase inhibitor. As a multi-target tyrosine kinase inhibitor, it plays a role in affecting tumor angiogenesis and proliferation signal transduction.
  • the main targets include : Receptor tyrosine kinases VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), EGFR, FGFR1-4, PDGFR ⁇ and ⁇ , and stem cell factor receptors (SCFR) 7, 8, and 9.
  • the present disclosure provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel; optionally, anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes a pharmaceutical composition containing anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition containing gemcitabine, and a pharmaceutical composition containing nab-paclitaxel; A pharmaceutical composition of rotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein with a unit dose of 200-1200 mg, gemcitabine with a unit dose of 0.2 g and/or 1.0 g, and nab-paclitaxel with a unit dose of 100 mg ;
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel can be packaged separately or packaged together. And wherein, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be packaged in a single or multiple equal parts, the gemcitabine can be packaged in a single or multiple equal parts, and the nab-paclitaxel can be packaged in a single or multiple equal portions for packaging.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof can be packaged separately or packaged together.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be packaged in a single or multiple equal parts
  • the gemcitabine can be packaged in a single or multiple equal parts
  • the nab-paclitaxel can be packaged in a single
  • the anlotinib or a pharmaceutically acceptable salt thereof can be packaged in single or multiple equal parts.
  • the drug combination is used to treat tumors. In some embodiments, the drug combination is used to treat pancreatic cancer.
  • the present disclosure provides a drug combination for treating pancreatic cancer, which includes anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel; optionally, also includes anlotinib or its pharmaceutically acceptable Accepted salt.
  • the present disclosure also provides a method of treating pancreatic cancer in a subject, comprising administering to the subject an effective amount of the pharmaceutical combination of the present disclosure.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating pancreatic cancer.
  • the present disclosure also provides an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel, and optionally, anlotinib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating pancreatic cancer use in .
  • the drug combination is a fixed combination.
  • the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
  • the drug combination is a non-fixed combination.
  • each of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel in the non-fixed combination is in the form of a pharmaceutical composition.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a liquid pharmaceutical composition.
  • the liquid pharmaceutical composition is an injection.
  • the gemcitabine-containing pharmaceutical composition in the non-fixed combination, is a solid pharmaceutical composition.
  • the pharmaceutical composition containing nab-paclitaxel is a solid pharmaceutical composition.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately.
  • each of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, which can be simultaneously, sequentially and / or alternating doses.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered at a dose of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg each time.
  • the gemcitabine is administered at a dose of 500-1000 mg/m 2 gemcitabine once a week, continuously for 2 weeks and rested for 1 week.
  • the nab-paclitaxel is administered at a dose of 75-125 mg/m 2 nab-paclitaxel once a week for 2 consecutive weeks and 1 week off.
  • the anlotinib or a pharmaceutically acceptable salt thereof is dosed once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg of anlotinib, administered continuously for 2 weeks, and rested for 1 week. medication.
  • the present disclosure provides a kit for treating pancreatic cancer comprising the pharmaceutical combination of the present disclosure.
  • the kit includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel; optionally, it also includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, and oxaliplatin; optionally, anlotinib or its pharmaceutically acceptable salt.
  • a drug combination for treating pancreatic cancer which includes anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin; optionally, also includes anlotinib Nephrine or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan and oxaliplatin, optionally, anlotinib or a pharmaceutically acceptable salt thereof Use in the preparation of medicines for treating pancreatic cancer tumors.
  • the present disclosure provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel; optionally, also includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, and oxaliplatin; acceptable salt.
  • the drug combination is used to treat tumors.
  • the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors.
  • the present disclosure also provides the use of the drug combination of the present disclosure for treating tumors.
  • the present disclosure also provides a method for treating tumors, comprising administering an effective amount of the drug combination of the present disclosure to a subject.
  • kits for treating tumors comprising the pharmaceutical combinations of the present disclosure.
  • the kit further includes instructions for treating a tumor with the drug combination of the present disclosure.
  • the present disclosure also provides an anti-PD-L1 antibody-TGF ⁇ RII fusion protein for treating tumors.
  • the present disclosure also provides the use of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein in the preparation of a drug for treating tumors.
  • the present disclosure also provides the use of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein for treating tumors.
  • the present disclosure also provides a method for treating tumors, comprising administering to a subject an effective amount of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein of the present disclosure.
  • the tumor is pancreatic cancer.
  • the present disclosure provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel.
  • the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof.
  • the drug combination is packaged in the same kit, and the kit also includes instructions for using anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel in combination to treat tumors.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel in the pharmaceutical combination are packaged separately in their respective kits, and the kits also include anti-PD-L1 antibody-TGF ⁇ RII Illustration of the combination of fusion protein, gemcitabine, and nab-paclitaxel for the treatment of tumors.
  • the drug combination is packaged in the same kit, and the kit also includes anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel and anlotinib or its pharmaceutically acceptable Instructions for the combined use of accepted salts in the treatment of neoplasms.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel and anlotinib or their pharmaceutically acceptable salts in the pharmaceutical combination are packaged separately in respective kits,
  • the kit also includes instructions for using anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel and anlotinib or a pharmaceutically acceptable salt thereof in combination to treat tumors.
  • the tumor is pancreatic cancer.
  • the pharmaceutical combination includes an anti-PD-L1 antibody-TGF ⁇ RII fusion protein with a unit dose of 200-1200 mg or 200-600 mg, gemcitabine with a unit dose of 0.2 g and/or 1.0 g, and a unit dose of 100 mg nab-paclitaxel.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical combination comprises a unit dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, About 1000 mg, about 1100 mg and/or about 1200 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a unit dose of 0.2 g and/or 1.0 g of gemcitabine, and a unit dose of 100 mg of nab-paclitaxel.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical combination includes a unit dose of about 200 mg, about 400 mg and/or about 600 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a unit dose of 0.2 g and/or 1.0 g of gemcitabine, and a unit dose of Nab-paclitaxel at a dose of 100 mg.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 8 mg, 10 mg and/or 12 mg.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein with a unit dose of 200-1200 mg or 200-600 mg, and the unit dose is 0.2 g and/or 1.0 g gemcitabine-containing pharmaceutical composition of gemcitabine, and a unit dose of 100 mg nab-paclitaxel-containing pharmaceutical composition of nab-paclitaxel; wherein, the pharmaceutical combination containing anti-PD-L1 antibody-TGF ⁇ RII fusion protein in single or multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination comprises a unit dose of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, About 1000mg, about 1100mg and/or about 1200mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein pharmaceutical composition containing anti-PD-L1 antibody-TGF ⁇ RII fusion protein, the unit dose is 0.2g and/or 1.0g gemcitabine-containing gemcitabine A pharmaceutical composition, and a pharmaceutical composition containing nab-paclitaxel with a unit dose of 100 mg nab-paclitaxel; wherein, the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a single dose or multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein with a unit dose of about 200 mg, about 400 mg, and/or about 600 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, unit A pharmaceutical composition containing gemcitabine with a dose of 0.2 g and/or 1.0 g of gemcitabine, and a pharmaceutical composition containing nab-paclitaxel with a unit dose of 100 mg nab-paclitaxel; wherein, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein
  • the pharmaceutical composition is a single dose or multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 8 mg, 10 mg and/or 12 mg of anlotinib.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination includes 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 100-3000 mg/m 2 , 200-2000 mg/m 2. 500-1500mg/m 2 , or 500-1000mg/m 2 gemcitabine, and 10-500mg/m 2 , 30-300mg/m 2 , 100-200mg/m 2 , or 75-125mg/m 2 gemcitabine protein paclitaxel.
  • the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, About 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, and/or about 2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 500-1000 mg/ m2 of gemcitabine, and 75-125 mg/ m2 of nab-paclitaxel .
  • the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes about 600 mg, about 1200 mg, about 1800 mg and/or about 2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 500-1000 mg/ m of gemcitabine, and 75-125 mg/m 2 nab-paclitaxel.
  • the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes about 1200 mg and/or about 1800 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 1000 mg/m 2 of gemcitabine, and 125 mg/m 2 of nab-paclitaxel.
  • the pharmaceutical combination further includes 8 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the content of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a daily dose. In some embodiments, in the pharmaceutical combination, the content of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is once a day.
  • the content of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a uniform dose.
  • the content of gemcitabine in the drug combination, is a daily dose. In some embodiments, in the pharmaceutical combination, the content of gemcitabine is once a day.
  • the content of nab-paclitaxel is a daily dose. In some embodiments, in the pharmaceutical combination, the content of nab-paclitaxel is once a day.
  • the content of anlotinib or a pharmaceutically acceptable salt thereof is a daily dose. In some embodiments, in the pharmaceutical combination, the content of anlotinib or a pharmaceutically acceptable salt thereof is once a day.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 200- 6000 mg/m 2 , 400-4000 mg/m 2 , 1000-3000 mg/m 2 , or 1000-2000 mg/m 2 gemcitabine, and 20-1000 mg/m 2 , 60-600 mg/m 2 , 200-400 mg/m 2 , or 150-250mg/m 2 of nab-paclitaxel.
  • the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg , about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg and/or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 1000-2000 mg/ m of gemcitabine, and Nab-paclitaxel at 150-250mg/ m2 .
  • the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and comprises about 600 mg, about 1200 mg, about 1800 mg, and/or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 1000-2000 mg/m 2 of gemcitabine, and 150-250mg/m 2 of nab-paclitaxel.
  • the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes about 1200 mg and/or about 1800 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, 2000 mg/ m of gemcitabine, and 250 mg/m 2 nab-paclitaxel.
  • the pharmaceutical combination further includes 112 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle and includes pharmaceutical combinations comprising 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein substances, pharmaceutical compositions containing 200-6000mg/m 2 , 400-4000mg/m 2 , 1000-3000mg/m 2 , or 1000-2000mg/m 2 gemcitabine, and 20-1000mg/m 2 , 60-600mg/ m 2 , 200-400 mg/m 2 , or 150-250 mg/m 2 nab-paclitaxel pharmaceutical composition; wherein, the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a single dose or multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg and/or about 2400mg of the pharmaceutical composition of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, containing 1000-2000mg/m 2.
  • the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes a pharmaceutical composition comprising about 600 mg, about 1200 mg, about 1800 mg, and/or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, comprising A pharmaceutical composition of 1000-2000 mg/m 2 gemcitabine, and a pharmaceutical composition containing 150-250 mg/m 2 nab-paclitaxel; wherein, the pharmaceutical composition containing anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a single dose or Multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes a pharmaceutical composition containing about 1200 mg and/or about 1800 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a drug composition containing 2000 mg/m gemcitabine A pharmaceutical composition, and a pharmaceutical composition containing 250 mg/m 2 of nab-paclitaxel; wherein, the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a single dose or multiple doses.
  • the pharmaceutical combination further includes a pharmaceutical composition containing 112 mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is in multiple doses.
  • the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to gemcitabine is (0.1-10):1, (0.125-2):1, (0.125-1.5) :1 or (0.25-1.5):1, the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein and nab-paclitaxel is (0.1-30):1, (1-15):1, (2-15 ): 1 or (2-10): 1; wherein, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel can be packaged separately or together.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be prepared in single or multiple equal parts (such as 2 equal parts, 3 equal parts, 4 equal parts, 5 equal parts, 6 equal parts, 7 equal parts, 8 equal parts , 9 equal parts, 10 equal parts, 12 equal parts or more equal parts) for packaging; gemcitabine can be packaged in single or multiple equal parts; nab-paclitaxel can be packaged in single or multiple equal parts.
  • the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to gemcitabine is (0.1-10):1, (0.125-2):1, (0.125-1.5 ):1 or (0.25-1.5):1, the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to nab-paclitaxel is (0.1-30):1, (1-15):1, (2- 15):1 or (2-10):1, the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to anlotinib or a pharmaceutically acceptable salt thereof is (3.5-29.0):1, ( 7.1-29.0):1, (7.1-21.5):1, (7.1-14.5):1, (10.5-21.5):1, 50:7 or 75:7; wherein, anti-PD-L1 antibody-TGF ⁇ RII fusion protein , gemcitabine, nab-paclitaxel and anlotinib or their pharmaceutically acceptable salts can be packaged separately
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be prepared in single or multiple equal parts (such as 2 equal parts, 3 equal parts, 4 equal parts, 5 equal parts, 6 equal parts, 7 equal parts, 8 equal parts , 9 equal parts, 10 equal parts, 12 equal parts or more) for packaging; gemcitabine can be packaged in single or multiple equal parts; nab-paclitaxel can be packaged in single or multiple equal parts; Rotinib or a pharmaceutically acceptable salt thereof can be packaged in single or multiple aliquots (eg, 7, 14, 28 or more aliquots).
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel, wherein the anti-PD-L1 antibody-
  • the pharmaceutical composition of the TGF ⁇ RII fusion protein is prepared to be suitable for administering to the patient a single dose or multiple doses of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein for the first administration.
  • the pharmaceutical composition containing gemcitabine is prepared to be suitable for 2 consecutive weeks, weekly administration to patient 100-3000mg/m 2 , 200-2000mg/m 2 , 500-1500mg/m 2 , or 500-1000mg/m 2 gemcitabine
  • a single dose or multiple doses of nab-paclitaxel the pharmaceutical composition containing nab-paclitaxel is prepared to be suitable for 2 consecutive weeks, weekly administration to patients 10-500mg/m 2 , 30-300mg/m 2 , 100-200mg/m 2 , or Single or multiple doses of nab-paclitaxel at 75-125 mg/ m2 .
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel, wherein the anti-PD-L1 antibody-
  • the pharmaceutical composition of the TGF ⁇ RII fusion protein is prepared to be suitable for administering about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1400 mg, about 1500 mg, Single or multiple doses of about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a gemcitabine-containing pharmaceutical composition is prepared For continuous 2 weeks, the single dose or multiple doses of 500-1000mg/ m2 gemcitabine are given to patients every week,
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel, wherein the anti-PD-L1 antibody-
  • the pharmaceutical composition of the TGF ⁇ RII fusion protein is prepared to be suitable for administering to the patient a single dose or multiple doses of about 600 mg, about 1200 mg, about 1800 mg or about 2400 mg of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein for the first administration, containing gemcitabine
  • the pharmaceutical composition is prepared as a single dose or multiple doses of 500-1000mg/ m2 gemcitabine to the patient every week for 2 consecutive weeks; Single or multiple doses of 75-125 mg/ m nab-paclitaxel were administered.
  • the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel, wherein the anti-PD-L1 antibody-
  • the pharmaceutical composition of the TGF ⁇ RII fusion protein is prepared to be suitable for giving a single dose or multiple doses of about 1200 mg or about 1800 mg of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to the patient during the first administration
  • the pharmaceutical composition containing gemcitabine is prepared as Suitable for administering single or multiple doses of 1000 mg/ m2 of gemcitabine weekly to a patient for 2 consecutive weeks
  • the pharmaceutical composition containing nab-paclitaxel is prepared to be suitable for administering 125 mg/ m2 of nab-paclitaxel to a patient every week for 2 consecutive weeks single or multiple doses.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering a single dose of 6-12 mg anlotinib to patients every day for 14 consecutive days. More specifically, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering a single dose of 6 mg, 8 mg, 10 mg or 12 mg of anlotinib to patients every day for 14 consecutive days. More specifically, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is prepared to be suitable for administering a single dose of 8 mg anlotinib to patients every day for 14 consecutive days.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel in the preparation of a drug for treating tumors.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel to treat tumors.
  • the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel.
  • the tumor is pancreatic cancer.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating tumors .
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof to treat tumors.
  • the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable Accepted salts in drug combinations.
  • the tumor is pancreatic cancer.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical combination comprising nab-paclitaxel Composition, and a description of the combined use of a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition containing gemcitabine, and a pharmaceutical composition containing nab-paclitaxel to treat tumors.
  • the tumor is pancreatic cancer.
  • the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition comprising gemcitabine, a pharmaceutical composition comprising nab-paclitaxel, and A pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition containing gemcitabine, a pharmaceutical composition containing nab-paclitaxel , and a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof are used in combination to treat tumors.
  • the tumor is pancreatic cancer.
  • the present disclosure also provides a pharmaceutical combination comprising anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin.
  • the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition containing calcium folinate, a pharmaceutical composition containing fluorouracil, and a pharmaceutical composition containing irinotecan and pharmaceutical compositions containing oxaliplatin.
  • the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan and oxaliplatin in preparing a drug for treating tumors.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan and oxaliplatin to treat tumors.
  • the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of a drug comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin combination.
  • a drug comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin combination.
  • the tumor is pancreatic cancer.
  • the present disclosure also provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and anlotinib or a pharmaceutically acceptable salt thereof for use in the preparation Use in medicines for treating tumors.
  • the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and anlotinib or a pharmaceutically acceptable salt thereof to treat tumors.
  • the present disclosure also provides a method for treating a tumor in a subject, comprising administering to the subject an effective amount of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and ammonium A pharmaceutical combination of rotinib or a pharmaceutically acceptable salt thereof.
  • the tumor is pancreatic cancer.
  • the present disclosure also provides a kit for treating tumors, the kit includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, a pharmaceutical composition containing calcium folinate, a pharmaceutical composition containing fluorouracil, a pharmaceutical composition containing i A pharmaceutical composition of rinotecan and a pharmaceutical composition containing oxaliplatin.
  • the kit further includes a pharmaceutical composition comprising anlotinib or a pharmaceutically acceptable salt thereof.
  • the tumor is pancreatic cancer.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition and administered sequentially.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition and administered alternately.
  • each of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel is in the form of a pharmaceutical composition, and each is administered at intervals.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are administered with the same or different dosage regimens.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are administered in different dosage regimens.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition forms, which may be administered simultaneously, sequentially and/or alternately.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition form, administered sequentially.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition form, alternate administration.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition form, and each administered at intervals.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are used in the same or different dosing regimen.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are administered in different doses, respectively plan for dosing.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is used every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) ) is applied once.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once every 3 weeks.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered at a dose of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg each time.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is dosed at about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, Doses of about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg are administered. In some embodiments, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered at a dose of about 600 mg, about 1200 mg, about 1800 mg, or about 2400 mg each time.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered at a dose of about 1200 mg each time. In some embodiments, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered at a dose of about 1800 mg each time.
  • the gemcitabine in the above methods of use or treatment, is administered once a week. In some embodiments, in the above use or treatment method, the gemcitabine is administered at a dose of 100-3000 mg/m 2 , 200-2000 mg/m 2 , 500-1500 mg/m 2 or 500-1000 mg/m 2 each time. In some embodiments, in the above use or treatment method, the gemcitabine is administered at a dose of 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 each time. In some embodiments, in the above use or treatment method, the gemcitabine is administered at a dose of 500-1000 mg/m 2 gemcitabine once a week, with continuous administration for 2 weeks and a rest period of 1 week.
  • the dosage of gemcitabine is 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 gemcitabine once a week. medication.
  • the gemcitabine is administered at a dose of 1000 mg/m 2 gemcitabine once a week, with continuous administration for 2 weeks and a rest period of 1 week.
  • the nab-paclitaxel is administered once a week. In some embodiments, in the above use or method of treatment, the nab-paclitaxel is dosed at 10-500 mg/m 2 , 30-300 mg/m 2 , 100-200 mg/m 2 or 75-125 mg/m 2 each time apply. In some embodiments, in the above use or treatment method, the nab-paclitaxel is administered at a dose of 75 mg/m 2 , 100 mg/m 2 or 125 mg/m 2 each time.
  • the nab-paclitaxel in the above-mentioned use or treatment method, is administered at a dosage of 75-125 mg/m 2 nab-paclitaxel once a week, continuously for 2 weeks and rested for 1 week. In some embodiments, in the above-mentioned use or treatment method, the nab-paclitaxel is administered at a dose of 75 mg/m 2 , 100 mg/m 2 or 125 mg/m 2 once a week for 2 consecutive weeks, followed by a 1-week break. dosing regimen.
  • the nab-paclitaxel is administered at a dose of 125 mg/m 2 nab-paclitaxel once a week, with continuous administration for 2 weeks and a rest period of 1 week.
  • the anlotinib or its pharmaceutically acceptable salt is administered at a dose of 6-12 mg anlotinib once a day for 2 consecutive weeks and 1 week off. Dosing regimen. In some embodiments, in the above-mentioned use or treatment method, the anlotinib or its pharmaceutically acceptable salt is administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg of anlotinib continuously for 2 weeks, Withdrawal from the dosing regimen for 1 week. In some embodiments, in the above-mentioned use or treatment method, the anlotinib or its pharmaceutically acceptable salt is administered at a dose of 8 mg anlotinib once a day for 2 consecutive weeks and 1 week off. Program dosing.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle .
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof have the same treatment cycle, for example, every 1 week, every 2 weeks , Every 3 weeks, or every 4 weeks is a treatment cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered in each cycle, and is administered in the first week and the second week of each cycle.
  • Gemcitabine and nab-paclitaxel were administered at weeks 1 and 2 of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once in each cycle, and the first and second weeks of each cycle are respectively Gemcitabine was given once, and nab-paclitaxel was given once at week 1 and week 2 of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day and the second day of each cycle.
  • Gemcitabine was administered on 8 days, and nab-paclitaxel was administered on days 1 and 8 of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once on the first day of each cycle, and once on the first day of each cycle.
  • Gemcitabine was given once on day 1 and day 8
  • nab-paclitaxel was given once on day 1 and day 8 of each cycle.
  • every 21 days is a treatment cycle
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered in each cycle, and is administered in the first week and the second week of each cycle.
  • gemcitabine nab-paclitaxel was administered at the first and second weeks of each cycle, and anlotinib or its pharmaceutically acceptable salt was administered daily on days 1-14 of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once in each cycle, and the first and second weeks of each cycle are respectively Gemcitabine was given once, nab-paclitaxel was given once in the first and second weeks of each cycle, and anlotinib or its pharmaceutically acceptable salt was given once a day on days 1-14 of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day and the second day of each cycle.
  • Gemcitabine was administered on 8 days, nab-paclitaxel was administered on the 1st and 8th day of each cycle, and anlotinib or its pharmaceutically acceptable salt was administered daily on the 1st-14th day of each cycle.
  • every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once on the first day of each cycle, and once on the first day of each cycle.
  • Gemcitabine was given once on days 1 and 8, nab-paclitaxel was given once on days 1 and 8 of each cycle, and anlotinib or its pharmaceutically acceptable drug was given daily on days 1-14 of each cycle. Accept the salt again.
  • every 21 days is a treatment cycle, and about 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of anti-PD is administered on the first day of each cycle.
  • -L1 antibody-TGF ⁇ RII fusion protein given 500-1000 mg/m 2 daily on days 1 and 8 of each cycle, or gemcitabine at 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 in each cycle Nab-paclitaxel was given at 75-125 mg/ m2 , or 75 mg/ m2 , 100 mg/ m2 or 125 mg/ m2 daily on days 1 and 8 of the cycle.
  • every 21 days is a treatment cycle, and about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg are administered on the first day of each cycle , about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, in each Gemcitabine 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 daily on days 1 and 8 of each cycle, 75 mg/m 2 , 100 mg/m 2 daily on days 1 and 8 of each cycle 2 or 125mg/m 2 of nab-paclitaxel.
  • every 21 days is a treatment cycle, and about 600 mg, about 1200 mg, about 1800 mg or about 2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion is administered on the first day of each cycle Protein, 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 of gemcitabine given daily on days 1 and 8 of each cycle and 75 mg/m2 given daily on days 1 and 8 of each cycle 2.
  • Nab-paclitaxel at 100 mg/m 2 or 125 mg/m 2 .
  • every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle 500mg/m 2 , 750mg/m 2 or 1000mg/m 2 of gemcitabine were administered daily on days 1 and 8 of each cycle, and 75mg/m 2 , 100mg/m 2 or 125mg/m 2 were administered daily on days 1 and 8 of each cycle.
  • nab-paclitaxel for m 2 is administered every 21 days.
  • every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle 500mg/m 2 , 750mg/m 2 or 1000mg/m 2 of gemcitabine were administered daily on days 1 and 8 of each cycle, and 75mg/m 2 , 100mg/m 2 or 125mg/m 2 were administered daily on days 1 and 8 of each cycle.
  • nab-paclitaxel for m 2 is administered every 21 days.
  • every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle Gemcitabine was administered at 1000 mg/ m2 daily on days 1 and 8, and nab-paclitaxel at 125 mg/ m2 was administered daily on days 1 and 8 of each cycle.
  • every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle Gemcitabine was given at 1000 mg/ m2 daily on days 1 and 8, and nab-paclitaxel at 125 mg/ m2 was given daily on days 1 and 8 of each cycle.
  • every 21 days is a treatment cycle, and about 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of anti-PD is administered on the first day of each cycle.
  • -L1 antibody-TGF ⁇ RII fusion protein given 500-1000 mg/m 2 daily on days 1 and 8 of each cycle, or gemcitabine at 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 in each cycle Nab-paclitaxel 75-125 mg/m 2 daily on days 1 and 8 of each cycle, or 75 mg/m 2 , 100 mg/m 2 , or 125 mg/m 2 daily on days 1-14 of each cycle 6mg, 8mg, 10mg and/or 12mg of anlotinib or a pharmaceutically acceptable salt thereof.
  • every 21 days is a treatment cycle, and about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg are administered on the first day of each cycle , about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, in each Gemcitabine 500 mg/m 2 , 750 mg/m 2 , or 1000 mg/m 2 daily on days 1 and 8 of each cycle, 75 mg/m 2 , 100 mg/m 2 daily on days 1 and 8 of each cycle Nab-paclitaxel at 2 or 125 mg/m 2 , and 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof per day on days 1-14 of each cycle.
  • every 21 days is a treatment cycle, and about 600 mg, about 1200 mg, about 1800 mg or about 2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion is administered on the first day of each cycle Protein, 500 mg/ m2 , 750 mg/ m2 , or 1000 mg/ m2 of gemcitabine given daily on days 1 and 8 of each cycle and 75 mg/m2 given daily on days 1 and 8 of each cycle 2.
  • 100mg/m 2 or 125mg/m 2 of nab-paclitaxel, 6mg, 8mg, 10mg and/or 12mg of anlotinib or its pharmaceutically acceptable salt is given daily on the 1st-14th day of each cycle .
  • every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle 500mg/m 2 , 750mg/m 2 or 1000mg/m 2 of gemcitabine were administered daily on days 1 and 8 of each cycle, and 75mg/m 2 , 100mg/m 2 or 125mg/m 2 were administered daily on days 1 and 8 of each cycle.
  • m2 of nab-paclitaxel, 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is given daily on days 1-14 of each cycle.
  • every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle 500mg/m 2 , 750mg/m 2 or 1000mg/m 2 of gemcitabine were administered daily on days 1 and 8 of each cycle, and 75mg/m 2 , 100mg/m 2 or 125mg/m 2 were administered daily on days 1 and 8 of each cycle.
  • m2 of nab-paclitaxel, 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is given daily on days 1-14 of each cycle.
  • every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle Gemcitabine 1000 mg/ m2 daily on days 1 and 8, nab-paclitaxel 125 mg/ m2 daily on days 1 and 8 of each cycle, 8 mg daily on days 1-14 of each cycle Anlotinib or a pharmaceutically acceptable salt thereof.
  • every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered on the first day of each cycle, and on the first day of each cycle Gemcitabine 1000 mg/ m2 daily on days 1 and 8, nab-paclitaxel 125 mg/ m2 daily on days 1 and 8 of each cycle, 8 mg daily on days 1-14 of each cycle Anlotinib or a pharmaceutically acceptable salt thereof.
  • anti-PD-L1 is dosed with (0.1-10):1, (0.125-2):1, (0.125-1.5):1 or (0.25-1.5):1 in each treatment cycle Mass ratio of antibody-TGF ⁇ RII fusion protein to gemcitabine, and (0.1-30):1, (1-15):1, (2-15):1 or (2-10):1 anti-PD-L1 antibody- Mass ratio of TGF ⁇ RII fusion protein and nab-paclitaxel, anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel were administered to the subjects.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, or nab-paclitaxel is administered in multiple doses or in a single dose. In some embodiments, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel are all administered in multiple doses.
  • anti-PD-L1 is dosed with (0.1-10):1, (0.125-2):1, (0.125-1.5):1 or (0.25-1.5):1 in each treatment cycle
  • the mass ratio of fusion protein and nab-paclitaxel and (3.5-29.0):1, (7.1-29.0):1, (7.1-21.5):1, (7.1-14.5):1, (10.5-21.5):1
  • the mass ratio of anti-PD-L1 antibody-TGF ⁇ RII fusion protein and anlotinib or a pharmaceutically acceptable salt thereof 50:7 or 75:7, anti-PD-L1 antibody-TGF ⁇ RII fusion protein, Gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, or anlotinib or a pharmaceutically acceptable salt thereof is administered in multiple doses or in a single dose. In some embodiments, the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are all administered in multiple doses, and anlotinib or a pharmaceutically acceptable salt thereof is administered in a single dose.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel are administered in multiple doses, and anlotinib or a pharmaceutically acceptable salt thereof is administered in a single dose give.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be selected from 0.01 to 50 mg/kg, 0.1 to 40 mg/kg, 0.1 to 35 mg/kg, 0.1 to 30 mg/kg , 0.1 to 25mg/kg, 0.1 to 20mg/kg, 0.1 to 15mg/kg, 0.1 to 10mg/kg, 1 to 40mg/kg, 1 to 35mg/kg, 1 to 30mg/kg, 1 to 25mg/kg, 1 to 20mg/kg, 1 to 15mg/kg, 1 to 10mg/kg, 1 to 3mg/kg, 3 to 40mg/kg, 3 to 35mg/kg, 3 to 30mg/kg, 3 to 25mg/kg, 3 to 20mg /kg, 3 to 15mg/kg, 3 to 10mg/kg, 10 to 40mg/kg, 20 to 40mg/kg, 20 to 30mg/kg, 25 to 35mg/kg, 3 to 20mg /kg, 3 to
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin are each in the form of a pharmaceutical composition, which can be simultaneously, Sequential and/or alternating administration.
  • the accepted salts are each in the form of a pharmaceutical composition which can be administered simultaneously, sequentially and/or alternately.
  • each of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, and oxaliplatin is in the form of a pharmaceutical composition, and each is in the form of Dosing at intervals.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and anlotinib or its pharmaceutically acceptable are each in the form of a pharmaceutical composition and are each administered at intervals.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin are administered with the same or different dosage regimens, respectively. medicine.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and anlotinib or its pharmaceutically acceptable were administered in the same or different dosage regimens, respectively.
  • the calcium folinate, fluorouracil, irinotecan and oxaliplatin are administered once every two weeks.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once every three weeks, and calcium folinate, fluorouracil, irinotecan, and oxaliplatin are each administered once every two weeks.
  • about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg are administered on the first day of every three weeks , about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, or about 2400 mg of anti-PD-L1 antibody-TGF ⁇ RII fusion protein once every two weeks on the first day of 400 mg/m 2 folinate, 2800mg/ m2 of fluorouracil on the first day of every two weeks, 180mg/ m2 of irinotecan on the first day of every two weeks, 85mg/ m2 on the first day of every two weeks oxaliplatin.
  • the tumor is pancreatic cancer.
  • the pancreatic cancer is a pancreatic endocrine tumor. In some embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor. In some embodiments, the pancreatic cancer is an exocrine pancreatic tumor. In some embodiments, the pancreatic cancer is ductal adenocarcinoma. In some embodiments, the pancreatic cancer is acinar cell carcinoma. In some embodiments, the pancreatic cancer is squamous and/or adenosquamous. In some embodiments, the pancreatic cancer is colloid carcinoma (also known as mucinous noncystic carcinoma). In some embodiments, the pancreatic cancer is hepatoid adenocarcinoma.
  • the pancreatic cancer is medullary carcinoma. In some embodiments, the pancreatic cancer is invasive micropapillary carcinoma. In some embodiments, the pancreatic cancer is signet ring cell carcinoma. In some embodiments, the pancreatic cancer is an undifferentiated carcinoma. In some embodiments, the pancreatic cancer is pancreaticoblastoma. In some embodiments, the pancreatic cancer is solid-pseudopapillary neoplasm.
  • the pancreatic cancer is refractory, unresectable, recurrent advanced and/or metastatic pancreatic cancer. In some embodiments, the pancreatic cancer is metastatic pancreatic cancer. In some aspects, the pancreatic cancer is advanced pancreatic cancer. In some aspects, the pancreatic cancer is locally advanced pancreatic cancer. In some embodiments, the pancreatic cancer is advanced metastatic pancreatic cancer.
  • the subject with pancreatic cancer has not previously treated pancreatic cancer (eg, metastatic pancreatic cancer).
  • the subject with pancreatic cancer has not previously received chemotherapy for the treatment of pancreatic cancer (eg, has not previously received chemotherapy in a metastatic setting).
  • the subject with pancreatic cancer has not previously received first-line systemic chemotherapy for the treatment of pancreatic cancer (eg, has not previously received first-line systemic chemotherapy in a metastatic setting).
  • the subject with pancreatic cancer has not previously received surgery, radiation therapy, and/or immunotherapy for pancreatic cancer (e.g., has not previously received surgery, radiation therapy, and/or immunotherapy in a metastatic setting) .
  • the subject with pancreatic cancer has not previously received adjuvant therapy for pancreatic cancer (eg, has not previously received adjuvant therapy in a metastatic setting).
  • the subject with pancreatic cancer has previously been treated for pancreatic cancer with one or more different antineoplastic therapies.
  • the subject with pancreatic cancer has previously been treated for pancreatic cancer (eg, treatment failed or was not indicated) with one or more of surgery, radiation therapy, chemotherapy, and immunotherapy.
  • the subject with pancreatic cancer has been treated with chemotherapy for pancreatic cancer (eg, failed treatment or is not amenable to chemotherapy).
  • the subject with pancreatic cancer has been treated for pancreatic cancer with a first-line systemic chemotherapy regimen (eg, failed treatment or is not amenable to systemic chemotherapy).
  • a first-line systemic chemotherapy regimen eg, failed treatment or is not amenable to systemic chemotherapy.
  • the subject with pancreatic cancer has disease progression during or after completion of first-line therapy.
  • the subject with pancreatic cancer has been treated with the FOLFIRINOX regimen (combination chemotherapy of leucovorin, fluorouracil, irinotecan, and oxaliplatin) for pancreatic cancer (e.g., failed treatment or is not amenable to systemic chemotherapy) .
  • FOLFIRINOX regimen combination chemotherapy of leucovorin, fluorouracil, irinotecan, and oxaliplatin
  • the subject with pancreatic cancer has been treated for pancreatic cancer with the FOLFIRINOX regimen in combination with a breast cancer susceptibility protein (BRCA) mutation-targeted therapy regimen (eg, treatment failure or inapplicability).
  • BRCA mutation-targeted therapy regimen eg, treatment failure or inapplicability.
  • the BRCA mutation-targeted treatment options include, but are not limited to, PARP inhibitors, such as olaparib.
  • the subject with pancreatic cancer has been treated with PD-1/PD-L1 inhibitor therapy for pancreatic cancer.
  • the pancreatic cancer subject is an insufficient responder to a PD-1/PD-L1 inhibitor.
  • the subject with pancreatic cancer is refractory to a PD-1/PD-L1 inhibitor, eg, after at least 2 doses.
  • the subject with pancreatic cancer has been treated for pancreatic cancer with the FOLFIRINOX regimen in combination with a PD-1/PD-L1 inhibitor regimen (eg, treatment failure or inapplicability).
  • a PD-1/PD-L1 inhibitor regimen eg, treatment failure or inapplicability
  • the PD-1 inhibitor in the PD-1/PD-L1 inhibitor therapy, is an anti-PD-1 antibody, such as nivolumab (Nivolumab), pembrolizumab ( Pembrolizumab), Toripalizumab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (BGB-A317), Batilizumab Anti-(Balstilimab), AK105, Genolimab (GB226), LZM009, HLX10, AK103 (HX008), CS1003, SCT-I10A, F520, SG001 or Cepalimumab (GLS-010).
  • nivolumab Nivolumab
  • pembrolizumab Pembrolizumab
  • Toripalizumab JS-001
  • Sintilimab IBI308
  • Camrelizumab Camrelizumab
  • the PD-L1 inhibitor in the PD-1/PD-L1 inhibitor therapy, is an anti-PD-L1 antibody, such as Atezolizumab, Durvalizumab Anti-(Durvalumab), Avelumab (Avelumab), Envolimumab (KN035), Sugemalimab (CS1001), TQB2450, SHR-1316, Socazolimab (ZKAB001), HS636, LP002, JS003, MSB2311, KL-A167 or STI-A1014.
  • an anti-PD-L1 antibody such as Atezolizumab, Durvalizumab Anti-(Durvalumab), Avelumab (Avelumab), Envolimumab (KN035), Sugemalimab (CS1001), TQB2450, SHR-1316, Socazolimab (ZKAB001), HS636, LP002, JS003, MSB2311, KL-
  • the subject with pancreatic cancer has been treated for pancreatic cancer (eg, treatment has failed or is inappropriate) with a S-1-containing regimen.
  • the subject with pancreatic cancer has been treated for pancreatic cancer (eg, treatment has failed or is inappropriate) with a platinum-containing (eg, oxaliplatin and/or cisplatin) regimen.
  • a platinum-containing eg, oxaliplatin and/or cisplatin
  • the subject with pancreatic cancer has been treated for pancreatic cancer with a neoadjuvant or adjuvant chemotherapy regimen (eg, treatment has failed or is not indicated).
  • a neoadjuvant or adjuvant chemotherapy regimen eg, treatment has failed or is not indicated.
  • the subject with pancreatic cancer has been treated with neoadjuvant chemotherapy or adjuvant chemotherapy regimens for pancreatic cancer, and has disease progression or recurrence during or within 6 months after completion of neoadjuvant chemotherapy or adjuvant chemotherapy.
  • the subject with pancreatic cancer has been treated for pancreatic cancer with local radiation therapy (eg, treatment has failed or is not indicated).
  • the subject with pancreatic cancer has been treated with local radiation therapy for pancreatic cancer, and local radiation therapy has been completed for more than 4 weeks (more than 2 weeks for brain radiation therapy), and the target lesion for this study is not within the radiation treatment field, or The target lesion is within the radiotherapy field but has confirmed progression.
  • Anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprising:
  • the TGF ⁇ binding domain is human TGF ⁇ RII or its TGF ⁇ binding fragment
  • the amino acid sequence has at least 80%, 81%, 82%, 83%, 84% of the amino acid sequence shown in SEQ ID NO:28 %, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical Peptides or peptide fragments, or any fragments described herein.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: heavy chain CDR (HCDR) 1 shown in SEQ ID NO: 1 or SEQ ID NO: 12, SEQ ID NO: 2 or SEQ ID HCDR2 shown in NO:13, HCDR3 shown in SEQ ID NO:3 or SEQ ID NO:14, light chain CDR (LCDR)1 shown in SEQ ID NO:4 or SEQ ID NO:15, SEQ ID NO: 5 or LCDR2 shown in SEQ ID NO:16, and LCDR3 shown in SEQ ID NO:6 or SEQ ID NO:17.
  • HCDR heavy chain CDR
  • LCDR light chain CDR
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises: HCDR1 shown in SEQ ID NO:1, HCDR2 shown in SEQ ID NO:2, HCDR3 shown in SEQ ID NO:3, LCDR1 shown in SEQ ID NO:4, LCDR2 shown in SEQ ID NO:5, and LCDR3 shown in SEQ ID NO:6; or HCDR1 shown in SEQ ID NO:12, shown in SEQ ID NO:13 HCDR2, HCDR3 set forth in SEQ ID NO:14, LCDR1 set forth in SEQ ID NO:15, LCDR2 set forth in SEQ ID NO:16, and LCDR3 set forth in SEQ ID NO:17.
  • Table 1 The above CDR sequences are provided in Table 1 below.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 80%, 81%, 82%, 83% of the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 18 , 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100
  • the heavy chain variable domain of % identity, and aminoacid sequence and the aminoacid sequence shown in SEQ ID NO:8 or SEQ ID NO:19 have at least 80%, 81%, 82%, 83%, 84%, 85%, A light chain that is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical may be variable domain.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 18, and comprising SEQ ID NO : 8 or the light chain variable domain of the amino acid sequence shown in SEQ ID NO: 19.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain of the amino acid sequence shown in SEQ ID NO:7, and a light chain variable domain of the amino acid sequence shown in SEQ ID NO:8. chain variable domain.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain of the amino acid sequence shown in SEQ ID NO: 18, and a heavy chain variable domain of the amino acid sequence shown in SEQ ID NO: 19 Light chain variable domain.
  • the anti-PD-L1 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant or derivative of the constant region.
  • the constant region is from a human immunoglobulin heavy chain, such as IgGl, IgG2, IgG3, and IgG4 or heavy chains of other classes of immunoglobulins, preferably IgGl.
  • the constant region may comprise any of the modifications described herein, such as insertions, deletions, substitutions or chemical modifications of amino acids.
  • the constant region contains mutations that alter the effector function, for example, mutating the lysine residue at the C-terminus of the antibody constant region to a hydrophobic amino acid, such as alanine or leucine, to reduce protease hydrolysis Cleavage, increases serum half-life.
  • any amino acid residue of the constant region may be substituted with an amino acid residue of any allotype, preferably, an amino acid residue of G1m(3) and/or nG1m(1).
  • the anti-PD-L1 antibody comprises an amino acid sequence that is at least 80%, 81 %, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, A heavy chain of 98%, 99% or 100% identity, and an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical light chain.
  • the anti-PD-L1 antibody comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85% of the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 23 %, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity chain, and the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, Light chains that are 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical.
  • the anti-PD-L1 antibody comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical
  • the heavy chain, and the amino acid sequence have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO:21 , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the light chain.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein further comprises a connecting peptide connecting the C-terminus of the anti-PD-L1 antibody or antigen-binding fragment thereof with the N-terminus of the TGF ⁇ -binding domain ;
  • the TGF ⁇ -binding domain is human TGF ⁇ RII or a TGF ⁇ -binding fragment thereof.
  • the connecting peptide can be a flexible connecting peptide or a rigid connecting peptide; optionally, the connecting peptide is composed of glycine and serine, for example, the connecting peptide shown in (G 4 S) x G, where x is optionally An integer of 3-6, preferably 4 or 5, most preferably 4 (ie the amino acid sequence shown in SEQ ID NO: 29). Linkages without linker peptides can also be used.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a TGF ⁇ -binding domain;
  • the antibody or an antigen-binding fragment thereof may optionally comprise an unmodified Or a modified constant region, such as a K mutation at the C-terminus of the constant region to A, or an allotype amino acid substitution;
  • the TGF ⁇ binding domain comprises human TGF ⁇ RII or a fragment or variant thereof capable of binding TGF ⁇ , such as a cell of human TGF ⁇ RII ectodomain.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) the amino acid sequence has at least 80%, 81%, 82%, 83%, and 84% of the amino acid sequence shown in SEQ ID NO:7 , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity
  • the heavy chain variable domain and amino acid sequence have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% of the amino acid sequence shown in SEQ ID NO:8 %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical light chain variable domain, or amino acid sequence and SEQ ID
  • the amino acid sequence shown in NO:18 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a heavy chain variable domain shown in SEQ ID NO:7 and a light chain variable domain shown in SEQ ID NO:8, Or a heavy chain variable domain shown in SEQ ID NO: 18 and a light chain variable domain shown in SEQ ID NO: 19; and (b) a TGF ⁇ binding domain.
  • the TGF ⁇ binding domain is human TGF ⁇ RII or its TGF ⁇ binding fragment or variant, for example, the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% Or 100% identical polypeptide or peptide segment.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) the amino acid sequence has at least 80%, 81%, 82%, 83%, and 84% of the amino acid sequence shown in SEQ ID NO:9 , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity
  • the heavy chain and amino acid sequence have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO: 10 , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical light chain, or the amino acid sequence and the amino acid sequence shown in SEQ ID NO:20 have At least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) the amino acid sequence has at least 80%, 81%, 82%, 83%, and 84% of the amino acid sequence shown in SEQ ID NO:23 , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity
  • the heavy chain and amino acid sequence have at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90% of the amino acid sequence shown in SEQ ID NO: 10 , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical light chain, or the amino acid sequence has the amino acid sequence shown in SEQ ID NO:25 At least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 91%,
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) heavy chain shown in SEQ ID NO:9 and light chain shown in SEQ ID NO:10, or shown in SEQ ID NO:20 A heavy chain and a light chain shown in SEQ ID NO: 21; and (b) a TGF ⁇ binding domain.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) heavy chain shown in SEQ ID NO:23 and light chain shown in SEQ ID NO:10, or shown in SEQ ID NO:25 A heavy chain and a light chain shown in SEQ ID NO: 21; and (b) a TGF ⁇ binding domain.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) heavy chain shown in SEQ ID NO:25 and light chain shown in SEQ ID NO:21; and (b) TGF ⁇ binding domain .
  • the TGF ⁇ binding domain is human TGF ⁇ RII or its TGF ⁇ binding fragment or variant, for example, the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% Or 100% identical polypeptide or peptide segment.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence is identical to that of SEQ ID NO: 11, SEQ ID NO: 22, SEQ ID NO: 24 or SEQ ID NO: 24 or SEQ ID NO: The amino acid sequence shown in ID NO:26 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% %, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity, and (b) a second polypeptide having an amino acid sequence identical to that of SEQ ID NO: 10 or SEQ ID NO: 21 The amino acid sequence shown has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% , 95%, 96%, 97%, 98%, 99% or 100% identity.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence has at least 80% of the amino acid sequence shown in SEQ ID NO:11 or SEQ ID NO:24 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99% or 100% identity, and (b) a second polypeptide whose amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence has at least 80% of the amino acid sequence shown in SEQ ID NO:22 or SEQ ID NO:26 , 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, 99% or 100% identity, and (b) a second polypeptide whose amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence is shown in SEQ ID NO: 11 or SEQ ID NO: 24, and (b) the first polypeptide The two polypeptides have an amino acid sequence as shown in SEQ ID NO:10.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence is shown in SEQ ID NO: 22 or SEQ ID NO: 26, and (b) the first polypeptide Two polypeptides, the amino acid sequence of which is shown in SEQ ID NO: 21.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises: (a) a first polypeptide whose amino acid sequence is shown in SEQ ID NO: 26, and (b) a second polypeptide whose amino acid The sequence is shown in SEQ ID NO:21.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) the amino acid sequence of the first polypeptide is the same as The amino acid sequence shown in SEQ ID NO:11, SEQ ID NO:22, SEQ ID NO:24 or SEQ ID NO:26 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; and (b) The amino acid sequence of the two polypeptides has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88% of the amino acid sequence shown in SEQ ID NO:10 or SEQ ID NO:21 , 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) the amino acid sequence of the first polypeptide is as follows Shown in SEQ ID NO:11 or SEQ ID NO:24; and (b) the amino acid sequence of the second polypeptide is shown in SEQ ID NO:10.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) the amino acid sequence of the first polypeptide is as follows Shown in SEQ ID NO:22 or SEQ ID NO:26; and (b) the amino acid sequence of the second polypeptide is shown in SEQ ID NO:21.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) the amino acid sequence of the first polypeptide is as follows Shown in SEQ ID NO:26; and (b) the amino acid sequence of the second polypeptide is shown in SEQ ID NO:21.
  • the amino acid sequence of the first polypeptide, from N-terminal to C-terminal, is as follows: antibody heavy chain variable domain recognizing PD-L1 epitope or antigen, antibody heavy chain constant region, connecting peptide, TGF ⁇ of human TGF ⁇ RII Sequence of combined fragments.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is the anti-PD-L1 antibody-TGF ⁇ receptor II fusion protein in CN106103488.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is the PD-L1/TGF- ⁇ trap fusion protein in CN110050000.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is the Bi-PLB-1 fusion protein in WO2020006509.
  • the unit dose of the pharmaceutical composition containing anti-PD-L1 antibody-TGF ⁇ RII fusion protein is 200-1200mg or other amounts of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, such as 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg or other amounts of anti-PD-L1 antibody-TGF ⁇ RII fusion protein.
  • the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein in the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is 1 mg/mL to 200 mg/mL, 2 mg/mL to 150 mg/mL , 5 mg/mL to 100 mg/mL, 10 mg/mL to 80 mg/mL, 10 mg/mL to 60 mg/mL, or 10 mg/mL to 50 mg/mL.
  • the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, About 40 mg/mL, about 45 mg/mL, about 50 mg/mL, about 55 mg/mL, about 60 mg/mL, about 80 mg/mL, or about 100 mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is about 20 mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is about 25 mg/mL.
  • the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is about 40 mg/mL. In other embodiments, the concentration of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is about 50 mg/mL.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein may also include one or more physiologically acceptable excipients or carriers to make a suitable preparation. Suitable formulations that may be used in the present disclosure may be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, PA, 1985.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein further includes one or more of a buffer, an isotonic regulator, a stabilizer, and a surfactant.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein further includes a buffer, a stabilizer and a surfactant.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a water-soluble injection, and the water-soluble injection includes but is not limited to a water-soluble preparation that has not been lyophilized or lyophilized Water-soluble formulation reconstituted from powder.
  • the pharmaceutical composition containing the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is a lyophilized preparation.
  • the lyophilized preparation refers to a preparation in which an aqueous solution undergoes a freeze-drying process, in which the substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent reaches a value that no longer supports biological activity or chemical reaction.
  • the lyophilized formulations of the present disclosure can also be dried by other methods known in the art, such as spray drying and bubble drying.
  • the chemical name of the gemcitabine is 2'-deoxy-2',2'-difluorocytidine ( ⁇ -isomer), which has the structural formula of formula (I):
  • the gemcitabine includes its free base form and pharmaceutically acceptable salts, and the non-salt forms or salts are all included in the protection scope of the present disclosure.
  • Gemcitabine can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of gemcitabine are within the scope of the present disclosure.
  • Said salts can be produced from various organic and inorganic acids according to methods known in the art.
  • the inorganic acids can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid or phosphoric acid
  • the organic acid may be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid or methanesulfonic acid.
  • the pharmaceutically acceptable salt of gemcitabine can be gemcitabine hydrochloride.
  • gemcitabine is administered as its hydrochloride salt. In some embodiments, gemcitabine is administered as its monohydrochloride salt.
  • the unit dose of the gemcitabine-containing pharmaceutical composition is 0.2 g or 1.0 g of gemcitabine.
  • the gemcitabine-containing pharmaceutical composition includes, but is not limited to, formulations suitable for intravenous, oral, parenteral, and topical administration.
  • the gemcitabine-containing pharmaceutical composition is a formulation suitable for injection.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for injection.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection.
  • the gemcitabine-containing pharmaceutical composition is a lyophilized formulation.
  • the gemcitabine-containing pharmaceutical composition is a lyophilized formulation suitable for injection.
  • the gemcitabine-containing pharmaceutical composition is a lyophilized formulation suitable for intravenous injection.
  • the lyophilized formulation suitable for injection can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • the pharmaceutically acceptable carrier of the lyophilized formulation suitable for injection includes mannitol, sodium acetate, hydrochloric acid, sodium hydroxide.
  • the nab-paclitaxel is albumin-bound paclitaxel; the chemical name of the paclitaxel is 5 ⁇ ,20-epoxy-1,2 ⁇ ,4,7 ⁇ ,10 ⁇ ,13 ⁇ -hexahydroxytaxane- 11-en-9-one-4,10-diacetate-2-benzoate-13-(2R,3S)-N-benzoyl-3-phenylisoserine ester having the formula ( II) the structural formula:
  • nab-paclitaxel unless otherwise stated, are based on the molecular weight of the compound of formula (II).
  • the unit dose of the nab-paclitaxel-containing pharmaceutical composition is 100 mg of nab-paclitaxel, which comprises 100 mg of paclitaxel and about 900 mg of human albumin.
  • the nab-paclitaxel-containing pharmaceutical composition includes, but is not limited to, formulations suitable for intravenous, oral, parenteral, and topical administration.
  • the nab-paclitaxel-containing pharmaceutical composition is a formulation suitable for injection.
  • the gemcitabine-containing pharmaceutical composition is a liquid formulation.
  • the nab-paclitaxel-containing pharmaceutical composition is a liquid formulation suitable for injection.
  • the nab-paclitaxel-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection.
  • the nab-paclitaxel-containing pharmaceutical composition is a lyophilized formulation.
  • the nab-paclitaxel-containing pharmaceutical composition is a lyophilized formulation suitable for injection. In some embodiments, the nab-paclitaxel-containing pharmaceutical composition is a freeze-dried formulation suitable for intravenous injection.
  • paclitaxel prepared in other preparation forms also falls within the scope of the present disclosure, such as paclitaxel injection, paclitaxel oral solution, paclitaxel liposome and the like.
  • anlotinib 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquin Lin-7-yl] oxy] methyl] cyclopropylamine, which has the structural formula of formula (III):
  • anlotinib can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salts of anlotinib are within the scope of the present disclosure, and the salts can be produced from different organic and inorganic acids according to methods known in the art, for example, the inorganic acids can be selected from hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid or phosphoric acid, the organic acid may be selected from succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid or methanesulfonic acid.
  • the pharmaceutically acceptable salt of anlotinib may be anlotinib hydrochloride (eg, anlotinib dihydrochloride).
  • anlotinib is administered as its hydrochloride salt. In some embodiments, the administration is as anlotinib monohydrochloride. In some embodiments of the present disclosure, the administration is in the form of anlotinib dihydrochloride. In some embodiments, the crystalline form of anlotinib hydrochloride is administered. In a specific embodiment, the crystalline form of anlotinib dihydrochloride is administered.
  • anlotinib or a pharmaceutically acceptable salt thereof involved in the present disclosure are based on the molecular weight of the compound of formula (III), unless otherwise specified.
  • the unit dose of the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.
  • Anlotinib or a pharmaceutically acceptable salt thereof is preferably a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the tablet can be ordinary tablet, dispersible tablet, effervescent tablet, sustained-release tablet, controlled-release tablet or enteric-coated tablet
  • the capsule can be ordinary capsule, sustained-release capsule, controlled-release capsule or enteric-coated capsule.
  • the oral preparations can be prepared by conventional methods using pharmaceutically acceptable carriers known in the art.
  • Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants and the like.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid preparation suitable for oral administration.
  • the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof may be in the form of tablets or capsules.
  • the pharmaceutical composition comprising anlotinib or a pharmaceutically acceptable salt thereof is in the form of a capsule.
  • the pharmaceutically acceptable carrier of the oral solid formulation of anlotinib or a pharmaceutically acceptable salt thereof includes mannitol, microcrystalline cellulose, hyprolose, and magnesium stearate.
  • the components in the pharmaceutical combination of the present disclosure may be administered independently, or some or all of them together, by any suitable route, including but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes) ) application.
  • the components of the pharmaceutical combination of the present disclosure may be administered independently or part or all of them together orally or by injection, such as intravenous injection, subcutaneous injection or intraperitoneal injection.
  • the components in the pharmaceutical combination of the present disclosure can be suitable dosage forms independently, or part or all of them together, including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral
  • suitable dosage forms independently, or part or all of them together, including but not limited to, tablets, buccal tablets, pills, capsules (such as hard capsules, soft capsules, enteric capsules, etc.) capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral
  • the components in the pharmaceutical combination of the present disclosure may each independently, or part or all of them jointly contain pharmaceutically acceptable carriers and/or excipients.
  • the pharmaceutical combinations of the present disclosure may also comprise additional therapeutic agents.
  • the additional therapeutic agent may be a cancer therapeutic agent known in the art.
  • the treated patients have a longer survival period (such as median survival period, progression-free survival period or overall survival period);
  • the term "pharmaceutical combination” refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts or esters, etc. administration in the form of derivatives, prodrugs or compositions).
  • the active ingredients may be administered to the subject each simultaneously as a single formulation, or each sequentially as a single formulation in any order.
  • fixed combination means that the active ingredients are administered to a subject simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.
  • non-fixed combination refers to the simultaneous, concurrent or sequential administration of two or more active ingredients to a subject as separate entities (e.g., pharmaceutical composition, preparation), wherein the active ingredients administered to the subject achieve a therapeutically effective volume level.
  • non-fixed combinations are cocktail therapy, eg administration of 3 or more active ingredients.
  • the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
  • the "non-fixed combination” also includes the combined use of "fixed combinations" or independent entities of any one or more active components.
  • TGF ⁇ RII or “TGF ⁇ receptor II” refers to a polypeptide or protein having a wild-type human TGF ⁇ receptor 2 isoform B sequence, such as the polypeptide shown in SEQ ID NO: 27, or having the same sequence as SEQ ID NO: 27
  • the amino acid sequence has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, A polypeptide of a sequence that is 95%, 96%, 97%, 98%, 99% or 100% identical.
  • TGF ⁇ -binding fragment or “TGF ⁇ -binding fragment” of TGF ⁇ RII refers to a fragment of TGF ⁇ RII that has TGF ⁇ -binding activity, accounting for at least 0.1%, 0.5%, 1%, 5%, 10%, 25%, 35% of the sequence of TGF ⁇ RII %, 50%, 75%, 90%, 95%, 99% or 100%.
  • the fragment is usually a soluble fragment, such as the extracellular domain of human TGF ⁇ RII or a variant thereof, non-limiting examples include the polypeptide shown in SEQ ID NO:28.
  • antibody refers to a binding protein having at least one antigen binding domain.
  • Antibodies and antigen-binding fragments thereof of the present disclosure may be whole antibodies or any fragments of antibodies. Accordingly, antibodies and antigen-binding fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates.
  • antibody fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, Fd fragments, Fd' fragments, isolated CDR regions, single chain Fv molecules (scFv) and others known in the art Fragments, and antibodies that have undergone any modification known in the art (eg, glycosylation modification, chemical modification, etc.).
  • Antibodies and antigen-binding fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies.
  • the anti-PD-L1 antibodies and antigen-binding fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3 or IgG4 isotype.
  • the term "isotype" refers to the antibody class encoded by the heavy chain constant region genes.
  • Antibodies and antigen-binding fragments thereof can be chimeric, humanized or fully human antibodies.
  • a “chimeric antibody” is an antibody that has at least a portion of a heavy chain variable domain and at least a portion of a light chain variable domain derived from one species; and a constant region derived from another species. at least partly.
  • a chimeric antibody may comprise murine variable domains and human constant regions.
  • a “humanized antibody” is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody.
  • CDRs complementarity determining regions
  • an anti-PD-L1 antibody can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions.
  • Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein can be generated using any human framework sequences and are also encompassed by the present disclosure.
  • framework sequences suitable for use in the present disclosure include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein.
  • Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or revert mutations to residues in the original germline sequence.
  • modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences.
  • one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acid in the parental murine antibody.
  • Antigen-binding fragment refers to fragments that retain the antigen-binding function of a full-length antibody, including Fab, Fab', F(ab')2, scFv, Fv, Fd, Fd', isolated CDR regions, and single domain VHH fragments and other antibody fragments known in the art, or fragments that have undergone any modification known in the art.
  • Identity refers to the similarity between two reference sequences, and the percentage of identity refers to the percentage obtained by comparing the sequences or specified regions of the sequences through sequence comparison algorithms well known to those skilled in the art.
  • treatment refers to an attempt to alter the natural course of a disease in an individual, and may be to prevent, ameliorate, or eliminate the disease or one or more symptoms associated with the disease, including but not limited to preventing the occurrence or recurrence of the disease, alleviating Symptoms, reduction of any direct or indirect pathological consequences of the disease, prevention of metastasis, slowing of the rate of disease progression, amelioration or palliation of the disease state, and regression or improved prognosis.
  • the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the disclosure required for the onset of one or more symptoms of a particular disease, condition or disorder as described.
  • the amount of an active substance (such as a fusion protein or compound of the present disclosure) that constitutes a "therapeutically effective amount” can vary depending on factors such as the individual's disease state, age, sex, and weight, and the therapeutic agent or combination of therapeutic agents in the individual. The ability to elicit the desired response. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.
  • administering means physically introducing a composition comprising a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • Routes of administration for fusion proteins include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion.
  • parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic , intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injections and infusions , and in vivo electroporation. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.
  • the amount of administration of anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and/or anlotinib or its pharmaceutically acceptable salt can be Determined or adjusted for disease severity, disease response, any treatment-related toxicities, and patient age and health status.
  • the single dose of gemcitabine can be: 100-3000 mg/m 2 , 500-3000 mg/m 2 , 600-2500 mg/m 2 , 200-2000 mg/m 2 , 800-2000 mg/m 2 m 2 , 500-1500 mg/m 2 , 500-1000 mg/m 2 or 1000-1500 mg/m 2 .
  • the single dose of gemcitabine can be: 100 mg/m 2 , 200 mg/m 2 , 500 mg/m 2 , 600 mg/m 2 , 750 mg/m 2 , 800 mg/m 2 , 1000 mg/m 2 , 1500 mg/m 2 , 2000 mg/m 2 , 2500 mg/m 2 or 3000 mg/m 2 .
  • a single dose of gemcitabine may be administered in the range of 600-4800 mg.
  • the single administration dose of nab-paclitaxel can be: 10-500 mg/m 2 , 30-400 mg/m 2 , 30-300 mg/m 2 , 50-300 mg/m 2 , 100 - 200 mg/m 2 , 50-200 mg/m 2 , 50-150 mg/m 2 or 75-125 mg/m 2 .
  • the single administration dose of nab-paclitaxel can be: 10mg/m 2 , 30mg/m 2 , 50mg/m 2 , 75mg/m 2 , 100mg/m 2 , 125mg/m 2 , 150mg/m 2 m 2 , 175 mg/m 2 , 200 mg/m 2 , 300 mg/m 2 , 400 mg/m 2 or 500 mg/m 2 .
  • nab-paclitaxel may be administered in a single dose of 90-300 mg.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 3-30 mg, 5-20 mg or 6-12 mg.
  • the daily dose of anlotinib or a pharmaceutically acceptable salt thereof administered may be 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg or 12 mg.
  • Gemcitabine, nab-paclitaxel, leucovorin, fluorouracil, irinotecan, and/or oxaliplatin may be administered one or more times per week.
  • Anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more than once a day.
  • gemcitabine and nab-paclitaxel are administered weekly as an injectable formulation; preferably, once weekly as an intravenous formulation.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered as an oral solid formulation once a day.
  • Anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, leucovorin, fluorouracil, irinotecan, oxaliplatin, and/or anlotinib or a pharmaceutically acceptable salt thereof can be comprehensively determined or adjusted according to the activity, toxicity, and tolerance of the patient, etc. of the drug.
  • one treatment cycle of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks or more.
  • gemcitabine and nab-paclitaxel are administered as a weekly dose.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered once daily.
  • gemcitabine and nab-paclitaxel are administered at intervals, for example, administration for 7 weeks and rest for 1 week, administration for 3 weeks and rest for 1 week, administration for 2 weeks and rest for 2 weeks, or The medicine is taken for 2 weeks and the medicine is stopped for 1 week; the interval dosing method can be repeated many times.
  • anlotinib or a pharmaceutically acceptable salt thereof is administered at intervals, such as continuous administration for 2 weeks with a break for 2 weeks, continuous administration for 2 weeks with a break for 1 week, or continuous administration for 2 weeks with a break of 1 week.
  • the drug is given for 5 days and the drug is stopped for 2 days; the interval dosing method can be repeated many times.
  • the interval dosing includes a dosing period and a dosing period, and in the dosing period, it can be given once or more than once a day.
  • gemcitabine, nab-paclitaxel, or anlotinib or a pharmaceutically acceptable salt thereof is administered continuously for 2 weeks, followed by 1 week of rest.
  • gemcitabine is administered intravenously at a dose of 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 gemcitabine once a week for 2 consecutive weeks and 1 week off.
  • nab-paclitaxel is administered intravenously once a week at a dose of 75 mg/m 2 , 100 mg/m 2 or 125 mg/m 2 nab-paclitaxel for 2 consecutive weeks and 1 week off.
  • anlotinib or a pharmaceutically acceptable salt thereof is orally administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg anlotinib once a day, for 2 consecutive weeks and 1 week off.
  • flat dose refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA).
  • the flat dose is therefore specified as an absolute amount of the agent (eg, anti-PD-L1 antibody-TGF ⁇ RII fusion protein), rather than as a mg/kg dose.
  • the agent eg, anti-PD-L1 antibody-TGF ⁇ RII fusion protein
  • mg/kg dose e.g., a 60kg person and a 100kg person will receive the same dose of antibody (eg, 1800mg anti-PD-L1 antibody-TGF ⁇ RII fusion protein).
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts of alkali ions and free acids or salts of acid ions and free bases such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, Acetate, Trifluoroacetate, Fumarate, Oxalate, Maleate, Citrate, Tartrate, Succinate, Methanesulfonate, Benzoate, Benzene Sulfonate or p-toluenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, formate Sulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc.
  • the term “subject”, “patient” or “subject” is used interchangeably herein.
  • the term “subject”, “patient” or “subject” is a mammal.
  • the subject, patient or subject is a mouse.
  • the subject, patient or subject is a human.
  • “about” means within a range of acceptable error for a particular value, as judged by one of ordinary skill in the art, which depends in part on how the value is measured or determined, ie, the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean up to ⁇ 5%, for example within ⁇ 2%, within ⁇ 1%, or within ⁇ 0.5% of the particular numerical range given. When a specific value is given in the disclosure or claims, unless otherwise stated, the meaning of "about” should be considered to be within an acceptable error range for the specific value.
  • values of step parameters or conditions are modified by "about” by default.
  • “combination” or “combined use” means that two or more active substances may be administered to a subject simultaneously, each as a single formulation, or sequentially, each as a single formulation, in any order.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and one capsule is a single dose; or a bottle of injection is a single dose.
  • multiple dose consists of a number of single doses.
  • Unit dose refers to the dose of the active ingredient contained in the smallest packaging unit containing a certain amount of medicine, for example, the dose of anlotinib contained in an anlotinib hydrochloride capsule is a unit dose; or a bottle The dose of the fusion protein contained in the fusion protein injection is a unit dose; or the dose of paclitaxel contained in a bottle of nab-paclitaxel freeze-dried powder is a unit dose.
  • pharmaceutical composition refers to a mixture of one or more active ingredients of the present disclosure or a pharmaceutical combination thereof and a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present disclosure, or a pharmaceutical combination thereof, to a subject.
  • pharmaceutical composition and “preparation” have the same meaning and are used interchangeably.
  • recurrent cancer is cancer that regenerates at the original site or at a distant site after a response to initial treatment (eg, surgery).
  • a "locally recurrent” cancer is one that, after treatment, arises in the same location as a previously treated cancer.
  • metalstatic cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.
  • treatment failure is defined as disease progression or relapse during or after last treatment.
  • Embodiment 1 A pharmaceutical combination comprising an anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, and nab-paclitaxel.
  • Embodiment 2 The pharmaceutical combination according to embodiment 1, wherein the pharmaceutical combination comprises an anti-PD-L1 antibody-TGF ⁇ RII fusion protein with a unit dose of 200-1200 mg, gemcitabine with a unit dose of 0.2 g and/or 1.0 g , and nab-paclitaxel with a unit dose of 100 mg.
  • Embodiment 3 The pharmaceutical combination according to embodiment 1 or 2, wherein the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to gemcitabine is (0.1-10):1, and the anti-PD-L1 antibody - The mass ratio of TGF ⁇ RII fusion protein to nab-paclitaxel is (0.1-30):1.
  • Embodiment 4 The pharmaceutical combination according to any one of embodiments 1-3, wherein said pharmaceutical combination is suitable for administration in a single treatment cycle and comprises 600-2400 mg of an anti-PD-L1 antibody-TGF ⁇ RII fusion protein , 1000-2000 mg/m 2 of gemcitabine, and 150-250 mg/m 2 of nab-paclitaxel.
  • Embodiment 5 The pharmaceutical combination according to any one of embodiments 1-4, wherein the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises:
  • the anti-PD-L1 antibody or its antigen-binding fragment comprises:
  • HCDR1 of the amino acid sequence shown in SEQ ID NO:12 HCDR2 of the amino acid sequence shown in SEQ ID NO:13
  • HCDR3 of the amino acid sequence shown in SEQ ID NO:14 LCDR1 of the amino acid sequence shown in SEQ ID NO:15
  • the LCDR2 of the amino acid sequence shown in SEQ ID NO:16 and the LCDR3 of the amino acid sequence shown in SEQ ID NO:17.
  • Embodiment 6 The pharmaceutical combination according to embodiment 5, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 7 The pharmaceutical combination according to embodiment 5 or 6, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:
  • Embodiment 8 The pharmaceutical combination according to any one of embodiments 5-7, wherein the human TGF ⁇ RII or a TGF ⁇ -binding fragment thereof comprises an amino acid having at least 80% identity to the amino acid sequence set forth in SEQ ID NO:28 sequence.
  • Embodiment 9 The pharmaceutical combination according to any one of embodiments 5-8, wherein the anti-PD-L1 antibody-TGF ⁇ RII fusion protein further comprises C of the anti-PD-L1 antibody or antigen-binding fragment thereof
  • the connecting peptide whose end is connected to the N-terminal of the human TGF ⁇ RII or its TGF ⁇ binding fragment; preferably, the connecting peptide is (G4S) x G, and x is an integer of 3-6; preferably, the connecting peptide has SEQ Amino acid sequence shown in ID NO:29.
  • Embodiment 10 The pharmaceutical combination according to any one of embodiments 5-9, wherein the anti-PD-L1 antibody-TGF ⁇ RII fusion protein comprises:
  • Embodiment 11 The pharmaceutical combination according to any one of embodiments 1-10, wherein the pharmaceutical combination further comprises anlotinib or a pharmaceutically acceptable salt thereof; optionally, the anlotinib
  • the pharmaceutically acceptable salt of Nisin is monohydrochloride or dihydrochloride.
  • Embodiment 12 The pharmaceutical combination according to embodiment 11, wherein the unit dose of anlotinib or a pharmaceutically acceptable salt thereof is 6 mg, 8 mg, 10 mg and/or 12 mg.
  • Embodiment 13 The pharmaceutical combination according to embodiment 11 or 12, wherein the mass ratio of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein to anlotinib or a pharmaceutically acceptable salt thereof is (3.5-29.0 ):1.
  • Embodiment 14 The pharmaceutical combination according to any one of embodiments 11-13, wherein said pharmaceutical combination is suitable for administration within a single treatment cycle, said anlotinib or a pharmaceutically acceptable salt thereof
  • the dosage is 84-168mg.
  • Embodiment 15 The pharmaceutical combination according to any one of embodiments 1-14, wherein said pharmaceutical combination is for the treatment of pancreatic cancer.
  • Embodiment 16 Use of the pharmaceutical combination of any one of embodiments 1-15 for the manufacture of a medicament for the treatment of pancreatic cancer.
  • Embodiment 17 The use according to embodiment 16, wherein the pancreatic cancer is refractory, unresectable, recurrent, advanced and/or metastatic pancreatic cancer; preferably, the pancreatic cancer is metastatic pancreatic cancer.
  • Embodiment 18 The use according to embodiment 16 or 17, wherein the pancreatic cancer is a pancreatic endocrine tumor and/or a pancreatic exocrine tumor.
  • Embodiment 19 The use according to any one of embodiments 16-18, wherein the subject with pancreatic cancer has not previously been treated for pancreatic cancer.
  • Embodiment 20 The use according to any one of embodiments 16-18, wherein the subject with pancreatic cancer has previously been treated for pancreatic cancer with one or more different antineoplastic therapies.
  • Embodiment 21 The use according to any one of embodiments 16-20, wherein each of the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine and nab-paclitaxel is in the form of a pharmaceutical composition, which can be simultaneously and sequentially and/or alternate administration.
  • Embodiment 22 The use according to any one of embodiments 16-20, wherein the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or its pharmaceutically acceptable
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or its pharmaceutically acceptable Each of the salts of is in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately.
  • Embodiment 23 The use according to any one of embodiments 16-22, wherein the anti-PD-L1 antibody-TGF ⁇ RII fusion protein is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks , administered at a dose of 600-2400 mg anti-PD-L1 antibody-TGF ⁇ RII fusion protein each time.
  • Embodiment 24 The use according to any one of embodiments 16-23, wherein the gemcitabine is dosed once a week at 500-1000 mg/m 2 , 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 gemcitabine The dosage is administered continuously for 2 weeks and stopped for 1 week.
  • Embodiment 25 The use according to any one of embodiments 16-24, wherein the nab-paclitaxel is administered once a week at 75-125 mg/m 2 , 75 mg/m 2 , 100 mg/m 2 or 125 mg/m 2 2.
  • the dosage of nab-paclitaxel is given in a regimen of continuous medication for 2 weeks and 1 week off.
  • Embodiment 26 The use according to any one of embodiments 16-20, 22-25, wherein the anlotinib or a pharmaceutically acceptable salt thereof is dosed at 6-12 mg, 6 mg, 8 mg once a day , 10mg or 12mg of anlotinib, continuous medication for 2 weeks, stop for 1 week of drug administration.
  • Embodiment 27 A kit for the treatment of pancreatic cancer comprising the pharmaceutical combination of any one of embodiments 1-15.
  • the anti-PD-L1 antibody-TGF ⁇ RII fusion protein hu5G11-hIgG1-TGF ⁇ RII in the embodiment is hu5G11-hIgG1-TGF ⁇ RII in WO2021037184, and the hu5G11-hIgG1-TGF ⁇ RII consists of two identical first polypeptides and two identical The composition of the second polypeptide, wherein: (1) the amino acid sequence of the first polypeptide is shown in SEQ ID NO: 26, and the first polypeptide is a fusion protein composed of an anti-human PD-L1 antibody (SEQ ID NO: ID NO: 25) heavy chain, human TGF ⁇ RII extracellular domain amino acid sequence (SEQ ID NO: 28) and the (G 4 S) 4 G linking peptide (SEQ ID NO: 29) that connects the two components; and (2) The amino acid sequence of the second polypeptide is shown in SEQ ID NO:21.
  • phase 1 it is required to include patients who have failed at least one line of systemic chemotherapy or who are considered by the investigator to be unsuitable for systemic chemotherapy;
  • Cohort 1 and cohort 2 of Phase 2 are required to enroll patients with newly diagnosed metastatic pancreatic cancer confirmed by histology or cytology;
  • Cohort 3 in phase 2 requires inclusion of patients with metastatic pancreatic cancer who have failed first-line FOLFIRINOX or FOLFIRINOX+BRCA mutation targeted therapy or PD-1/PD-L1 therapy;
  • first-line treatment failure a. Disease progression during first-line treatment or after treatment; b. Disease progression within 6 months after neoadjuvant or adjuvant treatment.
  • the ECOG score is 0-1, and the expected survival time is more than 3 months;
  • TBIL Total bilirubin
  • UPN upper limit of normal
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase
  • Thyroid function tests must meet the following criteria:
  • TSH Thyroid-stimulating hormone
  • LVEF left ventricular ejection fraction
  • hu5G11-hIgG1-TGF ⁇ RII injection 200mg (4mL)/bottle and 600mg (12mL)/bottle;
  • Gemcitabine 0.2g/bottle and 1.0g/bottle
  • Nab-paclitaxel 100mg/bottle
  • Anlotinib Hydrochloride Capsules Specifications are 6mg/capsule, 8mg/capsule, 10mg/capsule and 12mg/capsule.
  • hu5G11-hIgG1-TGF ⁇ RII injection 600mg, 1200mg, 1800mg or 2400mg, intravenous infusion, once every 3 weeks, 3 weeks is a treatment cycle.
  • Cohort 1 first-line treatment with hu5G11-hIgG1-TGF ⁇ RII injection + gemcitabine + nab-paclitaxel:
  • hu5G11-hIgG1-TGF ⁇ RII injection 600mg, 1200mg, 1800mg or 2400mg, intravenous infusion, once every 21 days;
  • Gemcitabine 1000mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and stop for 1 week;
  • Nab-paclitaxel 125mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and stop for 1 week;
  • Cohort 2 first-line treatment with hu5G11-hIgG1-TGF ⁇ RII injection + anlotinib hydrochloride capsules + gemcitabine + nab-paclitaxel:
  • hu5G11-hIgG1-TGF ⁇ RII injection 600mg, 1200mg, 1800mg or 2400mg, intravenous infusion, once every 21 days;
  • Anlotinib Hydrochloride Capsules 8 mg, orally, once a day, for 2 consecutive weeks and stop for 1 week;
  • Gemcitabine 1000mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and stop for 1 week;
  • Nab-paclitaxel 125mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and stop for 1 week;
  • hu5G11-hIgG1-TGF ⁇ RII injection 600mg, 1200mg, 1800mg or 2400mg, intravenous infusion, once every 21 days;
  • Gemcitabine 1000mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and stop for 1 week;
  • Nab-paclitaxel 125mg/m 2 , intravenous infusion, once every 7 days, for 2 consecutive weeks and 1 week off.
  • nab-paclitaxel is adjusted from 125 mg/m 2 to 100 mg/m 2 , or from 100 mg/m 2 to 100 mg/m 2 75mg/m 2 ; the dose of gemcitabine was adjusted from 1000mg/m 2 to 750mg/m 2 , or from 750mg/m 2 to 500mg/m 2 .
  • the RECIST 1.1 standard was used to judge the disease state, and the curative effect was confirmed and supplemented by the iRECIST standard.
  • DCR CR+PR+stable disease (SD)), duration of response (DOR), progression-free survival (PFS), overall survival (OS);
  • Immunogenicity such as the incidence of anti-drug antibody (ADA) and its titer in the subject, and the incidence of neutralizing antibody (Nab).
  • treatment-related biomarkers such as PD-L1 in tumor tissue and TGF- ⁇ in blood samples
  • anti-tumor efficacy of hu5G11-hIgG1-TGF ⁇ RII injection in the treatment of pancreatic cancer.
  • Metastatic pancreatic cancer CTA of hepatobiliary and pancreatic tumors and blood vessels showed that pancreatic cancer in the tail of the pancreas involved the splenic hilum with partial infarction of the spleen, multiple liver metastases, multiple peritoneal mesenteric implants and metastases, and splenomegaly. A needle biopsy was performed on the patient, and the pathology showed (liver biopsy specimen) poorly differentiated cancer metastasis or invasion.
  • Metastatic pancreatic cancer hepatobiliary and pancreatic tumors and blood vessel CTA (hepatobiliary, pancreatic and spleen) show that the pancreatic duct is dilated; intrahepatic and extrahepatic bile ducts are dilated; multiple slightly larger lymph nodes in the retroperitoneum; liver S4 occupies space, and metastasis is considered; multiple cysts in the liver; left hepatic artery and The left gastric artery co-drains; multiple cysts in both kidneys.
  • the liver space-occupying puncture biopsy of the patient was performed; immunohistochemistry showed (the puncture specimen of the S4 segment of the liver) pancreatic infiltration or metastasis, suggesting a pancreaticobiliary phenotype.
  • target lesion 65.16mm
  • target lesion 47.7mm
  • the best therapeutic effect was PR.
  • target lesion 17.7mm
  • the best therapeutic effect was PR.
  • target lesion 63.1mm
  • the best therapeutic effect was PR.
  • target lesion 46.2mm
  • target lesion 37.9mm
  • the best therapeutic effect was PR.
  • target lesion 39.3mm
  • the best therapeutic effect was PR.
  • target lesion 47.9mm
  • the best therapeutic effect was PR.

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Abstract

提供一种治疗肿瘤的联用药物，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；任选地，还包括安罗替尼或其药学上可接受的盐。还提供一种治疗肿瘤的联用药物，其包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸、氟尿嘧啶、伊立替康和奥沙利铂；任选地，还包括安罗替尼或其药学上可接受的盐。还提供用于治疗肿瘤的试剂盒，其包含所述的联用药物。此外，还提供所述联用药物在制备用于治疗肿瘤的药物中的用途以及所述联用药物治疗肿瘤的方法。

Description

治疗肿瘤的联用药物 技术领域
本公开属于生物医药领域，具体涉及治疗肿瘤的联用药物。
背景技术
胰腺癌是最具侵袭性的癌症，大多数患者初诊时已发生转移。转移性胰腺癌预后极差，即使随着科技的发展，治疗胰腺癌的外科手术技术和药物治疗等手段在不断改进，但胰腺癌患者存活率的提升仍然非常有限，在过去的45年内(1975-2020)，胰腺癌患者的5年生存率仅仅从3％提升到9％。
目前针对失去手术价值的转移性胰腺癌主要依靠药物治疗，全球多个国家包括我国胰腺癌治疗指南推荐的一线治疗方案有两种，即AG方案((吉西他滨(Gemcitabine)和白蛋白紫杉醇(Abraxane/nab-paclitaxel)联用)和FOLFIRINOX方案(亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂联用)。
程序性死亡配体1(Programmed death-ligand 1，PD-L1)是程序性死亡分子1(Programmed death，PD-1)的一个配体，高表达于各种实体恶性肿瘤，且表达水平和受试者的临床表现及预后紧密相关。在肿瘤微环境中，肿瘤细胞表面的PD-L1通过与T细胞表面的PD-1或CD80的结合，抑制T细胞的激活和增殖，促进效应T细胞进入衰竭或无反应状态，诱导T细胞的凋亡，刺激辅助T细胞分化为调节性T细胞，从而阻止T细胞对肿瘤细胞的杀伤作用。抗PD-L1抗体可以通过阻断PD-L1与PD-1及CD80的相互作用，避免肿瘤微环境中的效应T细胞的活性被抑制，增强内源性抗肿瘤免疫效应。TGF-β(Transforming growth factor β)属于调节细胞生长和分化的TGF-β超家族，通过介导SMAD通路促进肿瘤侵袭和转移，同时抑制T细胞的活化和分化，提高PD-L1表达，进而促进肿瘤生长。抗PD-L1抗体-TGFβRII融合蛋白能够在抑制PD-L1/PD-1通路的基础上抑制TGF-β信号通路，改善免疫微环境，增强免疫治疗的效果。
酪氨酸激酶(Tyrosine kinase)是一组催化蛋白质酪氨酸残基磷酸化的酶，在细胞内的信号转导中起着重要的作用，它参与正常细胞的调节、信号传递和发育，也与肿瘤细胞的增殖、分化、迁移和凋亡密切相关。许多受体酪氨酸激酶(Receptor tyrosine kinase，RTK)都与肿瘤的形成相关，根据其细胞外区域结构的不同可分为表皮生长因子受体(EGFR)、血小板衍生生长因子受体(PDGFR)、血管内皮生长因子受体(VEGFR)、成纤维细胞生长因子受体(FGFR)等。
安罗替尼(Anlotinib)是一种喹啉衍生物类酪氨酸激酶抑制剂，其作为多靶点酪氨酸激酶抑制剂在影响肿瘤血管生成和增殖信号传导方面发挥作用，主要靶点包括：受体酪氨酸激酶VEGFR1(FLT1)，VEGFR2(KDR)，VEGFR3(FLT4)，EGFR，FGFR1-4，PDGFRα和β，以及干细胞因子受体(SCFR)7、8和9。
因此，需要更为有效的治疗剂以供临床使用，例如一种以上药物的组合使用。
发明概述
在一方面，本公开提供药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；任选地，还包括安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物；任选地，还包括含安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合包括单位剂量为200-1200mg的抗PD-L1抗体-TGFβRII融合蛋白、单位剂量为0.2g和/或1.0g的吉西他滨、和单位剂量为100mg的白蛋白紫杉醇；任选地，所述药物组合还包括单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇可分开包装或包装在一起。并且其中，所述抗PD-L1抗体-TGFβRII融合蛋白能够以单份或多个等份进行包装，所述吉西他滨能够以单份或多个等份进行包装，所述白蛋白紫杉醇能够以单份或多个等份进行包装。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐可分开包装或包装在一起。并且其中，所述抗PD-L1抗体-TGFβRII融合蛋白能够以单份或多个等份进行包装，所述吉西他滨能够以单份或多个等份进行包装，所述白蛋白紫杉醇能够以单 份或多个等份进行包装，所述安罗替尼或其药学上可接受的盐能够以单份或多个等份进行包装。
在一些实施方案中，所述药物组合用于治疗肿瘤。在一些实施方案中，所述药物组合用于治疗胰腺癌。
在另一方面，本公开提供用于治疗胰腺癌的药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；任选地，还包括安罗替尼或其药学上可接受的盐。
在另一方面，本公开还提供在受试者中治疗胰腺癌的方法，其包括向受试者给予有效量的本公开的药物组合。另外，本公开还提供了本公开的药物组合在制备用于治疗胰腺癌的药物中的用途。或者，本公开还提供了抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇，任选地，还包括安罗替尼或其药学上可接受的盐在制备用于治疗胰腺癌的药物中的用途。
在一些实施方案中，所述药物组合是固定组合。在一些实施方案中，所述固定组合呈固体药物组合物的形式或液体药物组合物的形式。
在一些实施方案中，所述药物组合是非固定组合。在一些实施方案中，所述非固定组合中的抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式。在一些实施方案中，所述非固定组合中的抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式。
在一些实施方案中，所述非固定组合中，含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为液体药物组合物。在一些具体实施方案中，所述液体药物组合物为注射液。
在一些实施方案中，所述非固定组合中，含吉西他滨的药物组合物为固体药物组合物。
在一些实施方案中，所述非固定组合中，含白蛋白紫杉醇的药物组合物为固体药物组合物。
在一些实施方案中，所述非固定组合中，含安罗替尼或其药学上可接受的盐的药物组合物为固体药物组合物。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后和/或交替给药。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每1周、每2周、每3周、或每4周施用一次。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的剂量施用。
在一些实施方案中，所述吉西他滨以每周一次500-1000mg/m 2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，所述白蛋白紫杉醇以每周一次75-125mg/m 2白蛋白紫杉醇的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，所述安罗替尼或其药学上可接受的盐以每日一次6mg、8mg、10mg或12mg安罗替尼的剂量、连续用药2周、停1周的给药方案给药。
在另一方面，本公开提供用于治疗胰腺癌的试剂盒，其包括本公开的药物组合。在一些实施方案中，所述试剂盒包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；任选地，还包括安罗替尼或其药学上可接受的盐。
在另一方面，本公开还提供药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂；任选地，还包括安罗替尼或其药学上可接受的盐。另外，本公开提供用于治疗胰腺癌的药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂；任选地，还包括安罗替尼或其药学上可接受的盐。另外，本公开还提供了抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂，任选地，还包括安罗替尼或其药学上可接受的盐在制备用于治疗胰腺癌肿瘤的药物中的用途。
发明详述
本公开提供药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；任选地，还包括安罗替尼或其药学上可接受的盐。或者，本公开还提供药物组合，其包括抗PD-L1抗体-TGFβRII 融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂；任选地，还包括安罗替尼或其药学上可接受的盐。在一些实施方案中，所述药物组合用于治疗肿瘤。
本公开还提供本公开的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供本公开的药物组合治疗肿瘤的用途。本公开还提供治疗肿瘤的方法，包括向受试者给予有效量的本公开的药物组合。
本公开还提供用于治疗肿瘤的试剂盒，所述试剂盒包括本公开的药物组合。在一些实施方案中，所述试剂盒还包括本公开的药物组合治疗肿瘤的说明。
此外，本公开还提供用于治疗肿瘤的抗PD-L1抗体-TGFβRII融合蛋白。本公开还提供抗PD-L1抗体-TGFβRII融合蛋白在制备用于治疗肿瘤的药物中的用途。本公开还提供抗PD-L1抗体-TGFβRII融合蛋白治疗肿瘤的用途。本公开还提供治疗肿瘤的方法，包括向受试者给予有效量的本公开的抗PD-L1抗体-TGFβRII融合蛋白。
在一些实施方案中，所述肿瘤为胰腺癌。
药物组合
在一方面，本公开提供一种药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇。任选地，所述药物组合还包括安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物。任选地，所述药物组合还包括含安罗替尼或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括将抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇联合使用以治疗肿瘤的说明。在一些实施方案中，所述药物组合中的抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇分开包装于各自的药盒中，所述药盒还包括将抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇联合使用以治疗肿瘤的说明。在另外一些实施方案中，所述药物组合包装于同一试剂盒中，所述试剂盒还包括将抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐联合使用以治疗肿瘤的说明。在另外一些实施方案中，所述药物组合中的抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐分开包装于各自的药盒中，所述药盒还包括将抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐联合使用以治疗肿瘤的说明。在一些实施方案中，所述肿瘤为胰腺癌。
在一些实施方案中，所述药物组合包括单位剂量为200-1200mg或200-600mg的抗PD-L1抗体-TGFβRII融合蛋白、单位剂量为0.2g和/或1.0g的吉西他滨、和单位剂量为100mg的白蛋白紫杉醇。任选地，所述药物组合还包括单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括单位剂量为约200mg、约250mg、约300mg、约350mg、约400mg、约450mg、约500mg、约550mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg和/或约1200mg的抗PD-L1抗体-TGFβRII融合蛋白，单位剂量为0.2g和/或1.0g的吉西他滨，和单位剂量为100mg的白蛋白紫杉醇。任选地，所述药物组合还包括单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括单位剂量为约200mg、约400mg和/或约600mg的抗PD-L1抗体-TGFβRII融合蛋白，单位剂量为0.2g和/或1.0g的吉西他滨，和单位剂量为100mg的白蛋白紫杉醇。任选地，所述药物组合还包括单位剂量为8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括单位剂量为200-1200mg或200-600mg抗PD-L1抗体-TGFβRII融合蛋白的含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、单位剂量为0.2g和/或1.0g吉西他滨的含吉西他滨的药物组合物、和单位剂量为100mg白蛋白紫杉醇的含白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括单位剂量为6mg、8mg、10mg和/或12mg安罗替尼的含安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合包括单位剂量为约200mg、约250mg、约300mg、约350mg、约 400mg、约450mg、约500mg、约550mg、约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg和/或约1200mg抗PD-L1抗体-TGFβRII融合蛋白的含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物，单位剂量为0.2g和/或1.0g吉西他滨的含吉西他滨的药物组合物，和单位剂量为100mg白蛋白紫杉醇的含白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括单位剂量为6mg、8mg、10mg和/或12mg安罗替尼的含安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合包括单位剂量为约200mg、约400mg和/或约600mg抗PD-L1抗体-TGFβRII融合蛋白的含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物，单位剂量为0.2g和/或1.0g吉西他滨的含吉西他滨的药物组合物，和单位剂量为100mg白蛋白紫杉醇的含白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括单位剂量为8mg、10mg和/或12mg安罗替尼的含安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合包括600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的抗PD-L1抗体-TGFβRII融合蛋白，100-3000mg/m 2、200-2000mg/m 2、500-1500mg/m 2、或500-1000mg/m 2的吉西他滨，和10-500mg/m 2、30-300mg/m 2、100-200mg/m 2、或75-125mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg和/或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，500-1000mg/m 2的吉西他滨，和75-125mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括约600mg、约1200mg、约1800mg和/或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，500-1000mg/m 2的吉西他滨，和75-125mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括约1200mg和/或约1800mg的抗PD-L1抗体-TGFβRII融合蛋白、1000mg/m 2的吉西他滨、和125mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括8mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合中，抗PD-L1抗体-TGFβRII融合蛋白的含量为一日剂量。在一些实施方案中，所述药物组合中，抗PD-L1抗体-TGFβRII融合蛋白的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，抗PD-L1抗体-TGFβRII融合蛋白的含量为统一剂量。
在一些实施方案中，所述药物组合中，吉西他滨的含量为一日剂量。在一些实施方案中，所述药物组合中，吉西他滨的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，白蛋白紫杉醇的含量为一日剂量。在一些实施方案中，所述药物组合中，白蛋白紫杉醇的含量为一日一次剂量。
在一些实施方案中，所述药物组合中，安罗替尼或其药学上可接受的盐的含量为一日剂量。在一些实施方案中，所述药物组合中，安罗替尼或其药学上可接受的盐的含量为一日一次剂量。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的抗PD-L1抗体-TGFβRII融合蛋白，200-6000mg/m 2、400-4000mg/m 2、1000-3000mg/m 2、或1000-2000mg/m 2的吉西他滨，和20-1000mg/m 2、60-600mg/m 2、200-400mg/m 2、或150-250mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括84-168mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg和/或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，1000-2000mg/m 2的吉西他滨，和150-250mg/m 2的白蛋白 紫杉醇。任选地，所述药物组合还包括84-168mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约600mg、约1200mg、约1800mg和/或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，1000-2000mg/m 2的吉西他滨，和150-250mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括84-168mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括约1200mg和/或约1800mg的抗PD-L1抗体-TGFβRII融合蛋白、2000mg/m 2的吉西他滨、和250mg/m 2的白蛋白紫杉醇。任选地，所述药物组合还包括112mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括含600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg抗PD-L1抗体-TGFβRII融合蛋白的药物组合物，含200-6000mg/m 2、400-4000mg/m 2、1000-3000mg/m 2、或1000-2000mg/m 2吉西他滨的药物组合物，和含20-1000mg/m 2、60-600mg/m 2、200-400mg/m 2、或150-250mg/m 2白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括含84-168mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括含约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg和/或约2400mg抗PD-L1抗体-TGFβRII融合蛋白的药物组合物，含1000-2000mg/m 2吉西他滨的药物组合物，和含150-250mg/m 2白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括含84-168mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括含约600mg、约1200mg、约1800mg和/或约2400mg抗PD-L1抗体-TGFβRII融合蛋白的药物组合物，含1000-2000mg/m 2吉西他滨的药物组合物，和含150-250mg/m 2白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括含84-168mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合适用于在单个治疗周期内施用，其包括含约1200mg和/或约1800mg抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含2000mg/m 2吉西他滨的药物组合物、和含250mg/m 2白蛋白紫杉醇的药物组合物；其中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为单剂量或多剂量。任选地，所述药物组合还包括含112mg安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为多剂量。
在一些实施方案中，所述药物组合中，所述抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比为(0.1-10):1、(0.125-2):1、(0.125-1.5):1或(0.25-1.5):1，所述抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比为(0.1-30):1、(1-15):1、(2-15):1或(2-10):1；其中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇可分开包装或包装在一起。并且其中，抗PD-L1抗体-TGFβRII融合蛋白能够以单份或多个等份(例如2等份、3等份、4等份、5等份、6等份、7等份、8等份、9等份、10等份、12等份或更多等份)进行包装；吉西他滨能够以单份或多个等份进行包装；白蛋白紫杉醇能够以单份或多个等份进行包装。
在另外一些实施方案中，所述药物组合中，所述抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比为(0.1-10):1、(0.125-2):1、(0.125-1.5):1或(0.25-1.5):1，所述抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比为(0.1-30):1、(1-15):1、(2-15):1或(2-10):1，所述抗PD-L1抗体-TGFβRII融合蛋白和安罗替尼或其药学上可接受的盐的质量比为(3.5-29.0):1、(7.1-29.0):1、(7.1-21.5):1、(7.1-14.5):1、(10.5-21.5):1、50:7或75:7；其中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐可分开包装或包装在一起。并且其中，抗PD-L1抗体-TGFβRII融合蛋白能够以单份或多个等份(例如2等份、3等份、4等份、5等份、6等份、7等份、8等份、9等份、10等份、12等份或更多等 份)进行包装；吉西他滨能够以单份或多个等份进行包装；白蛋白紫杉醇能够以单份或多个等份进行包装；安罗替尼或其药学上可接受的盐能够以单份或多个等份(例如7等份、14等份、28等份或更多等份)进行包装。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物，其中含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物被制备为适合第一次给药时向患者给予600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg抗PD-L1抗体-TGFβRII融合蛋白的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续2周、每周向患者给予100-3000mg/m 2、200-2000mg/m 2、500-1500mg/m 2、或500-1000mg/m 2吉西他滨的单剂量或多剂量，含白蛋白紫杉醇的药物组合物被制备为适合连续2周、每周向患者给予10-500mg/m 2、30-300mg/m 2、100-200mg/m 2、或75-125mg/m 2白蛋白紫杉醇的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物，其中含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物被制备为适合第一次给药时向患者给予约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg或约2400mg抗PD-L1抗体-TGFβRII融合蛋白的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续2周、每周向患者给予500-1000mg/m 2吉西他滨的单剂量或多剂量，含白蛋白紫杉醇的药物组合物被制备为适合连续2周、每周向患者给予75-125mg/m 2白蛋白紫杉醇的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物，其中含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物被制备为适合第一次给药时向患者给予约600mg、约1200mg、约1800mg或约2400mg抗PD-L1抗体-TGFβRII融合蛋白的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续2周、每周向患者给予500-1000mg/m 2吉西他滨的单剂量或多剂量，含白蛋白紫杉醇的药物组合物被制备为适合连续2周、每周向患者给予75-125mg/m 2白蛋白紫杉醇的单剂量或多剂量。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物，其中含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物被制备为适合第一次给药时向患者给予约1200mg或约1800mg抗PD-L1抗体-TGFβRII融合蛋白的单剂量或多剂量，含吉西他滨的药物组合物被制备为适合连续2周、每周向患者给予1000mg/m 2吉西他滨的单剂量或多剂量，含白蛋白紫杉醇的药物组合物被制备为适合连续2周、每周向患者给予125mg/m 2白蛋白紫杉醇的单剂量或多剂量。
在另外一些实施方案中，所述含安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天、每天向患者给予6-12mg安罗替尼的单剂量。更具体地，所述含安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天、每天向患者给予6mg、8mg、10mg或12mg安罗替尼的单剂量。更具体地，所述含安罗替尼或其药学上可接受的盐的药物组合物被制备为适合连续14天、每天向患者给予8mg安罗替尼的单剂量。
在另一方面，本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇的药物组合治疗肿瘤的用途。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予有效量的包含抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇的药物组合。在一些实施方案中，所述肿瘤为胰腺癌。
或者，本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐的药物组合治疗肿瘤的用途。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予有效量的包含抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐的药物组合。在一些实施方案中，所述肿瘤为胰腺癌。
在另一方面，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物，以及将含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物和含白蛋白紫杉醇的药物组合物联合使用以治疗肿瘤的说明。在一些实施方案中，所述肿瘤为胰腺癌。
或者，本公开提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物、含白蛋白紫杉醇的药物组合物、和含安罗替尼或其药学上可接受的盐的药物组合物，以及将含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含吉西他滨的药物组合物、含白蛋白紫杉醇的药物组合物、和含安罗替尼或其药学上可接受的盐的药物组合物联合使用以治疗肿瘤的说明。在一些实施方案中，所述肿瘤为胰腺癌。
另外，本公开还提供药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂。任选地，所述药物组合还包括安罗替尼或其药学上可接受的盐。
在一些实施方案中，所述药物组合包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含亚叶酸钙的药物组合物、含氟尿嘧啶的药物组合物、含伊立替康的药物组合物和含奥沙利铂的药物组合物。任选地，所述药物组合还包括含安罗替尼或其药学上可接受的盐的药物组合物。
本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂的药物组合治疗肿瘤的用途。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予有效量的包含抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂的药物组合。在一些实施方案中，所述肿瘤为胰腺癌。
或者，本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂和安罗替尼或其药学上可接受的盐的药物组合在制备用于治疗肿瘤的药物中的用途。本公开还提供包括抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂和安罗替尼或其药学上可接受的盐的药物组合治疗肿瘤的用途。本公开还提供在受试者中治疗肿瘤的方法，包括向受试者给予有效量的包含抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂和安罗替尼或其药学上可接受的盐的药物组合。在一些实施方案中，所述肿瘤为胰腺癌。
本公开还提供用于治疗肿瘤的试剂盒，所述试剂盒包括含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物、含亚叶酸钙的药物组合物、含氟尿嘧啶的药物组合物、含伊立替康的药物组合物和含奥沙利铂的药物组合物。在一些实施方案中，所述试剂盒还包括含安罗替尼或其药学上可接受的盐的药物组合物。在一些实施方案中，所述肿瘤为胰腺癌。
药物组合的给药/治疗方案
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，先后给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，且各自以间隔给药的方式给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇分别以相同或不同的给药方案进行给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇分别以不同的给药方案进行给药。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，先后给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各 自呈药物组合物的形式，且各自以间隔给药的方式给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐分别以相同或不同的给药方案进行给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐分别以不同的给药方案进行给药。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白每周(q1w)、每2周(q2w)、每3周(q3w)、或每4周(q4w)施用一次。在一个具体的实施方案中，每3周给予抗PD-L1抗体-TGFβRII融合蛋白一次。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg或约2400mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以约600mg、约1200mg、约1800mg或约2400mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以约1200mg的剂量施用。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白每次以约1800mg的剂量施用。
在一些实施方案中，上述用途或治疗方法中，所述吉西他滨每周施用一次。在一些实施方案中，上述用途或治疗方法中，所述吉西他滨每次以100-3000mg/m 2、200-2000mg/m 2、500-1500mg/m 2或500-1000mg/m 2的剂量施用。在一些实施方案中，上述用途或治疗方法中，所述吉西他滨每次以500mg/m 2、750mg/m 2或1000mg/m 2的剂量施用。在一些实施方案中，上述用途或治疗方法中，所述吉西他滨以每周一次500-1000mg/m 2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述吉西他滨以每周一次500mg/m 2、750mg/m 2或1000mg/m 2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述吉西他滨以每周一次1000mg/m 2吉西他滨的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇每周施用一次。在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇每次以10-500mg/m 2、30-300mg/m 2、100-200mg/m 2或75-125mg/m 2的剂量施用。在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇每次以75mg/m 2、100mg/m 2或125mg/m 2的剂量施用。在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇以每周一次75-125mg/m 2白蛋白紫杉醇的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇以每周一次75mg/m 2、100mg/m 2或125mg/m 2白蛋白紫杉醇的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述白蛋白紫杉醇以每周一次125mg/m 2白蛋白紫杉醇的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，上述用途或治疗方法中，所述安罗替尼或其药学上可接受的盐以每日一次6-12mg安罗替尼的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述安罗替尼或其药学上可接受的盐以每日一次6mg、8mg、10mg或12mg安罗替尼的剂量、连续用药2周、停1周的给药方案给药。在一些实施方案中，上述用途或治疗方法中，所述安罗替尼或其药学上可接受的盐以每日一次8mg安罗替尼的剂量、连续用药2周、停1周的给药方案给药。
在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇分别具有相同或不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇具有相同的治疗周期，例如每1周、每2周、每3周、或每4周为一个治疗周期。
在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐分别具有相同或不同的治疗周期。在一些具体的实施方案中，抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇和安罗替尼或其药学上可接受的盐具有相同的治疗周期，例如每1周、每2周、每3周、或每4周为一个治疗周期。
在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期给予抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1周和第2周分别给予吉西他滨，在每个周期的第1周和第2周分别给予白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周 期给予抗PD-L1抗体-TGFβRII融合蛋白一次，在每个周期的第1周和第2周分别给予吉西他滨一次，在每个周期的第1周和第2周分别给予白蛋白紫杉醇一次。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天分别给予吉西他滨，在每个周期的第1天和第8天分别给予白蛋白紫杉醇。在一个具体的实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予抗PD-L1抗体-TGFβRII融合蛋白一次，在每个周期的第1天和第8天分别给予吉西他滨一次，在每个周期的第1天和第8天分别给予白蛋白紫杉醇一次。
在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期给予抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1周和第2周分别给予吉西他滨，在每个周期的第1周和第2周分别给予白蛋白紫杉醇，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期给予抗PD-L1抗体-TGFβRII融合蛋白一次，在每个周期的第1周和第2周分别给予吉西他滨一次，在每个周期的第1周和第2周分别给予白蛋白紫杉醇一次，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐一次。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天分别给予吉西他滨，在每个周期的第1天和第8天分别给予白蛋白紫杉醇，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐。在一个具体的实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予抗PD-L1抗体-TGFβRII融合蛋白一次，在每个周期的第1天和第8天分别给予吉西他滨一次，在每个周期的第1天和第8天分别给予白蛋白紫杉醇一次，在每个周期的第1-14天每天给予安罗替尼或其药学上可接受的盐一次。
在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500-1000mg/m 2，或者500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75-125mg/m 2，或者75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600mg、约1200mg、约1800mg或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1200mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1800mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1200mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予125mg/m 2的白蛋白紫杉醇。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1800mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予125mg/m 2的白蛋白紫杉醇。
在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600-2400mg、1200-2400mg、1200-1800mg、或1800-2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每 个周期的第1天和第8天每天给予500-1000mg/m 2，或者500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75-125mg/m 2，或者75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约600mg、约1200mg、约1800mg或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1200mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1800mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予500mg/m 2、750mg/m 2或1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予75mg/m 2、100mg/m 2或125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1200mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予8mg的安罗替尼或其药学上可接受的盐。在一些实施方案中，上述用途或治疗方法中，每21天为一个治疗周期，在每个周期的第1天给予约1800mg的抗PD-L1抗体-TGFβRII融合蛋白，在每个周期的第1天和第8天每天给予1000mg/m 2的吉西他滨，在每个周期的第1天和第8天每天给予125mg/m 2的白蛋白紫杉醇，在每个周期的第1-14天每天给予8mg的安罗替尼或其药学上可接受的盐。
在一些实施方案中，在每一个治疗周期中，以(0.1-10):1、(0.125-2):1、(0.125-1.5):1或(0.25-1.5):1的抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比，以及(0.1-30):1、(1-15):1、(2-15):1或(2-10):1的抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比，向受试者给予抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨或白蛋白紫杉醇以多剂量或单剂量给予。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇均以多剂量给予。
在一些实施方案中，在每一个治疗周期中，以(0.1-10):1、(0.125-2):1、(0.125-1.5):1或(0.25-1.5):1的抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比，(0.1-30):1、(1-15):1、(2-15):1或(2-10):1的抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比，以及(3.5-29.0):1、(7.1-29.0):1、(7.1-21.5):1、(7.1-14.5):1、(10.5-21.5):1、50:7或75:7的抗PD-L1抗体-TGFβRII融合蛋白和安罗替尼或其药学上可接受的盐的质量比，向受试者给予抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、或安罗替尼或其药学上可接受的盐以多剂量或单剂量给予。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇均以多剂量给予，安罗替尼或其药学上可接受的盐以单剂量给予。在一些实施方案中，每一次给药时，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇均以多剂量给予，安罗替尼或其药学上可接受的盐以单剂量给予。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白可以选自0.01至 50mg/kg、0.1至40mg/kg、0.1至35mg/kg、0.1至30mg/kg、0.1至25mg/kg、0.1至20mg/kg、0.1至15mg/kg、0.1至10mg/kg、1至40mg/kg、1至35mg/kg、1至30mg/kg、1至25mg/kg、1至20mg/kg、1至15mg/kg、1至10mg/kg、1至3mg/kg、3至40mg/kg、3至35mg/kg、3至30mg/kg、3至25mg/kg、3至20mg/kg、3至15mg/kg、3至10mg/kg、10至40mg/kg、20至40mg/kg、20至30mg/kg、25至35mg/kg、或者30至40mg/kg的剂量给予受试者；或者以60mg至2400mg、90mg至2400mg、120mg至2400mg、180mg至2400mg、300mg至2400mg、600mg至2400mg、900mg至2400mg、1200mg至2400mg、1500mg至2400mg、1800mg至2400mg、300mg至2000mg、600mg至2000mg、900mg至2000mg、1200mg至2000mg、1500mg至2000mg、300mg至1800mg、600mg至1800mg、900mg至1800mg、1200mg至1800mg、1200mg至1600mg、1400mg至1800mg、1500mg至1800mg、或者1600mg至1800mg的统一剂量施用于受试者。
在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后和/或交替给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂各自呈药物组合物的形式，且各自以间隔给药的方式给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，且各自以间隔给药的方式给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂分别以相同或不同的给药方案进行给药。在一些实施方案中，上述用途或治疗方法中，所述抗PD-L1抗体-TGFβRII融合蛋白、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂、和安罗替尼或其药学上可接受的盐分别以相同或不同的给药方案进行给药。
在一些实施方案中，上述用途或治疗方法中，所述亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂每两周施用一次。在一些实施方案中，上述用途或治疗方法中，每三周给予抗PD-L1抗体-TGFβRII融合蛋白一次，每两周施用亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂各一次。在一些实施方案中，上述用途或治疗方法中，每三周的第1天给予约600mg、约700mg、约800mg、约900mg、约1000mg、约1100mg、约1200mg、约1300mg、约1400mg、约1500mg、约1600mg、约1700mg、约1800mg、约1900mg、约2000mg、约2100mg、约2200mg、约2300mg或约2400mg的抗PD-L1抗体-TGFβRII融合蛋白一次，每两周的第1天给予400mg/m 2的亚叶酸钙，每两周的第1天给予2800mg/m 2的氟尿嘧啶，每两周的第1天给予180mg/m 2的伊立替康，每两周的第1天给予85mg/m 2的奥沙利铂。在上述实施方案中，所述肿瘤为胰腺癌。
在一些实施方案中，所述胰腺癌是胰腺内分泌肿瘤。在一些实施方案中，所述胰腺癌是胰腺神经内分泌肿瘤。在一些实施方案中，所述胰腺癌是胰腺外分泌肿瘤。在一些实施方案中，所述胰腺癌是导管腺癌。在一些实施方案中，所述胰腺癌是腺泡细胞癌。在一些实施方案中，所述胰腺癌是鳞癌和/或腺鳞癌。在一些实施方案中，所述胰腺癌是胶样癌(又称为黏液性非囊性癌)。在一些实施方案中，所述胰腺癌是肝样腺癌。在一些实施方案中，所述胰腺癌是髓样癌。在一些实施方案中，所述胰腺癌是浸润性微乳头状癌。在一些实施方案中，所述胰腺癌是印戒细胞癌。在一些实施方案中，所述胰腺癌是未分化癌。在一些实施方案中，所述胰腺癌是胰母细胞癌。在一些实施方案中，所述胰腺癌是实性-假乳头状肿瘤。
在一些实施方案中，所述胰腺癌为难治的、不可切除的、复发性的晚期的和/或转移性的胰腺癌。在一些实施方案中，所述胰腺癌为转移性胰腺癌。在一些方案中，所述胰腺癌为晚期胰腺癌。在一些方案中，所述胰腺癌为局部晚期胰腺癌。在一些实施方案中，所述胰腺癌为晚期转移性胰腺癌。
在一些实施方案中，所述胰腺癌的主体先前未治疗过胰腺癌(例如，转移性胰腺癌)。
在一些实施方案中，所述胰腺癌的主体先前未接受过化学疗法以治疗胰腺癌(例如，先前未在转移性环境中接受过化疗)。
在一些实施方案中，所述胰腺癌的主体先前未接受过一线系统化疗以治疗胰腺癌(例如，先前未在转移性环境中接受过一线系统化疗)。
在一些实施方案中，所述胰腺癌的主体先前未接受过手术、放射治疗和/或免疫治疗以治疗胰腺癌(例如，先前未在转移性环境中接受手术、放射治疗和/或免疫治疗)。
在一些实施方案中，所述胰腺癌的主体先前未接受过辅助疗法以治疗胰腺癌(例如，先前未在转移性环境中接受辅助疗法)。
在一些实施方案中，所述胰腺癌的主体先前已经用一种或多种不同的抗肿瘤治疗方法治疗过胰腺癌。
在一些实施方案中，所述胰腺癌的主体先前已经用手术、放射疗法、化学疗法和免疫疗法中的一种或多种治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述胰腺癌的主体已经用化学疗法治疗过胰腺癌(例如治疗失败或不适用于化疗)。
在一些实施方案中，所述胰腺癌的主体已经用一线系统化疗方案治疗过胰腺癌(例如治疗失败或不适用于系统化疗)。在一些实施方案中，所述胰腺癌的主体在一线治疗过程中出现疾病进展或治疗结束后进展。
在一些实施方案中，所述胰腺癌的主体已经用FOLFIRINOX方案(亚叶酸钙、氟尿嘧啶、伊立替康和奥沙利铂的联合化疗)治疗过胰腺癌(例如治疗失败或不适用于系统化疗)。
在一些实施方案中，所述胰腺癌的主体已经用FOLFIRINOX方案联合乳腺癌易感蛋白(BRCA)突变靶向治疗方案治疗过胰腺癌(例如治疗失败或不适用)。在一些实施方案中，所述BRCA突变靶向治疗方案包括但不限于PARP抑制剂，例如奥拉帕利。
在一些实施方案中，所述胰腺癌的主体已经用PD-1/PD-L1抑制剂疗法治疗过胰腺癌。在一些实施方案中，所述胰腺癌的主体是PD-1/PD-L1抑制剂不充分响应者。在一些实施方案中，所述胰腺癌的主体用PD-1/PD-L1抑制剂难以治疗，例如在至少2个剂量之后。
在一些实施方案中，所述胰腺癌的主体已经用FOLFIRINOX方案联合PD-1/PD-L1抑制剂治疗方案治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述PD-1/PD-L1抑制剂疗法中，所述PD-1抑制剂为抗PD-1抗体，例如纳武利尤单抗(Nivolumab)、帕博利珠单抗(Pembrolizumab)、特瑞普利单抗(JS-001)、信迪利单抗(IBI308)、卡瑞利珠单抗(Camrelizumab)、替雷利珠单抗(BGB-A317)、巴替利单抗(Balstilimab)、AK105、杰诺单抗(GB226)、LZM009、HLX10、AK103(HX008)、CS1003、SCT-I10A、F520、SG001或赛帕利单抗(GLS-010)。
在一些实施方案中，所述PD-1/PD-L1抑制剂疗法中，所述PD-L1抑制剂为抗PD-L1抗体，例如阿替利珠单抗(Atezolizumab)、度伐利尤单抗(Durvalumab)、阿利库单抗(Avelumab)、恩沃利单抗(KN035)、舒格利单抗(CS1001)、TQB2450、SHR-1316、Socazolimab(ZKAB001)、HS636、LP002、JS003、MSB2311、KL-A167或STI-A1014。
在一些实施方案中，所述胰腺癌的主体已经用含替吉奥的治疗方案治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述胰腺癌的主体已经用含铂类(例如，奥沙利铂和/或顺铂)的治疗方案治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述胰腺癌的主体已经用新辅助化疗或辅助化疗方案治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述胰腺癌的主体已经用新辅助化疗或辅助化疗方案治疗过胰腺癌，且在新辅助化疗或辅助治疗期间或治疗结束后6个月以内出现疾病进展或复发。
在一些实施方案中，所述胰腺癌的主体已经用局部放疗治疗过胰腺癌(例如治疗失败或不适用)。
在一些实施方案中，所述胰腺癌的主体已经用局部放疗治疗过胰腺癌，且局部放疗结束超过4周(脑部放疗超过2周)，并且本次研究的靶病灶不在放疗区域内，或靶病灶位于放疗区域内，但已确认进展。
抗PD-L1抗体-TGFβRII融合蛋白
抗PD-L1抗体-TGFβRII融合蛋白包含：
(a)抗PD-L1抗体或其抗原结合片段；和
(b)TGFβ结合结构域。
在一些实施方案中，所述TGFβ结合结构域是人TGFβRII或其TGFβ结合片段，例如是氨基酸序列与 SEQ ID NO:28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的多肽或肽段，或任何文本所述的片段。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含：SEQ ID NO:1或SEQ ID NO:12所示的重链CDR(HCDR)1，SEQ ID NO:2或SEQ ID NO:13所示的HCDR2，SEQ ID NO:3或SEQ ID NO:14所示的HCDR3，SEQ ID NO:4或SEQ ID NO:15所示的轻链CDR(LCDR)1，SEQ ID NO:5或SEQ ID NO:16所示的LCDR2，和SEQ ID NO:6或SEQ ID NO:17所示的LCDR3。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含：SEQ ID NO:1所示的HCDR1，SEQ ID NO:2所示的HCDR2，SEQ ID NO:3所示的HCDR3，SEQ ID NO:4所示的LCDR1，SEQ ID NO:5所示的LCDR2，和SEQ ID NO:6所示的LCDR3；或SEQ ID NO:12所示的HCDR1，SEQ ID NO:13所示的HCDR2，SEQ ID NO:14所示的HCDR3，SEQ ID NO:15所示的LCDR1，SEQ ID NO:16所示的LCDR2，和SEQ ID NO:17所示的LCDR3。上述CDR序列提供于下表1中。
表1.CDR序列
Figure PCTCN2022127280-appb-000001
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段包含氨基酸序列与SEQ ID NO:7或SEQ ID NO:18所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变结构域，和氨基酸序列与SEQ ID NO:8或SEQ ID NO:19所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变结构域。在一些的实施方案中，所述抗PD-L1抗体或其抗原结合片段包括包含SEQ ID NO:7或SEQ ID NO:18所示的氨基酸序列的重链可变结构域，和包含SEQ ID NO:8或SEQ ID NO:19所示的氨基酸序列的轻链可变结构域。在一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:7所示氨基酸序列的重链可变结构域，和SEQ ID NO:8所示氨基酸序列的轻链可变结构域。在另一些具体的实施方案中，所述抗PD-L1抗体或其抗原结合片段包含SEQ ID NO:18所示氨基酸序列的重链可变结构域，和SEQ ID NO:19所示氨基酸序列的轻链可变结构域。
在一些实施方案中，所述抗PD-L1抗体或其抗原结合片段还可包含免疫球蛋白的恒定区，或所述恒定区的片段、类似物、变体或衍生物。在一些实施方案中，所述恒定区来自人免疫球蛋白重链，例如IgG1、IgG2、IgG3和IgG4或其他类别免疫球蛋白的重链，优选为IgG1的重链。在一些实施方案中，所述恒定区可包含任何文本所述的修饰，例如氨基酸的插入、缺失、取代或化学修饰。在一些实施方案中，所述恒定区包含改变效应功能的突变，例如，将抗体恒定区C末端的赖氨酸残基突变为疏水性氨基酸，如丙氨酸或亮氨酸，减少蛋白酶的水解切割，增加血清半衰期。在一些实施方案中，所述恒定区的任意氨基酸残基可用任意同种异型(allotype)的氨基酸残基取代，优选地，用G1m(3)和/或nG1m(1)的氨基酸残基取代。
在一些实施方案中，所述抗PD-L1抗体包含氨基酸序列与SEQ ID NO:9、SEQ ID NO:20、SEQ ID NO:23或SEQ ID NO:25所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:10或SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在一些实施方案中，所述抗PD-L1抗体包含氨基酸序列与SEQ ID NO:9或SEQ ID NO:23所示氨基酸序列具有至 少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。在另一些实施方案中，所述抗PD-L1抗体包含氨基酸序列与SEQ ID NO:20或SEQ ID NO:25所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链，和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白还包含将所述抗PD-L1抗体或其抗原结合片段的C末端与所述TGFβ结合结构域的N末端相连接的连接肽；可选地，所述TGFβ结合结构域是人TGFβRII或其TGFβ结合片段。所述连接肽可以采用柔性连接肽或刚性连接肽；可选地，所述连接肽由甘氨酸和丝氨酸组合而成，例如，(G 4S) xG所示的连接肽，其中x可选地为3-6的一个整数，优选为4或5，最优选为4(即SEQ ID NO:29所示的氨基酸序列)。也可以采用不含连接肽的连接方式。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含抗PD-L1抗体或其抗原结合片段，和TGFβ结合结构域；所述抗体或其抗原结合片段可任选地包含未修饰或经修饰的恒定区，例如恒定区C末端的K突变为A，或同种异型氨基酸取代；所述TGFβ结合结构域包含人TGFβRII或其能够结合TGFβ的片段或变体，例如人TGFβRII的胞外结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)氨基酸序列与SEQ ID NO:7所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变结构域和氨基酸序列与SEQ ID NO:8所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变结构域，或者氨基酸序列与SEQ ID NO:18所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链可变结构域和氨基酸序列与SEQ ID NO:19所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链可变结构域；和(b)TGFβ结合结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)SEQ ID NO:7所示重链可变结构域和SEQ ID NO:8所示轻链可变结构域，或者SEQ ID NO:18所示重链可变结构域和SEQ ID NO:19所示轻链可变结构域；和(b)TGFβ结合结构域。在一些具体实施方案中，所述TGFβ结合结构域是人TGFβRII或其TGFβ结合片段或变体，例如是氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的多肽或肽段。
Figure PCTCN2022127280-appb-000002
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)氨基酸序列与SEQ ID NO:9所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、 94％、95％、96％、97％、98％、99％或100％同一性的轻链，或者氨基酸序列与SEQ ID NO:20所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链；和(b)TGFβ结合结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)氨基酸序列与SEQ ID NO:23所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链，或者氨基酸序列与SEQ ID NO:25所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的重链和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的轻链；和(b)TGFβ结合结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)SEQ ID NO:9所示重链和SEQ ID NO:10所示轻链，或者SEQ ID NO:20所示重链和SEQ ID NO:21所示轻链；和(b)TGFβ结合结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)SEQ ID NO:23所示重链和SEQ ID NO:10所示轻链，或者SEQ ID NO:25所示重链和SEQ ID NO:21所示轻链；和(b)TGFβ结合结构域。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)SEQ ID NO:25所示重链和SEQ ID NO:21所示轻链；和(b)TGFβ结合结构域。在一些具体实施方案中，所述TGFβ结合结构域是人TGFβRII或其TGFβ结合片段或变体，例如是氨基酸序列与SEQ ID NO:28所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％同一性的多肽或肽段。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列与SEQ ID NO:11、SEQ ID NO:22、SEQ ID NO:24或SEQ ID NO:26所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性，和(b)第二多肽，其氨基酸序列与SEQ ID NO:10或SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列与SEQ ID NO:11或SEQ ID NO:24所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性，和(b)第二多肽，其氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列与SEQ ID NO:22或SEQ ID NO:26所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性，和(b)第二多肽，其氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列如SEQ ID NO:11或SEQ ID NO:24所示，和(b)第二多肽，其氨基酸序列如SEQ ID NO:10所示。在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列如SEQ ID NO:22或SEQ ID NO:26所示，和(b)第二多肽，其氨基酸序列如SEQ ID NO:21所示。
在一些实施方案中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：(a)第一多肽，其氨基酸序列如SEQ ID NO:26所示，和(b)第二多肽，其氨基酸序列如SEQ ID NO:21所示。
在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白由两个完全相同的第一多肽和两个完全相同的第二多肽组成，其中：(a)第一多肽的氨基酸序列与SEQ ID NO:11、SEQ ID NO:22、SEQ ID NO:24或SEQ  ID NO:26所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性；且(b)第二多肽的氨基酸序列与SEQ ID NO:10或SEQ ID NO:21所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的同一性。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白由两个完全相同的第一多肽和两个完全相同的第二多肽组成，其中：(a)第一多肽的氨基酸序列如SEQ ID NO:11或SEQ ID NO:24所示；且(b)第二多肽的氨基酸序列如SEQ ID NO:10所示。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白由两个完全相同的第一多肽和两个完全相同的第二多肽组成，其中：(a)第一多肽的氨基酸序列如SEQ ID NO:22或SEQ ID NO:26所示；且(b)第二多肽的氨基酸序列如SEQ ID NO:21所示。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白由两个完全相同的第一多肽和两个完全相同的第二多肽组成，其中：(a)第一多肽的氨基酸序列如SEQ ID NO:26所示；且(b)第二多肽的氨基酸序列如SEQ ID NO:21所示。其中所述第一多肽的氨基酸序列从N端到C端依次为：识别PD-L1抗原表位或抗原的抗体重链可变结构域、抗体重链恒定区、连接肽、人TGFβRII的TGFβ结合片段的序列。
在另一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白为CN106103488中的抗PD-L1抗体-TGFβ受体II融合蛋白。
在另一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白为CN110050000中的PD-L1/TGF-βtrap融合蛋白。
在另一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白为WO2020006509中的Bi-PLB-1融合蛋白。
含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物
在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物的单位剂量为200-1200mg或其他量的抗PD-L1抗体-TGFβRII融合蛋白，例如200mg、250mg、300mg、350mg、400mg、450mg、500mg、550mg、600mg、700mg、800mg、900mg、1000mg、1100mg、1200mg或其他量的抗PD-L1抗体-TGFβRII融合蛋白。
在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物中抗PD-L1抗体-TGFβRII融合蛋白的浓度为1mg/mL至200mg/mL、2mg/mL至150mg/mL、5mg/mL至100mg/mL、10mg/mL至80mg/mL、10mg/mL至60mg/mL、或10mg/mL至50mg/mL。在一些具体的实施方案中，抗PD-L1抗体-TGFβRII融合蛋白的浓度为约10mg/mL、约15mg/mL、约20mg/mL、约25mg/mL、约30mg/mL、约35mg/mL、约40mg/mL、约45mg/mL、约50mg/mL、约55mg/mL、约60mg/mL、约80mg/mL、或约100mg/mL。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白的浓度为约20mg/mL。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白的浓度为约25mg/mL。在一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白的浓度为约40mg/mL。在另一些实施方案中，抗PD-L1抗体-TGFβRII融合蛋白的浓度为约50mg/mL。
在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物中还可包含一种或多种生理学上可接受的赋形剂或载体以制成合适的制剂。可用于本公开的合适制剂可见《雷明顿药物科学》第17版，宾夕法尼亚州伊斯顿的马克出版公司(Mack PublishingCompany)，1985。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物中还包含缓冲液、等渗调节剂、稳定剂、表面活性剂中的一种或几种。在一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物中还包含缓冲液、稳定剂和表面活性剂。
在一个具体实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为水溶性注射液，所述水溶性注射液包括但不限于未经冻干的水溶性制剂或冻干粉重构的水溶性制剂。在另一些实施方案中，所述含抗PD-L1抗体-TGFβRII融合蛋白的药物组合物为冻干制剂。所述冻干制剂是指水溶液经历冻干过程制备的制剂，在该过程中物质首先被冷冻，然后先通过升华降低溶剂数量(初级干燥过程)，然后通过脱附作用降低溶剂数量(二级干燥过程)，直到溶剂数量为不再支持生物学活性或化学反应的值。本公开的冻干制剂还可以通过本领域已知的其它方法干燥，如喷雾干燥和鼓泡干燥(bubble drying)。
吉西他滨
如本公开所用，所述吉西他滨的化学名为2’-脱氧-2’,2’-二氟胞苷(β-异构体)，其具有式(I)的结构式：
Figure PCTCN2022127280-appb-000003
如本公开所用，所述吉西他滨包括其游离碱形式，也包括药学上可接受的盐，所述非盐形式或盐都纳入本公开的保护范围内。吉西他滨可以以其游离碱形式给药，也可以以其药学上可接受的盐的形式给药。例如吉西他滨的药学上可接受的盐在本公开的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐，例如无机酸可选自盐酸、氢溴酸、硫酸、硝酸或磷酸，有机酸可选自琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸或甲磺酸。在一些实施方案中，吉西他滨的药学上可接受的盐可以是吉西他滨的盐酸盐。
在本公开的一些实施方案中，吉西他滨以其盐酸盐的形式给药。在一些实施方案中，吉西他滨以其一盐酸盐的形式给药。
本公开中涉及的吉西他滨的剂量，除非另有说明，均基于式(I)化合物的分子量。
含吉西他滨的药物组合物
在本公开的一些实施方案中，所述含吉西他滨的药物组合物的单位剂量为0.2g或1.0g吉西他滨。
在一些实施方案中，所述含吉西他滨的药物组合物为包括但不限于适合静脉内、口服、肠道外、局部给药的制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合注射的制剂。在一些实施方案中，所述含吉西他滨的药物组合物为液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合注射的液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合静脉注射的液体制剂。在一些实施方案中，所述含吉西他滨的药物组合物为冻干制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合注射的冻干制剂。在一些实施方案中，所述含吉西他滨的药物组合物为适合静脉注射的冻干制剂。
所述适合注射的冻干制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。在一个特定实施方案中，所述适合注射的冻干制剂的药学上可接受的载体包括甘露醇、醋酸钠、盐酸、氢氧化钠。
白蛋白紫杉醇
如本公开所用，所述白蛋白紫杉醇为白蛋白结合型的紫杉醇；所述紫杉醇的化学名为5β,20-环氧-1,2α,4,7β,10β,13α-六羟基紫杉烷-11-烯-9-酮-4,10-二乙酸酯-2-苯甲酸酯-13-(2R,3S)-N-苯甲酰-3-苯基异丝氨酸酯，其具有式(II)的结构式：
Figure PCTCN2022127280-appb-000004
本公开中涉及的白蛋白紫杉醇的剂量，除非另有说明，均基于式(II)化合物的分子量。
含白蛋白紫杉醇的药物组合物
在本公开的一些实施方案中，所述含白蛋白紫杉醇的药物组合物的单位剂量为100mg白蛋白紫杉醇，其包含100mg紫杉醇和约900mg人血白蛋白。
在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为包括但不限于适合静脉内、口服、肠道外、局部给药的制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为适合注射的制剂。在一些实施方案中，所述含吉西他滨的药物组合物为液体制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为适合注射的液体制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为适合静脉注射的液体制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为冻干制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为适合注射的冻干制剂。在一些实施方案中，所述含白蛋白紫杉醇的药物组合物为适合静脉注射的冻干制剂。
此外，其他制剂形式制备的紫杉醇也同样涵盖在本公开的范围内，例如紫杉醇注射液、紫杉醇口服液、紫杉醇脂质体等。
安罗替尼或其药学上可接受的盐
如本公开所用，所述安罗替尼的化学名为1-[[[4-(4-氟-2-甲基-1H-吲哚-5-基)氧基-6-甲氧基喹啉-7-基]氧基]甲基]环丙胺，其具有式(III)的结构式：
Figure PCTCN2022127280-appb-000005
如本公开所用，安罗替尼可以以其游离碱形式给药，也可以以其药学上可接受的盐的形式给药。例如安罗替尼的药学上可接受的盐在本公开的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐，例如无机酸可选自盐酸、氢溴酸、硫酸、硝酸或磷酸，有机酸可选自琥珀酸、马来酸、乙酸、富马酸、柠檬酸、酒石酸、苯甲酸、对甲苯磺酸或甲磺酸。在一些实施方案中，安罗替尼的药学上可接受的盐可以是安罗替尼的盐酸盐(例如安罗替尼的二盐酸盐)。
在本公开的一些实施方案中，安罗替尼以其盐酸盐的形式给药。在一些实施方案中，以安罗替尼一盐酸盐的形式给药。在本公开的一些实施方案中，以安罗替尼二盐酸盐的形式给药。在一些实施方案中，以安罗替尼盐酸盐的晶体形式给药。在特定的实施方案中，以安罗替尼二盐酸盐的晶体形式给药。
本公开中涉及的安罗替尼或其药学上可接受的盐的剂量，除非另有说明，均基于式(III)化合物的分子量。
含安罗替尼或其药学上可接受的盐的药物组合物
在本公开的一些实施方案中，所述含安罗替尼或其药学上可接受的盐的药物组合物的的单位剂量为6mg、8mg、10mg、或12mg安罗替尼。
安罗替尼或其药学上可接受的盐优选适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。其中片剂可以是普通片剂、分散片、泡腾片、缓释片、控释片或肠溶片，胶囊剂可以是普通胶囊、缓释胶囊、控释胶囊或肠溶胶囊。所述的口服制剂可使用本领域公知的药学上可接受的载体通过常规方法制得。药学上可接受的载体包括填充剂、吸收剂、润湿剂、粘合剂、崩解剂、润滑剂等。
在一个实施方案中，含安罗替尼或其药学上可接受的盐的药物组合物是适于口服的固体制剂。在一个实施方案中，含安罗替尼或其药学上可接受的盐的药物组合物可以是片剂或胶囊的形式。在一个特定实施 方案中，含安罗替尼或其药学上可接受的盐的药物组合物是胶囊的形式。在一个特定实施方案中，安罗替尼或其药学上可接受的盐的口服固体制剂的药学上可接受的载体包括甘露醇、微晶纤维素、羟丙纤维素、硬脂酸镁。
施用方式
下述内容并非限制本公开药物组合的施用方式。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同以适合的各种途径施用，包括但不限于，口服或肠胃外(通过静脉内、肌内、局部或皮下途径)施用。在一些实施方案中，本公开的药物组合的组分可以各自独立地、或者其中的部分或全部共同口服施用或注射施用，例如静脉注射、皮下注射或腹腔注射。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同是适合的剂型，包括但不限于，片剂、含片、丸剂、胶囊剂(例如硬胶囊、软胶囊、肠溶胶囊、微囊剂)、酏剂、颗粒剂、糖浆剂、注射剂(肌肉内、静脉内、腹腔内、皮下)、颗粒剂、乳剂、悬浮液、溶液、分散剂和用于口服或非口服给药的缓释制剂的剂型。
本公开的药物组合中的组分可以各自独立地、或者其中的部分或全部共同含有药学上可接受的载体和/或赋形剂。
本公开的药物组合还可以包含另外的治疗剂。在一个实施方案中，所述另外的治疗剂可以是本领域已知的癌症治疗剂。
技术效果
通常，使用上述的本公开的药物组合将有助于：
(1)与单独给予该组合中的任一药物相比，在减少肿瘤的生长或甚至消除肿瘤方面产生更好的疗效；
(2)与该组合中的任一药物单独给药相比，提供更少量的给药；
(3)提供在患者中具有良好耐受的治疗，与单一给予的任一药物相比，其不良反应和/或并发症更少；
(4)提供在所治疗患者之中的更好的疾病控制率；
(5)提供在所治疗的患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(6)提供相比于标准的化疗而言，所治疗患者具有更长的生存期(例如中位生存期、无进展生存期或总生存期)；
(7)提供更长时间的疾病缓解持续时间(DOR)；和/或
(8)与单独给予该组合中的任一药物相比，具有良好的治疗胰腺癌的活性，表现出更优异的抗肿瘤协同效果。
定义和说明
除非另有说明，本公开中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本公开中出现商品名时，意在指代其对应的商品或其活性成分。
如文本所用，术语“药物组合”是指同时或先后施用的两种或两种以上的活性成分(以各自的活性成分本身的形式施用，或者以其各自的药学上可接受的盐或酯等衍生物、前药或组合物的形式施用)的组合。所述活性成分可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
术语“固定组合”指活性组分以固定总剂量或剂量比例，或以单一实体、药物组合物或制剂的形式同时给予受试者。
术语“非固定组合”指两种以上活性组分作为独立的实体(例如药物组合物、制剂)同时、并行或依序地给予受试者，其中所述给予受试者的活性成份达到治疗有效量水平。非固定组合可列举的例子是鸡尾酒疗法，例如给予3种或以上之活性组分。在非固定组合中，所述各个活性组分可以作为完全独立的药物组合物进行包装、销售或给药。所述“非固定组合”也包括“固定组合”之间、或“固定组合”与任一或多种活性组分的独立实体的联合使用。
“TGFβRII”或“TGFβ受体II”是指具有野生型人TGFβ受体2同种型B序列的多肽或蛋白，例如SEQ ID NO:27所示的多肽，或具有与SEQ ID NO:27所示氨基酸序列具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％ 同一性的序列的多肽。
TGFβRII的“结合TGFβ的片段”或“TGFβ结合片段”是指TGFβRII中具有TGFβ结合活性的片段，约占TGFβRII序列的至少0.1％、0.5％、1％、5％、10％、25％、35％、50％、75％、90％、95％、99％或100％。该片段通常是可溶片段，例如人TGFβRII的胞外结构域或其变体，非限制性实例包括SEQ ID NO:28所示的多肽。
如本文所用，术语“抗体”是指具有至少一个抗原结合结构域的结合蛋白。本公开的抗体和其抗原结合片段可以是整个抗体或抗体的任何片段。因此，本公开的抗体和其抗原结合片段包括单克隆抗体或其片段和抗体变体或其片段，以及免疫缀合物。抗体片段的实例包括Fab片段、Fab'片段、F(ab)'2片段、Fv片段、Fd片段、Fd’片段、分离的CDR区、单链Fv分子(scFv)和本领域已知的其他抗体片段，以及经过任何本领域已知修饰的抗体(例如糖基化修饰、化学修饰等)。抗体和其抗原结合片段还可以包括重组多肽、融合蛋白和双特异性抗体。本文公开的抗PD-L1抗体和其抗原结合片段可以是IgG1、IgG2、IgG3或IgG4同种型。术语“同种型”是指由重链恒定区基因编码的抗体种类。抗体和其抗原结合片段可以是嵌合抗体、人源化抗体或完整的人抗体。
“嵌合抗体”是下述抗体：所述抗体具有衍生自一种物种的重链可变结构域的至少一部分和轻链可变结构域的至少一部分；以及衍生自另一物种的恒定区的至少一部分。例如，在一个实施方案中，嵌合抗体可以包含鼠类可变结构域和人恒定区。
“人源化抗体”是下述抗体：所述抗体含有衍生自非人抗体的互补决定区(CDR)；和衍生自人抗体的框架区以及恒定区。例如，抗PD-L1抗体可以包含衍生自一种或多种鼠类抗体的CDR以及人框架区和恒定区。本文提供了示例性人源化抗体。包含本文提供的HCDR和LCDR的另外的抗PD-L1抗体或其变体可以使用任何人框架序列产生，并且也包括在本公开中。在一个实施方案中，适用于在本公开中使用的框架序列包括在结构上与本文提供的框架序列类似的那些框架序列。可以在框架区中进行另外修饰以改进本文提供的抗体的特性。此类另外的框架修饰可以包括化学修饰；点突变以降低免疫原性或去除T细胞表位；或使突变回复为原始种系序列中的残基。在一些实施方案中，此类修饰包括对应于本文示例的突变的那些修饰，包括对种系序列的回复突变。例如，在一个实施方案中，本文提供的人源化抗体的VH和/或VL的人框架区中的一个或多个氨基酸被回复突变为亲本鼠类抗体中对应的氨基酸。
“抗原结合片段”是指保留全长抗体的抗原结合功能的片段，包括Fab、Fab’、F(ab’)2、scFv、Fv、Fd、Fd’、分离的CDR区和单一结构域VHH片段和本领域已知的其他抗体片段，或将上述片段进行任何本领域已知修饰的片段。
“同一性”是指两个参考序列之间的相似性，同一性百分比是指通过本领域技术人员熟知的序列比较算法，将序列或序列指定区域进行比较所得出的百分数。
术语“治疗”指试图改变治疗个体中疾病的自然进程，并且可以是为了预防、改善或消除疾病或与所述疾病相关的一个或多个症状，包括但不限于预防疾病的发生或复发，缓解症状，降低疾病的任何直接或间接病理学后果，预防转移，减缓疾病进展率，改善或减轻疾病状态，及消退或改善的预后。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本公开化合物的用量。构成“治疗有效量”的活性物质(例如本公开的融合蛋白或化合物)的量可根据一些因素而变化，诸如个体的疾病状态、年龄、性别和重量，以及治疗剂或治疗剂组合在个体中引发所需应答的能力。有效量也可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“施用”表示，使用本领域技术人员已知的多种方法和递送系统中的任一种，向主体物理引入包含治疗剂的组合物。
融合蛋白(例如，抗PD-L1抗体-TGFβRII融合蛋白)的施用途径包括静脉内、肌肉内、皮下、腹膜内、脊柱或其它胃肠外施用途径，例如通过注射或输注。本文中使用的短语“胃肠外施用“是指，通常通过注射进行的除了肠内和局部施用以外的施用模式，且包括但不限于，静脉内、肌肉内、动脉内、鞘内、淋巴管内、病灶内、囊内、眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、硬膜外和胸骨内注射和输注、以及体内电穿孔。还可以执行施用，例如，一次、多次，和/或在一个或多个延长的时间段中。
给予抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂、和/或者安罗替尼或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定或进行调整。例如，在一些实施方案中，吉西他滨的单次给药剂量可以为：100-3000mg/m 2、500-3000mg/m 2、600-2500mg/m 2、200-2000mg/m 2、800-2000mg/m 2、500-1500mg/m 2、500-1000mg/m 2或1000-1500mg/m 2。在一些实施方案中，吉西他滨的单次给药剂量可以为：100mg/m 2、200mg/m 2、500mg/m 2、600mg/m 2、750mg/m 2、800mg/m 2、1000mg/m 2、1500mg/m 2、2000mg/m 2、2500mg/m 2或3000mg/m 2。在一些实施方案中，吉西他滨的单次给药剂量可以为600-4800mg。又例如，在一些实施方案中，白蛋白紫杉醇的单次给药剂量可以为：10-500mg/m 2、30-400mg/m 2、30-300mg/m 2、50-300mg/m 2、100-200mg/m 2、50-200mg/m 2、50-150mg/m 2或75-125mg/m 2。在一些实施方案中，白蛋白紫杉醇的单次给药剂量可以为：10mg/m 2、30mg/m 2、50mg/m 2、75mg/m 2、100mg/m 2、125mg/m 2、150mg/m 2、175mg/m 2、200mg/m 2、300mg/m 2、400mg/m 2或500mg/m 2。在一些实施方案中，白蛋白紫杉醇的单次给药剂量可以为90-300mg。又例如，给予安罗替尼或其药学上可接受的盐的日剂量可以为3-30mg、5-20mg或6-12mg。在一些实施方案中，给予安罗替尼或其药学上可接受的盐的日剂量可为3mg、4mg、5mg、6mg、8mg、10mg或12mg。吉西他滨、白蛋白紫杉醇、亚叶酸钙、氟尿嘧啶、伊立替康和/或奥沙利铂可以每周施用一次或多次。安罗替尼或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，吉西他滨和白蛋白紫杉醇以注射制剂每周给药一次；优选地，以静脉注射制剂每周给药一次。在一些实施方案中，安罗替尼或其药学上可接受的盐以口服固体制剂每天给药一次。
抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、亚叶酸钙、氟尿嘧啶、伊立替康、奥沙利铂、和/或者安罗替尼或其药学上可接受的盐的给药方案(例如，给药周期等)可根据药物的活性、毒性以及患者的耐受性等来综合确定或进行调整。例如，可以将抗PD-L1抗体-TGFβRII融合蛋白的一个治疗周期调整为4周、5周、6周、7周、8周、9周、10周、11周、12周或更多周。在一些实施方案中，吉西他滨和白蛋白紫杉醇以每周给药一次的方式给予。在一些实施方案中，安罗替尼或其药学上可接受的盐以每日给药一次的方式给予。在一些实施方案中，吉西他滨和白蛋白紫杉醇各自以间隔给药的方式给予，例如给药7周停药1周、给药3周停药1周、给药2周停药2周、或给药2周停药1周；所述间隔给药方式可以反复进行多次。在一些实施方案中，安罗替尼或其药学上可接受的盐以间隔给药的方式给予，例如连续给药2周停药2周、连续给药2周停药1周、或连续给药5天停药2天；所述间隔给药方式可以反复进行多次。所述的间隔给药包括给药期和停药期，在给药期内可以每天一次或多次给予。在一些实施方案中，吉西他滨、白蛋白紫杉醇、或者安罗替尼或其药学上可接受的盐连续给药2周、停药1周。在一些实施方案中，吉西他滨以每周一次500mg/m 2、750mg/m 2或1000mg/m 2吉西他滨的剂量静脉注射给药，连续给药2周、停1周。在一些实施方案中，白蛋白紫杉醇以每周一次75mg/m 2、100mg/m 2或125mg/m 2白蛋白紫杉醇的剂量静脉注射给药，连续给药2周、停1周。在一些实施方案中，安罗替尼或其药学上可接受的盐以每日一次6mg、8mg、10mg或12mg安罗替尼的剂量口服给药，连续用药2周、停1周。
术语“统一剂量(flat dose)”的应用是指，不考虑患者的重量或体表面积(BSA)施用给患者的剂量。因此将统一剂量规定为药剂(例如，抗PD-L1抗体-TGFβRII融合蛋白)的绝对量，而不是规定为mg/kg剂量。例如，60kg人和100kg人将接受相同剂量的抗体(例如，1800mg抗PD-L1抗体-TGFβRII融合蛋白)。
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”，包括碱根离子与自由酸形成的盐或酸根离子与自由碱形成的盐，例如包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、草酸盐、马来酸盐、柠檬酸盐、酒石酸盐、琥珀酸盐、甲磺酸盐、苯甲酸盐、苯磺酸盐或对甲基苯磺酸盐，优选盐酸盐、氢溴酸盐、硫酸盐、甲酸盐、乙酸盐、三氟乙酸盐、富马酸盐、马来酸盐、甲磺酸盐、对甲基苯磺酸盐、钠盐、钾盐、铵盐、氨基酸盐等。
在本文中，术语“受试者”、“患者”或“主体”可互换使用。在一些实施方案中，术语“受试者”、“患者”或“主体”是哺乳动物。在部分实施方案中，所述受试者、患者或主体是小鼠。在部分实施方案中， 所述受试者、患者或主体是人。
如本文所用，“约”表示在本领域普通技术人员判定的对特定值可以接受的误差范围内，其部分取决于如何测量或测定该值，即测量系统的限制。例如，“约”按照本领域实践可表示1倍或超过1倍标准偏差以内。或者，“约”可以表示多至±5％的范围，例如在所给定的具体数值范围±2％范围内、±1％范围内或±0.5％范围内波动。当本公开或权利要求中给出特定值时，除非另有说明，“约”的含义应认为是在该特定值的可接受的误差范围内。在本文中，除非另有说明，步骤参数或条件的值默认均由“约”修饰。
如本文所用，“联用”或“联合使用”意指两种或更多种活性物质可以各自作为单一制剂同时地、或各自作为单一制剂以任何顺序依次地施用于受试者。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则一粒胶囊为单剂量；或者一瓶注射液为单剂量。术语“多剂量”由多个单剂量组成。
“单位剂量”是指含有一定量药品的最小包装单元中所含的活性成分的剂量，例如则一粒盐酸安罗替尼胶囊中所含的安罗替尼的剂量为单位剂量；或者一瓶融合蛋白注射液中所含的融合蛋白的剂量为单位剂量；或者一瓶白蛋白紫杉醇冻干粉中所含的紫杉醇的剂量为单位剂量。
术语“药物组合物”是指一种或多种本公开的活性成分或其药物组合与药学上可接受的载体组成的混合物。药物组合物的目的是有利于对受试者给予本公开的化合物或其药物组合。在本文中，术语“药物组合物”和“制剂”具有相同的含义，并可互换使用。
术语“复发性”癌症是在对初始治疗(例如手术)产生应答后，在初始部位或远处部位再生的癌症。“局部复发性”癌症是在治疗后，在与先前治疗的癌症相同的位置出现的癌症。
术语“转移性”癌症是指从身体的一部分(例如肺部)扩散到身体的另一部分的癌症。
如本文所用，“治疗失败”的定义为在治疗过程中或末次治疗后出现疾病进展或复发。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本公开的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
本公开还提供了以下一些具体的实施方案，但本公开的保护范围不限于此：
实施方案1.一种药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇。
实施方案2.根据实施方案1所述的药物组合，其中，所述药物组合包括单位剂量为200-1200mg的抗PD-L1抗体-TGFβRII融合蛋白、单位剂量为0.2g和/或1.0g的吉西他滨、和单位剂量为100mg的白蛋白紫杉醇。
实施方案3.根据实施方案1或2所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比为(0.1-10):1，所述抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比为(0.1-30):1。
实施方案4.根据实施方案1-3中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，其包括600-2400mg的抗PD-L1抗体-TGFβRII融合蛋白、1000-2000mg/m 2的吉西他滨、和150-250mg/m 2的白蛋白紫杉醇。
实施方案5.根据实施方案1-4中任一项所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：
(a)抗PD-L1抗体或其抗原结合片段；和
(b)人TGFβRII或其TGFβ结合片段；
其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3；或
(b)SEQ ID NO:12所示氨基酸序列的HCDR1，SEQ ID NO:13所示氨基酸序列的HCDR2，SEQ ID NO:14所示氨基酸序列的HCDR3，SEQ ID NO:15所示氨基酸序列的LCDR1，SEQ ID NO:16所示氨基酸 序列的LCDR2，和SEQ ID NO:17所示氨基酸序列的LCDR3。
实施方案6.根据实施方案5所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)SEQ ID NO:7所示氨基酸序列的重链可变结构域，和SEQ ID NO:8所示氨基酸序列的轻链可变结构域；或
(b)SEQ ID NO:18所示氨基酸序列的重链可变结构域，和SEQ ID NO:19所示氨基酸序列的轻链可变结构域。
实施方案7.根据实施方案5或6所述的药物组合，其中，所述抗PD-L1抗体或其抗原结合片段包含：
(a)氨基酸序列与SEQ ID NO:9或SEQ ID NO:23所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链；或
(b)氨基酸序列与SEQ ID NO:20或SEQ ID NO:25所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少95％同一性的轻链。
实施方案8.根据实施方案5-7中任一项所述的药物组合，其中，所述人TGFβRII或其TGFβ结合片段包含与SEQ ID NO:28所示氨基酸序列具有至少80％同一性的氨基酸序列。
实施方案9.根据实施方案5-8中任一项所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白还包含将所述抗PD-L1抗体或其抗原结合片段的C末端与所述人TGFβRII或其TGFβ结合片段的N末端相连接的连接肽；优选地，所述连接肽为(G4S) xG，x为3-6的一个整数；优选所述连接肽具有SEQ ID NO:29所示的氨基酸序列。
实施方案10.根据实施方案5-9中任一项所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：
(a)氨基酸序列与SEQ ID NO:11或SEQ ID NO:24所示氨基酸序列具有至少95％同一性的第一多肽，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的第二多肽；或
(b)氨基酸序列与SEQ ID NO:22或SEQ ID NO:26所示氨基酸序列具有至少95％同一性的第一多肽，和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少95％同一性的第二多肽。
实施方案11.根据实施方案1-10中任一项所述的药物组合，其中，所述药物组合还包括安罗替尼或其药学上可接受的盐；可选地，所述安罗替尼的药学上可接受的盐为一盐酸盐或二盐酸盐。
实施方案12.根据实施方案11所述的药物组合，其中，所述安罗替尼或其药学上可接受的盐的单位剂量为6mg、8mg、10mg和/或12mg。
实施方案13.根据实施方案11或12所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白和安罗替尼或其药学上可接受的盐的质量比为(3.5-29.0):1。
实施方案14.根据实施方案11-13中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，所述安罗替尼或其药学上可接受的盐的剂量为84-168mg。
实施方案15.根据实施方案1-14中任一项所述的药物组合，其中，所述药物组合用于治疗胰腺癌。
实施方案16.实施方案1-15中任一项所述的药物组合在制备用于治疗胰腺癌的药物中的用途。
实施方案17.根据实施方案16所述的用途，其中所述胰腺癌为难治的、不可切除的、复发性的、晚期的和/或转移性的胰腺癌；优选地，所述胰腺癌为转移性胰腺癌。
实施方案18.根据实施方案16或17所述的用途，其中所述胰腺癌为胰腺内分泌肿瘤和/或胰腺外分泌肿瘤。
实施方案19.根据实施方案16-18中任一项所述的用途，其中所述胰腺癌的主体先前未治疗过胰腺癌。
实施方案20.根据实施方案16-18中任一项所述的用途，其中所述胰腺癌的主体先前已经用一种或多种不同的抗肿瘤治疗方法治疗过胰腺癌。
实施方案21.根据实施方案16-20中任一项所述的用途，其中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，可同时、先后和/或交替给药。
实施方案22.根据实施方案16-20中任一项所述的用途，其中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后和/或交替给药。
实施方案23.根据实施方案16-22中任一项所述的用途，其中，所述抗PD-L1抗体-TGFβRII融合蛋白每1周、每2周、每3周、或每4周施用一次，每次以600-2400mg抗PD-L1抗体-TGFβRII融合蛋白的剂量施用。
实施方案24.根据实施方案16-23中任一项所述的用途，其中，所述吉西他滨以每周一次500-1000mg/m 2、500mg/m 2、750mg/m 2或1000mg/m 2吉西他滨的剂量，连续用药2周、停1周的给药方案给药。
实施方案25.根据实施方案16-24中任一项所述的用途，其中，所述白蛋白紫杉醇以每周一次75-125mg/m 2、75mg/m 2、100mg/m 2或125mg/m 2白蛋白紫杉醇的剂量，连续用药2周、停1周的给药方案给药。
实施方案26.根据实施方案16-20、22-25中任一项所述的用途，其中，所述安罗替尼或其药学上可接受的盐以每日一次6-12mg、6mg、8mg、10mg或12mg安罗替尼的剂量，连续用药2周、停1周的给药方案给药。
实施方案27.一种用于治疗胰腺癌的试剂盒，其包含实施方案1-15中任一项所述的药物组合。
实施例
为清楚起见，进一步用实施例来阐述本公开，但是实施例并非限制本公开的范围。本公开所使用的所有试剂是市售的，无需进一步纯化即可使用。
本公开中抗PD-L1抗体-TGFβRII融合蛋白的制备、纯化方法已在公开号为WO2021037184的专利申请文件中记载，WO2021037184专利申请文件的全部内容均引入本公开。实施例中的抗PD-L1抗体-TGFβRII融合蛋白hu5G11-hIgG1-TGFβRII为WO2021037184中的hu5G11-hIgG1-TGFβRII，所述hu5G11-hIgG1-TGFβRII由两个完全相同的第一多肽和两个完全相同的第二多肽组成，其中：(1)所述第一多肽的氨基酸序列如SEQ ID NO:26所示，所述第一多肽是融合蛋白，其由抗人PD-L1抗体(SEQ ID NO:25)的重链、人TGFβRII的胞外结构域氨基酸序列(SEQ ID NO:28)以及将两者相连的(G 4S) 4G连接肽(SEQ ID NO:29)组成；且(2)所述第二多肽的氨基酸序列如SEQ ID NO:21所示。
hu5G11-hIgG1-TGFβRII第一多肽的氨基酸序列(SEQ ID NO:26)：
Figure PCTCN2022127280-appb-000006
hu5G11-hIgG1-TGFβRII第二多肽的氨基酸序列(SEQ ID NO:21)：
Figure PCTCN2022127280-appb-000007
实施例1：晚期转移性胰腺癌的临床试验
1.入选标准
(1)受试者自愿加入本研究，签署知情同意书；
(2)年龄18-75周岁(签署知情同意书时间)；
(3)第1阶段，要求纳入既往至少一线系统化疗失败或研究者认为不适合接受系统化疗的患者；
第2阶段的队列1和队列2，要求纳入初诊经组织或细胞学确诊的转移性胰腺癌患者；
第2阶段的队列3，要求纳入经过一线FOLFIRINOX或FOLFIRINOX+BRCA突变靶向治疗或PD-1/PD-L1治疗失败后的转移性胰腺癌患者；
注：一线治疗失败的定义：a.一线治疗过程中出现疾病进展或治疗结束后进展；b.新辅助或辅助治疗 后6个月内疾病进展。
(4)第1阶段要求根据RECIST 1.1标准证实具有至少一个可评估病灶；第2阶段要求根据RECIST 1.1标准证实具有至少一个可测量病灶；
(5)ECOG评分0-1分，预计生存期大于3个月；
(6)主要器官功能良好，符合下列标准：
1)血常规检查标准(检查前7天内未输血、未使用造血刺激因子类药物纠正)：
a)血红蛋白(HGB)≥90g/L；
b)中性粒细胞绝对值(NEUT)≥1.5×10 9/L；
c)血小板计数(PLT)≥100×10 9/L。
2)生化检查需符合以下标准：
a)总胆红素(TBIL)≤1.5倍正常值上限(ULN)(允许有胆道支架)；
b)丙氨酸氨基转移酶(ALT)和天门冬氨酸氨基转移酶(AST)≤2.5×ULN。若伴肝转移，则ALT和AST≤5×ULN；
c)血清肌酐(CR)≤1.5×ULN或肌酐清除率(CCR)≥60mL/min。
3)凝血功能需符合以下标准：
国际标准化比值(INR)≤1.5×ULN(未接受过抗凝治疗)；
4)甲状腺功能检查需符合以下标准：
促甲状腺激素(TSH)≤ULN；如果异常应考察三碘甲状腺原氨酸(T3)和甲状腺素(T4)水平，T3和T4水平正常则可以入选。
5)心脏彩超评估：左室射血分数(LVEF)≥50％。
(7)患者在研究期间和研究期结束后6个月内必须采用可靠避孕措施；在研究入组前的7天内血清妊娠/尿妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避孕措施；
2.试验药物
hu5G11-hIgG1-TGFβRII注射液：规格为200mg(4mL)/瓶和600mg(12mL)/瓶；
吉西他滨：规格为0.2g/瓶和1.0g/瓶；
白蛋白紫杉醇：规格为100mg/瓶；
盐酸安罗替尼胶囊：规格为6mg/粒、8mg/粒、10mg/粒和12mg/粒。
3.给药方案
3.1第1阶段：
hu5G11-hIgG1-TGFβRII注射液：600mg、1200mg、1800mg或2400mg，静脉滴注，每3周给药一次，3周为1个治疗周期。
3.2第2阶段：
队列1：hu5G11-hIgG1-TGFβRII注射液+吉西他滨+白蛋白紫杉醇一线治疗：
hu5G11-hIgG1-TGFβRII注射液：600mg、1200mg、1800mg或2400mg，静脉滴注，每21天一次；
吉西他滨：1000mg/m 2，静脉滴注，每7天一次，连用2周停1周；
白蛋白紫杉醇：125mg/m 2，静脉滴注，每7天一次，连用2周停1周；
给药顺序：先输注hu5G11-hIgG1-TGFβRII注射液，白蛋白紫杉醇，最后吉西他滨。
队列2：hu5G11-hIgG1-TGFβRII注射液+盐酸安罗替尼胶囊+吉西他滨+白蛋白紫杉醇一线治疗：
hu5G11-hIgG1-TGFβRII注射液：600mg、1200mg、1800mg或2400mg，静脉滴注，每21天一次；
盐酸安罗替尼胶囊：8mg，口服，每日1次，连用2周停1周；
吉西他滨：1000mg/m 2，静脉滴注，每7天一次，连用2周停1周；
白蛋白紫杉醇：125mg/m 2，静脉滴注，每7天一次，连用2周停1周；
给药顺序：先口服盐酸安罗替尼胶囊，后输注hu5G11-hIgG1-TGFβRII注射液，白蛋白紫杉醇，最后吉西他滨。
队列3：hu5G11-hIgG1-TGFβRII注射液+吉西他滨+白蛋白紫杉醇二线治疗：
hu5G11-hIgG1-TGFβRII注射液：600mg、1200mg、1800mg或2400mg，静脉滴注，每21天一次；
吉西他滨：1000mg/m 2，静脉滴注，每7天一次，连用2周停1周；
白蛋白紫杉醇：125mg/m 2，静脉滴注，每7天一次，连用2周停1周。
给药顺序：先输注hu5G11-hIgG1-TGFβRII注射液，白蛋白紫杉醇，最后吉西他滨。
研究过程中允许根据受试者的情况进行用药延迟或者剂量下调，但不允许跨剂量下调：例如白蛋白紫杉醇的剂量从125mg/m 2调整至100mg/m 2，或从100mg/m 2调整至75mg/m 2；吉西他滨的剂量从1000mg/m 2调整至750mg/m 2，或从750mg/m 2调整至500mg/m 2。
4.评价标准
采用RECIST 1.1标准为主判断疾病状态，并通过iRECIST标准对疗效进行确认补充。
5.终点指标
客观缓解率(ORR)＝(完全缓解(CR)+部分缓解(PR))；
疾病控制率(DCR＝CR+PR+疾病稳定(SD))、缓解持续时间(DOR)、无进展生存期(PFS)、总生存期(OS)；
不良事件(AE)发生率及严重程度；
免疫原性，如受试者的抗药抗体(ADA)的发生率及其滴度，中和抗体(Nab)的发生率。
并评估治疗相关的生物标志物，如肿瘤组织中PD-L1和血液样本中TGF-β与hu5G11-hIgG1-TGFβRII注射液治疗胰腺癌抗肿瘤疗效的关系。
6.治疗效果
转移性胰腺癌的受试者经hu5G11-hIgG1-TGFβRII注射液(1200mg)+吉西他滨+白蛋白紫杉醇一线治疗后，可显著提升临床疗效和生存获益，在8名被诊断为转移性胰腺癌的受试者中，2名受试者(患者A和患者B)达到部分缓解PR(25％)，达到疾病稳定(SD)的受试者中多名受试者肿瘤缩小20％以上；具体示例性结果如下所述。
转移性胰腺癌的受试者经hu5G11-hIgG1-TGFβRII注射液(600mg-1800mg)+盐酸安罗替尼胶囊+吉西他滨+白蛋白紫杉醇一线治疗后，可显著提升临床疗效和生存获益，在4名被诊断为转移性胰腺癌的受试者(患者C、患者D、患者E和患者F)中，所有受试者均达到部分缓解(PR)；具体示例性结果如下所述。
初步结果表明，hu5G11-hIgG1-TGFβRII、吉西他滨和白蛋白紫杉醇联合使用，以及hu5G11-hIgG1-TGFβRII、吉西他滨、白蛋白紫杉醇和盐酸安罗替尼胶囊联合使用，可以安全、有效地治疗转移性胰腺癌，并具有延长转移性胰腺癌受试者无进展生存期FPS和总生存期OS的潜在优势。
6.1治疗前诊断结果
患者A：
转移性胰腺癌：肝胆胰肿瘤及血管CTA显示，胰腺尾部胰腺癌累及脾门伴脾局部梗死，肝多发转移，腹膜网膜系膜多发种植转移，脾大。对患者进行穿刺活检术，病理显示，(肝穿刺标本)低分化癌转移或浸润。
患者B：
转移性胰腺癌：肝胆胰肿瘤及血管CTA(肝胆胰脾)显示，胰管扩张；肝内外胆管扩张；腹膜后多发稍大淋巴结；肝脏S4占位，考虑转移；肝多发囊肿；肝左动脉与胃左动脉共干；两肾多发囊肿。对患者肝占位穿刺活检术；免疫组化显示，(肝S4段穿刺标本)胰腺浸润或转移，提示胰胆管表型。
患者C-F：
转移性胰腺癌。
6.2治疗效果及评估
患者A：
筛选期：靶病灶：81.61mm；
第2周期给药后：靶病灶：65.16mm；
第4周期给药后：靶病灶：47.7mm；
根据疗效评估标准，最佳治疗效果为PR。
患者B：
筛选期：靶病灶：33.10mm；
第2周期给药后：靶病灶：17.7mm；
根据疗效评估标准，最佳治疗效果为PR。
患者C：
筛选期：靶病灶：90.9mm；
第2周期给药后：靶病灶：63.1mm；
根据疗效评估标准，最佳治疗效果为PR。
患者D：
筛选期：靶病灶：66.79mm；
第2周期给药后：靶病灶：46.2mm；
第4周期给药后：靶病灶：37.9mm；
根据疗效评估标准，最佳治疗效果为PR。
患者E：
筛选期：靶病灶：79.19mm；
第2周期给药后：靶病灶：39.3mm；
根据疗效评估标准，最佳治疗效果为PR。
患者F：
筛选期：靶病灶：53.06mm；
第2周期给药后：靶病灶：47.9mm；
第4周期给药后：靶病灶：35.3mm；
根据疗效评估标准，最佳治疗效果为PR。

Claims (15)

  1. 一种药物组合，其包括抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇；其中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：
    (a)抗PD-L1抗体或其抗原结合片段；和
    (b)人TGFβRII或其TGFβ结合片段；
    其中，所述抗PD-L1抗体或其抗原结合片段包含：
    (a)SEQ ID NO:12所示氨基酸序列的HCDR1，SEQ ID NO:13所示氨基酸序列的HCDR2，SEQ ID NO:14所示氨基酸序列的HCDR3，SEQ ID NO:15所示氨基酸序列的LCDR1，SEQ ID NO:16所示氨基酸序列的LCDR2，和SEQ ID NO:17所示氨基酸序列的LCDR3；
    (b)SEQ ID NO:1所示氨基酸序列的HCDR1，SEQ ID NO:2所示氨基酸序列的HCDR2，SEQ ID NO:3所示氨基酸序列的HCDR3，SEQ ID NO:4所示氨基酸序列的LCDR1，SEQ ID NO:5所示氨基酸序列的LCDR2，和SEQ ID NO:6所示氨基酸序列的LCDR3；
    (c)SEQ ID NO:18所示氨基酸序列的重链可变结构域，和SEQ ID NO:19所示氨基酸序列的轻链可变结构域；
    (d)SEQ ID NO:7所示氨基酸序列的重链可变结构域，和SEQ ID NO:8所示氨基酸序列的轻链可变结构域；
    (e)氨基酸序列与SEQ ID NO:20或SEQ ID NO:25所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少95％同一性的轻链；或
    (f)氨基酸序列与SEQ ID NO:9或SEQ ID NO:23所示氨基酸序列具有至少95％同一性的重链，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的轻链。
  2. 根据权利要求1所述的药物组合，其中，所述人TGFβRII或其TGFβ结合片段包含与SEQ ID NO:28所示氨基酸序列具有至少80％同一性的氨基酸序列。
  3. 根据权利要求1或2所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白还包含将所述抗PD-L1抗体或其抗原结合片段的C末端与所述人TGFβRII或其TGFβ结合片段的N末端相连接的连接肽；优选地，所述连接肽为(G4S) xG，x为3-6的一个整数；优选地，所述连接肽具有SEQ ID NO:29所示的氨基酸序列。
  4. 根据权利要求1-3中任一项所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白包含：
    (a)氨基酸序列与SEQ ID NO:22或SEQ ID NO:26所示氨基酸序列具有至少95％同一性的第一多肽，和氨基酸序列与SEQ ID NO:21所示氨基酸序列具有至少95％同一性的第二多肽；或
    (b)氨基酸序列与SEQ ID NO:11或SEQ ID NO:24所示氨基酸序列具有至少95％同一性的第一多肽，和氨基酸序列与SEQ ID NO:10所示氨基酸序列具有至少95％同一性的第二多肽。
  5. 根据权利要求1-4中任一项所述的药物组合，其中，所述药物组合包括单位剂量为200-1200mg的抗PD-L1抗体-TGFβRII融合蛋白、单位剂量为0.2g和/或1.0g的吉西他滨、和单位剂量为100mg的白蛋白紫杉醇。
  6. 根据权利要求1-5中任一项所述的药物组合，其中，所述抗PD-L1抗体-TGFβRII融合蛋白和吉西他滨的质量比为(0.1-10):1，所述抗PD-L1抗体-TGFβRII融合蛋白和白蛋白紫杉醇的质量比为(0.1-30):1。
  7. 根据权利要求1-6中任一项所述的药物组合，其中，所述药物组合适用于在单个治疗周期内施用，其包括600-2400mg的抗PD-L1抗体-TGFβRII融合蛋白、1000-2000mg/m 2的吉西他滨、和150-250mg/m 2的白蛋白紫杉醇。
  8. 根据权利要求1-7中任一项所述的药物组合，其中，所述药物组合还包括安罗替尼或其药学上可接受的盐；可选地，所述安罗替尼的药学上可接受的盐为一盐酸盐或二盐酸盐。
  9. 根据权利要求8所述的药物组合，其中，所述药物组合包括单位剂量为6mg、8mg、10mg和/或12mg的安罗替尼或其药学上可接受的盐；可选地，所述抗PD-L1抗体-TGFβRII融合蛋白和安罗替尼或其药学上可接受的盐的质量比为(3.5-29.0):1；可选地，所述药物组合适用于在单个治疗周期内施用，所述药物组合还包括84-168mg的安罗替尼或其药学上可接受的盐。
  10. 权利要求1-9中任一项所述的药物组合在制备用于治疗胰腺癌的药物中的用途；优选地，所述胰腺癌为难治的、不可切除的、复发性的、晚期的和/或转移性的胰腺癌；更优选地，所述胰腺癌为转移性胰腺癌。
  11. 根据权利要求10所述的用途，其中所述胰腺癌为胰腺内分泌肿瘤和/或胰腺外分泌肿瘤。
  12. 根据权利要求10或11所述的用途，其中所述胰腺癌的主体先前未治疗过胰腺癌；或
    所述胰腺癌的主体先前已经用一种或多种不同的抗肿瘤治疗方法治疗过胰腺癌。
  13. 根据权利要求10-12中任一项所述的用途，其中，所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨和白蛋白紫杉醇各自呈药物组合物的形式，可同时、先后和/或交替给药；或
    所述抗PD-L1抗体-TGFβRII融合蛋白、吉西他滨、白蛋白紫杉醇、和安罗替尼或其药学上可接受的盐各自呈药物组合物的形式，可同时、先后和/或交替给药。
  14. 根据权利要求10-13中任一项所述的用途，其中，所述抗PD-L1抗体-TGFβRII融合蛋白每1周、每2周、每3周、或每4周施用一次，每次以600-2400mg抗PD-L1抗体-TGFβRII融合蛋白的剂量施用；
    任选地，所述吉西他滨以每周一次500-1000mg/m 2、500mg/m 2、750mg/m 2或1000mg/m 2吉西他滨的剂量，连续用药2周、停1周的给药方案给药；
    任选地，所述白蛋白紫杉醇以每周一次75-125mg/m 2、75mg/m 2、100mg/m 2或125mg/m 2白蛋白紫杉醇的剂量，连续用药2周、停1周的给药方案给药；
    任选地，所述安罗替尼或其药学上可接受的盐以每日一次6-12mg、6mg、8mg、10mg或12mg安罗替尼的剂量，连续用药2周、停1周的给药方案给药。
  15. 一种用于治疗胰腺癌的试剂盒，其包含权利要求1-9中任一项所述的药物组合。
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