CN118176017A

CN118176017A - Combined medicine for treating tumor

Info

Publication number: CN118176017A
Application number: CN202280066732.3A
Authority: CN
Inventors: 李许; 张喜全; 王训强; 于鼎; 梁洪铭; 黄剑强
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2021-10-26
Filing date: 2022-10-25
Publication date: 2024-06-11
Also published as: WO2023072043A1; WO2023072043A8

Abstract

Provided is a combination for treating tumors comprising an anti-PD-L1 antibody-TGF-beta RII fusion protein, gemcitabine and albumin paclitaxel; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. Also provided is a combination for treating tumors comprising an anti-PD-L1 antibody-TGF-beta RII fusion protein, folinic acid, fluorouracil, irinotecan, and oxaliplatin; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. Also provided are kits for treating tumors comprising the combination. In addition, the application of the combination medicine in preparing a medicine for treating tumors and a method for treating tumors by using the combination medicine are also provided.

Description

Combined medicine for treating tumor

Technical Field

The present disclosure belongs to the field of biological medicine, and is especially one kind of combined medicine for treating tumor.

Background

Pancreatic cancer is the most invasive cancer and metastasis has occurred at the beginning of the majority of patients. Metastatic pancreatic cancer prognosis is extremely poor, and even though surgical techniques, drug treatments, and the like for treating pancreatic cancer are continuously improved with the development of technology, improvement of survival rate of pancreatic cancer patients is still very limited, and in the past 45 years (1975-2020), survival rate of pancreatic cancer patients in 5 years is only improved from 3% to 9%.

Currently, there are two first line treatment regimens recommended in many countries around the world, including the guidelines for pancreatic cancer treatment, for metastatic pancreatic cancer that lose surgical value, mainly rely on drug therapy, namely the AG regimen (Gemcitabine) and albumin paclitaxel (Abraxane/nab-paclitaxel) in combination, and the FOLFIRINOX regimen (calcium folinate, fluorouracil, irinotecan and oxaliplatin in combination).

Programmed death ligand 1 (PD-L1) is a ligand of Programmed death molecule 1 (PD-1), highly expressed in various solid malignant tumors, and the expression level is closely related to the clinical manifestation and prognosis of the subject. In the tumor microenvironment, the PD-L1 on the surface of the tumor cells inhibits the activation and proliferation of the T cells through the combination with the PD-1 or CD80 on the surface of the T cells, promotes the effector T cells to enter a failure or non-reaction state, induces the apoptosis of the T cells, stimulates the helper T cells to differentiate into regulatory T cells, and further prevents the T cells from killing the tumor cells. The anti-PD-L1 antibody can prevent the activity of effector T cells in the tumor microenvironment from being inhibited by blocking the interaction of PD-L1, PD-1 and CD80, and enhance the endogenous anti-tumor immune effect. TGF-beta (Transforming growth factor beta) belongs to the TGF-beta superfamily that regulates cell growth and differentiation, promotes tumor invasion and metastasis by mediating SMAD pathways, and simultaneously inhibits activation and differentiation of T cells, improves PD-L1 expression, and further promotes tumor growth. The anti-PD-L1 antibody-TGF beta RII fusion protein can inhibit the TGF-beta signal channel on the basis of inhibiting the PD-L1/PD-1 channel, improve the immune microenvironment and enhance the effect of immunotherapy.

Tyrosine kinases (Tyrosine kinase) are a group of enzymes that catalyze the phosphorylation of protein Tyrosine residues, play an important role in intracellular signal transduction, and are involved in the regulation, signal transmission and development of normal cells, and are also closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases (Receptor tyrosine kinase, RTKs) are involved in tumor formation and can be classified into Epidermal Growth Factor Receptor (EGFR), platelet Derived Growth Factor Receptor (PDGFR), vascular Endothelial Growth Factor Receptor (VEGFR), fibroblast Growth Factor Receptor (FGFR) and the like, depending on the structure of their extracellular regions.

An Luoti Ni (Anlotinib) is a quinoline derivative tyrosine kinase inhibitor, and the quinoline derivative tyrosine kinase inhibitor plays a role in influencing tumor angiogenesis and proliferation signal transduction, and main targets comprise: receptor tyrosine kinases VEGFR1 (FLT 1), VEGFR2 (KDR), VEGFR3 (FLT 4), EGFR, FGFR1-4, pdgfrα and β, and Stem Cell Factor Receptors (SCFR) 7, 8 and 9.

Thus, there is a need for more effective therapeutic agents for clinical use, such as the use of a combination 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-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel; optionally, a pharmaceutical composition comprising An Luoti Ni or a pharmaceutically acceptable salt thereof is also included.

In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody-tgfbetarii fusion protein in a unit dose of 200-1200mg, gemcitabine in a unit dose of 0.2g and/or 1.0g, and albumin paclitaxel in a unit dose of 100 mg; optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof in unit doses of 6mg, 8mg, 10mg and/or 12 mg.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel may be packaged separately or together. And wherein the anti-PD-L1 antibody-tgfbetarii fusion protein is capable of being packaged in a single or multiple aliquots, the gemcitabine is capable of being packaged in a single or multiple aliquots, and the albumin paclitaxel is capable of being packaged in a single or multiple aliquots.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, may be packaged separately or together. And wherein the anti-PD-L1 antibody-tgfbetarii fusion protein is capable of being packaged in one or more aliquots, the gemcitabine is capable of being packaged in one or more aliquots, the albumin paclitaxel is capable of being packaged in one or more aliquots, and the An Luoti ni or pharmaceutically acceptable salt thereof is capable of being packaged in one or more aliquots.

In some embodiments, the pharmaceutical combination is for treating a tumor. In some embodiments, the pharmaceutical combination is for treating pancreatic cancer.

In another aspect, the present disclosure provides a pharmaceutical combination for treating pancreatic cancer comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included.

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 a 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 manufacture of a medicament for the treatment of pancreatic cancer. Or the disclosure also provides the use of an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel, optionally, also including An Luoti ni or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pancreatic cancer.

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

In some embodiments, the pharmaceutical combination is a non-fixed combination. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel in the non-fixed combination are each in the form of a pharmaceutical composition. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof, in the non-fixed combination are each in the form of a pharmaceutical composition.

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

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

In some embodiments, the non-fixed combination, the pharmaceutical composition comprising albumin paclitaxel is a solid pharmaceutical composition.

In some embodiments, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof in the non-fixed combination is a solid pharmaceutical composition.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially, and/or alternately. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially, and/or alternately.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered at a dose of 600-2400mg, 1200-1800mg, or 1800-2400mg at a time.

In some embodiments, the gemcitabine is administered in a dosage regimen of 500-1000mg/m ² gemcitabine once a week for 2 weeks, and for 1 week on a continuous basis.

In some embodiments, the albumin paclitaxel is administered in a dose of 75-125mg/m ² albumin paclitaxel once a week, a regimen of 2 weeks continuous, and 1 week off.

In some embodiments, the An Luoti ni, or pharmaceutically acceptable salt thereof, is administered in a dose of 6mg, 8mg, 10mg, or 12mg An Luoti ni once daily, a regimen of 2 weeks consecutive, 1 week off.

In another aspect, the present disclosure provides a kit for treating pancreatic cancer comprising a pharmaceutical combination of the present disclosure. In some embodiments, the kit comprises an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included.

In another aspect, the present disclosure also provides a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. In addition, the present disclosure provides a pharmaceutical combination for treating pancreatic cancer comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. In addition, the disclosure also provides the use of an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin, optionally, also including An Luoti ni or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pancreatic cancer tumors.

Detailed Description

The present disclosure provides pharmaceutical combinations comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. Or the present disclosure also provides a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin; optionally, an Luoti Ni or a pharmaceutically acceptable salt thereof is also included. In some embodiments, the pharmaceutical combination is for treating a tumor.

The present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the manufacture of a medicament for the treatment of a tumor. The present disclosure also provides for the use of the pharmaceutical combinations of the present disclosure for the treatment of tumors. The present disclosure also provides a method of treating a tumor comprising administering to a subject an effective amount of a pharmaceutical combination of the present disclosure.

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

In addition, the present disclosure also provides anti-PD-L1 antibody-TGF-beta RII fusion proteins for use in the treatment of tumors. The disclosure also provides for the use of an anti-PD-L1 antibody-tgfbetarii fusion protein in the manufacture of a medicament for treating a tumor. The disclosure also provides for the use of an anti-PD-L1 antibody-tgfbetarii fusion protein for treating a tumor. The present disclosure also provides methods of treating a tumor comprising administering to a subject an effective amount of an anti-PD-L1 antibody-tgfbetarii fusion protein of the present disclosure.

In some embodiments, the tumor is pancreatic cancer.

Pharmaceutical combination

In one aspect, the present disclosure provides a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel. Optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is packaged in the same kit, which further includes instructions for the combined use of an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel to treat tumors. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel in the pharmaceutical combination are packaged separately in separate kits, which further include instructions for the combined use of the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel to treat the tumor. In other embodiments, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for the combined use of an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof, to treat a tumor. In still other embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, an Luoti ni, or a pharmaceutically acceptable salt thereof in the pharmaceutical combination are separately packaged in separate kits that further include instructions for the combined use of the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, an Luoti ni, or a pharmaceutically acceptable salt thereof, to treat a tumor. In some embodiments, the tumor is pancreatic cancer.

In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody-TGF-beta RII fusion protein in a unit dose of 200-1200mg or 200-600mg, gemcitabine in a unit dose of 0.2g and/or 1.0g, and albumin paclitaxel in a unit dose of 100 mg. Optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof in unit doses of 6mg, 8mg, 10mg and/or 12 mg.

In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody-tgfbetarii fusion protein in a unit dose of about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, and/or about 1200mg, gemcitabine in a unit dose of 0.2g and/or 1.0g, and paclitaxel in an albumin in unit dose of 100 mg. Optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof in unit doses of 6mg, 8mg, 10mg and/or 12 mg.

In some embodiments, the pharmaceutical combination comprises an anti-PD-L1 antibody-tgfbetarii fusion protein in a unit dose of about 200mg, about 400mg, and/or about 600mg, gemcitabine in a unit dose of 0.2g and/or 1.0g, and albumin paclitaxel in a unit dose of 100 mg. Optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof in unit dose of 8mg, 10mg and/or 12 mg.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein in a unit dose of 200-1200mg or 200-600mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine in a unit dose of 0.2g and/or 1.0g of gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel in a unit dose of 100mg of albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in unit dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination comprises a unit dose of about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 550mg, about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, and/or about 1200mg of an anti-PD-L1 antibody-tgfbetarii fusion protein-containing pharmaceutical composition, a unit dose of 0.2g and/or 1.0g of gemcitabine-containing pharmaceutical composition, and a unit dose of 100mg of albumin-paclitaxel-containing pharmaceutical composition; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in unit dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein in a unit dose of about 200mg, about 400mg, and/or about 600mg of the anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine in a unit dose of 0.2g and/or 1.0g of gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel in a unit dose of 100mg of albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in unit dose of 8mg, 10mg and/or 12mg An Luoti ni. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination comprises 600-2400mg, 1200-1800mg, or 1800-2400mg of an anti-PD-L1 antibody-TGF-beta RII fusion protein, 100-3000mg/m ²、200-2000mg/m ²、500-1500mg/m ², or 500-1000mg/m ² of gemcitabine, and 10-500mg/m ²、30-300mg/m ²、100-200mg/m ², or 75-125mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 8mg, 10mg and/or 12mg An Luoti mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 500-1000mg/m ² of gemcitabine, and 75-125mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 8mg, 10mg and/or 12mg An Luoti mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises about 600mg, about 1200mg, about 1800mg, and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 500-1000mg/m ² of gemcitabine, and 75-125mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 8mg, 10mg and/or 12mg An Luoti mg of An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises about 1200mg and/or about 1800mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 1000mg/m ² of gemcitabine, and 125mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 8mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the amount of anti-PD-L1 antibody-tgfbetarii fusion protein in the pharmaceutical combination is one daily dose. In some embodiments, the amount of anti-PD-L1 antibody-tgfbetarii fusion protein in the pharmaceutical combination is a daily dose.

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

In some embodiments, the amount of gemcitabine in the pharmaceutical combination is one daily dose. In some embodiments, the amount of gemcitabine in the pharmaceutical combination is one daily dose.

In some embodiments, the amount of albumin paclitaxel in the pharmaceutical combination is one daily dose. In some embodiments, the amount of albumin paclitaxel in the pharmaceutical combination is a once daily dose.

In some embodiments, the amount of An Luoti n or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is one daily dose. In some embodiments, the amount of An Luoti n or a pharmaceutically acceptable salt thereof in the pharmaceutical combination is one daily dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising 600-2400mg, 1200-1800mg, or 1800-2400mg of an anti-PD-L1 antibody-TGF-beta RII fusion protein, 200-6000mg/m ²、400-4000mg/m ²、1000-3000mg/m ², or 1000-2000mg/m ² of gemcitabine, and 20-1000mg/m ²、60-600mg/m ²、200-400mg/m ², or 150-250mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 1000-2000mg/m ² of gemcitabine, and 150-250mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising about 600mg, about 1200mg, about 1800mg, and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 1000-2000mg/m ² of gemcitabine, and 150-250mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, comprising about 1200mg and/or about 1800mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, 2000mg/m ² of gemcitabine, and 250mg/m ² of albumin paclitaxel. Optionally, the pharmaceutical combination further comprises 112mg An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, including a pharmaceutical composition comprising 600-2400mg, 1200-1800mg, or 1800-2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising 200-6000mg/m ²、400-4000mg/m ²、1000-3000mg/m ², or 1000-2000mg/m ² gemcitabine, and a pharmaceutical composition comprising 20-1000mg/m ²、60-600mg/m ²、200-400mg/m ², or 150-250mg/m ² albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle and includes a pharmaceutical composition comprising about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising 1000-2000mg/m ² gemcitabine, and a pharmaceutical composition comprising 150-250mg/m ² albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, including a pharmaceutical composition comprising about 600mg, about 1200mg, about 1800mg, and/or about 2400mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising 1000-2000mg/m ² gemcitabine, and a pharmaceutical composition comprising 150-250mg/m ² albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising 84-168mg An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination is suitable for administration within a single treatment cycle, including a pharmaceutical composition comprising about 1200mg and/or about 1800mg of an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising 2000mg/m ² gemcitabine, and a pharmaceutical composition comprising 250mg/m ² albumin paclitaxel; wherein the pharmaceutical composition containing the anti-PD-L1 antibody-TGF-beta RII fusion protein is in single dose or multiple doses. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising 112mg An Luoti of a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a multi-dose.

In some embodiments, the pharmaceutical combination wherein the mass ratio of the anti-PD-L1 antibody-TGF-beta RII fusion protein to gemcitabine is (0.1-10): 1, (0.125-2): 1, (0.125-1.5): 1 or (0.25-1.5): 1, and the mass ratio of the anti-PD-L1 antibody-TGF-beta RII fusion protein to albumin paclitaxel is (0.1-30): 1, (1-15): 1, (2-15): 1 or (2-10): 1; wherein the anti-PD-L1 antibody-TGF-beta RII fusion protein, gemcitabine, and albumin paclitaxel may be packaged separately or together. And wherein the anti-PD-L1 antibody-tgfbetarii fusion protein can be packaged in a single or multiple aliquots (e.g., 2, 3,4, 5, 6, 7, 8,9, 10, 12 or more aliquots); gemcitabine may be packaged in single or multiple aliquots; albumin paclitaxel can be packaged in single or multiple aliquots.

In still other embodiments, the pharmaceutical combination has a mass ratio of (0.1-10): 1, (0.125-2): 1, (0.125-1.5): 1 or (0.25-1.5): 1, the anti-PD-L1 antibody-tgfbetarii fusion protein and albumin paclitaxel of (0.1-30): 1, (1-15): 1, (2-15): 1 or (2-10): 1, the anti-PD-L1 antibody-tgfbetarii fusion protein and An Luoti or a pharmaceutically acceptable salt thereof of (3.5-29.0): 1, (7.1-21.5): 1, (7.1-14.5): 1, (10.5-21.5): 1, 50:7 or 75:7; wherein the anti-PD-L1 antibody-TGF-beta RII fusion protein, gemcitabine, albumin paclitaxel, an Luoti or a pharmaceutically acceptable salt thereof may be packaged separately or together. And wherein the anti-PD-L1 antibody-tgfbetarii fusion protein can be packaged in a single or multiple aliquots (e.g., 2,3, 4,5, 6, 7, 8, 9, 10, 12 or more aliquots); gemcitabine may be packaged in single or multiple aliquots; albumin paclitaxel can be packaged in single or multiple aliquots; an Luoti Ni or a pharmaceutically acceptable salt thereof can be packaged in single or multiple aliquots (e.g., 7, 14, 28 or more aliquots).

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel, wherein the pharmaceutical composition comprising anti-PD-L1 antibody-tgfbetarii fusion protein is prepared to be suitable for administration of a single dose or multiple doses of 600-2400mg, 1200-1800mg, or 1800-2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein to a patient at the first administration, and the pharmaceutical composition comprising gemcitabine is prepared to be suitable for administration of a single dose or multiple doses of 100-3000mg/m ²、200-2000mg/m ²、500-1500mg/m ², or 500-1000mg/m ² gemcitabine to a patient at the second administration of 10-500mg/m ²、30-300mg/m ²、100-200mg/m ², or 75-125mg/m ² albumin paclitaxel to a patient at the first administration.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel, wherein the pharmaceutical composition comprising gemcitabine is prepared to be suitable for administration of a single dose or multiple doses of about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein to a patient when the pharmaceutical composition comprising gemcitabine is prepared to be suitable for continuous 2 weeks, a single dose or multiple doses of 500-1000mg/m ² gemcitabine to the patient, and the pharmaceutical composition comprising albumin paclitaxel is prepared to be suitable for continuous 2 weeks, a single dose or multiple doses of ² mg/m paclitaxel to the patient when the pharmaceutical composition comprises gemcitabine.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel, wherein the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is prepared to be suitable for administration to a patient at a single dose or multiple doses of about 600mg, about 1200mg, about 1800mg, or about 2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein at the first administration, the pharmaceutical composition comprising gemcitabine is prepared to be suitable for administration to a patient for a single dose or multiple doses of 500-1000mg/m ² gemcitabine for a continuous 2 weeks, and the pharmaceutical composition comprising albumin paclitaxel is prepared to be suitable for administration to a patient for a single dose or multiple doses of 75-125mg/m ² albumin paclitaxel for a continuous 2 weeks.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, and a pharmaceutical composition comprising albumin paclitaxel, wherein the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is prepared to be suitable for administration to a patient of about 1200mg or about 1800mg of the single dose or multiple doses of the anti-PD-L1 antibody-tgfbetarii fusion protein when administered for the first time, the pharmaceutical composition comprising gemcitabine is prepared to be suitable for administration of 1000mg/m ² gemcitabine to a patient for 2 consecutive weeks, and the pharmaceutical composition comprising albumin paclitaxel is prepared to be suitable for administration of 125mg/m ² of albumin paclitaxel to a patient for 2 consecutive weeks.

In other embodiments, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administration to a patient of 6-12mg An Luoti n daily for 14 consecutive days. More specifically, the pharmaceutical composition containing An Luoti ni or a pharmaceutically acceptable salt thereof is prepared as a single dose suitable for administration of 6mg, 8mg, 10mg or 12mg An Luoti ni to a patient daily for 14 consecutive days. More specifically, the pharmaceutical composition containing An Luoti n or a pharmaceutically acceptable salt thereof is prepared as a single dose of 8mg An Luoti n administered daily to a patient for 14 consecutive days.

In another aspect, the present disclosure also provides the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine and albumin paclitaxel in the manufacture of a medicament for the treatment of a tumor. The present disclosure also provides for the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine and albumin paclitaxel for the treatment of tumors. The present disclosure also provides a method of treating a tumor in a subject comprising administering to the subject an effective amount of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel. In some embodiments, the tumor is pancreatic cancer.

Or the disclosure also provides the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor. The present disclosure also provides for the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof, to treat a tumor. The disclosure also provides methods of treating a tumor in a subject comprising administering to the subject an effective amount of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is pancreatic cancer.

In another aspect, the present disclosure provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine and a pharmaceutical composition comprising albumin paclitaxel, and instructions for using the pharmaceutical composition comprising the anti-PD-L1 antibody-tgfbetarii fusion protein, the pharmaceutical composition comprising gemcitabine and the pharmaceutical composition comprising albumin paclitaxel in combination to treat the tumor. In some embodiments, the tumor is pancreatic cancer.

Or the present disclosure provides a kit for treating a tumor comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising gemcitabine, a pharmaceutical composition comprising albumin paclitaxel, and a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof, and instructions for using the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, the pharmaceutical composition comprising gemcitabine, the pharmaceutical composition comprising albumin paclitaxel, and the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof in combination to treat a tumor. In some embodiments, the tumor is pancreatic cancer.

In addition, the present disclosure also provides pharmaceutical combinations comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin. Optionally, the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising calcium folinate, a pharmaceutical composition comprising fluorouracil, a pharmaceutical composition comprising irinotecan, and a pharmaceutical composition comprising oxaliplatin. Optionally, the pharmaceutical combination further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof.

The present disclosure also provides the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan and oxaliplatin in the manufacture of a medicament for the treatment of a tumor. The present disclosure also provides for the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin for the treatment of tumors. The present disclosure also provides a method of treating a tumor in a subject comprising administering to the subject an effective amount of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin. In some embodiments, the tumor is pancreatic cancer.

Or the disclosure also provides the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin and An Luoti ni, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a tumor. The present disclosure also provides for the use of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin and An Luoti ni, or a pharmaceutically acceptable salt thereof, for the treatment of a tumor. The present disclosure also provides a method of treating a tumor in a subject comprising administering to the subject an effective amount of a pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is pancreatic cancer.

The present disclosure also provides kits for treating tumors comprising a pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, a pharmaceutical composition comprising calcium folinate, a pharmaceutical composition comprising fluorouracil, a pharmaceutical composition comprising irinotecan, and a pharmaceutical composition comprising oxaliplatin. In some embodiments, the kit further comprises a pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof. In some embodiments, the tumor is pancreatic cancer.

Drug combination dosing/treatment regimen

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each in the form of a pharmaceutical composition for simultaneous, sequential, and/or alternative administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each administered sequentially in the form of a pharmaceutical composition for use or method of treatment as described above. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each administered alternately in the form of a pharmaceutical composition for use or method of treatment as described above. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each in the form of a pharmaceutical composition and are each administered in a separate administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are administered separately on the same or different dosing schedules. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are administered separately in different dosing regimens for the above uses or methods of treatment.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially, and/or alternately. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are each administered sequentially in the form of a pharmaceutical composition for use or method of treatment as described above. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition for alternate administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition and are each administered in a separate administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are administered separately on the same or different dosing schedules. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or a pharmaceutically acceptable salt thereof, are administered separately in different dosing regimens.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered weekly (q 1 w), every 2 weeks (q 2 w), every 3 weeks (q 3 w), or every 4 weeks (q 4 w) in the above uses or methods of treatment. In a specific embodiment, the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered once every 3 weeks. In some embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered at a dose of 600-2400mg, 1200-1800mg, or 1800-2400mg at a time. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered at a dose of about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg at a time. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered at a dose of about 600mg, about 1200mg, about 1800mg, or about 2400mg at a time. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered at a dose of about 1200mg at a time. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered at a dose of about 1800mg at a time.

In some embodiments, the above-described use or method of treatment, the gemcitabine is administered once a week. In some embodiments, the above uses or methods of treatment, the gemcitabine is administered at a dose of 100-3000mg/m ²、200-2000mg/m ²、500-1500mg/m ² or 500-1000mg/m ² at a time. In some embodiments, the above uses or methods of treatment, the gemcitabine is administered at a dose of 500mg/m ²、750mg/m ² or 1000mg/m ² at a time. In some embodiments, in the above uses or methods of treatment, the gemcitabine is administered in a dosage of 500-1000mg/m ² gemcitabine once a week, 2 weeks of continuous dosing, 1 week of dosing regimen. In some embodiments, in the above uses or methods of treatment, the gemcitabine is administered in a dose of 500mg/m ²、750mg/m ² or 1000mg/m ² gemcitabine once a week, a2 week continuous regimen, a 1 week off regimen. In some embodiments, in the above uses or methods of treatment, the gemcitabine is administered in a 1000mg/m ² gemcitabine dose once a week, 2 weeks continuous, 1 week off regimen.

In some embodiments, the albumin paclitaxel is administered once a week in the above uses or methods of treatment. In some embodiments, the albumin paclitaxel is administered at a dose of 10-500mg/m ²、30-300mg/m ²、100-200mg/m ² or 75-125mg/m ² at a time in the above uses or methods of treatment. In some embodiments, the albumin paclitaxel is administered at a dose of 75mg/m ²、100mg/m ² or 125mg/m ² at a time in the above uses or methods of treatment. In some embodiments, the albumin paclitaxel is administered in a dose of 75-125mg/m ² albumin paclitaxel once a week, a regimen of 2 weeks continuous, and 1 week off. In some embodiments, in the above uses or methods of treatment, the albumin paclitaxel is administered in a dose of 75mg/m ²、100mg/m ² or 125mg/m ² albumin paclitaxel once a week, a2 week continuous regimen, a 1 week off regimen. In some embodiments, in the above uses or methods of treatment, the albumin paclitaxel is administered in a dose of 125mg/m ² albumin paclitaxel once a week, a regimen of 2 weeks continuous administration, and 1 week withdrawal.

In some embodiments, in the above uses or methods of treatment, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 6-12mg An Luoti ni once daily, a regimen of 2 weeks of continuous administration, and 1 week of discontinuation. In some embodiments, in the above uses or methods of treatment, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 6mg, 8mg, 10mg, or 12mg An Luoti ni once daily, a regimen of 2 weeks continuous, 1 week off. In some embodiments, in the above uses or methods of treatment, the An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 8mg An Luoti ni once daily, a regimen of 2 weeks of continuous administration, and 1 week of discontinuation.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel each have the same or different treatment cycles. In some specific embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel have the same treatment cycle, e.g., one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti b, or pharmaceutically acceptable salts thereof, each have the same or different treatment cycles. In some specific embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, an Luoti, or a pharmaceutically acceptable salt thereof, has the same treatment cycle, e.g., one treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks.

In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered in each cycle, gemcitabine is administered at week 1 and week 2 of each cycle, and albumin paclitaxel is administered at weeks 1 and 2 of each cycle, respectively. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once per cycle, gemcitabine is administered once per week 1 and 2 of each cycle, and albumin paclitaxel is administered once per week 1 and 2 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, gemcitabine is administered on days 1 and 8 of each cycle, and albumin paclitaxel is administered on days 1 and 8 of each cycle, respectively. In a specific embodiment, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered once on day 1 of each cycle, gemcitabine is administered once on days 1 and 8 of each cycle, and albumin paclitaxel is administered once on days 1 and 8 of each cycle, respectively.

In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered every cycle, gemcitabine is administered at week 1 and week 2 of each cycle, albumin paclitaxel is administered at week 1 and week 2 of each cycle, and An Luoti or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once per cycle, gemcitabine is administered once per week 1 and 2 of each cycle, albumin paclitaxel is administered once per week 1 and 2 of each cycle, and An Luoti ni or a pharmaceutically acceptable salt thereof is administered once per day on days 1-14 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, gemcitabine is administered on days 1 and 8 of each cycle, respectively, albumin paclitaxel is administered on days 1 and 8 of each cycle, and An Luoti of each cycle, or a pharmaceutically acceptable salt thereof, is administered daily on days 1-14 of each cycle. In a specific embodiment, the above use or method of treatment is one treatment cycle every 21 days, the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered once on day 1 of each cycle, gemcitabine is administered once on days 1 and 8 of each cycle, albumin paclitaxel is administered once on days 1 and 8 of each cycle, and An Luoti Ni or a pharmaceutically acceptable salt thereof is administered once per day on days 1-14 of each cycle.

In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, about 600-2400mg, 1200-1800mg, or 1800-2400mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500-1000mg/m ², or 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on day 1 and 8 of each cycle, 75-125mg/m ² is administered daily on day 1 and 8 of each cycle, or 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, with about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg of an anti-PD-L1 antibody-TGF-beta RII fusion protein administered on day 1 of each cycle, gemcitabine at 500mg/m ²、750mg/m ² or 1000mg/m ² is administered daily on days 1 and 8 of each cycle, and albumin paclitaxel at 75mg/m ²、100mg/m ² or 125mg/m ² is administered daily on days 1 and 8 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 600mg, about 1200mg, about 1800mg or about 2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, and 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, about 1200mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, and 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 1800mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, and 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 1200mg of the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, and 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 1800mg of the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, and 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle.

In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, about 600-2400mg, 1200-1800mg, or 1800-2400mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500-1000mg/m ², or 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on day 1 and 8 of each cycle, 75-125mg/m ² is administered daily on day 1 and 8 of each cycle, or 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel, 6mg, 8mg, 10mg and/or 12mg of An Luoti Ni or a pharmaceutically acceptable salt thereof, are administered daily on days 1-14 of each cycle. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, with about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg of an anti-PD-L1 antibody-TGF-beta RII fusion protein administered on day 1 of each cycle, gemcitabine at 500mg/m ²、750mg/m ² or 1000mg/m ² is administered daily on days 1 and 8 of each cycle, paclitaxel at 75mg/m ²、100mg/m ² or 125mg/m ² is administered daily on days 1 and 8 of each cycle, and paclitaxel at An Luoti, or a pharmaceutically acceptable salt thereof at 6, 8, 10, and/or 12mg daily on days 1-14 of each cycle. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, with about 600mg, about 1200mg, about 1800mg, or about 2400mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine administered daily on days 1 and 8 of each cycle, 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel administered daily on days 1 and 8 of each cycle, an Luoti Ni or a pharmaceutically acceptable salt thereof is administered at 6mg, 8mg, 10mg and/or 12mg daily on days 1-14 of each cycle. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, about 1200mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle, 6 mg/m, An Luoti mg, 10mg and/or 12mg of An Luoti mg or a pharmaceutically acceptable salt thereof. In some embodiments, the above uses or methods of treatment are one treatment cycle every 21 days, about 1800mg of the anti-PD-L1 antibody-TGF-beta RII fusion protein is administered on day 1 of each cycle, 500mg/m ²、750mg/m ² or 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, 75mg/m ²、100mg/m ² or 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle, 6 mg/m, An Luoti mg, 10mg and/or 12mg of An Luoti mg or a pharmaceutically acceptable salt thereof. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 1200mg of the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle, and 8mg of An Luoti of paclitaxel or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle. In some embodiments, the above use or method of treatment is one treatment cycle every 21 days, about 1800mg of the anti-PD-L1 antibody-tgfbetarii fusion protein is administered on day 1 of each cycle, 1000mg/m ² of gemcitabine is administered daily on days 1 and 8 of each cycle, 125mg/m ² of albumin paclitaxel is administered daily on days 1 and 8 of each cycle, and 8mg of An Luoti ni or a pharmaceutically acceptable salt thereof is administered daily on days 1-14 of each cycle.

In some embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein, gemcitabine, and albumin paclitaxel are administered to the subject at a mass ratio of (0.1-10): 1, (0.125-2): 1, (0.125-1.5): 1 or (0.25-1.5): 1 to the anti-PD-L1 antibody-TGF-beta RII fusion protein and gemcitabine, and (0.1-30): 1, (1-15): 1, (2-15): 1 or (2-10): 1 to the anti-PD-L1 antibody-TGF-beta RII fusion protein and albumin paclitaxel. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, or albumin paclitaxel is administered in multiple doses or in a single dose. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are administered in multiple doses.

In some embodiments, the anti-PD-L1 antibody-TGF beta RII fusion protein and gemcitabine mass ratio of (0.1-10): 1, (0.125-2): 1, (0.125-1.5): 1 or (0.25-1.5): 1, (0.1-30): 1, (1-15): 1, (2-15): 1 or (2-10): 1 to albumin paclitaxel mass ratio, and (3.5-29.0): 1, (7.1-21.5): 1, (7.1-14.5): 1, (10.5-21.5): 1, 50:7 or 75:7 anti-PD-L1 antibody-TGF beta RII fusion protein and An Luoti or pharmaceutically acceptable salt thereof are administered to the subject. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, or erlotinib, or a pharmaceutically acceptable salt thereof, is administered in multiple doses or in a single dose. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are administered in multiple doses and An Luoti ni, or a pharmaceutically acceptable salt thereof, is administered in a single dose. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are administered in multiple doses and An Luoti n or a pharmaceutically acceptable salt thereof is administered in a single dose at each administration.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein may be administered at a dose selected from the group consisting of 0.01 to 50mg/kg, 0.1 to 40mg/kg, 0.1 to 35mg/kg, 0.1 to 30mg/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 10mg/kg, 10 to 40mg/kg, 20 to 30mg/kg, 25 to 35mg/kg, or 30mg/kg to a subject; or a uniform dose of 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 2000mg, 600mg to 2000mg, 900mg to 2000mg, 1200mg to 2000mg, 1500mg to 2000mg, 300mg to 1800mg, 600mg to 1800mg, 900mg to 1800mg, 1200mg to 1600mg, 1400mg to 1800mg, 1500mg to 1800mg, or 1600mg to 1800 mg.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin are each in the form of a pharmaceutical composition for simultaneous, sequential, and/or alternative administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and An Luoti ni, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition, for simultaneous, sequential and/or alternative administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin are each in the form of a pharmaceutical composition and are each administered in a divided administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and An Luoti ni, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition and are each administered in a separate administration. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, and oxaliplatin are administered separately in the same or different dosing regimen. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and An Luoti ni, or a pharmaceutically acceptable salt thereof, are administered separately in the same or different dosing regimens.

In some embodiments, the above use or method of treatment, the calcium folinate, fluorouracil, irinotecan, and oxaliplatin are administered once every two weeks. In some embodiments, the above-described use or method of treatment, the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once every three weeks, and each of calcium folinate, fluorouracil, irinotecan, and oxaliplatin is administered once every two weeks. In some embodiments, the above use or method of treatment is administered about 600mg, about 700mg, about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, about 1400mg, about 1500mg, about 1600mg, about 1700mg, about 1800mg, about 1900mg, about 2000mg, about 2100mg, about 2200mg, about 2300mg, or about 2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein once every three weeks of 1 day, 400mg/m ² of calcium folinate once every two weeks of 1 day, 2800mg/m ² of fluorouracil every two weeks of 1 day, 180mg/m ² of irinotecan administered every two weeks of 1 day, and 85mg/m ² of oxaliplatin every two weeks of 1 day. 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 a pancreatic exocrine tumor. In some embodiments, the pancreatic cancer is ductal adenocarcinoma. In some embodiments, the pancreatic cancer is acinar cell cancer. In some embodiments, the pancreatic cancer is squamous carcinoma and/or adenosquamous carcinoma. In some embodiments, the pancreatic cancer is a glioblastoma (also known as mucinous non-cystic carcinoma). In some embodiments, the pancreatic cancer is a liver-like adenocarcinoma. In some embodiments, the pancreatic cancer is a medullary cancer. In some embodiments, the pancreatic cancer is invasive micro-papillary carcinoma. In some embodiments, the pancreatic cancer is a ring cell cancer. In some embodiments, the pancreatic cancer is an undifferentiated carcinoma. In some embodiments, the pancreatic cancer is pancreatic blast cancer. In some embodiments, the pancreatic cancer is a solid-pseudopapillary tumor.

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 embodiments, the pancreatic cancer is advanced pancreatic cancer. In some embodiments, the pancreatic cancer is locally advanced pancreatic cancer. In some embodiments, the pancreatic cancer is advanced metastatic pancreatic cancer.

In some embodiments, the subject of pancreatic cancer has not previously been treated for pancreatic cancer (e.g., metastatic pancreatic cancer).

In some embodiments, the subject of pancreatic cancer has not previously received chemotherapy to treat pancreatic cancer (e.g., has not previously received chemotherapy in a metastatic environment).

In some embodiments, the subject of pancreatic cancer has not previously received first-line systemic chemotherapy to treat pancreatic cancer (e.g., has not previously received first-line systemic chemotherapy in a metastatic environment).

In some embodiments, the subject of pancreatic cancer has not previously received surgery, radiation therapy, and/or immunotherapy to treat pancreatic cancer (e.g., has not previously received surgery, radiation therapy, and/or immunotherapy in a metastatic environment).

In some embodiments, the subject of pancreatic cancer has not previously received adjuvant therapy to treat pancreatic cancer (e.g., has not previously received adjuvant therapy in a metastatic environment).

In some embodiments, the subject of pancreatic cancer has previously been treated with one or more different anti-tumor therapies.

In some embodiments, the subject of pancreatic cancer has previously been treated for pancreatic cancer (e.g., failed or inapplicable) with one or more of surgery, radiation therapy, chemotherapy, and immunotherapy.

In some embodiments, the subject of pancreatic cancer has been treated with chemotherapy for pancreatic cancer (e.g., failed treatment or is unsuitable for chemotherapy).

In some embodiments, the subject of pancreatic cancer has been treated with a first-line systemic chemotherapy regimen (e.g., failed treatment or inapplicable to systemic chemotherapy). In some embodiments, the subject of pancreatic cancer develops disease progression during the first-line treatment or progresses after the treatment is completed.

In some embodiments, the subject of pancreatic cancer has been treated with FOLFIRINOX regimen (combination chemotherapy of calcium folinate, fluorouracil, irinotecan, and oxaliplatin) with pancreatic cancer (e.g., treatment failure or inapplicability to systemic chemotherapy).

In some embodiments, the subject of pancreatic cancer has been treated with a FOLFIRINOX regimen in combination with a breast cancer susceptible protein (BRCA) mutation targeted treatment regimen (e.g., failed or inapplicable). In some embodiments, the BRCA mutation targeted therapy regimen includes, but is not limited to, PARP inhibitors, such as olapari.

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

In some embodiments, the subject of pancreatic cancer has been treated (e.g., failed or inapplicable) with a FOLFIRINOX regimen in combination with a PD-1/PD-L1 inhibitor treatment regimen.

In some embodiments, the PD-1/PD-L1 inhibitor therapy is an anti-PD-1 antibody, such as nal Wu Liyou mab (Nivolumab), pamil mab (Pembrolizumab), terlipressin Li Shan mab (JS-001), singal Li Shan mab (IBI 308), karellizumab (Camrelizumab), tirelimumab (BGB-a 317), batelimumab (Balstilimab), AK105, jernomumab (GB 226), LZM009, HLX10, AK103 (HX 008), CS1003, SCT-I10A, F520, SG001, or sirolimumab (GLS-010).

In some embodiments, the PD-1/PD-L1 inhibitor therapy is an anti-PD-L1 antibody, such as, for example, atilizumab (Atezolizumab), dulcis You Shan anti (Durvalumab), alikumab (Avelumab), en Wo Lishan anti (KN 035), shu Geli mab (CS 1001), TQB2450, SHR-1316, socazolimab (ZKAB 001), HS636, LP002, JS003, MSB2311, KL-a167, or STI-a1014.

In some embodiments, the subject of pancreatic cancer has been treated with a treatment regimen comprising tegafur (e.g., failed or inapplicable to treatment).

In some embodiments, the subject of pancreatic cancer has been treated (e.g., failed or inapplicable) with a treatment regimen comprising a platinum group (e.g., oxaliplatin and/or cisplatin).

In some embodiments, the subject of pancreatic cancer has been treated with neoadjuvant chemotherapy or adjuvant chemotherapy regimen (e.g., failed or inapplicable).

In some embodiments, the subject of pancreatic cancer has been treated with neoadjuvant chemotherapy or a adjuvant chemotherapy regimen, and disease progression or recurrence occurs during neoadjuvant chemotherapy or adjuvant therapy or within 6 months after the end of therapy.

In some embodiments, the subject of pancreatic cancer has been treated for pancreatic cancer with localized radiation therapy (e.g., failed or inapplicable).

In some embodiments, the subject of pancreatic cancer has been treated with localized radiation therapy, and localized radiation therapy has ended for more than 4 weeks (brain radiation therapy for more than 2 weeks), and the target lesion of the current study is not within the radiation therapy region, or the target lesion is within the radiation therapy region, but progression has been confirmed.

Anti-PD-L1 antibody-TGF-beta RII fusion protein

The anti-PD-L1 antibody-TGF-beta RII fusion protein comprises:

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

(B) Tgfβ binding domains.

In some embodiments, the TGF-beta binding domain is a human TGF-beta RII or TGF-beta binding fragment thereof, e.g., a polypeptide or peptide fragment having an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO. 28, or a fragment of any of the text.

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, HCDR2 shown in SEQ ID NO. 2 or SEQ ID 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, LCDR2 shown in SEQ ID NO. 5 or 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, HCDR2 shown in SEQ ID NO. 13, HCDR3 shown in SEQ ID NO. 14, LCDR1 shown in SEQ ID NO. 15, LCDR2 shown in SEQ ID NO.16, and LCDR3 shown in SEQ ID NO. 17. The CDR sequences described above are provided in table 1 below.

TABLE 1 CDR sequences

In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 7 or SEQ ID NO. 18, and a light chain variable domain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 8 or SEQ ID NO. 19. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising the amino acid sequence set forth in SEQ ID NO. 7 or SEQ ID NO. 18 and a light chain variable domain comprising the amino acid sequence set forth in SEQ ID NO. 8 or 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 set forth in SEQ ID NO. 7 and a light chain variable domain of the amino acid sequence set forth in SEQ ID NO. 8. 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 set forth in SEQ ID NO. 18 and a light chain variable domain of the amino acid sequence set forth in SEQ ID NO. 19.

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 the heavy chain of IgG1, igG2, igG3, and IgG4 or other classes of immunoglobulins, preferably the heavy chain of IgG 1. In some embodiments, the constant region may comprise any of the modifications described herein, such as amino acid insertions, deletions, substitutions, or chemical modifications. In some embodiments, the constant region comprises a mutation that alters effector function, e.g., mutates a lysine residue at the C-terminal end of the antibody constant region to a hydrophobic amino acid, such as alanine or leucine, reducing hydrolytic cleavage by proteases, increasing 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 (allotype), preferably with an amino acid residue of G1m (3) and/or nG1m (1).

In some embodiments, the anti-PD-L1 antibody comprises a heavy chain having an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO 9, SEQ ID NO 20, SEQ ID NO 23, or SEQ ID NO 25, and a light chain having an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO 10 or SEQ ID NO 21. In some embodiments, the anti-PD-L1 antibody comprises a heavy chain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 9 or SEQ ID NO. 23, and a light chain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 10. In other embodiments, the anti-PD-L1 antibody comprises a heavy chain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 20 or SEQ ID NO. 25, and a light chain having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 21.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein further comprises a linking peptide that links the C-terminus of the anti-PD-L1 antibody or antigen binding fragment thereof to the N-terminus of the tgfbeta binding domain; alternatively, the tgfβ binding domain is human tgfβrii or a tgfβ binding fragment thereof. The connecting peptide can adopt flexible connecting peptide or rigid connecting peptide; alternatively, the linker peptide is formed by combining glycine and serine, for example, (G ₄S) _x G wherein x is optionally an integer from 3 to 6, preferably 4 or 5, most preferably 4 (i.e., the amino acid sequence shown in SEQ ID NO: 29)) a linker peptide-free linker may be used.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises an anti-PD-L1 antibody, or antigen-binding fragment thereof, and a tgfbeta binding domain; the antibody or antigen binding fragment thereof may optionally comprise an unmodified or modified constant region, e.g., the C-terminal K of the constant region is mutated to a, or an allotype amino acid substitution; the TGF-beta binding domain comprises a human TGF-beta RII or a fragment or variant thereof capable of binding TGF-beta, such as an extracellular domain of human TGF-beta RII. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) 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% identity to the amino acid sequence shown in SEQ ID NO. 7 and the heavy chain variable domain and amino acid sequence has at least 80%, 81%, 82% identity to the amino acid sequence shown in SEQ ID NO. 8, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical light chain variable domain, or a heavy chain variable domain and 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% identity to the amino acid sequence shown in SEQ ID NO:18 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 light chain variable domain; and (b) a TGF-beta binding domain. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A heavy chain variable domain shown in SEQ ID NO. 7 and a light chain variable domain shown in SEQ ID NO. 8, or a heavy chain variable domain shown in SEQ ID NO. 18 and a light chain variable domain shown in SEQ ID NO. 19; and (b) a TGF-beta binding domain. In some embodiments, the TGF-beta binding domain is human TGF-beta RII or a TGF-beta binding fragment or variant thereof, e.g., a polypeptide or peptide fragment having an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO. 28.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) The heavy chain and 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% identity of the amino acid sequence with the amino acid sequence shown in SEQ ID NO. 9 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 light chain or heavy chain and 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% identity to the amino acid sequence shown in SEQ ID NO. 20 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 light chain; and (b) a TGF-beta binding domain. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) The heavy chain and 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% identity of the amino acid sequence with the amino acid sequence shown in SEQ ID NO. 23 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 light chain, or heavy chain and 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% identity to the amino acid sequence shown in SEQ ID NO. 25 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 light chain; and (b) a TGF-beta binding domain. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A heavy chain shown in SEQ ID NO. 9 and a light chain shown in SEQ ID NO. 10, or a heavy chain shown in SEQ ID NO. 20 and a light chain shown in SEQ ID NO. 21; and (b) a TGF-beta binding domain. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A heavy chain shown in SEQ ID NO. 23 and a light chain shown in SEQ ID NO. 10, or a heavy chain shown in SEQ ID NO. 25 and a light chain shown in SEQ ID NO. 21; and (b) a TGF-beta binding domain. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A heavy chain shown in SEQ ID NO. 25 and a light chain shown in SEQ ID NO. 21; and (b) a TGF-beta binding domain. In some embodiments, the TGF-beta binding domain is human TGF-beta RII or a TGF-beta binding fragment or variant thereof, e.g., a polypeptide or peptide fragment having an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO. 28.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 11, SEQ ID NO. 22, SEQ ID NO. 24 or SEQ ID NO. 26, and (b) a second polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 10 or SEQ ID NO. 21. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 11 or SEQ ID NO. 24, and (b) a second polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 10. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 22 or SEQ ID NO. 26, and (b) a second polypeptide having 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%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO. 21.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having an amino acid sequence as shown in SEQ ID NO. 11 or SEQ ID NO. 24, and (b) a second polypeptide having an amino acid sequence as shown in SEQ ID NO. 10. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having an amino acid sequence as set forth in SEQ ID NO. 22 or SEQ ID NO. 26, and (b) a second polypeptide having an amino acid sequence as set forth in SEQ ID NO. 21.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein comprises: (a) A first polypeptide having an amino acid sequence as set forth in SEQ ID NO. 26, and (b) a second polypeptide having an amino acid sequence as set forth in SEQ ID NO. 21.

In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) The amino acid sequence of the first polypeptide 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 to the amino acid sequence shown in SEQ ID NO. 11, SEQ ID NO. 22, SEQ ID NO. 24 or SEQ ID NO. 26; and (b) the amino acid sequence of the second polypeptide 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 to the amino acid sequence shown in SEQ ID NO. 10 or SEQ ID NO. 21. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) The amino acid sequence of the first polypeptide is shown as SEQ ID NO. 11 or SEQ ID NO. 24; and the amino acid sequence of the second polypeptide is shown as SEQ ID NO. 10. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) The amino acid sequence of the first polypeptide is shown as SEQ ID NO. 22 or SEQ ID NO. 26; and the amino acid sequence of the second polypeptide is shown as SEQ ID NO. 21. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein consists of two identical first polypeptides and two identical second polypeptides, wherein: (a) The amino acid sequence of the first polypeptide is shown as SEQ ID NO. 26; and the amino acid sequence of the second polypeptide is shown as SEQ ID NO. 21. Wherein the amino acid sequence of the first polypeptide is as follows from the N-terminal to the C-terminal: the sequence of an antibody heavy chain variable domain, an antibody heavy chain constant region, a linker peptide, a tgfβ binding fragment of human tgfβrii that recognizes a PD-L1 epitope or antigen.

In other embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein is an anti-PD-L1 antibody-TGF-beta receptor II fusion protein in CN 106103488.

In other embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein is a PD-L1/TGF-beta trap fusion protein in CN 110050000.

In other embodiments, the anti-PD-L1 antibody-TGF-beta RII fusion protein is a Bi-PLB-1 fusion protein of WO 2020006509.

Pharmaceutical composition containing anti-PD-L1 antibody-TGF beta RII fusion protein

In some embodiments, the unit dose of the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is 200-1200mg or other amount of an anti-PD-L1 antibody-tgfbetarii fusion protein, e.g., 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550mg, 600mg, 700mg, 800mg, 900mg, 1000mg, 1100mg, 1200mg or other amount of an anti-PD-L1 antibody-tgfbetarii fusion protein.

In some embodiments, the concentration of the anti-PD-L1 antibody-tgfbetarii fusion protein in the pharmaceutical composition comprising the anti-PD-L1 antibody-tgfbetarii fusion protein is 1mg/mL to 200mg/mL, 2mg/mL to 150mg/mL, 5mg/mL to 100mg/mL, 10mg/mL to 80mg/mL, 10mg/mL to 60mg/mL, or 10mg/mL to 50mg/mL. In some specific embodiments, the concentration of the anti-PD-L1 antibody-TGF-beta RII fusion protein is about 10mg/mL, about 15mg/mL, about 20mg/mL, about 25mg/mL, about 30mg/mL, about 35mg/mL, about 40mg/mL, about 45mg/mL, about 50mg/mL, about 55mg/mL, about 60mg/mL, about 80mg/mL, or about 100mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGF-beta RII fusion protein is about 20mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGF-beta RII fusion protein is about 25mg/mL. In some embodiments, the concentration of the anti-PD-L1 antibody-TGF-beta RII fusion protein is about 40mg/mL. In other embodiments, the concentration of the anti-PD-L1 antibody-TGF-beta RII fusion protein is about 50mg/mL.

In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-TGF-beta RII fusion protein may further comprise one or more physiologically acceptable excipients or carriers to form a suitable formulation. Suitable formulations for use in the present disclosure can be found in Lemmington pharmaceutical sciences, 17 th edition, mark publishing company (Mack PublishingCompany), iston, pa., 1985. In some embodiments, the pharmaceutical composition comprising the anti-PD-L1 antibody-tgfbetarii fusion protein further comprises one or more of a buffer, an isotonicity modifier, a stabilizer, and a surfactant. In some embodiments, the anti-PD-L1 antibody-tgfbetarii fusion protein-containing pharmaceutical composition further comprises a buffer, a stabilizer, and a surfactant.

In a specific embodiment, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a water-soluble injection, including, but not limited to, a water-soluble formulation that has not been lyophilized or a water-soluble formulation that has been reconstituted from a lyophilized powder. In other embodiments, the pharmaceutical composition comprising an anti-PD-L1 antibody-tgfbetarii fusion protein is a lyophilized formulation. The lyophilized preparation refers to a preparation prepared by subjecting an aqueous solution to a lyophilization process in which a 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 is a value that no longer supports biological activity or chemical reaction. The lyophilized formulations of the present disclosure may also be dried by other methods known in the art, such as spray drying and bubble drying (bubble drying).

Gemcitabine

As used in the present disclosure, the gemcitabine has the chemical name 2' -deoxy-2 ',2' -difluorocytidine (β -isomer) having the structural formula (I):

As used in the present disclosure, the gemcitabine includes both its free base form and a pharmaceutically acceptable salt, and such non-salt forms or salts are within the scope of the present disclosure. Gemcitabine may be administered in the form of its free base or in the form of its pharmaceutically acceptable salt. Pharmaceutically acceptable salts of e.g. gemcitabine are within the scope of the present disclosure, which salts may be produced according to methods well known in the art from different organic and inorganic acids, e.g. the inorganic acid may 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 may be the hydrochloride salt of gemcitabine.

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

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

Gemcitabine-containing pharmaceutical composition

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

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

The lyophilized formulation suitable for injection may be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like. In a particular embodiment, the pharmaceutically acceptable carrier of the lyophilized formulation suitable for injection comprises mannitol, sodium acetate, hydrochloric acid, sodium hydroxide.

Albumin taxol

As used in the present disclosure, the albumin paclitaxel is albumin-bound paclitaxel; the chemical name of the taxol is 5 beta, 20-epoxy-1, 2 alpha, 4,7 beta, 10 beta, 13 alpha-hexahydroxytaxane-11-alkene-9-ketone-4, 10-diacetate-2-benzoate-13- (2R, 3S) -N-benzoyl-3-phenylisoserine ester, which has the structural formula (II):

the doses of albumin paclitaxel referred to in the present disclosure are based on the molecular weight of the compound of formula (II), unless otherwise indicated.

Pharmaceutical composition containing albumin paclitaxel

In some embodiments of the present disclosure, the unit dose of the albumin-containing pharmaceutical composition is 100mg of albumin paclitaxel comprising 100mg of paclitaxel and about 900mg of human serum albumin.

In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a formulation including, but not limited to, a formulation suitable for intravenous, oral, parenteral, topical administration. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a formulation suitable for injection. In some embodiments, the gemcitabine-comprising pharmaceutical composition is a liquid formulation. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a liquid formulation suitable for injection. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a liquid formulation suitable for intravenous injection. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a lyophilized formulation. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a lyophilized formulation suitable for injection. In some embodiments, the pharmaceutical composition comprising albumin paclitaxel is a lyophilized formulation suitable for intravenous injection.

In addition, paclitaxel prepared in other formulations is also contemplated within the scope of the present disclosure, such as paclitaxel injection, paclitaxel oral liquid, paclitaxel liposome, and the like.

An Luoti Ni or a pharmaceutically acceptable salt thereof

As used in the present disclosure, the An Luoti ni has the chemical name 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine having the structural formula (III):

As used in the present disclosure, erlotinib may be administered in its free base form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts of An Luoti, for example, are within the scope of this disclosure, which salts may be produced according to methods well known in the art from different organic and inorganic acids, for example, the inorganic acid may be selected from hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, and the organic acid may be selected from succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic or methanesulfonic acid. In some embodiments, the pharmaceutically acceptable salt of An Luoti n may be the hydrochloride salt of An Luoti n (e.g., the dihydrochloride salt of An Luoti n).

In some embodiments of the present disclosure, an Luoti n is administered in the form of its hydrochloride salt. In some embodiments, the administration is in the form of An Luoti nim-hydrochloride. In some embodiments of the present disclosure, the administration is in the form of An Luoti nim dihydrochloride. In some embodiments, the administration is in the crystalline form of An Luoti% of the hydrochloride salt. In a particular embodiment, the pharmaceutical composition is administered in the form of a crystalline form of An Luoti nim dihydrochloride.

Dosages of An Luoti Ni or a pharmaceutically acceptable salt thereof referred to in this disclosure are based on the molecular weight of the compound of formula (III), unless otherwise indicated.

Pharmaceutical composition containing An Luoti Ni or pharmaceutically acceptable salt thereof

In some embodiments of the present disclosure, the unit dose of the pharmaceutical composition comprising An Luoti ni or a pharmaceutically acceptable salt thereof is 6mg, 8mg, 10mg, or 12mg An Luoti ni.

An Luoti Ni or a pharmaceutically acceptable salt thereof is preferably suitable for oral formulations including tablets, capsules, powders, granules, dripping pills, pastes, powders and the like, preferably tablets and capsules. Wherein the tablet can be common tablet, dispersible tablet, effervescent tablet, sustained release tablet, controlled release tablet or enteric-coated tablet, and the capsule can be common capsule, sustained release capsule, controlled release capsule or enteric-coated capsule. The oral formulations may be prepared by conventional methods using pharmaceutically acceptable carriers well known in the art. Pharmaceutically acceptable carriers include fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.

In one embodiment, the pharmaceutical composition comprising An Luoti n or a pharmaceutically acceptable salt thereof is a solid formulation suitable for oral administration. In one embodiment, the pharmaceutical composition comprising An Luoti% or a pharmaceutically acceptable salt thereof may be in the form of a tablet or capsule. In a particular embodiment, the pharmaceutical composition comprising An Luoti% or a pharmaceutically acceptable salt thereof is in the form of a capsule. In a particular embodiment, the pharmaceutically acceptable carrier of the oral solid formulation of An Luoti ni or a pharmaceutically acceptable salt thereof comprises mannitol, microcrystalline cellulose, hydroxypropyl cellulose, magnesium stearate.

Mode of administration

The following is not intended to limit the manner of administration of the pharmaceutical combinations of the present disclosure.

The components of the pharmaceutical combinations of the present disclosure may each be administered independently, or some or all of them together, in a suitable variety of routes, including, but not limited to, oral or parenteral (via intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combinations of the present disclosure may each be administered orally or by injection, e.g., intravenous, subcutaneous, or intraperitoneal, independently, or some or all of them together.

The components of the pharmaceutical combinations of the present disclosure may each independently, or some or all of them together, be in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (e.g., hard, soft, enteric, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal, subcutaneous), granules, emulsions, suspensions, solutions, dispersions, and dosage forms of sustained release formulations for oral or non-oral administration.

The components of the pharmaceutical combinations of the present disclosure may each independently, or some or all of them together contain a pharmaceutically acceptable carrier and/or excipient.

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 effects

Generally, the use of the pharmaceutical combinations of the present disclosure described above will help:

(1) Producing a better therapeutic effect in reducing the growth of or even eliminating the tumor than either drug administered alone in the combination;

(2) Providing a smaller amount of administration compared to either drug administered alone in the combination;

(3) Providing a treatment with good tolerance in the patient with fewer adverse reactions and/or complications than either drug administered alone;

(4) Providing better disease control rate among treated patients;

(5) Providing a longer survival (e.g., median survival, progression free survival, or total survival) in the treated patient;

(6) Providing a longer survival (e.g., median survival, progression free survival, or total survival) for the treated patient compared to standard chemotherapy;

(7) Provide longer duration of disease remission (DOR); and/or

(8) Compared with any one of the medicines singly administered in the combination, the composition has good activity of treating pancreatic cancer and shows more excellent anti-tumor synergistic effect.

Definition and description

The following terms used in this disclosure have the following meanings, unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented in this disclosure, it is intended to refer to their corresponding commercial products or active ingredients thereof.

As used herein, the term "pharmaceutical combination" refers to a combination of two or more active ingredients administered simultaneously or sequentially (either as the respective active ingredients themselves or as derivatives, prodrugs or compositions of their respective pharmaceutically acceptable salts or esters). The active ingredients may each be administered to the subject simultaneously as a single formulation, or sequentially in any order, each as a single formulation.

The term "fixed combination" refers to the simultaneous administration of the active ingredients in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation, to a subject.

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (e.g., pharmaceutical compositions, formulations) to a subject, wherein the administration of the active ingredients to the subject achieves a therapeutically effective amount level. An example of a non-fixed combination is a cocktail therapy, e.g., administration of 3 or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, marketed or administered as a fully independent pharmaceutical composition. The term "non-immobilized combination" also includes the use of "immobilized combinations" between, or in combination with, separate entities of any one or more of the active ingredients.

"TGF-beta RII" or "TGF-beta receptor II" refers to a polypeptide or protein having a wild-type human TGF-beta receptor 2 isoform B sequence, such as the polypeptide shown in SEQ ID NO. 27, or a polypeptide having a sequence that is 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 to the amino acid sequence shown in SEQ ID NO. 27.

"Fragment of TGF-beta binding-fragment" or "TGF-beta binding-fragment" of TGF-beta RII refers to a fragment of TGF-beta RII that has TGF-beta binding activity that is about at least 0.1%, 0.5%, 1%, 5%, 10%, 25%, 35%, 50%, 75%, 90%, 95%, 99% or 100% of the TGF-beta RII sequence. Such fragments are typically soluble fragments, such as the extracellular domain of human TGF-beta RII or variants thereof, non-limiting examples of which include the polypeptides shown in SEQ ID NO. 28.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and antigen binding fragments thereof of the present disclosure may be whole antibodies or any fragment of an antibody. Thus, 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, isolated CDR regions, single chain Fv molecules (scFv) and other antibody fragments known in the art, as well as antibodies that have been subjected to any modification known in the art (e.g., 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 may be of the IgG1, igG2, igG3 or IgG4 isotype. The term "isotype" refers to the type of antibody encoded by the heavy chain constant region gene. The antibodies and antigen binding fragments thereof may be chimeric, humanized or fully human antibodies.

"Chimeric antibody" is the following antibody: the antibodies have at least a portion of a heavy chain variable domain and at least a portion of a light chain variable domain derived from a species; and at least a portion of a constant region derived from another species. For example, in one embodiment, a chimeric antibody may comprise a murine variable domain and a human constant region.

"Humanized antibodies" are the following antibodies: the antibodies contain Complementarity Determining Regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from human antibodies. For example, an anti-PD-L1 antibody may 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 HCDR and LCDR provided herein can be generated using any human framework sequences and are also included in the disclosure. In one embodiment, framework sequences suitable for use in the present disclosure include those framework sequences that are similar in structure to the framework sequences provided herein. Additional modifications may 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 to remove T cell epitopes; or reverting the mutation to a residue in the original germline sequence. In some embodiments, such modifications include those corresponding to the 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 VH and/or VL of a humanized antibody provided herein are back mutated to corresponding amino acids in a parent murine antibody.

"Antigen binding fragment" refers to a fragment that retains 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 any modification of the above fragments known in the art.

"Identity" refers to the similarity between two reference sequences and percent identity refers to the percentage of sequences or designated regions of sequences that are compared by sequence comparison algorithms well known to those skilled in the art.

The term "treating" refers to attempting to alter the natural course of a disease in a treated individual and may be in order 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, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and regression or improved prognosis.

The term "effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of active agent (e.g., fusion protein or compound of the present disclosure) that comprises a "therapeutically effective amount" can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. An effective amount can also be routinely determined by one of ordinary skill in the art based on its own knowledge and 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 of skill in the art.

Routes of administration of fusion proteins (e.g., anti-PD-L1 antibody-tgfbetarii fusion proteins) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

The amount of anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and/or An Luoti ni or a pharmaceutically acceptable salt thereof administered may be determined or adjusted depending on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. For example, in some embodiments, a single dose of gemcitabine may be ：100-3000mg/m ²、500-3000mg/m ²、600-2500mg/m ²、200-2000mg/m ²、800-2000mg/m ²、500-1500mg/m ²、500-1000mg/m ² or 1000-1500mg/m ². In some embodiments, the single dose of gemcitabine may be ：100mg/m ²、200mg/m ²、500mg/m ²、600mg/m ²、750mg/m ²、800mg/m ²、1000mg/m ²、1500mg/m ²、2000mg/m ²、2500mg/m ² or 3000mg/m ². In some embodiments, a single dose of gemcitabine may be 600-4800mg. For another example, in some embodiments, a single dose of albumin paclitaxel may be ：10-500mg/m ²、30-400mg/m ²、30-300mg/m ²、50-300mg/m ²、100-200mg/m ²、50-200mg/m ²、50-150mg/m ² or 75-125mg/m ². In some embodiments, the single dose of albumin paclitaxel may be ：10mg/m ²、30mg/m ²、50mg/m ²、75mg/m ²、100mg/m ²、125mg/m ²、150mg/m ²、175mg/m ²、200mg/m ²、300mg/m ²、400mg/m ² or 500mg/m ². In some embodiments, a single dose of albumin paclitaxel may be 90-300mg. For another example, the daily dose of An Luoti or a pharmaceutically acceptable salt thereof may be 3-30mg, 5-20mg, or 6-12mg. In some embodiments, the daily dose of An Luoti ni, or a pharmaceutically acceptable salt thereof, administered may be 3mg, 4mg, 5mg, 6mg, 8mg, 10mg, or 12mg. Gemcitabine, albumin paclitaxel, calcium folinate, fluorouracil, irinotecan, and/or oxaliplatin may be administered once or more times per week. An Luoti Ni or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, the gemcitabine and albumin paclitaxel are administered once a week in an injectable formulation; preferably, the administration is once a week in an intravenous formulation. In some embodiments, an Luoti ni, or a pharmaceutically acceptable salt thereof, is administered once daily in an oral solid formulation.

The dosing regimen (e.g., dosing cycle, etc.) of the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, calcium folinate, fluorouracil, irinotecan, oxaliplatin, and/or An Luoti ni or a pharmaceutically acceptable salt thereof can be determined or adjusted in combination depending on the activity, toxicity, tolerance of the patient, etc. of the drug. For example, one treatment cycle of an anti-PD-L1 antibody-tgfbetarii fusion protein may 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, the gemcitabine and albumin paclitaxel are administered once a week. In some embodiments, an Luoti ni, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, each of gemcitabine and albumin paclitaxel is administered at intervals, for example, 7 weeks off for 1 week, 3 weeks off for 1 week, 2 weeks off for 2 weeks, or 2 weeks off for 1 week; the intermittent administration mode can be repeated for a plurality of times. In some embodiments, an Luoti or a pharmaceutically acceptable salt thereof is administered at intervals, for example 2 weeks off for 2 weeks, 1 week off for 2 weeks, or 2 days off for 5 days off for 2 days on a continuous basis; the intermittent administration mode can be repeated for a plurality of times. The interval administration includes administration period and withdrawal period, and can be administered once or multiple times daily during administration period. In some embodiments, gemcitabine, albumin paclitaxel, or An Luoti% of its pharmaceutically acceptable salts are administered for 2 weeks, followed by 1 week of discontinuation. In some embodiments, gemcitabine is administered intravenously at a dose of 500mg/m ²、750mg/m ² or 1000mg/m ² gemcitabine once a week for 2 weeks, for 1 week. In some embodiments, the albumin paclitaxel is administered intravenously at a dose of 75mg/m ²、100mg/m ² or 125mg/m ² albumin paclitaxel once a week for 2 weeks, for 1 week. In some embodiments, an Luoti ni, or a pharmaceutically acceptable salt thereof, is orally administered at a dose of 6mg, 8mg, 10mg, or 12mg An Luoti ni once daily for 2 weeks, for 1 week.

The use of the term "flat dose" refers to the dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient. The uniform dose is therefore specified as an absolute amount of agent (e.g., anti-PD-L1 antibody-tgfbetarii fusion protein) rather than as a mg/kg dose. For example, 60kg human and 100kg human will receive the same dose of antibody (e.g., 1800mg anti-PD-L1 antibody-TGF-beta RII fusion protein).

The term "pharmaceutically acceptable" is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salts" includes salts of a base ion with a free acid or salts of a acid ion with a free base, including for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, tartrate, succinate, methanesulfonate, benzoate, benzenesulfonate or p-toluenesulfonate salts, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium, potassium, ammonium, amino acid salts and the like.

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 an acceptable error range for a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" may mean within 1 or more than 1 standard deviation per the practice of the art. Or "about" may mean a range of up to + -5%, e.g., fluctuating within + -2%, within + -1%, or within + -0.5% of a given specific numerical range. When a particular value is given in the disclosure or claims, unless otherwise indicated, the meaning of "about" is to be considered within the acceptable error range for that particular value. In this context, unless otherwise indicated, the values of step parameters or conditions are by default modified by "about".

As used herein, "combined" or "combined" means that two or more active substances can each be administered to a subject simultaneously as a single formulation, or each as a single formulation sequentially in any order.

The term "single dose" refers to the smallest unit of packaging containing a quantity of a drug, e.g., a box of seven capsules, a capsule being a single dose; or one bottle of injection is in single dose. The term "multi-dose" consists of a plurality of single doses.

"Unit dose" refers to the dosage of the active ingredient contained in the smallest packaging unit containing a quantity of pharmaceutical product, e.g., an Luoti Ni contained in a single capsule of An Luoti Ni hydrochloride as a unit dose; or the dosage of the fusion protein contained in a bottle of fusion protein injection is unit dosage; or the dosage of paclitaxel contained in a bottle of albumin paclitaxel lyophilized powder is unit dosage.

The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present disclosure or pharmaceutical combinations 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. The terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably herein.

The term "recurrent" cancer is a cancer that regenerates at an initial site or a distant site after responding to an initial treatment (e.g., surgery). A "locally recurrent" cancer is a cancer that occurs at the same location after treatment as the previously treated cancer.

The term "metastatic" cancer refers to cancer that spreads from one part of the body (e.g., the lungs) to another part of the body.

As used herein, "failure to treat" is defined as the occurrence of disease progression or recurrence during or after the last treatment.

All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purpose 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 or representation as to 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 or contents of these documents. Moreover, any reference to such publications in this document does not constitute an admission that the publications are part of the common general knowledge in the art, in any country.

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

Embodiment 1. A pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel.

Embodiment 2. The pharmaceutical combination according to embodiment 1, wherein the pharmaceutical combination comprises an anti-PD-L1 antibody-TGF-beta RII fusion protein in a unit dose of 200-1200mg, gemcitabine in a unit dose of 0.2g and/or 1.0g, and albumin paclitaxel in a unit dose of 100 mg.

Embodiment 3. The pharmaceutical combination according to embodiment 1 or 2, wherein the mass ratio of the anti-PD-L1 antibody-TGF-beta RII fusion protein to gemcitabine is (0.1-10): 1 and the mass ratio of the anti-PD-L1 antibody-TGF-beta RII fusion protein to albumin paclitaxel is (0.1-30): 1.

Embodiment 4. The pharmaceutical combination according to any one of embodiments 1-3, wherein the pharmaceutical combination is suitable for administration within a single treatment cycle comprising 600-2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein, 1000-2000mg/m ² of gemcitabine, and 150-250mg/m ² of albumin paclitaxel.

Embodiment 5. The pharmaceutical combination according to any one of embodiments 1-4, wherein the anti-PD-L1 antibody-tgfbetarii 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 antigen-binding fragment thereof 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)

(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, LCDR2 of the amino acid sequence shown in SEQ ID NO. 16, and 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) 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; or (b)

(B) 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.

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

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

Embodiment 8. The pharmaceutical combination according to any of embodiments 5-7, wherein the human TGF-beta RII or TGF-beta binding fragment thereof comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID NO. 28.

Embodiment 9. The pharmaceutical combination of any one of embodiments 5-8, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein further comprises a connecting peptide that links the C-terminus of the anti-PD-L1 antibody or antigen-binding fragment thereof to the N-terminus of the human tgfbetarii or tgfbetabinding fragment thereof; preferably, the linker peptide is (G4S) _x G, x is an integer from 3 to 6; preferably, the linker peptide has the amino acid sequence shown in SEQ ID NO. 29.

Embodiment 10. The pharmaceutical combination according to any one of embodiments 5-9, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein comprises:

(a) A first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 11 or SEQ ID NO. 24, and a second polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 10; or (b)

(B) A first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 22 or SEQ ID NO. 26, and a second polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 21.

Embodiment 11. The pharmaceutical combination according to any one of embodiments 1-10, wherein the pharmaceutical combination further comprises An Luoti ni or a pharmaceutically acceptable salt thereof; optionally, the pharmaceutically acceptable salt of An Luoti is a monohydrochloride or dihydrochloride.

Embodiment 12. The pharmaceutical combination according to embodiment 11, wherein the unit dose of An Luoti n or a pharmaceutically acceptable salt thereof is 6mg, 8mg, 10mg and/or 12mg.

Embodiment 13. The pharmaceutical combination according to embodiment 11 or 12, wherein the mass ratio of the anti-PD-L1 antibody-TGF-beta RII fusion protein to An Luoti Ni 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 the pharmaceutical combination is suitable for administration within a single treatment cycle, the dose of An Luoti n or a pharmaceutically acceptable salt thereof being 84-168mg.

Embodiment 15 the pharmaceutical combination according to any one of embodiments 1-14, wherein the pharmaceutical combination is for use in the treatment of pancreatic cancer.

Embodiment 16. Use of the pharmaceutical combination of any of embodiments 1-15 in 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 of any one of embodiments 16-18, wherein the subject of pancreatic cancer has not previously been treated for pancreatic cancer.

Embodiment 20. The use according to any of embodiments 16-18, wherein the subject of pancreatic cancer has previously been treated with one or more different anti-tumor treatment methods.

Embodiment 21 the use according to any one of embodiments 16-20, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine and albumin paclitaxel are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially and/or alternately.

Embodiment 22. The use of any of embodiments 16-20, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, albumin paclitaxel, and An Luoti ni, or a pharmaceutically acceptable salt thereof, are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially, and/or alternately.

Embodiment 23 the use of any one of embodiments 16-22, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 600-2400mg of the anti-PD-L1 antibody-tgfbetarii fusion protein.

Embodiment 24 the use of any one of embodiments 16-23, wherein the gemcitabine is administered in a dosage of 500-1000mg/m ²、500mg/m ²、750mg/m ² or 1000mg/m ² gemcitabine once a week, on a 2 week, off 1 week regimen.

Embodiment 25 the use according to any one of embodiments 16-24, wherein the albumin paclitaxel is administered in a dose of 75-125mg/m ²、75mg/m ²、100mg/m ² or 125mg/m ² albumin paclitaxel once a week, on a 2 week, off 1 week regimen.

Embodiment 26. The use according to any of embodiments 16-20, 22-25, wherein said An Luoti ni or pharmaceutically acceptable salt thereof is administered in a dose of 6-12mg, 6mg, 8mg, 10mg or 12mg An Luoti ni once daily, on a2 week, off 1 week regimen.

Embodiment 27 a kit for treating pancreatic cancer comprising the pharmaceutical combination of any one of embodiments 1-15.

Examples

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

Methods for preparing and purifying anti-PD-L1 antibody-TGF-beta RII fusion proteins of the present disclosure are described in WO2021037184, the entire contents of which WO2021037184 is incorporated into the present disclosure. The anti-PD-L1 antibody-TGF-beta RII fusion protein hu5G11-hIgG 1-TGF-beta RII in the examples is hu5G11-hIgG 1-TGF-beta RII in WO2021037184, said hu5G11-hIgG 1-TGF-beta RII consisting of two identical first polypeptides and two identical second polypeptides, wherein: (1) The amino acid sequence of the first polypeptide is shown as SEQ ID NO. 26, the first polypeptide is a fusion protein which consists of a heavy chain of an anti-human PD-L1 antibody (SEQ ID NO. 25), an extracellular domain amino acid sequence of human TGF-beta RII (SEQ ID NO. 28) and a G ₄S) ₄ G connecting peptide (SEQ ID NO. 29) connecting the heavy chain and the extracellular domain amino acid sequence of human TGF-beta RII (SEQ ID NO. 21), and the amino acid sequence of the second polypeptide is shown as SEQ ID NO. 21.

The amino acid sequence of the hu5G11-hIgG 1-TGF-beta RII first polypeptide (SEQ ID NO: 26):

The amino acid sequence of the hu5G11-hIgG 1-TGF-beta RII second polypeptide (SEQ ID NO: 21):

Example 1: clinical trial of advanced metastatic pancreatic cancer

1. Criteria for inclusion

(1) Subjects voluntarily joined the study and signed informed consent;

(2) Age 18-75 years (time to sign informed consent);

(3) Stage 1, requiring the inclusion of patients who failed prior to at least one line of systemic chemotherapy or who the researcher deems unsuitable for receiving systemic chemotherapy;

stage 2, cohort 1 and cohort 2, require inclusion of primary histologically or cytologically confirmed metastatic pancreatic cancer patients;

cohort 3, stage 2, requires inclusion of metastatic pancreatic cancer patients following first line FOLFIRINOX or folfirinox+brca mutation targeted therapy or failure of PD-1/PD-L1 therapy;

Note that: definition of first line treatment failure: a. disease progression occurs during the course of first-line therapy or after the end of therapy; b. disease progression was within 6 months after neoadjuvant or adjuvant therapy.

(4) Stage 1 requires that there be at least one evaluable lesion as evidenced by RECIST 1.1 criteria; stage 2 requires that there be at least one measurable lesion as demonstrated according to RECIST 1.1 criteria;

(5) ECOG scores 0-1 score, expected lifetime greater than 3 months;

(6) The main organ functions well, meeting the following criteria:

1) Blood routine examination criteria (no blood transfusion, no correction with hematopoietic stimulatory factor type drug within 7 days prior to examination):

a) Hemoglobin (HGB) is more than or equal to 90g/L;

b) The absolute value (NEUT) of the neutrophil is more than or equal to 1.5X10 ⁹/L;

c) Platelet count (PLT) was ≡100× ⁹/L.

2) The biochemical examination needs to meet the following criteria:

a) Total Bilirubin (TBIL) is less than or equal to 1.5 times the upper limit of normal value (ULN) (biliary tract scaffolds are allowed);

b) Alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) are less than or equal to 2.5 XULN. If liver metastasis is accompanied, ALT and AST are less than or equal to 5 XULN;

c) Serum Creatinine (CR) is less than or equal to 1.5 XULN or Creatinine Clearance (CCR) is less than or equal to 60mL/min.

3) The coagulation function is required to meet the following criteria:

International Normalized Ratio (INR) is less than or equal to 1.5 x ULN (anticoagulation treatment not received);

4) Thyroid function examination should meet the following criteria:

Thyroid Stimulating Hormone (TSH) is less than or equal to ULN; if the abnormality should examine the levels of triiodothyronine (T3) and thyroxine (T4), T3 and T4 levels are normal, then inclusion may be made.

5) Heart color Doppler ultrasound evaluation: left Ventricular Ejection Fraction (LVEF) is greater than or equal to 50%.

(7) Patients must take reliable contraceptive measures during the study period and within 6 months after the end of the study period; serum pregnancy/urinary pregnancy tests were negative within 7 days prior to study entry and had to be non-lactating subjects; male subjects should agree that contraceptive measures must be taken during the study period and within 6 months after the end of the study period;

2. Test drug

Hu5G11-hIgG1-TGFβRII injection: specifications were 200mg (4 mL)/bottle and 600mg (12 mL)/bottle;

gemcitabine: specifications of 0.2 g/bottle and 1.0 g/bottle;

albumin paclitaxel: the specification is 100 mg/bottle;

an Luoti Ni capsule of hydrochloric acid: specifications were 6 mg/pellet, 8 mg/pellet, 10 mg/pellet and 12 mg/pellet.

3. Dosing regimen

3.1 Stage 1:

hu5G11-hIgG1-TGFβRII injection: 600mg, 1200mg, 1800mg or 2400mg, is administered by intravenous drip once every 3 weeks for 1 treatment cycle every 3 weeks.

3.2 Phase 2:

queue 1: hu5G11-hIgG 1-tgfbetarii injection + gemcitabine + albumin paclitaxel first line treatment:

hu5G11-hIgG1-TGFβRII injection: 600mg, 1200mg, 1800mg or 2400mg, for intravenous drip, once every 21 days;

Gemcitabine: 1000mg/m ², intravenous drip, once every 7 days, for 2 weeks and 1 week stop;

Albumin paclitaxel: 125mg/m ², intravenous drip, once every 7 days, for 2 weeks and 1 week stop;

order of administration: the hu5G11-hIgG1-TGF beta RII injection, the albumin paclitaxel and the gemcitabine were infused first.

Queue 2: hu5G11-hIgG1-TGFβRII injection+ An Luoti Nib hydrochloride capsule+gemcitabine+albumin paclitaxel first line treatment:

an Luoti Ni capsule of hydrochloric acid: 8mg, orally taken, 1 time daily, for 2 weeks and 1 week stop;

Order of administration: oral administration of An Luoti Ni hydrochloride capsule, infusion of hu5G11-hIgG1-TGF beta RII injection, albumin taxol, and finally gemcitabine.

Queue 3: hu5G11-hIgG 1-tgfbetarii injection + gemcitabine + albumin paclitaxel two-line treatment:

Albumin paclitaxel: 125mg/m ², intravenous infusion, once every 7 days, for 2 weeks and 1 week stop.

Drug delay or dose down-regulation is allowed during the study depending on the subject's situation, but not cross-dose down-regulation: for example, the dose of albumin paclitaxel is adjusted from 125mg/m ² to 100mg/m ², or from 100mg/m ² to 75mg/m ²; the dose of gemcitabine is adjusted from 1000mg/m ² to 750mg/m ², or from 750mg/m ² to 500mg/m ².

4. Evaluation criteria

The disease state is judged by adopting RECIST 1.1 standard as a main rule, and the curative effect is confirmed and supplemented by iRECIST standard.

5. Endpoint index

Objective Remission Rate (ORR) = (complete remission (CR) +partial remission (PR));

disease control rate (dcr=cr+pr+disease Stabilization (SD)), duration of remission (DOR), progression Free Survival (PFS), total survival (OS);

incidence and severity of Adverse Events (AEs);

Immunogenicity, such as the incidence of anti-drug antibodies (ADA) and their titers in a subject, the incidence of neutralizing antibodies (Nab).

And evaluating the relationship between the therapeutic related biomarkers, such as PD-L1 in tumor tissue and the anti-tumor effect of TGF-beta and hu5G11-hIgG1-TGFβRII injection in blood sample.

6. Therapeutic effects

After the subjects with metastatic pancreatic cancer are subjected to first-line treatment by hu5G11-hIgG1-TGF beta RII injection (1200 mg) +gemcitabine+albumin paclitaxel, the clinical curative effect and survival benefit can be remarkably improved, and in 8 subjects diagnosed with metastatic pancreatic cancer, 2 subjects (patient A and patient B) achieve partial remission PR (25%), and tumors of a plurality of subjects in subjects with Stable Disease (SD) are reduced by more than 20%; specific exemplary results are described below.

The subjects with metastatic pancreatic cancer can significantly improve clinical efficacy and survival benefit after first-line treatment by hu5G11-hIgG1-TGF beta RII injection (600 mg-1800 mg) + An Luoti Nicapsule hydrochloride+gemcitabine+albumin paclitaxel, and among 4 subjects diagnosed with metastatic pancreatic cancer (patient C, patient D, patient E and patient F), all subjects achieve Partial Remission (PR); specific exemplary results are described below.

Preliminary results show that hu5G11-hIgG1-TGF beta RII, gemcitabine and albumin paclitaxel are used in combination, and hu5G11-hIgG1-TGF beta RII, gemcitabine, albumin paclitaxel and An Luoti Ni hydrochloride capsules are used in combination, so that metastatic pancreatic cancer can be safely and effectively treated, and the potential advantages of prolonging the progression-free survival FPS and the total survival OS of metastatic pancreatic cancer subjects are achieved.

6.1 Pre-treatment diagnostic results

Patient a:

Metastatic pancreatic cancer: hepatobiliary pancreatic tumors and vascular CTA show that pancreatic cancer at the tail of the pancreas involves splenomegaly with local infarction of the spleen, multiple metastasis of the liver, multiple implantation and metastasis of the peritoneum omentum system membrane, and splenomegaly. Patients were subjected to needle biopsies and pathology revealed that (liver puncture specimens) poorly differentiated cancers metastasized or infiltrated.

Patient B:

Metastatic pancreatic cancer: hepatobiliary pancreatic tumors and vascular CTA (hepatobiliary pancreatic spleen) show that the pancreatic duct expands; expansion of intrahepatic bile duct; retroperitoneal multiple slightly larger lymph nodes; liver S4 takes place, considering metastasis; multiple cysts of liver; the hepatic left artery and the gastric left artery are co-dried; multiple cysts of both kidneys. Performing a needle biopsy on the liver of a patient; immunohistochemistry showed that pancreas (S4 segment of liver puncture specimen) infiltrated or metastasized, suggesting the pancreatic bile duct phenotype.

Patients C-F:

metastatic pancreatic cancer.

6.2 Treatment Effect and evaluation

Patient a:

screening period: target lesions: 81.61mm;

After period 2 dosing: target lesions: 65.16mm;

after period 4 dosing: target lesions: 47.7mm;

according to the efficacy evaluation criteria, the optimal therapeutic effect is PR.

Patient B:

screening period: target lesions: 33.10mm;

after period 2 dosing: target lesions: 17.7mm;

Patient C:

Screening period: target lesions: 90.9mm;

after period 2 dosing: target lesions: 63.1mm;

Patient D:

screening period: target lesions: 66.79mm;

After period 2 dosing: target lesions: 46.2mm;

after period 4 dosing: target lesions: 37.9mm;

Patient E:

Screening period: target lesions: 79.19mm;

After period 2 dosing: target lesions: 39.3mm;

Patient F:

Screening period: target lesions: 53.06mm;

After period 2 dosing: target lesions: 47.9mm;

After period 4 dosing: target lesions: 35.3mm;

Claims

A pharmaceutical combination comprising an anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel; wherein the anti-PD-L1 antibody-tgfbetarii 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 antigen-binding fragment thereof 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, LCDR2 of the amino acid sequence shown in SEQ ID NO. 16, and 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 at least 95% identity in amino acid sequence to the amino acid sequence shown in SEQ ID NO. 20 or SEQ ID NO. 25, and a light chain having at least 95% identity in amino acid sequence to the amino acid sequence shown in SEQ ID NO. 21; or (b)

(F) A heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 23, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 10.
A pharmaceutical combination according to claim 1, wherein the human tgfβrii or tgfβ binding fragment thereof comprises an amino acid sequence having at least 80% identity to the amino acid sequence set forth in SEQ ID No. 28.
The pharmaceutical combination of claim 1 or 2, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein further comprises a linking peptide that links the C-terminus of the anti-PD-L1 antibody or antigen-binding fragment thereof to the N-terminus of the human tgfbetarii or tgfbeta binding fragment thereof; preferably, the linker peptide is (G4S) _x G, x is an integer from 3 to 6; preferably, the linker peptide has the amino acid sequence shown in SEQ ID NO. 29.
A pharmaceutical combination according to any one of claims 1-3, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein comprises:

(a) A first polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 22 or SEQ ID NO. 26, and a second polypeptide having an amino acid sequence at least 95% identical to the amino acid sequence shown in SEQ ID NO. 21; or (b)

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

The subject of pancreatic cancer has previously been treated with one or more different anti-tumor therapies.
The use of any one of claims 10-12, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein, gemcitabine, and albumin paclitaxel are each in the form of a pharmaceutical composition for simultaneous, sequential, and/or alternate administration; or (b)

The anti-PD-L1 antibody-TGF-beta RII fusion protein, gemcitabine, albumin paclitaxel, and An Luoti n or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition that may be administered simultaneously, sequentially, and/or alternately.
The use of any one of claims 10-13, wherein the anti-PD-L1 antibody-tgfbetarii fusion protein is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each at a dose of 600-2400mg of anti-PD-L1 antibody-tgfbetarii fusion protein;

Optionally, the gemcitabine is administered in a dosage of 500-1000mg/m ²、500mg/m ²、750mg/m ² or 1000mg/m ² gemcitabine once a week, on a 2 week, 1 week stop regimen;

Optionally, the albumin paclitaxel is administered in a dose of 75-125mg/m ²、75mg/m ²、100mg/m ² or 125mg/m ² albumin paclitaxel once a week, on a 2 week, 1 week stop regimen;

optionally, the An Luoti-or pharmaceutically acceptable salt thereof is administered in a dose of 6-12mg, 6mg, 8mg, 10mg, or 12mg An Luoti-of-one-day, on a continuous 2-week, 1-week-stop dosing regimen.
A kit for treating pancreatic cancer comprising the pharmaceutical combination of any one of claims 1-9.