WO2023072043A1

WO2023072043A1 - Combined drug for treating tumors

Info

Publication number: WO2023072043A1
Application number: PCT/CN2022/127280
Authority: WO
Inventors: 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
Priority date: 2021-10-26
Filing date: 2022-10-25
Publication date: 2023-05-04
Also published as: WO2023072043A8

Abstract

Provided is a combined drug for treating tumors, comprising an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and abraxane, and optionally, further comprising anlotinib or a pharmaceutically acceptable salt thereof. Also provided is a combined drug for treating tumors, comprising an anti-PD-L1 antibody-TGFβRII fusion protein, folinic acid, fluorouracil, irinotecan and oxaliplatin, and optionally, further comprising anlotinib or a pharmaceutically acceptable salt thereof. Also provided is a kit for treating tumors, comprising the combined drug. In addition, also provided are the use of the combined drug in preparation for a drug for treating tumors and a method for treating tumors by using the combined drug.

Description

Combination drugs for cancer treatment

technical field

The disclosure belongs to the field of biomedicine, and in particular relates to combined drugs for treating tumors.

Background technique

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%.

At present, the metastatic pancreatic cancer that loses the value of surgery mainly relies on drug treatment. There are two first-line treatment options recommended by many countries around the world, including my country's 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 (PD-L1) 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. In the tumor microenvironment, 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-β (Transforming growth factor β) belongs to the TGF-β superfamily that regulates cell growth and differentiation. It promotes tumor invasion and metastasis by mediating the SMAD pathway, while inhibiting the activation and differentiation of T cells, increasing the expression of PD-L1, and promoting Tumor growth. The anti-PD-L1 antibody-TGFβRII fusion protein can inhibit the TGF-β 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 (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.

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, PDGFRα and β, and stem cell factor receptors (SCFR) 7, 8, and 9.

Therefore, there is a need for more effective therapeutic agents for clinical use, such as combinations of more than one drug.

Summary of the invention

In one aspect, the present disclosure provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel; optionally, anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the pharmaceutical combination includes an anti-PD-L1 antibody-TGFβRII 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 ; Optionally, 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel can be packaged separately or packaged together. And wherein, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof can be packaged separately or packaged together. And wherein, the anti-PD-L1 antibody-TGFβRII 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 The anlotinib or a pharmaceutically acceptable salt thereof can be packaged in single or multiple equal parts.

In some embodiments, the drug combination is used to treat tumors. In some embodiments, the drug combination is used to treat pancreatic cancer.

In another aspect, the present disclosure provides a drug combination for treating pancreatic cancer, which includes anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel; optionally, also includes anlotinib or its pharmaceutically acceptable Accepted salt.

In another aspect, 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. In addition, 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. Alternatively, the present disclosure also provides an anti-PD-L1 antibody-TGFβRII 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 .

In some embodiments, the drug combination is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.

In some embodiments, the drug combination is a non-fixed combination. In some embodiments, each of the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel in the non-fixed combination is in the form of a pharmaceutical composition. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, in the non-fixed combination, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII fusion protein is a liquid pharmaceutical composition. In some embodiments, the liquid pharmaceutical composition is an injection.

In some embodiments, in the non-fixed combination, the gemcitabine-containing pharmaceutical composition is a solid pharmaceutical composition.

In some embodiments, in the non-fixed combination, the pharmaceutical composition containing nab-paclitaxel is a solid pharmaceutical composition.

In some embodiments, in the non-fixed combination, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately. In some embodiments, each of the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein is administered at a dose of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg each time.

In some embodiments, 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.

In some embodiments, 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.

In some embodiments, 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.

In another aspect, the present disclosure provides a kit for treating pancreatic cancer comprising the pharmaceutical combination of the present disclosure. In some embodiments, the kit includes an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel; optionally, it also includes anlotinib or a pharmaceutically acceptable salt thereof.

In another aspect, the present disclosure also provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, and oxaliplatin; optionally, anlotinib or its pharmaceutically acceptable salt. In addition, the present disclosure provides a drug combination for treating pancreatic cancer, which includes anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin; optionally, also includes anlotinib Nephrine or a pharmaceutically acceptable salt thereof. In addition, the present disclosure also provides an anti-PD-L1 antibody-TGFβRII 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.

Detailed description of the invention

The present disclosure provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel; optionally, also includes anlotinib or a pharmaceutically acceptable salt thereof. Alternatively, the present disclosure also provides a pharmaceutical combination, which includes an anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, and oxaliplatin; acceptable salt. In some embodiments, 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.

The present disclosure also provides kits for treating tumors, the kits comprising the pharmaceutical combinations of the present disclosure. In some embodiments, the kit further includes instructions for treating a tumor with the drug combination of the present disclosure.

In addition, the present disclosure also provides an anti-PD-L1 antibody-TGFβRII fusion protein for treating tumors. The present disclosure also provides the use of the anti-PD-L1 antibody-TGFβRII fusion protein in the preparation of a drug for treating tumors. The present disclosure also provides the use of the anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein of the present disclosure.

In some embodiments, the tumor is pancreatic cancer.

drug combination

In one aspect, the present disclosure provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel. Optionally, the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising nab-paclitaxel. Optionally, the pharmaceutical combination further includes a pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the drug combination is packaged in the same kit, and the kit also includes instructions for using anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel in combination to treat tumors. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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-TGFβRII Illustration of the combination of fusion protein, gemcitabine, and nab-paclitaxel for the treatment of tumors. In other embodiments, the drug combination is packaged in the same kit, and the kit also includes anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel and anlotinib or its pharmaceutically acceptable Instructions for the combined use of accepted salts in the treatment of neoplasms. In some other embodiments, the anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein, gemcitabine, nab-paclitaxel and anlotinib or a pharmaceutically acceptable salt thereof in combination to treat tumors. In some embodiments, the tumor is pancreatic cancer.

In some embodiments, the pharmaceutical combination includes an anti-PD-L1 antibody-TGFβRII 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. Optionally, 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.

In some embodiments, 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-TGFβRII 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. Optionally, 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.

In some embodiments, the pharmaceutical combination includes a unit dose of about 200 mg, about 400 mg and/or about 600 mg of anti-PD-L1 antibody-TGFβRII 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. Optionally, 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.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein in single or multiple doses. Optionally, 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. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, 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-TGFβRII fusion protein pharmaceutical composition containing anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein is a single dose or multiple doses. Optionally, 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. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGFβRII fusion protein with a unit dose of about 200 mg, about 400 mg, and/or about 600 mg of an anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein The pharmaceutical composition is a single dose or multiple doses. Optionally, 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. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, the pharmaceutical combination includes 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg of anti-PD-L1 antibody-TGFβRII 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. Optionally, the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, 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-TGFβRII fusion protein, 500-1000 mg/ ^m2 of gemcitabine, and 75-125 mg/ ^m2 of nab-paclitaxel . Optionally, the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes about 600 mg, about 1200 mg, about 1800 mg and/or about 2400 mg of anti-PD-L1 antibody-TGFβRII fusion protein, 500-1000 mg/ ^m of gemcitabine, and 75-125 mg/m ² nab-paclitaxel. Optionally, the pharmaceutical combination further includes 8 mg, 10 mg and/or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes about 1200 mg and/or about 1800 mg of an anti-PD-L1 antibody-TGFβRII fusion protein, 1000 mg/m ² of gemcitabine, and 125 mg/m ² of nab-paclitaxel. Optionally, the pharmaceutical combination further includes 8 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, in the pharmaceutical combination, the content of the anti-PD-L1 antibody-TGFβRII fusion protein is a daily dose. In some embodiments, in the pharmaceutical combination, the content of the anti-PD-L1 antibody-TGFβRII fusion protein is once a day.

In some embodiments, in the pharmaceutical combination, the content of the anti-PD-L1 antibody-TGFβRII fusion protein is a uniform dose.

In some embodiments, in the drug combination, the content of gemcitabine is a daily dose. In some embodiments, in the pharmaceutical combination, the content of gemcitabine is once a day.

In some embodiments, in the pharmaceutical combination, 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.

In some embodiments, in the pharmaceutical combination, 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.

In some embodiments, 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-TGFβRII 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. Optionally, the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, 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-TGFβRII fusion protein, 1000-2000 mg/ ^m of gemcitabine, and Nab-paclitaxel at 150-250mg/ ^m2 . Optionally, the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, 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-TGFβRII fusion protein, 1000-2000 mg/m ² of gemcitabine, and 150-250mg/m ² of nab-paclitaxel. Optionally, the pharmaceutical combination further includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, 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-TGFβRII fusion protein, 2000 mg/ ^m of gemcitabine, and 250 mg/m ² nab-paclitaxel. Optionally, the pharmaceutical combination further includes 112 mg of anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, 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-TGFβRII 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-TGFβRII fusion protein is a single dose or multiple doses. Optionally, the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, 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-TGFβRII fusion protein, containing 1000-2000mg/m ^2. A pharmaceutical composition of gemcitabine, and a pharmaceutical composition containing 150-250 mg/m ² of nab-paclitaxel; wherein, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII fusion protein is a single dose or multiple doses. Optionally, the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, 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-TGFβRII 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-TGFβRII fusion protein is a single dose or Multiple doses. Optionally, the pharmaceutical combination further includes a pharmaceutical composition containing 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, 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-TGFβRII 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-TGFβRII fusion protein is a single dose or multiple doses. Optionally, the pharmaceutical combination further includes a pharmaceutical composition containing 112 mg of anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGFβRII fusion protein is in multiple doses.

In some embodiments, in the pharmaceutical combination, the mass ratio of the anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein, gemcitabine and nab-paclitaxel can be packaged separately or together. And wherein, the anti-PD-L1 antibody-TGFβRII 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.

In other embodiments, in the drug combination, the mass ratio of the anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein , gemcitabine, nab-paclitaxel and anlotinib or their pharmaceutically acceptable salts can be packaged separately or together. And wherein, the anti-PD-L1 antibody-TGFβRII 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).

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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 TGFβRII 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-TGFβRII fusion protein for the first administration. Dosage, 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 .

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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 TGFβRII 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-TGFβRII 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, and the pharmaceutical composition containing nab-paclitaxel is prepared to be suitable for continuous 2 weeks, and 75-125mg/m2 gemcitabine is given to patients every week. m ² single or multiple doses of nab-paclitaxel.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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 TGFβRII 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-TGFβRII 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.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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 TGFβRII 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-TGFβRII fusion protein to the patient during the first administration, and 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.

In some other embodiments, 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.

In another aspect, the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel. In some embodiments, the tumor is pancreatic cancer.

Alternatively, the present disclosure also provides the use of a drug combination comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable Accepted salts in drug combinations. In some embodiments, the tumor is pancreatic cancer.

In another aspect, the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein, a pharmaceutical composition containing gemcitabine, and a pharmaceutical composition containing nab-paclitaxel to treat tumors. In some embodiments, the tumor is pancreatic cancer.

Alternatively, the present disclosure provides a kit for treating tumors, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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. In some embodiments, the tumor is pancreatic cancer.

In addition, the present disclosure also provides a pharmaceutical combination comprising anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin. Optionally, the pharmaceutical combination further includes anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination includes a pharmaceutical composition containing an anti-PD-L1 antibody-TGFβRII fusion protein, a pharmaceutical composition containing calcium folinate, a pharmaceutical composition containing fluorouracil, and a pharmaceutical composition containing irinotecan and pharmaceutical compositions containing oxaliplatin. Optionally, 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-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin combination. In some embodiments, the tumor is pancreatic cancer.

Alternatively, the present disclosure also provides a pharmaceutical combination comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and ammonium A pharmaceutical combination of rotinib or a pharmaceutically acceptable salt thereof. In some embodiments, 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-TGFβRII 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. In some embodiments, the kit further includes a pharmaceutical composition comprising anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is pancreatic cancer.

Drug Combination Dosing/Treatment Regimen

In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition and administered sequentially. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition and administered alternately. In some embodiments, in the above use or treatment method, each of the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel is in the form of a pharmaceutical composition, and each is administered at intervals. In some embodiments, in the above uses or treatment methods, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are administered with the same or different dosage regimens. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are administered in different dosage regimens.

In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are used in the same or different dosing regimen. In some embodiments, in the above-mentioned use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are administered in different doses, respectively plan for dosing.

In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein is used every week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) ) is applied once. In a specific embodiment, the anti-PD-L1 antibody-TGFβRII fusion protein is administered once every 3 weeks. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is administered at a dose of 600-2400 mg, 1200-2400 mg, 1200-1800 mg, or 1800-2400 mg each time. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein is administered at a dose of about 600 mg, about 1200 mg, about 1800 mg, or about 2400 mg each time. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is administered at a dose of about 1200 mg each time. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is administered at a dose of about 1800 mg each time.

In some embodiments, in the above methods of use or treatment, the gemcitabine 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. In some embodiments, in the above-mentioned use or treatment method, the dosage of gemcitabine is 500 mg/m ² , 750 mg/m ² or 1000 mg/m ² gemcitabine once a week. medication. In some embodiments, in the above use or treatment method, 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.

In some embodiments, in the above uses or methods of treatment, 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. In some embodiments, in the above-mentioned use or treatment method, the nab-paclitaxel 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. In some embodiments, in the above-mentioned use or treatment method, 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.

In some embodiments, in the above-mentioned use or treatment method, 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel have the same or different treatment cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody-TGFβRII 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 .

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof have the same or different treatment cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned uses or treatment methods, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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. In a specific embodiment, in the above use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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, and nab-paclitaxel was given once on day 1 and day 8 of each cycle.

In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII fusion protein is administered in each cycle, and is administered in the first week and the second week of each cycle. For 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned uses or treatment methods, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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. In a specific embodiment, in the above use or treatment method, every 21 days is a treatment cycle, and the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, in the above-mentioned use or treatment method, 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-TGFβRII 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. In some embodiments, in the above use or treatment method, 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-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, 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-TGFβRII 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 . In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGFβRII 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 . In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGFβRII 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 . In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, in the above-mentioned use or treatment method, 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-TGFβRII 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. In some embodiments, in the above use or treatment method, 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-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, 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-TGFβRII 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 . In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1200 mg of anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above-mentioned use or treatment method, every 21 days is a treatment cycle, and about 1800 mg of anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, 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-TGFβRII 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 TGFβRII fusion protein and nab-paclitaxel, anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel were administered to the subjects. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, or nab-paclitaxel is administered in multiple doses or in a single dose. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, and nab-paclitaxel are all administered in multiple doses.

In some embodiments, 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 antibody-TGFβRII fusion protein to gemcitabine, (0.1-30):1, (1-15):1, (2-15):1 or (2-10):1 anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein and anlotinib or a pharmaceutically acceptable salt thereof of 50:7 or 75:7, anti-PD-L1 antibody-TGFβRII fusion protein, Gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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. In some embodiments, during each administration, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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, or 30 to 40mg/kg dose administration or 60mg to 2400mg, 90mg to 2400mg, 120mg to 2400mg, 180mg to 2400mg, 300mg to 2400mg, 600mg to 2400mg, 900mg to 2400mg, 1200mg to 2400mg, 1500mg to 2400mg, 1800mg to 2400mg, 300mg to 2 000mg, 600mg to 2000mg, 900mg to 2000mg, 1200mg to 2000mg, 1500mg to 2000mg, 300mg to 1800mg, 600mg to 1800mg, 900mg to 1800mg, 1200mg to 1800mg, 1200mg to 1600mg, 1400mg to 1800mg, 1500mg to 1800mg , or a flat dose of 1600mg to 1800mg administered on the subject.

In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and anlotinib or its pharmaceutically acceptable The accepted salts are each in the form of a pharmaceutical composition which can be administered simultaneously, sequentially and/or alternately. In some embodiments, in the above-mentioned use or treatment method, each of the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and anlotinib or its pharmaceutically acceptable The accepted salts are each in the form of a pharmaceutical composition and are each administered at intervals. In some embodiments, in the above-mentioned use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan and oxaliplatin are administered with the same or different dosage regimens, respectively. medicine. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein, leucovorin, fluorouracil, irinotecan, oxaliplatin, and anlotinib or its pharmaceutically acceptable The accepted salts were administered in the same or different dosage regimens, respectively.

In some embodiments, in the above use or treatment method, the calcium folinate, fluorouracil, irinotecan and oxaliplatin are administered once every two weeks. In some embodiments, in the above use or treatment method, the anti-PD-L1 antibody-TGFβRII fusion protein is administered once every three weeks, and calcium folinate, fluorouracil, irinotecan, and oxaliplatin are each administered once every two weeks. In some embodiments, in the above use or method of treatment, 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-TGFβRII 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. In the above embodiments, the tumor is pancreatic cancer.

In some embodiments, 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. In some embodiments, 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.

In some embodiments, 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.

In some embodiments, the subject with pancreatic cancer has not previously treated pancreatic cancer (eg, metastatic pancreatic cancer).

In some embodiments, 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).

In some embodiments, 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).

In some embodiments, 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) .

In some embodiments, 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).

In some embodiments, the subject with pancreatic cancer has previously been treated for pancreatic cancer with one or more different antineoplastic therapies.

In some embodiments, 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.

In some embodiments, the subject with pancreatic cancer has been treated with chemotherapy for pancreatic cancer (eg, failed treatment or is not amenable to chemotherapy).

In some embodiments, 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). In some embodiments, the subject with pancreatic cancer has disease progression during or after completion of first-line therapy.

In some embodiments, 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) .

In some embodiments, 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). In some embodiments, the BRCA mutation-targeted treatment options include, but are not limited to, PARP inhibitors, such as olaparib.

In some embodiments, the subject with pancreatic cancer has been treated with PD-1/PD-L1 inhibitor therapy for pancreatic cancer. In some embodiments, the pancreatic cancer subject is an insufficient responder to a PD-1/PD-L1 inhibitor. In some embodiments, the subject with pancreatic cancer is refractory to a PD-1/PD-L1 inhibitor, eg, after at least 2 doses.

In some embodiments, 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).

In some embodiments, in the PD-1/PD-L1 inhibitor therapy, the PD-1 inhibitor 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).

In some embodiments, in the PD-1/PD-L1 inhibitor therapy, the PD-L1 inhibitor 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.

In some embodiments, the subject with pancreatic cancer has been treated for pancreatic cancer (eg, treatment has failed or is inappropriate) with a S-1-containing regimen.

In some embodiments, 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.

In some embodiments, 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).

In some embodiments, 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.

In some embodiments, the subject with pancreatic cancer has been treated for pancreatic cancer with local radiation therapy (eg, treatment has failed or is not indicated).

In some embodiments, 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-TGFβRII fusion protein

Anti-PD-L1 antibody-TGFβRII fusion protein comprising:

(a) an anti-PD-L1 antibody or antigen-binding fragment thereof; and

(b) TGFβ binding domain.

In some embodiments, the TGFβ binding domain is human TGFβRII or its TGFβ binding fragment, for example, 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.

In some embodiments, 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.

In some embodiments, 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. The above CDR sequences are provided in Table 1 below.

Table 1. CDR sequences

In some embodiments, 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. In some embodiments, 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. In some specific embodiments, 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. In other specific embodiments, 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.

In some embodiments, 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. In some embodiments, 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. In some embodiments, the constant region may comprise any of the modifications described herein, such as insertions, deletions, substitutions or chemical modifications of amino acids. In some embodiments, 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. In some embodiments, 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).

In some embodiments, 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. In some embodiments, 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. In other embodiments, 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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 TGFβ-binding domain ; Optionally, the TGFβ-binding domain is human TGFβRII or a TGFβ-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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein comprises an anti-PD-L1 antibody or an antigen-binding fragment thereof, and a TGFβ-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 TGFβ binding domain comprises human TGFβRII or a fragment or variant thereof capable of binding TGFβ, such as a cell of human TGFβRII ectodomain. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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%, 91%, 92%, 93% The heavy chain variable domain and amino acid sequence of 94%, 95%, 96%, 97%, 98%, 99% or 100% identity and the amino acid sequence shown in SEQ ID NO: 19 have 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 variable domain; and (b) a TGFβ binding domain. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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 TGFβ binding domain. In some specific embodiments, the TGFβ binding domain is human TGFβRII or its TGFβ 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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%, 92%, 93%, 94%, 95%, 96% The heavy chain and amino acid sequence of %, 97%, 98%, 99% or 100% identity is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence shown in SEQ ID NO:21 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical light chain and (b) a TGFβ binding domain. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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%, 92%, 93%, 94%, 95%, 96% The heavy chain and amino acid sequence of %, 97%, 98%, 99% or 100% identity is at least 80%, 81%, 82%, 83%, 84%, 85% identical to the amino acid sequence shown in SEQ ID NO:21 , 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical light chain and (b) a TGFβ binding domain. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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 TGFβ binding domain. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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 TGFβ binding domain. In some embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein comprises: (a) heavy chain shown in SEQ ID NO:25 and light chain shown in SEQ ID NO:21; and (b) TGFβ binding domain . In some specific embodiments, the TGFβ binding domain is human TGFβRII or its TGFβ 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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.

In some embodiments, the anti-PD-L1 antibody-TGFβRII 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%, 99% or 100% identity. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the anti-PD-L1 antibody-TGFβRII 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, TGFβ of human TGFβRII Sequence of combined fragments.

In other embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is the anti-PD-L1 antibody-TGFβ receptor II fusion protein in CN106103488.

In other embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is the PD-L1/TGF-βtrap fusion protein in CN110050000.

In other embodiments, the anti-PD-L1 antibody-TGFβRII fusion protein is the Bi-PLB-1 fusion protein in WO2020006509.

Pharmaceutical composition containing anti-PD-L1 antibody-TGFβRII fusion protein

In some embodiments, the unit dose of the pharmaceutical composition containing anti-PD-L1 antibody-TGFβRII fusion protein is 200-1200mg or other amounts of anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein.

In some embodiments, the concentration of the anti-PD-L1 antibody-TGFβRII fusion protein in the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII 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. In some specific embodiments, the concentration of the anti-PD-L1 antibody-TGFβRII 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-TGFβRII fusion protein is about 20 mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGFβRII fusion protein is about 25 mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGFβRII fusion protein is about 40 mg/mL. In other embodiments, the concentration of the anti-PD-L1 antibody-TGFβRII fusion protein is about 50 mg/mL.

In some embodiments, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII fusion protein further includes one or more of a buffer, an isotonic regulator, a stabilizer, and a surfactant. In some embodiments, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII fusion protein further includes a buffer, a stabilizer and a surfactant.

In a specific embodiment, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII 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. In other embodiments, the pharmaceutical composition containing the anti-PD-L1 antibody-TGFβRII 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.

Gemcitabine

As used in this disclosure, the chemical name of the gemcitabine is 2'-deoxy-2',2'-difluorocytidine (β-isomer), which has the structural formula of formula (I):

As used in the present disclosure, 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. For example, 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. 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. In some embodiments, the pharmaceutically acceptable salt of gemcitabine can be gemcitabine hydrochloride.

In some embodiments of the present disclosure, gemcitabine is administered as its hydrochloride salt. In some embodiments, gemcitabine is administered as its monohydrochloride salt.

The dosages of gemcitabine referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (I).

Pharmaceutical composition containing gemcitabine

In some embodiments of the present disclosure, the unit dose of the gemcitabine-containing pharmaceutical composition is 0.2 g or 1.0 g of gemcitabine.

In some embodiments, the gemcitabine-containing pharmaceutical composition includes, but is not limited to, formulations suitable for intravenous, oral, parenteral, and topical administration. In some embodiments, the gemcitabine-containing pharmaceutical composition is a formulation suitable for injection. In some embodiments, the gemcitabine-containing pharmaceutical composition is a liquid formulation. In some embodiments, the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for injection. In some embodiments, the gemcitabine-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection. In some embodiments, the gemcitabine-containing pharmaceutical composition is a lyophilized formulation. In some embodiments, the gemcitabine-containing pharmaceutical composition is a lyophilized formulation suitable for injection. In some embodiments, 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. In a specific embodiment, the pharmaceutically acceptable carrier of the lyophilized formulation suitable for injection includes mannitol, sodium acetate, hydrochloric acid, sodium hydroxide.

Nab-paclitaxel

As used in this disclosure, the nab-paclitaxel is albumin-bound paclitaxel; the chemical name of the paclitaxel is 5β,20-epoxy-1,2α,4,7β,10β,13α-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:

The dosages of nab-paclitaxel referred to in this disclosure, unless otherwise stated, are based on the molecular weight of the compound of formula (II).

Pharmaceutical composition containing nab-paclitaxel

In some embodiments of the present disclosure, 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.

In some embodiments, the nab-paclitaxel-containing pharmaceutical composition includes, but is not limited to, formulations suitable for intravenous, oral, parenteral, and topical administration. In some embodiments, the nab-paclitaxel-containing pharmaceutical composition is a formulation suitable for injection. In some embodiments, the gemcitabine-containing pharmaceutical composition is a liquid formulation. In some embodiments, the nab-paclitaxel-containing pharmaceutical composition is a liquid formulation suitable for injection. In some embodiments, the nab-paclitaxel-containing pharmaceutical composition is a liquid formulation suitable for intravenous injection. In some embodiments, the nab-paclitaxel-containing pharmaceutical composition is a lyophilized formulation. In some embodiments, 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.

In addition, 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 or its pharmaceutically acceptable salt

As used in this disclosure, the chemical name of the anlotinib is 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):

As used in this disclosure, anlotinib can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt. For example, 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. In some embodiments, the pharmaceutically acceptable salt of anlotinib may be anlotinib hydrochloride (eg, anlotinib dihydrochloride).

In some embodiments of the present disclosure, 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.

The doses of 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.

Pharmaceutical composition containing anlotinib or pharmaceutically acceptable salt thereof

In some embodiments of the present disclosure, 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. Wherein the tablet can be ordinary tablet, dispersible tablet, effervescent tablet, sustained-release tablet, controlled-release tablet or enteric-coated tablet, and 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.

In one embodiment, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof is a solid preparation suitable for oral administration. In one embodiment, the pharmaceutical composition containing anlotinib or a pharmaceutically acceptable salt thereof may be in the form of tablets or capsules. In a specific embodiment, the pharmaceutical composition comprising anlotinib or a pharmaceutically acceptable salt thereof is in the form of a capsule. In a specific embodiment, 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.

Application method

The following is not intended to limit the manner in which the disclosed drug combinations can be administered.

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. In some embodiments, 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 The dosage form of the sustained-release preparation for administration.

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. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art.

technical effect

In general, use of the drug combinations of the present disclosure described above will help to:

(1) Compared with the single administration of any drug in the combination, it produces better curative effect in reducing the growth of tumor or even eliminating tumor;

(2) provide a smaller amount of administration than any drug in the combination administered alone;

(3) provide a treatment that is well tolerated in patients, with fewer adverse reactions and/or complications than either drug administered alone;

(4) Provide better disease control rates among treated patients;

(5) Provide longer survival period (such as median survival period, progression-free survival period or overall survival period) in the treated patients;

(6) Provide that compared with standard chemotherapy, the treated patients have a longer survival period (such as median survival period, progression-free survival period or overall survival period);

(7) provide a longer duration of disease response (DOR); and/or

(8) Compared with the single administration of any drug in the combination, it has good activity in treating pancreatic cancer and exhibits a more excellent anti-tumor synergistic effect.

Definition and Description

Unless otherwise specified, the following terms used in this disclosure have the following meanings. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this disclosure, it is intended to refer to its corresponding trade name or its active ingredient.

As used herein, 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.

The term "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.

The term "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. Examples of non-fixed combinations are cocktail therapy, eg administration of 3 or more active ingredients. In non-fixed combinations, 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.

"TGFβRII" or "TGFβ receptor II" refers to a polypeptide or protein having a wild-type human TGFβ 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.

"TGFβ-binding fragment" or "TGFβ-binding fragment" of TGFβRII refers to a fragment of TGFβRII that has TGFβ-binding activity, accounting for at least 0.1%, 0.5%, 1%, 5%, 10%, 25%, 35% of the sequence of TGFβRII %, 50%, 75%, 90%, 95%, 99% or 100%. The fragment is usually a soluble fragment, such as the extracellular domain of human TGFβRII or a variant thereof, non-limiting examples include the polypeptide shown in SEQ ID NO:28.

As used herein, the term "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. Examples of 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. For example, in one embodiment, 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. For example, 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. In one embodiment, 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. In some embodiments, such modifications include those corresponding to mutations exemplified herein, including back mutations to germline sequences. For example, in one embodiment, 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.

The term "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.

The term "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 (eg, anti-PD-L1 antibody-TGFβRII fusion proteins) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "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-TGFβRII 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. For example, in some embodiments, 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 . In some embodiments, 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 . In some embodiments, a single dose of gemcitabine may be administered in the range of 600-4800 mg. As another example, in some embodiments, 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 . In some embodiments, 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 . In some embodiments, nab-paclitaxel may be administered in a single dose of 90-300 mg. For another example, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be 3-30 mg, 5-20 mg or 6-12 mg. In some embodiments, 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. In some embodiments, gemcitabine and nab-paclitaxel are administered weekly as an injectable formulation; preferably, once weekly as an intravenous formulation. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered as an oral solid formulation once a day.

Anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, leucovorin, fluorouracil, irinotecan, oxaliplatin, and/or anlotinib or a pharmaceutically acceptable salt thereof (For example, the administration period, etc.) can be comprehensively determined or adjusted according to the activity, toxicity, and tolerance of the patient, etc. of the drug. For example, one treatment cycle of the anti-PD-L1 antibody-TGFβRII 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. In some embodiments, gemcitabine and nab-paclitaxel are administered as a weekly dose. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, 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. In some embodiments, 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. In some embodiments, gemcitabine, nab-paclitaxel, or anlotinib or a pharmaceutically acceptable salt thereof is administered continuously for 2 weeks, followed by 1 week of rest. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

The use of the term "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-TGFβRII fusion protein), rather than as a mg/kg dose. For example, a 60kg person and a 100kg person will receive the same dose of antibody (eg, 1800mg anti-PD-L1 antibody-TGFβRII fusion protein).

The term "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.

The term "pharmaceutically acceptable salt" includes 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 terms "subject", "patient" or "subject" are used interchangeably herein. In some embodiments, the term "subject", "patient" or "subject" is a mammal. In some embodiments, the subject, patient or subject is a mouse. In some embodiments, the subject, patient or subject is a human.

As used herein, "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. Herein, unless otherwise stated, values of step parameters or conditions are modified by "about" by default.

As used herein, "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.

The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, a box of medicine has seven capsules, and one capsule is a single dose; or a bottle of injection is a single dose. The term "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.

The term "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. Herein, the terms "pharmaceutical composition" and "preparation" have the same meaning and are used interchangeably.

The term "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.

The term "metastatic" cancer refers to cancer that has spread from one part of the body, such as the lungs, to another part of the body.

As used herein, "treatment failure" is defined as disease progression or relapse during or after last treatment.

All patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference for the purposes of description and disclosure. These publications are provided solely for their disclosure prior to the filing date of the present disclosure. All statements as to the date of these documents or representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation herein of these publications does not constitute an admission that the publications form part of the common general knowledge in the field in any country.

The present disclosure also provides the following specific embodiments, but the protection scope of the present disclosure is not limited thereto:

Embodiment 1. A pharmaceutical combination comprising an anti-PD-L1 antibody-TGFβRII 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-TGFβRII 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-TGFβRII fusion protein to gemcitabine is (0.1-10):1, and the anti-PD-L1 antibody - The mass ratio of TGFβRII 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-TGFβRII 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-TGFβRII fusion protein comprises:

(a) an anti-PD-L1 antibody or antigen-binding fragment thereof; and

(b) human TGFβRII or a TGFβ-binding fragment thereof;

Wherein, the anti-PD-L1 antibody or its antigen-binding fragment comprises:

(a) HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4 , LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6; or

(b) 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:

(a) the heavy chain variable domain of the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable domain of the amino acid sequence shown in SEQ ID NO: 8; or

(b) the heavy chain variable domain of the amino acid sequence shown in SEQ ID NO:18, and the light chain variable domain of the amino acid sequence shown in SEQ ID NO:19.

Embodiment 7. The pharmaceutical combination according to embodiment 5 or 6, wherein the anti-PD-L1 antibody or antigen-binding fragment thereof comprises:

(a) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:23, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:10 light chain; or

(b) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:20 or SEQ ID NO:25, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:21 light chain.

Embodiment 8. The pharmaceutical combination according to any one of embodiments 5-7, wherein the human TGFβRII or a TGFβ-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-TGFβRII 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 TGFβRII or its TGFβ 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-TGFβRII fusion protein comprises:

(a) a first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:11 or SEQ ID NO:24, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:10 the second polypeptide of identity; or

(b) a first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:22 or SEQ ID NO:26, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:21 the second polypeptide of identity.

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-TGFβRII 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-TGFβRII 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-TGFβRII 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-TGFβRII 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-TGFβRII 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.

Example

For clarity, the present disclosure is further illustrated by examples, but the examples do not limit the scope of the present disclosure. All reagents used in this disclosure are commercially available and used without further purification.

The preparation and purification methods of the anti-PD-L1 antibody-TGFβRII fusion protein in this disclosure have been described in the patent application document with publication number WO2021037184, and the entire content of the patent application document of WO2021037184 is incorporated into this disclosure. The anti-PD-L1 antibody-TGFβRII fusion protein hu5G11-hIgG1-TGFβRII in the embodiment is hu5G11-hIgG1-TGFβRII in WO2021037184, and the hu5G11-hIgG1-TGFβRII 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 TGFβRII 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.

Amino acid sequence (SEQ ID NO: 26) of the first polypeptide of hu5G11-hIgG1-TGFβRII:

Amino acid sequence (SEQ ID NO: 21) of the second polypeptide of hu5G11-hIgG1-TGFβRII:

Example 1: Clinical Trial in Advanced Metastatic Pancreatic Cancer

1. Inclusion criteria

(1) Subjects voluntarily join the study and sign the informed consent;

(2) Age 18-75 years old (time of signing informed consent);

(3) In 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;

Note: Definition of 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.

(4) Stage 1 requires at least one measurable lesion to be confirmed according to RECIST 1.1 standards; stage 2 requires at least one measurable lesion to be confirmed according to RECIST 1.1 standards;

(5) The ECOG score is 0-1, and the expected survival time is more than 3 months;

(6) The major organs are in good function and meet the following standards:

1) Standards of blood routine examination (no blood transfusion within 7 days before examination, no correction by hematopoietic stimulating factor drugs):

a) Hemoglobin (HGB) ≥ 90g/L;

b) Neutrophil absolute value (NEUT) ≥ 1.5×10 ⁹ /L;

c) Platelet count (PLT) ≥ 100×10 ⁹ /L.

2) Biochemical examination must meet the following standards:

a) Total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN) (biliary stent is allowed);

b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN. If accompanied by liver metastasis, ALT and AST≤5×ULN;

c) Serum creatinine (CR)≤1.5×ULN or creatinine clearance rate (CCR)≥60mL/min.

3) The blood coagulation function must meet the following standards:

International normalized ratio (INR) ≤ 1.5 × ULN (not received anticoagulation therapy);

4) Thyroid function tests must meet the following criteria:

Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, the levels of triiodothyronine (T3) and thyroxine (T4) should be investigated, and those with normal T3 and T4 levels can be selected.

5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

(7) Patients must use reliable contraceptive measures during the study period and within 6 months after the end of the study period; the serum pregnancy/urine pregnancy test is negative within 7 days before the study enrollment, and they must be non-lactating subjects; male subjects The subjects should agree to use contraceptive measures during the study period and within 6 months after the end of the study period;

2. Experimental drug

hu5G11-hIgG1-TGFβRII 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.

3. Dosing regimen

3.1 Phase 1:

hu5G11-hIgG1-TGFβRII injection: 600mg, 1200mg, 1800mg or 2400mg, intravenous infusion, once every 3 weeks, 3 weeks is a treatment cycle.

3.2 Phase 2:

Cohort 1: first-line treatment with hu5G11-hIgG1-TGFβRII injection + gemcitabine + nab-paclitaxel:

hu5G11-hIgG1-TGFβRII 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;

Sequence of administration: first infusion of hu5G11-hIgG1-TGFβRII injection, nab-paclitaxel, and finally gemcitabine.

Cohort 2: first-line treatment with hu5G11-hIgG1-TGFβRII injection + anlotinib hydrochloride capsules + gemcitabine + nab-paclitaxel:

Anlotinib Hydrochloride Capsules: 8 mg, orally, once a day, for 2 consecutive weeks and stop for 1 week;

Sequence of administration: oral administration of anlotinib hydrochloride capsules, followed by infusion of hu5G11-hIgG1-TGFβRII injection, nab-paclitaxel, and finally gemcitabine.

Cohort 3: hu5G11-hIgG1-TGFβRII injection + gemcitabine + nab-paclitaxel second-line treatment:

Nab-paclitaxel: 125mg/m ² , intravenous infusion, once every 7 days, for 2 consecutive weeks and 1 week off.

During the study, medication delay or dose reduction is allowed according to the subject’s condition, but cross-dose reduction is not allowed: for example, the dose of 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 .

4. Evaluation criteria

The RECIST 1.1 standard was used to judge the disease state, and the curative effect was confirmed and supplemented by the iRECIST standard.

5. End point indicators

Objective response rate (ORR) = (complete response (CR) + partial response (PR));

Disease control rate (DCR=CR+PR+stable disease (SD)), duration of response (DOR), progression-free survival (PFS), overall survival (OS);

The incidence and severity of adverse events (AEs);

Immunogenicity, such as the incidence of anti-drug antibody (ADA) and its titer in the subject, and the incidence of neutralizing antibody (Nab).

And evaluate the relationship between treatment-related biomarkers, such as PD-L1 in tumor tissue and TGF-β in blood samples, and the anti-tumor efficacy of hu5G11-hIgG1-TGFβRII injection in the treatment of pancreatic cancer.

6. Therapeutic effect

After first-line treatment with hu5G11-hIgG1-TGFβRII injection (1200mg) + gemcitabine + nab-paclitaxel for subjects with metastatic pancreatic cancer, the clinical efficacy and survival benefits can be significantly improved. Eight subjects diagnosed with metastatic pancreatic cancer Among the subjects, 2 subjects (Patient A and Patient B) achieved a partial response PR (25%), and among the subjects who achieved stable disease (SD), the tumors of many subjects shrank by more than 20%; specific examples Sexual results are described below.

After first-line treatment with hu5G11-hIgG1-TGFβRII injection (600mg-1800mg) + anlotinib hydrochloride capsules + gemcitabine + nab-paclitaxel for subjects with metastatic pancreatic cancer, the clinical efficacy and survival benefit can be significantly improved. Of the subjects diagnosed with metastatic pancreatic cancer (Patient C, Patient D, Patient E, and Patient F), all subjects achieved a partial response (PR); specific exemplary results are described below.

Preliminary results suggest that the combination of hu5G11-hIgG1-TGFβRII, gemcitabine, and nab-paclitaxel, and the combination of hu5G11-hIgG1-TGFβRII, gemcitabine, nab-paclitaxel, and anlotinib hydrochloride capsules are safe and effective in the treatment of metastatic pancreatic cancer , and has the potential advantage of prolonging progression-free survival (FPS) and overall survival (OS) in subjects with metastatic pancreatic cancer.

6.1 Diagnosis results before treatment

Patient A:

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.

Patient B:

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.

Patients C-F:

metastatic pancreatic cancer.

6.2 Treatment effect and evaluation

Patient A:

Screening period: target lesion: 81.61mm;

After the second cycle of administration: target lesion: 65.16mm;

After the fourth cycle of administration: target lesion: 47.7mm;

According to the curative effect evaluation standard, the best therapeutic effect was PR.

Patient B:

Screening period: target lesion: 33.10mm;

After the second cycle of administration: target lesion: 17.7mm;

Patient C:

Screening period: target lesion: 90.9mm;

After the second cycle of administration: target lesion: 63.1mm;

Patient D:

Screening period: target lesion: 66.79mm;

After the second cycle of administration: target lesion: 46.2mm;

After the fourth cycle of administration: target lesion: 37.9mm;

Patient E:

Screening period: target lesion: 79.19mm;

After the second cycle of administration: target lesion: 39.3mm;

Patient F:

Screening period: target lesion: 53.06mm;

After the second cycle of administration: target lesion: 47.9mm;

After the fourth cycle of administration: target lesion: 35.3mm;

Claims

A pharmaceutical combination comprising an anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel; wherein the anti-PD-L1 antibody-TGFβRII fusion protein comprises:

(a) an anti-PD-L1 antibody or antigen-binding fragment thereof; and

(b) human TGFβRII or a TGFβ-binding fragment thereof;

Wherein, the anti-PD-L1 antibody or its antigen-binding fragment comprises:

(a) 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;

(b) HCDR1 of the amino acid sequence shown in SEQ ID NO:1, HCDR2 of the amino acid sequence shown in SEQ ID NO:2, HCDR3 of the amino acid sequence shown in SEQ ID NO:3, LCDR1 of the amino acid sequence shown in SEQ ID NO:4 , LCDR2 of the amino acid sequence shown in SEQ ID NO:5, and LCDR3 of the amino acid sequence shown in SEQ ID NO:6;

(c) a heavy chain variable domain of the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable domain of the amino acid sequence shown in SEQ ID NO: 19;

(d) 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;

(e) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:20 or SEQ ID NO:25, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:21 light chain; or

(f) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:23, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:10 light chain.
The pharmaceutical combination according to claim 1, wherein said human TGFβRII or its TGFβ binding fragment comprises an amino acid sequence having at least 80% identity with the amino acid sequence shown in SEQ ID NO:28.
The pharmaceutical combination according to claim 1 or 2, wherein the anti-PD-L1 antibody-TGFβRII fusion protein further comprises combining the C-terminus of the anti-PD-L1 antibody or its antigen-binding fragment with the human TGFβRII or its The connecting peptide connected to the N-terminus of the TGFβ binding fragment; preferably, the connecting peptide is (G4S) x G, and x is an integer of 3-6; preferably, the connecting peptide has SEQ ID NO:29 amino acid sequence.
The pharmaceutical combination according to any one of claims 1-3, wherein the anti-PD-L1 antibody-TGFβRII fusion protein comprises:

(a) a first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:22 or SEQ ID NO:26, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:21 the second polypeptide of identity; or

(b) a first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:11 or SEQ ID NO:24, and an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO:10 the second polypeptide of identity.
The pharmaceutical combination according to any one of claims 1-4, wherein the pharmaceutical combination comprises an anti-PD-L1 antibody-TGFβRII fusion protein with a unit dose of 200-1200 mg, and a unit dose of 0.2 g and/or 1.0 g gemcitabine, and nab-paclitaxel with a unit dose of 100 mg.
The pharmaceutical combination according to any one of claims 1-5, wherein the mass ratio of the anti-PD-L1 antibody-TGFβRII fusion protein to gemcitabine is (0.1-10):1, and the anti-PD-L1 antibody - The mass ratio of TGFβRII fusion protein to nab-paclitaxel is (0.1-30):1.
The pharmaceutical combination according to any one of claims 1-6, wherein the pharmaceutical combination is suitable for administration in a single treatment cycle, comprising 600-2400 mg of anti-PD-L1 antibody-TGFβRII fusion protein, 1000-2000 mg /m 2 of gemcitabine, and 150-250mg/m 2 of nab-paclitaxel.
The pharmaceutical combination according to any one of claims 1-7, wherein the pharmaceutical combination further comprises anlotinib or a pharmaceutically acceptable salt thereof; optionally, the pharmaceutical combination of the anlotinib Acceptable salts are monohydrochloride or dihydrochloride.
The pharmaceutical combination according to claim 8, wherein the pharmaceutical combination comprises anlotinib or a pharmaceutically acceptable salt thereof with a unit dose of 6 mg, 8 mg, 10 mg and/or 12 mg; optionally, the anti- The mass ratio of PD-L1 antibody-TGFβRII fusion protein to anlotinib or a pharmaceutically acceptable salt thereof is (3.5-29.0):1; optionally, the drug combination is suitable for administration within a single treatment cycle, The pharmaceutical combination also includes 84-168 mg of anlotinib or a pharmaceutically acceptable salt thereof.
Use of the pharmaceutical combination according to any one of claims 1-9 in the preparation of a medicament for the treatment of pancreatic cancer; preferably, the pancreatic cancer is refractory, unresectable, recurrent, advanced and/or or metastatic pancreatic cancer; more preferably, the pancreatic cancer is metastatic pancreatic cancer.
The use according to claim 10, wherein the pancreatic cancer is a pancreatic endocrine tumor and/or a pancreatic exocrine tumor.
The use according to claim 10 or 11, wherein the subject with pancreatic cancer has not previously been treated for pancreatic cancer; or

The subject with pancreatic cancer has previously been treated for pancreatic cancer with one or more different antineoplastic therapies.
The use according to any one of claims 10-12, wherein the anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine and nab-paclitaxel are each in the form of a pharmaceutical composition, which can be simultaneously, successively and/or alternately administration; or

The anti-PD-L1 antibody-TGFβRII fusion protein, gemcitabine, nab-paclitaxel, and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially and/or alternately.
The use according to any one of claims 10-13, wherein the anti-PD-L1 antibody-TGFβRII fusion protein is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at Dose administration of 600-2400 mg anti-PD-L1 antibody-TGFβRII fusion protein;

Optionally, the gemcitabine is administered with a dose of 500-1000 mg/m 2 , 500 mg/m 2 , 750 mg/m 2 or 1000 mg/m 2 gemcitabine once a week in a regimen of continuous medication for 2 weeks and rest for 1 week ;

Optionally, the nab-paclitaxel is administered at a dose of 75-125 mg/m 2 , 75 mg/m 2 , 100 mg/m 2 or 125 mg/m 2 once a week for 2 consecutive weeks and 1 week off. drug regimen;

Optionally, the anlotinib or a pharmaceutically acceptable salt thereof is given once a day at a dose of 6-12 mg, 6 mg, 8 mg, 10 mg or 12 mg of anlotinib, administered continuously for 2 weeks and stopped for 1 week. Medication regimen.
A kit for treating pancreatic cancer, comprising the drug combination according to any one of claims 1-9.