CN118267469A

CN118267469A - Combined pharmaceutical composition for treating driving gene positive lung cancer

Info

Publication number: CN118267469A
Application number: CN202410318299.9A
Authority: CN
Inventors: 于浩; 潘茂琼
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Nanjing Shunxin Pharmaceutical Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd; Nanjing Shunxin Pharmaceutical Co Ltd
Priority date: 2019-06-10
Filing date: 2020-06-10
Publication date: 2024-07-02

Abstract

A combination pharmaceutical composition for treating driving gene positive lung cancer, comprising an anti-PD-L1 antibody and An Luoti n, which has good anti-driving gene positive lung cancer activity.

Description

Combined pharmaceutical composition for treating driving gene positive lung cancer

The application relates to a combined drug composition for treating driving gene positive lung cancer, which is a divisional application of an application patent application with the application number 202080039208.8, wherein the application date is 6/10/2020.

Technical Field

The application belongs to the field of biological medicine, and relates to a combined medicine composition for treating driving gene positive lung cancer.

Background

Tyrosine kinases 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, signaling and development of normal cells, and are also closely related to proliferation, differentiation, migration and apoptosis of tumor cells. Many receptor tyrosine kinases 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), etc. according to the structure of their extracellular regions.

PD-L1 (Programmed deth-ligand), also known as CD247 and B7-H1, is a ligand for Programmed death molecule 1 (PD-1). PD-L1 is highly expressed on the surfaces of various tumor cells, and the malignancy of tumors and poor prognosis are closely related to the expression level of PD-L1. In the tumor microenvironment, the PD-L1 on the surface of the cancer cells inhibits the activation and proliferation of 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 related negative regulation signals from being started and conducted by blocking the interaction of PD-L1, PD-1 and CD80, so that the activity of effector T cells in a tumor microenvironment is prevented from being inhibited, and the T cells can play a role in killing and inhibiting tumor cells. The anti-PD-L1 antibody can directly act on tumor tissues, so that the anti-PD-L1 antibody has higher specificity and safety.

Cancer is a major public health problem in many parts of the world. Among them, lung cancer has high morbidity and mortality, and is a major cause of cancer death worldwide. In 2012, approximately 180 ten thousand people worldwide are new to develop lung cancer, and 160 ten thousand people die. Lung cancer is a common cause of cancer death in men, and is second only to breast cancer in women, second to the list. The lung cancer driving genes mainly comprise an Epidermal Growth Factor Receptor (EGFR), an Anaplastic Lymphoma Kinase (ALK), a c-ROS protooncogene 1 receptor tyrosine kinase (ROS 1), a MET gene receptor tyrosine kinase (MET), a human epidermal growth factor receptor 2 (HER-2) and the like. Despite the great progress made at present in targeted therapies for driver genes, there are a number of problems. Therefore, there is a need to develop other therapeutic modalities besides targeted therapy, chemotherapy, in order to further enhance the therapeutic effect and improve the prognosis of patients.

WO2016022630 discloses a PD-L1 antibody which has higher affinity to PD-L1, can remarkably inhibit interaction between PD-L1 and PD-1 on the cell surface, and remarkably promote T cells to secrete IL-2 and INF-gamma.

Despite the many therapeutic options available for patients with proliferative diseases (cancers), there is still a need for more effective therapeutic agents for clinical use, especially in combination with more than one drug.

Summary of The Invention

In one aspect, the application provides a combination pharmaceutical composition for treating driving gene positive lung cancer comprising an anti-PD-L1 antibody and An Luoti ni.

Further, an Luoti ni is in the free base form, or in the form of a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt of An Luoti n may be the hydrochloride or dihydrochloride salt.

Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12. Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; A light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO 9 or SEQ ID NO 12. Still further, the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 2, a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 3; And a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 9. Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16. Still further, the anti-PD-L1 antibody comprises: a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies.

Furthermore, the combined pharmaceutical composition is packaged in the same kit, and the kit further comprises instructions for combined use of the PD-L1 antibody and An Luoti Ni for treating driving gene positive lung cancer.

Further, the application provides a combination pharmaceutical composition which comprises a pharmaceutical composition containing 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition with single dose of 6mg, 8mg, 10mg and/or 12mg An Luoti n. Wherein the pharmaceutical composition containing the anti-PD-L1 antibody is in single dose or multiple doses.

Further, the present application provides a combination pharmaceutical composition comprising a pharmaceutical composition comprising 600 to 2400mg of an anti-PD-L1 antibody provided in a multi-dose form and a single dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni of the pharmaceutical composition.

Further, the present application provides a combination pharmaceutical composition which is a formulation suitable for administration over a single treatment cycle (e.g., one treatment cycle of 21 days), including a pharmaceutical composition comprising 600 to 2400mg of an anti-PD-L1 antibody and a pharmaceutical composition comprising 84 to 168mg An Luoti ni.

Further, the present application provides a combination pharmaceutical composition comprising (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1, by weight, anti-PD-L1 antibody and An Luoti ni. Wherein the anti-PD-L1 antibody and An Luoti are packaged separately or together. And wherein An Luoti ni can be packaged in multiple aliquots (e.g., 2, 7, 14, 28, or more aliquots); anti-PD-L1 antibodies can be packaged in single aliquots or multiple aliquots (e.g., 2 aliquots, 4 aliquots, or more).

In another aspect, the application also provides the use of the combination pharmaceutical composition herein in the manufacture of a medicament for the treatment of driving gene positive lung cancer. Alternatively, the application also provides a method of treating driving gene positive lung cancer comprising administering to a subject an effective amount of a combination pharmaceutical composition of the application. The application also provides application of the combined pharmaceutical composition in treating driving gene positive lung cancer. The combination pharmaceutical composition comprises an anti-PD-L1 antibody and An Luoti Ni.

On the other hand, the application also provides application of the anti-PD-L1 antibody and An Luoti Ni in preparing medicaments for treating driving gene positive lung cancer. Alternatively, the application also provides a method of treating driving gene positive lung cancer comprising administering to a subject an effective amount of an anti-PD-L1 antibody and An Luoti n. The application also provides the use of the anti-PD-L1 antibody and An Luoti in combination therapy to drive gene-positive lung cancer. Or the application also provides a combination of an anti-PD-L1 antibody and An Luoti n for use in the treatment of driving gene positive lung cancer.

Further, the anti-PD-L1 antibody and An Luoti n are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially or at intervals. Still further, the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600 to 2400mg each time. Still further, an Luoti times daily at a dose of 6mg, 8mg, 10mg, or 12mg was administered for 2 weeks continuously, with a 1 week regimen.

In addition, the application provides kits for treating driver-positive lung cancer comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni, and instructions for using the anti-PD-L1 antibody in combination with An Luoti ni to treat driver-positive lung cancer.

Further, the above kit is a kit suitable for administration in a single treatment cycle (e.g., one treatment cycle of 21 days), including a pharmaceutical composition containing 600 to 2400mg of an anti-PD-L1 antibody and a pharmaceutical composition containing 84 to 168mg An Luoti ni.

Detailed Description

In some embodiments of the application, the combination pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni.

In some embodiments of the application, the combination pharmaceutical composition is packaged in the same kit, which further comprises instructions for the combined use of the PD-L1 antibody and An Luoti ni for the treatment of driving gene positive lung cancer.

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a single dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni of the pharmaceutical composition. Wherein the pharmaceutical composition containing the anti-PD-L1 antibody is in single dose or multiple doses.

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided, comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody provided in a multi-dose form and a single dose of 6mg, 8mg, 10mg, and/or 12mg An Luoti ni of the pharmaceutical composition.

In some embodiments, a combination pharmaceutical composition for treating driver gene positive lung cancer is provided that includes anti-PD-L1 antibodies and An Luoti Ni in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1. Wherein the anti-PD-L1 antibody and An Luoti are packaged separately or together. And wherein An Luoti ni can be packaged in multiple aliquots (e.g., 2, 7, 14, 28, or more aliquots).

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni, wherein the pharmaceutical composition of the anti-PD-L1 antibody is prepared to be suitable for administration to a patient at the first time of administration of a single dose or multiple doses of 600-2400 mg of the anti-PD-L1 antibody, and the pharmaceutical composition of An Luoti ni is prepared to be suitable for administration to a patient for 14 consecutive days, daily of a single dose of 6mg, 8mg, 10mg, and/or 12mg An Luoti ni.

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided comprising a pharmaceutical composition of an anti-PD-L1 antibody at an anti-PD-L1 antibody concentration of 10-60mg/mL and a single dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni of the pharmaceutical composition.

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided comprising a pharmaceutical composition of an anti-PD-L1 antibody at an anti-PD-L1 antibody concentration of 10mg/mL and a single dose of 8mg and/or 10mg and/or 12mg An Luoti ni of the pharmaceutical composition.

In some embodiments, a combination pharmaceutical composition for treating driving gene positive lung cancer is provided comprising a pharmaceutical composition comprising 1200mg of an anti-PD-L1 antibody provided in a multi-dose form and a single dose of 8mg and/or 10mg and/or 12mg An Luoti ni.

In another aspect, the application also provides the use of the combination pharmaceutical composition in the manufacture of a medicament for the treatment of driving gene positive lung cancer. The application also provides a method of treating driving gene positive lung cancer comprising administering to a subject an effective amount of the combination pharmaceutical composition of the application. The application also provides the use of the combination pharmaceutical composition for treating driving gene positive lung cancer. In some embodiments, the combination pharmaceutical composition comprises an anti-PD-L1 humanized monoclonal antibody and An Luoti ni.

On the other hand, the application also provides application of the anti-PD-L1 antibody and An Luoti Ni in preparing medicaments for treating driving gene positive lung cancer. The application also provides a method of treating driving gene positive lung cancer comprising administering to a subject an effective amount of an anti-PD-L1 antibody and An Luoti n. The application also provides the use of the anti-PD-L1 antibody and An Luoti in combination therapy to drive gene-positive lung cancer. The application also provides a combination of an anti-PD-L1 antibody and An Luoti n for use in the treatment of driving gene positive lung cancer.

In yet another aspect, the application provides a kit for treating driver-positive lung cancer, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni, and instructions for using the anti-PD-L1 antibody in combination with An Luoti ni to treat driver-positive lung cancer.

In yet another aspect, the application also provides an anti-PD-L1 antibody for use in the treatment of driving gene positive lung cancer. The application also provides a method of treating driving gene positive lung cancer comprising administering to a subject an effective amount of an anti-PD-L1 antibody of the application. The application also provides the use of an anti-PD-L1 antibody for the treatment of driving gene positive lung cancer. The application also provides application of the anti-PD-L1 antibody in preparing a medicament for treating driving gene positive lung cancer.

Administration/treatment regimen for combination pharmaceutical compositions

In one aspect, the invention provides a combination pharmaceutical composition comprising an anti-PD-L1 antibody and An Luoti n.

In some embodiments of the application, the anti-PD-L1 antibody and An Luoti n are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially or at intervals.

In some embodiments of the application, the anti-PD-L1 antibody and An Luoti n are each administered as a separate administration in the above uses or methods of treatment. In some embodiments the antibody and An Luoti n are administered separately on the same or different dosing regimens. In some embodiments, the administration is performed separately in different dosing regimens.

In some embodiments of the application, the anti-PD-L1 antibody may be 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 a specific embodiment, the anti-PD-L1 antibody is administered once every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per time.

The An Luoti% can be administered in a dose of 6mg, 8mg, 10mg, or 12mg once daily, for 2 weeks, with a dosing regimen of 1 week down.

In some embodiments, the anti-PD-L1 antibody and An Luoti n each have the same or different treatment cycles. In some specific embodiments, the anti-PD-L1 antibody and An Luoti n 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 of the application, the use or method of treatment is one treatment cycle for 21 days, PD-L1 antibody is administered on the first day of each cycle, and An Luoti ni is administered daily on days 1-14 of each cycle. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle and An Luoti n is administered once daily on days 1-14 of each cycle.

In some embodiments of the application, the use or method of treatment, wherein the anti-PD-L1 antibody may comprise administration to the subject of a dose selected from 0.01 to 40mg/kg,0.1 to 30mg/kg,0.1 to 20mg/kg,0.1 to 15mg/kg,0.1 to 10mg/kg,1 to 15mg/kg,1 to 20mg/kg,1 to 3mg/kg,3 to 10mg/kg,3 to 15mg/kg,3 to 20mg/kg,3 to 30mg/kg,10 to 20mg/kg, or 15 to 20 mg/kg; or from 60mg to 2400mg,90mg to about 1500mg, 120mg to 1500mg,300mg to 900mg,600mg to 900mg,300mg to 1200mg, or 900mg to 1200 mg.

In some embodiments of the use or method of treatment, 21 days is a treatment cycle, 1200mg of PD-L1 antibody is administered on the first day of each cycle, and 6mg, 8mg, 10mg and/or 12mg An Luoti mg per day on days 1-14 of each cycle.

In some embodiments of the application, the anti-PD-L1 antibody and An Luoti ni are administered to the subject in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1, in one treatment cycle every three weeks, wherein the anti-PD-L1 antibody and An Luoti ni are administered in a single dose and multiple dose, respectively.

Pharmaceutical composition of anti-PD-L1 antibody

In some embodiments of the application, a single dose of the pharmaceutical composition of the anti-PD-L1 antibody comprises 300mg or 600mg of the anti-PD-L1 antibody.

In some embodiments of the application, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody is 600-2400 mg. In some embodiments, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody comprises a range selected from 600mg, 900mg, 1200mg, 1500mg, 1800mg, 2100mg, 2400mg, or any of the above. In some embodiments, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody is preferably 600-2100 mg, or 900-1500 mg.

In some embodiments of the application, the pharmaceutical composition of the anti-PD-L1 antibody comprises one or more of a buffer, an isotonicity adjusting agent, a stabilizer, and/or a surfactant. In particular, the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150mg/mL of the anti-PD-L1 antibody (e.g., monoclonal antibody), 3-50mM buffer, 2-150mg/mL of an isotonicity modifier/stabilizer, and 0.01-0.8mg/mL of a surfactant, and has a pH of about 4.5-6.8.

In some embodiments of the application, the pharmaceutical composition of the anti-PD-L1 antibody has an anti-PD-L1 mab concentration of about 5-150mg/mL, calculated as w/v; preferably about 10-60mg/mL; more preferably about 10-30mg/mL. In some embodiments, the anti-PD-L1 mab is present in a mass volume concentration of about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, or about 120mg/mL, preferably about 10mg/mL, about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, or about 60mg/mL, more preferably about 10mg/mL, about 20mg/mL, or about 30mg/mL. In some embodiments, the anti-PD-L1 mab mass volume concentration is about 10mg/mL. In other embodiments, the anti-PD-L1 mab is about 30mg/mL in mass volume concentration. In other embodiments, the anti-PD-L1 mab is about 60mg/mL in mass volume concentration.

In some embodiments of the application, the buffer is a histidine salt buffer. The histidine salt buffer concentration is about 5-30mM, preferably about 10-25mM, more preferably about 10-20mM, and most preferably about 10-15mM. In some embodiments, the histidine salt buffer concentration is about 5mM, about 10mM, about 15mM, about 20mM, about 25mM or about 30mM. In some embodiments, the histidine salt buffer concentration is about 10mM. In other embodiments, the histidine salt buffer concentration is about 15mM. In other embodiments, the histidine salt buffer concentration is about 20mM. Wherein the histidine salt buffer comprises histidine and hydrochloric acid.

In some embodiments of the application, the isotonicity modifier/stabilizer is from about 20 to 150mg/mL sucrose, preferably from about 40 to 100mg/mL sucrose, more preferably from about 60 to 80mg/mL sucrose, calculated as w/v. In some embodiments, the sucrose is at a concentration of about 40mg/mL, 50mg/mL, 60mg/mL, 70mg/mL, 80mg/mL, 90mg/mL, or 100mg/mL. In some embodiments, the sucrose is at a concentration of about 60mg/mL. In some embodiments, the sucrose is at a concentration of about 70mg/mL. In some embodiments, the sucrose is at a concentration of about 80mg/mL. In some embodiments, the sucrose is at a concentration of about 90mg/mL.

In some embodiments of the application, the surfactant is selected from polysorbate 80, polysorbate 20, poloxamer 188; preferably polysorbate 80 or polysorbate 20; more preferably polysorbate 80. In some embodiments, the surfactant is present at a concentration of about 0.05 to about 0.6mg/mL, preferably about 0.1 to about 0.4mg/mL, and more preferably about 0.2 to about 0.3mg/mL, calculated as w/v.

In some embodiments of the application, the surfactant is about 0.01 to 0.8mg/mL of polysorbate 80 or polysorbate 20 calculated as w/v. In some embodiments, the surfactant is about 0.05 to about 0.6mg/mL polysorbate 80, preferably about 0.1 to about 0.4mg/mL polysorbate 80, more preferably about 0.2 to about 0.3mg/mL polysorbate 80, and most preferably about 0.2mg/mL polysorbate 80. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1mg/mL, 0.2mg/mL, 0.3mg/mL, 0.4mg/mL, 0.5mg/mL, or 0.6mg/mL; preferably, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/mL, 0.3mg/mL, 0.4mg/mL or 0.5mg/mL; more preferably, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/mL, 0.3mg/mL or 0.4mg/mL; optimally, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.2mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.3mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.4mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.5mg/mL.

In some embodiments of the application, the aqueous solution of the pharmaceutical composition has a pH value selected from 4.0-6.8; preferably 4.5 to 6.5; more preferably 5.5 to 6.0; most preferably 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 4.5, about 4.8, about 5.0, about 5.2, about 5.4, about 5.5, about 5.6, about 5.8, or about 6.0, preferably about 5.0, about 5.2, about 5.4, about 5.5, or about 5.6, more preferably about 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.0. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.2. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.4. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.5. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.6. In some embodiments, the aqueous pharmaceutical composition has a pH of about 5.8. In some embodiments, the aqueous pharmaceutical composition has a pH of about 6.0.

In some embodiments of the application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 20mg/mL, (b) sucrose at a mass-volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.1mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.0. In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 mab at a mass volume concentration of about 20mg/mL, (b) sucrose at a mass volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.1mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.0.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 10mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 50mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.3mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 100mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.5mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 30mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 60mg/mL, (b) sucrose at a mass-volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 10mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass-volume concentration of about 10mg/mL, (b) sucrose at a mass-volume concentration of about 70mg/mL, (c) polysorbate 80 at a mass-volume concentration of about 0.4mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, an appropriate amount of acetic acid, and adjusting the pH of the composition to about 6.5.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 mab at a mass volume concentration of about 10mg/mL, (b) sucrose at a mass volume concentration of about 80mg/mL, (c) polysorbate 80 at a mass volume concentration of about 0.2mg/mL, (d) histidine at a molar concentration of about 20mM, (e) optionally, an appropriate amount of hydrochloric acid, and adjusting the pH of the composition to about 5.5.

In another embodiment of the application, the pharmaceutical composition 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 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 formulation of the present application may also be dried by other methods known in the art, such as spray drying and bubble drying (bubble drying).

An Luoti Nib pharmaceutical composition

In some embodiments of the application, the single dose of An Luoti n pharmaceutical composition comprises 6mg, 8mg, 10mg, or 12mg of An Luoti n.

In some embodiments of the application, the total dose of An Luoti-Ni pharmaceutical composition administered per cycle comprises 84-168 mg, following a treatment cycle of 2 weeks of administration for 1 week. In some embodiments, the total dose of the An Luoti-Ni pharmaceutical composition includes a range selected from 84mg, 112mg, 140mg, 168mg, or any of the values set forth above. In some embodiments, the total dose of An Luoti% pharmaceutical composition preferably comprises 112mg to 168mg.

Anti-PD-L1 antibodies

In some embodiments of the application, the anti-PD-L1 antibody is an antibody in WO2016022630 or CN107001463 a.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 1 or SEQ ID No. 4; a heavy chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 2 or SEQ ID No. 5; a heavy chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 3 or SEQ ID No. 6; a light chain CDR1 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 7 or SEQ ID No. 10; a light chain CDR2 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID No. 8 or SEQ ID No. 11; a light chain CDR3 region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence set forth in SEQ ID No. 9 or SEQ ID No. 12.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO 9 or SEQ ID NO 12.

In some embodiments of the application, an isolated anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 2, a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 3; and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 9.

Each CDR region described herein and the various variants thereof described above are capable of specifically recognizing and binding to PD-L1, thereby effectively blocking signaling between PD-L1 and PD-1.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO. 13; the light chain variable region as shown in SEQ ID NO. 15.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO. 14; the light chain variable region as shown in SEQ ID NO. 16.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 17; the light chain amino acid sequence is shown as SEQ ID NO. 18.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 19; the light chain amino acid sequence is shown as SEQ ID NO. 20.

In some embodiments of the application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO. 21; the light chain amino acid sequence is shown as SEQ ID NO. 18.

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibodies provided herein comprise conservative substitution variants selected from one or more of SEQ ID NO:1、SEQ ID NO:2、SEQ ID NO:3、SEQ ID NO:4、SEQ ID NO:5、SEQ ID NO:6、SEQ ID NO:7、SEQ ID NO:8、SEQ ID NO:9、SEQ ID NO:10、SEQ ID NO:11、SEQ ID NO:12、SEQ ID NO:13、SEQ ID NO:14、SEQ ID NO:15、SEQ ID NO:16、SEQ ID NO.17、SEQ ID NO.18、SEQ ID NO.19、SEQ ID NO.20、SEQ ID NO.21. anti-PD-L1 humanized monoclonal antibodies comprising the conservative substitution variants retain the ability to specifically recognize and bind PD-L1.

In some embodiments of the application, the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.

In some embodiments of the application, the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.

In some embodiments of the application, the anti-PD-L1 antibody comprises a heavy chain Complementarity Determining Region (CDR) selected from the group consisting of a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from the group consisting of a 13C5 or 5G11 antibody. In one embodiment, the anti-PD-L1 antibodies of the application comprise a variable heavy chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, a ch13C5-hIgG4 chimeric antibody, and a variable light chain selected from the group consisting of a ch5G11-hIgG1, a ch5G11-hIgG4, a ch13C5-hIgG1, a ch13C5-hIgG4 chimeric antibody. In one embodiment, the anti-PD-L1 antibodies of the application comprise a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies. Reference may be made to the description of patent documents WO2016022630 or CN107001463 a: the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1, or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5), the HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12); 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 has an HCDR1 sequence of TYGVH (SEQ ID NO: 1), an HCDR2 sequence of VIWRGVTTDYNAAFMS (SEQ ID NO: 2), an HCDR3 sequence of LGFYAMDY (SEQ ID NO: 3), an LCDR1 sequence of KASQSVSNDVA (SEQ ID NO: 7), an LCDR2 sequence of YAANRYT (SEQ ID NO: 8), and an LCDR3 sequence of QQDYTSPYT (SEQ ID NO: 9).

In some embodiments of the application, the anti-PD-L1 antibodies in the pharmaceutical combination may be selected from one or more. As used herein, the term "plurality" may be more than one, for example, two, three, four, five or more. For example, in some embodiments of the application, the anti-PD-L1 antibody is selected from the group consisting of a heavy chain variable region as set forth in SEQ ID NO. 13 and a light chain variable region as set forth in SEQ ID NO. 15, or from the group consisting of a heavy chain variable region as set forth in SEQ ID NO. 14 and a light chain variable region as set forth in SEQ ID NO. 16, or from a combination of the foregoing. For another example, the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence set forth in SEQ ID NO. 17 and the light chain amino acid sequence set forth in SEQ ID NO. 18, or from the heavy chain amino acid sequence set forth in SEQ ID NO. 19 and the light chain amino acid sequence set forth in SEQ ID NO. 20, or from the heavy chain amino acid sequence set forth in SEQ ID NO. 21 and the light chain amino acid sequence set forth in SEQ ID NO. 18, or from a combination of any of the foregoing.

An Luoti Ni

As used herein, the chemical name of the An Luoti ni free base is 1- [ [ [4- (4-fluoro-2-methyl-1H-indol-5-yl) oxy-6-methoxyquinolin-7-yl ] oxy ] methyl ] cyclopropylamine, which has the structural formula:

As used herein, an Luoti n includes both its non-salt form (e.g., free base) and its pharmaceutically acceptable salt, both of which are included within the scope of the present application. For example, the pharmaceutically acceptable salt of An Luoti n may be the hydrochloride or dihydrochloride salt. The dosages of An Luoti Ni or salts thereof referred to in this application are based on the molecular weight of An Luoti Ni free base unless otherwise indicated.

Driving gene positive lung cancer

In some embodiments of the application, the driver-positive lung cancer is selected from driver-positive non-small cell lung cancer. In some embodiments, the driver-positive non-small cell lung cancer comprises lung squamous carcinoma or lung adenocarcinoma. In some embodiments, the driver gene positive non-small cell lung cancer is non-squamous non-small cell lung cancer. In some embodiments, the driver gene positive non-small cell lung cancer is advanced and/or metastatic lung cancer.

In some embodiments, the driver-positive lung cancer includes, but is not limited to, lung cancer that is an EGFR mutation (e.g., EGFR-T790M), an ALK mutation, an ROS1 mutation, a KRAS mutation, a MET mutation, a HER-2 mutation, a BRAF mutation, a KIF5B mutation, a RET mutation, or any two or more thereof.

In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that failed therapy with at least one platinum group drug.

In some embodiments, the driver gene positive lung cancer is lung cancer that failed therapy with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver gene positive lung cancer is lung cancer that failed therapy with a platinum-based drug and one other chemotherapeutic drug.

In some embodiments, the driver gene positive lung cancer is lung cancer that has previously failed treatment with one or more kinase inhibitors.

In some embodiments, the driver-positive lung cancer is lung cancer that failed treatment with a platinum-based drug and at least one other chemotherapeutic drug, including, but not limited to, one or more of EGFR mutation, ALK mutation, ROS1 mutation, KRAS mutation, MET mutation, HER-2 mutation, BRAF mutation, KIF5B mutation, RET mutation, NTRK fusion mutation.

In some embodiments, the driver-positive lung cancer is lung cancer that failed treatment with one or more kinase inhibitors, including, but not limited to, one or more of EGFR mutations, ALK mutations, ROS1 mutations, KRAS mutations, MET mutations, HER-2 mutations, BRAF mutations, KIF5B mutations, RET mutations.

In some embodiments, the driver-positive lung cancer is lung cancer that failed prior treatment with a platinum-based drug, at least one other chemotherapeutic drug, and one or more kinase inhibitors, wherein driver-positive includes, but is not limited to, one or more of an EGFR mutation, an ALK mutation, a ROS1 mutation, a KRAS mutation, a MET mutation, a HER-2 mutation, a BRAF mutation, a KIF5B mutation, a RET mutation.

In some embodiments, the driver gene positive lung cancer is non-small cell lung cancer that has previously undergone EGFR gene mutation that failed treatment with at least one EGFR inhibitor; in some embodiments, the driver gene positive lung cancer is non-small cell lung cancer that has previously undergone EGFR gene mutation that has failed treatment with at least one EGFR-TKI inhibitor (EGFR tyrosine kinase inhibitor); in some embodiments, the driver gene positive lung cancer is non-small cell lung cancer that has previously received an EGFR gene mutation that failed treatment with at least one EGFR inhibitor and at least one chemotherapeutic agent; in some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received an EGFR gene mutation that failed treatment with at least one EGFR inhibitor and at least one platinum-based drug. In some embodiments, the driver-positive lung cancer is EGFR-mutated, non-small cell lung cancer that has previously received a platinum-group drug and at least one other chemotherapeutic drug, and one or more EGFR tyrosine kinase inhibitors.

In some embodiments, the driver-positive lung cancer is EGFR-T790M mutated non-small cell lung cancer that has previously received a platinum-based drug, at least one other chemotherapeutic drug, and one or more EGFR-T790M tyrosine kinase inhibitor treatment failures.

In some embodiments, the driver gene positive lung cancer is ALK mutated non-small cell lung cancer that has previously received failure to be treated with at least one ALK inhibitor; in some embodiments, the driver gene positive lung cancer is ALK mutated non-small cell lung cancer that has previously received failure to be treated with at least one ALK inhibitor; in some embodiments, the driver gene positive lung cancer is non-small cell lung cancer that has previously received an ALK mutation that failed treatment with at least one ALK inhibitor and at least one chemotherapeutic agent; in some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received ALK mutations that failed treatment with at least one ALK inhibitor and at least one platinum-based drug. In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a platinum-based drug and at least one other chemotherapeutic drug, and at least one ALK inhibitor to treat an ALK mutation that failed.

In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a platinum-group drug and at least one other chemotherapeutic drug, and two or more ALK inhibitors, including crizotinib, failed to treat the ALK mutant.

In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously undergone ROS1 mutation that failed treatment with at least one ROS1 inhibitor; in some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously undergone ROS1 mutation that failed treatment with at least one ROS1 inhibitor; in some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received at least one ROS1 inhibitor and at least one ROS1 mutation that failed treatment with a chemotherapeutic; in some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received ROS1 mutations that failed treatment with at least one ROS1 inhibitor and at least one platinum-based drug. In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a platinum-based drug and at least one other chemotherapeutic drug, and one or more ROS1 inhibitors to treat failed ROS1 mutations.

In some embodiments, the driver-positive lung cancer is KRAS mutated non-small cell lung cancer that has previously received treatment with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver-positive lung cancer is a KRAS mutated non-small cell lung cancer that has previously received a platinum-based drug and at least one other chemotherapeutic drug, and one or more KRAS inhibitors to treat failure.

In some embodiments, the driver-positive lung cancer is MET-mutated non-small cell lung cancer that has previously received treatment with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver-positive lung cancer is MET-mutated non-small cell lung cancer that has previously received treatment with a platinum-based drug and at least one other chemotherapeutic drug, and one or more c-MET inhibitors.

In some embodiments, the driver-positive lung cancer is HER-2 mutated, non-small cell lung cancer that has previously received treatment with a platinum-based agent and at least one other chemotherapeutic agent. In some embodiments, the driver-positive lung cancer is HER-2 mutated non-small cell lung cancer that has previously received a platinum-based drug and at least one other chemotherapeutic drug, and one or more HER-2 inhibitors.

In some embodiments, the driver-positive lung cancer is BRAF mutated non-small cell lung cancer that has previously received treatment with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a BRAF mutation that has been treated with a platinum-based agent and at least one other chemotherapeutic agent, and one or more BRAF inhibitors.

In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a KIF5B mutation that failed treatment with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a platinum-based drug and at least one other chemotherapeutic drug, and one or more KIF5B inhibitors to treat the KIF5B mutation.

In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a RET mutation that failed treatment with a platinum-based drug and at least one other chemotherapeutic drug. In some embodiments, the driver-positive lung cancer is non-small cell lung cancer that has previously received a RET mutation that has been treated with a platinum-based drug and at least one other chemotherapeutic drug, and one or more RET inhibitors.

In some embodiments, the EGFR mutation includes, but is not limited to, one or more of the 19 exon deletion mutation 19DEL, the 20 exon T790M mutation, the 20 exon C797S mutation, the 21 exon L858R mutation, and the copy number amplified EGFR mutation.

In some embodiments, the ALK mutations include, but are not limited to, one or more mutations in EML4-ALK, NPM-ALK fusion gene positivity.

In some embodiments, the ROS1 mutation includes, but is not limited to, one or more mutations in the CD74-ROS1, SDC-ROS1 fusion gene positive.

In some embodiments, the KRAS mutation includes, but is not limited to, one or more of a2 exon G12C mutation, a2 exon G12V mutation, a2 exon G12A mutation, a3 exon G61H mutation.

In some embodiments, the BRAF mutation includes, but is not limited to, a mutation of exon 15V 600E.

In some embodiments of the application, the Met gene mutation includes, but is not limited to, an exon 14 jump mutation, met gene amplification, which causes a c-Met abnormality.

In the present application, the chemotherapeutic agents (chemotherapy drugs) include, but are not limited to, alkylating agents (ALKYLATING AGENTS, including but not limited to bendamustine, carmustine, chlorambucil, nitrogen mustard, roflumilast, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide), antimetabolites (antimetabolites, including but not limited to azacytidine, cytarabine, 5-fluorouracil, 6-mercaptopurine, capecitabine, decitabine, gemcitabine, fludarabine, nedaplidine, hydroxyurea, methotrexate, pralatrexed, pemetrexed, pentazocine, trifluourea/dipivefrin combinations), plant alkaloids (plant aloid, including but not limited to camptothecine), and antitumor antibiotics (antitumor antibiotics, including but not limited to daunorubicin, doxorubicin, epirubicin, idarubicin, valubicin, mitomycin, anthraquinone, mitomycin (including but not limited to mitomycin), mitomycin (including but not limited to trimethoprim), topotecan inhibitor (including but not limited to paclitaxel), topotecan inhibitor (Topoisomerase inhibitors), paclitaxel, or combinations thereof.

In some embodiments, the chemotherapeutic agent includes, but is not limited to, one or more of platinum, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllia, antineoplastic, antimetabolites, examples that may be cited include, but are not limited to, platins (e.g., oxaliplatin, miplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin (dicycloplatin), leplatin (Lobaplatin), triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, lobaplatin), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, ancitabine, fluorouracil, bififluracine, doxifluridine, tegafur, carmofur, trifluouridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, and docetaxel, camptothecins (e.g., camptothecins, hydroxycamptothecins, 9-aminocamptothecins, 7-ethylcamptothecins, irinotecan, topotecan) vinblastine (vinorelbine, vinblastine, vincristine, vindesine, vin Funing (vinflunine), norvinblastine), anthracyclines (epirubicin, doxorubicin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxantrone, doxorubicin, valrubicin, zorubicin, pitaxan, doxorubicin, cytarabine, mercaptoguanine, pemetrexed, carmustine, melphalan, etoposide, teniposide, mitomycin, ifosfamide, cyclophosphamide, azacytidine, methotrexate, bendamustine, liposomal doxorubicin, actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, amamide, perlomycin, eribulin, plinabulin (plinabulin), sapacitabine, trosovalve (treosulfan), 153Sm-EDTMP, tigio, levo-asparaginase, perfarnesase, and encequidar.

In some embodiments, the platinum-based agent includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, dicycloplatin, picoplatin, satraplatin, phenanthreneplatin, tetranitrotriplatin, or lobaplatin. In some embodiments, the additional chemotherapeutic agent is a chemotherapeutic agent other than a platinum-based agent, including, but not limited to, gemcitabine, paclitaxel, docetaxel, vinorelbine, pemetrexed, etoposide, irinotecan, or topotecan.

In some embodiments, the platinum-based agent and one other chemotherapeutic agent are selected from the group consisting of: cisplatin and gemcitabine, cisplatin and docetaxel, cisplatin and paclitaxel, cisplatin and vinorelbine, cisplatin and pemetrexed, cisplatin and etoposide, cisplatin and irinotecan, cisplatin and topotecan, carboplatin and gemcitabine, carboplatin and docetaxel, carboplatin and paclitaxel, carboplatin and vinorelbine, carboplatin and pemetrexed, carboplatin and etoposide, carboplatin and irinotecan, or carboplatin and topotecan.

In some embodiments, the patient with driving gene positive lung cancer has previously been treated with an additional drug selected from docetaxel and nedaplatin, pemetrexed and carboplatin, pemetrexed, carboplatin and bevacizumab, pemetrexed and bevacizumab, and octreotide in combination of one or more thereof.

In some embodiments, the kinase inhibitor includes, but is not limited to, bucabatinib Brigatinib, octreotide (Osimertinib) Dacomitinib, gefitinib (Gefitinib), afatinib (Afatinib), erlotinib (Eerlotinib), necitumumab, icotinib (Icotinib), olmutinib, aletinib (Alectinib), crizotinib (Crizotinib), lorlatinib, ceritinib (Certinib), olmesatinib, cabozantinib, dacomitinib, dabrafenib, elpercatinib, vorolanib, ponatinib, sitravatinib, lenvatinib, or dovitinib.

In some embodiments, the EGFR inhibitor includes, but is not limited to Brigatinib, octenib (Osimertinib), dacominib, gefitinib (Gefitinib), afatinib (Afatinib), erlotinib (Eerlotinib), necitumumab, icotinib (Icotinib), or Olmutinib. In some embodiments, the EGFR-T790M inhibitor comprises octenib (Osimertinib).

In some embodiments, the ALK inhibitor includes, but is not limited to Brigatinib, aletinib (Alectinib), crizotinib (Crizotinib), lorlatinib, or ceritinib (Certinib).

In some embodiments, the ROS1 inhibitor includes, but is not limited to Brigatinib, crizotinib (Crizotinib), lorlatinib, or ceritinib (Certinib).

In some embodiments, the c-MET inhibitor includes, but is not limited to, crizotinib (Crizotinib), or Cabozantinib.

In some embodiments, the HER-2 inhibitor includes, but is not limited to, dacomitinib, or Afatinib (Afatinib).

In some embodiments, the BRAF inhibitor includes, but is not limited to Dabrafenib.

In some embodiments, the RET inhibitor includes, but is not limited to Selpercatinib, vorolanib, ponatinib, sitravatinib, lenvatinib, or Dovitinib.

In some embodiments, the driver-positive lung cancer is lung adenocarcinoma and the driver-positive is a BRAF p.v600e mutation. In some embodiments, the driver-positive lung cancer is lung adenocarcinoma and the driver-positive is a BRAF p.v600e mutation, and the patient with driver-positive lung cancer has been treated with one or more of the following regimens: 1) docetaxel and nedaplatin, 2) pemetrexed and nedaplatin, 3) pemetrexed and carboplatin, 4) pemetrexed, 5) erlotinib.

In some embodiments, the driver-positive lung cancer is lung adenocarcinoma and the driver-positive is an EGFR del mutation and/or an EGFR-T790M mutation. In some embodiments, the driver-positive lung cancer is lung adenocarcinoma, the driver-positive is an EGFR del mutation and/or an EGFR-T790M mutation, and the patient with driver-positive lung cancer has been treated with one or more of the following regimens: 1) pemetrexed, carboplatin and bevacizumab, 2) pemetrexed and bevacizumab, 3) bevacizumab and octreotide, 4) gefitinib, 5) octreotide.

In some embodiments, the driver-positive lung cancer is lung adenocarcinoma and the driver-positive is KIF5B-RET fusion gene-positive. In some embodiments, the driver-positive lung cancer is lung adenocarcinoma, the driver-positive is KIF5B-RET fusion gene-positive, and the patient with driver-positive lung cancer is treated with one or both of the following regimens: 1) Pemetrexed and carboplatin, 2) pemetrexed.

In some embodiments, the patient with the driver-positive lung cancer is a non-small cell lung cancer patient who has received anti-VEGFR mab (e.g., bevacizumab), antimetabolites (e.g., pemetrexed), taxanes (e.g., docetaxel), platins (e.g., nedaplatin and/or carboplatin), and/or EGFR inhibitors (e.g., afatinib, erlotinib, gefitinib, and/or octreotide) for treatment failure with a BRAF mutation, KIF5B mutation, RET mutation, and/or EGFR mutation (e.g., BRAF p.v600e mutation, EGFR del mutation, and/or EGFR-T790M mutation, KIF5B-RET fusion gene mutation).

Mode of administration

The following is not intended to limit the manner of administration of the pharmaceutical combination of the application.

The components of the pharmaceutical compositions of the present application may each be administered independently, or some or all of them together, in a suitable variety of ways, including, but not limited to, orally or parenterally (via intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application may each independently, or some or all of them may be co-administered orally or by injection, such as intravenous or intraperitoneal injection.

The components of the combination pharmaceutical compositions of the present application 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 capsules, soft capsules, enteric capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and dosage forms of sustained release formulations for oral or non-oral administration.

The components of the combination pharmaceutical composition of the application may each independently, or some or all of them together comprise a pharmaceutically acceptable carrier and/or excipient.

The combination pharmaceutical combination of the application may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.

Technical effects

In general, the use of the combination pharmaceutical composition of the application as 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 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 drug which is singly administered in the combination, the compound has good inhibition activity for driving gene positive lung cancer and shows more excellent anti-tumor synergistic effect.

Definition and description

The following terms used in the present application 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 present in the present application, it is intended to refer to their corresponding commercial products or active ingredients thereof.

As used herein, the term "combination pharmaceutical composition" 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 terms "combination pharmaceutical composition" and "pharmaceutical combination" are used interchangeably herein.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragment thereof. Thus, antibodies and fragments of the application 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, isolated CDR regions, single chain Fv molecules (scFv), fd fragments and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and 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. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The anti-PD-L1 antibodies and fragments thereof of the application may be derived from any species including, but not limited to, mice, rats, rabbits, primates, llamas, and humans. The anti-PD-L1 antibody and fragments thereof may be chimeric, humanized or fully human antibodies. In one embodiment, the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.

"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 provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, the humanized antibodies provided herein bind to the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibodies are derived. Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising heavy and light chain CDRs provided herein can be generated using any human framework sequences and are also included in the application. In one embodiment, framework sequences suitable for use in the present application 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. for example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites of framework amino acids of the above template human antibodies were back mutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, the amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are back mutated to the corresponding amino acids found at said positions in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser (S) to Asp (D) and the amino acid at position 67 is mutated from Ser (S) to Tyr (Y); and a heavy chain variable region wherein the amino acid at position 24 is mutated from Phe (F) to Val (V), the amino acid at position 49 is mutated from Ala (a) to Gly (G), the amino acid at position 73 is mutated from Thr (T) to Asn (N), and the amino acid at position 83 is mutated from Thr (T) to Asn (N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region, wherein the amino acid at position 28 is mutated from Thr (T) to Ile (I), the amino acid at position 30 is mutated from Ser (S) to Arg (R), the amino acid at position 49 is mutated from Ser (S) to Ala (a), and the amino acid at position 94 is mutated from Tyr (Y) to Asp (D). Additional or alternative back mutations may be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies. The application also includes humanized antibodies that bind PD-L1 and comprise framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other framework modifications that otherwise improve the properties of the antibodies.

The present application provides isolated antibodies or fragments thereof that bind PD-L1, wherein the antibodies can be produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5, 5G 11. Thus, the application also includes hybridomas 13C5, 5G11, as well as any hybridomas that produce the antibodies disclosed herein. The application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.

The term "isolated antibody" means an antibody that: which is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind antigens other than PD-1). However, the isolated antibody that specifically binds PD-1 may have cross-reactivity with other antigens (such as PD-1 molecules from different species). In addition, the isolated antibodies may be substantially free of other cellular material and/or chemicals.

The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of antibody molecules of single molecular composition (i.e., antibody molecules whose basic sequences are substantially identical and which exhibit a single binding specificity and affinity for a particular epitope). A mAb is one example of an isolated antibody. Mabs may be produced by hybridoma techniques, recombinant techniques, transgenic techniques, or other techniques known to those skilled in the art.

The antibodies and antigen binding fragments thereof disclosed herein are specific for PD-L1. In one embodiment, the antibody or fragment thereof is specific for PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but do not bind to PD-L1 from any other mammal. In another embodiment, the antibody or fragment thereof does not bind to mouse PD-L1. The terms "human PD-L1", "hPD-L1", and "huPD-L1", and the like, are used interchangeably herein and refer to human PD-L1 and variants or isoforms of human PD-L1. By "specific" is meant that the antibody and fragments thereof bind PD-L1 with greater affinity than any other target.

The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic, partially or completely stabilizing or curing the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.

The term "effective amount" means an amount of a compound of the application that (i) treats a given disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of active agent (e.g., an antibody or compound of the application) 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 immune checkpoint inhibitors (e.g., anti-PD-1 antibodies or anti-PD-L1 antibodies) 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. In certain embodiments, the immune checkpoint inhibitor (e.g., an anti-PD-1 antibody or an anti-PD-L1 antibody) is administered by a non-parenteral route, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration may also be performed, for example, one, multiple times, and/or over one or more extended periods of time.

Unless otherwise indicated, the use of the term "dose" refers to the dose administered to a patient irrespective of the weight or Body Surface Area (BSA) of the patient. For example, 60kg of humans and 100kg of humans will receive the same dose of antibody (e.g., 240mg of anti-PD-1 antibody).

The term "weight-based dose" as referred to herein refers to the dose calculated based on the weight of the patient that is administered to the patient. For example, when a patient having a body weight of 60kg requires 3mg/kg of an anti-PD-1 antibody, one can withdraw an appropriate amount of the anti-PD-1 antibody (i.e., 180 mg) at a time from a fixed dose formulation of the anti-PD-1 antibody.

An Luoti the drug may be administered by a variety of routes including, but not limited to, oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalational, vaginal, intraocular, topical, subcutaneous, intrafat, intra-articular, intraperitoneal and intrathecal. In some particular embodiments, the administration is by oral administration. The amount of An Luoti% administered may be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. For example, the daily dose of An Luoti nig may be from 2 mg to 20mg, and in some embodiments, the daily dose of An Luoti nig or a pharmaceutically acceptable salt thereof may be 2,3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg. An Luoti can be administered one or more times daily. In some embodiments, an Luoti ni is administered once daily as an oral solid formulation.

An Luoti the dosage regimen can be determined in combination based on the activity, toxicity, tolerance of the drug, etc. Preferably An Luoti n is administered as a separate administration. The interval administration includes administration period and withdrawal period, and An Luoti times or once a day can be administered during administration period. For example, the ratio of the administration period to the withdrawal period in days is 2:0.5 to 5, preferably 2:0.5 to 3, more preferably 2:0.5 to 2, still more preferably 2:0.5 to 1. In some embodiments, administration is stopped for 2 weeks following 2 weeks of administration. In some embodiments, administration is stopped for 1 week for 2 weeks. In some embodiments, administration is stopped for 2 days 5 days continuously. For example An Luoti Ni can be administered orally at a dose of 6mg, 8mg, 10mg or 12mg once daily for 2 weeks, and administered by a regimen of 1 week down.

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, succinate, methanesulfonate, 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. In the present application, when a pharmaceutically acceptable salt is formed, the molar amount ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8.

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

The term "about" is to be understood to include within three standard deviations of the average value or within standard tolerances in the particular field. In certain embodiments, a variation of no more than about 0.5 is understood. "about" modifies all values recited thereafter. For example, "about 1,2, 3" means "about 1", "about 2", "about 3".

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 packaging unit containing a quantity of a drug, e.g., a box of seven capsules, each capsule being a single dose; or a single dose per bottle of injectate. The terms "single dose" and "unit dose" have the same meaning and are used interchangeably herein.

The term "multi-dose" consists of a plurality of single doses.

The term "pharmaceutical composition" refers to a mixture of one or more of the active ingredients of the present application or a pharmaceutical combination thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compound of the application or a pharmaceutical combination thereof to a subject.

In this document, the terms "comprises," "comprising," and "includes," or equivalents thereof, unless otherwise specified, are open ended and mean that other, unspecified elements, components, and steps are contemplated in addition to those listed.

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 application. 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.

Detailed Description

The application is further illustrated by examples, which are not intended to limit the scope of the application, for clarity. All reagents used in the present application are commercially available and can be used without further purification. The anti-PD-L1 antibodies of the examples were prepared as described in WO2016022630, and after affinity chromatography, the eluate containing the antibodies was obtained by conventional antibody purification methods.

Example 1 clinical trial

1.1 Criteria for enrollment

1. The sex is unlimited, and the age is more than or equal to 18 years old;

2, ECOG scoring is 0-1 min, and the expected lifetime is more than or equal to 12 weeks;

3. A stage IIIB/IV subject diagnosed histologically or cytologically as driving gene positive non-small cell lung cancer (including but not limited to EGFK/ALK/ROS-1/c-MET/RET/HER-2/BRAF-V600E, methods of detection reference clinical practice) and defined by the IASLC version 8 TNM staging system;

4. The definition of failure to undergo standard treatment includes, but is not limited to, the following:

4.1EGFR Gene sensitive mutation positivity: treatment with at least one EGFR-TKI inhibitor is failed, and at least one chemotherapeutic regimen, including a platinum-containing bifocal regimen, is failed; patients with EGFR-T790M mutation, if any, may be eligible for treatment with a third generation EGFR inhibitor after failure;

4.2 patients positive for ALK gene rearrangement have failed treatment with an ALK inhibitor, and at least one chemotherapeutic regimen including a platinum-containing double regimen; if the patient is only treated with prochloraz, then a new generation of ALK inhibitor treatment will be needed to fail.

4.3ROS1 patients positive for gene rearrangement are subject to treatment failure with a ROS1 inhibitor, and at least one chemotherapeutic regimen, including a platinum-containing double regimen;

4.4 the remaining patients positive for genetic variation, need to receive at least one chemotherapeutic regimen including a platinum-containing double regimen for treatment failure;

5. according to the efficacy evaluation standard RECIST 1.1 of the solid tumor, at least one measurable focus is provided;

6. the major organs in the screening period were functioning normally, i.e. met the following criteria:

① Blood routine examination (no transfusion within 14 days):

Absolute value of neutrophil (ANC) 1.5X10 ⁹/L;

Platelet count (PLT). Gtoreq.75X10 ⁹/L;

Hemoglobin (Hb). Gtoreq.80 g/L;

② Biochemical blood examination:

Total Bilirubin (TBIL) is less than or equal to 1.5 XULN;

Glutamic-pyruvic transaminase (ALT) and glutamic-pyruvic transaminase (AST) are less than or equal to 3 XULN (tumor liver metastasis is less than or equal to 5 XULN);

Serum creatinine (Cr) less than or equal to 1.5 XULN, and creatinine clearance (Ccr) less than or equal to 50ml/min (according to the standard Cockcroft-Gault formula);

③ Routine urine

Urine protein <2+ (urine protein is quantitatively detected within 7 days for 24 hours when the baseline urine protein is more than or equal to 2+, and can be selected when the urine protein is less than 1 g);

④ Coagulation function

INR and APTT.ltoreq.1.5XULN;

⑤ Heart function

Left Ventricular Ejection Fraction (LVEF) is greater than or equal to 50%;

7. Women must meet one of the following conditions:

① Surgical sterilization has been performed;

② Menopausal, stop menstruation for at least 1 year;

③ Has fertility and needs to meet the following conditions:

Serum/urine pregnancy test results were negative before the study was entered into the group; throughout the study period, it was agreed to take an approved method of contraception (e.g., oral, injectable or implanted, barrier contraception, spermicide and condom, or intrauterine contraceptive) and the contraceptive method was unchanged throughout the study period.

The male must meet one of the following conditions:

① Surgical sterilization has been performed;

② An approved contraceptive method must be used throughout the study and will not change during the study.

1.2 Test drug

Anti-PD-L1 antibody injection hu5G11-hIgG1:1200mg of the PD-L1 antibody injection is diluted to 250mL by normal saline, the infusion time is 60+/-10 min, and after the infusion is finished, the normal saline is used for flushing according to the conventional requirements of hospitals, and the administration is carried out once every 21 days, namely 21 days is a treatment period.

Specification of anti-PD-L1 antibody injection: 100mg/10mL.

An Luoti Nile hydrochloride capsule (An Luoti Nile dihydrochloride as active ingredient): the initial dose was 12mg. The anti-PD-L1 antibody injection starts to be infused for + -5 min, and the hydrochloric acid An Luoti-Ni capsule is taken on an empty stomach, one capsule is taken every day, and the oral administration is continuously carried out for 2 weeks and 1 week, namely 21 days is a treatment period.

For the An Luoti Ni HCl capsule, 3 dosage levels were designed, starting at 12mg, dosage level 1 at 10mg and dosage level 2 at 8mg. Any subject would continue to receive reduced dose treatment for the subsequent period if he/she were to reduce the An Luoti ni capsule dose of hydrochloric acid.

Specification of: 12mg, 10mg, 8mg, or 6mg.

1.3 Evaluation criteria

Disease states were determined according to RECIST 1.1.

1.4 Evaluation of efficacy

ORR (objective remission rate): the proportion of subjects with confirmed disease assessed as CR (complete remission) +pr (partial remission);

PFS (progression free survival): group randomization to disease progression or death (on the first occurrence);

OS (total lifetime): the time to total death was randomized. Subjects who survived the last follow-up, whose OS was deleted for data in the last follow-up time. Subjects with no visit, whose OS was deleted for data in the time of last confirmed survival prior to no visit;

DCR (disease control rate): tumor shrinkage or stabilization and a proportion of patients who remain for a certain period of time, including cases of CR, PR and SD (disease stabilization); or alternatively

Health related quality of life (EORTC QLQ-C30 and EORTC QLQ-LC 13): and (3) observing the relevant clinical symptoms of the tumor patients before and after treatment and the changes of objective examination results, scoring, and recording scoring results in various fields of the scale in EDC according to the requirements of the quality of life scale.

1.5 Results

1.6 Past history of treatment for each patient

Patients 001 had previously received chemotherapy and targeted therapy:

Description of chemotherapy regimens	Treatment cycle
		Docetaxel + nedaplatin	3
Pemetrexed+nedaplatin	1
		Pemetrexed+carboplatin	6
Pemetrexed	37

Targeted therapeutic drug: erlotinib.

008 Patients had previously received chemotherapy and targeted therapy:

Description of chemotherapy regimens	Treatment cycle
		Pemetrexed, carboplatin and bevacizumab	3
Pemetrexed plus bevacizumab	2
		Bevacizumab + octreotide	--

Targeted therapeutic drug: gefitinib and octreotide.

024 Patients had previously received chemotherapy:

Description of chemotherapy regimens	Treatment cycle
		Pemetrexed+carboplatin	4
Pemetrexed	6

In the above examples, the amount of An Luoti% hydrochloric acid capsules based on the weight of An Luoti% free base contained therein was 21 days for each dosing cycle, and C6, C14, and C17 represent 6, 14, and 17 cycles of dosing, respectively.

Claims

1. A combination pharmaceutical composition for treating driving gene positive lung cancer comprising an anti-PD-L1 antibody and An Luoti ni.

2. The combination pharmaceutical composition of claim 1, wherein the combination pharmaceutical composition comprises a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni.

3. The combination pharmaceutical composition of any one of claims 1 or 2, wherein the combination pharmaceutical composition is packaged in the same kit, the kit further comprising instructions for the combined use of a PD-L1 antibody and An Luoti ni to treat driving gene positive lung cancer.

4. The combination pharmaceutical composition according to any one of claims 1-3, wherein the combination pharmaceutical composition comprises a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a single dose of 6mg, 8mg, 10mg and/or 12mg An Luoti ni of the pharmaceutical composition.

5. The combination pharmaceutical composition according to any one of claims 1-4, wherein the combination pharmaceutical composition comprises anti-PD-L1 antibody and An Luoti ni in a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably (7-14.5): 1.

6. The combination pharmaceutical composition according to any one of claims 1-5, wherein the combination pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g. one treatment cycle of 21 days), comprising a pharmaceutical composition comprising 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg An Luoti ni.

7. Use of a combination pharmaceutical composition according to any one of claims 1-6 for the manufacture of a medicament for the treatment of driving gene positive lung cancer.

8. Use of an anti-PD-L1 antibody and An Luoti ni in the manufacture of a medicament for the treatment of driving gene positive lung cancer.

9. The use of any one of claims 7 or 8, wherein the anti-PD-L1 antibody and An Luoti ni are each in the form of a pharmaceutical composition, which may be administered simultaneously, sequentially or at intervals.

10. The use according to any one of claims 7-9, wherein the anti-PD-L1 antibody is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks, preferably at a dose of 600-2400 mg each time.

11. The use of any one of claims 7-10, wherein the An Luoti ni is administered in a dose of 6mg, 8mg, 10mg, or 12mg once daily, for 2 weeks, at a dosing regimen of 1 week stop.

12. A kit for treating driver-positive lung cancer, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of An Luoti ni, and instructions for using the anti-PD-L1 antibody in combination with An Luoti ni to treat driver-positive lung cancer.

13. The kit of claim 12, wherein the kit is a kit suitable for administration over a single treatment cycle (e.g., one treatment cycle of 21 days), comprising a pharmaceutical composition comprising 600-2400 mg of the anti-PD-L1 antibody and a pharmaceutical composition comprising 84-168 mg An Luoti ni.

14. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 9 or SEQ ID NO. 12.

15. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO. 1 or SEQ ID NO. 4; a heavy chain CDR2 region selected from SEQ ID NO. 2 or SEQ ID NO. 5; a heavy chain CDR3 region selected from SEQ ID NO. 3 or SEQ ID NO. 6; a light chain CDR1 region selected from SEQ ID NO. 7 or SEQ ID NO. 10; a light chain CDR2 region selected from SEQ ID NO. 8 or SEQ ID NO. 11; a light chain CDR3 region selected from SEQ ID NO 9 or SEQ ID NO 12.

16. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 2, a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 3; and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO. 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO. 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO. 9.

17. The combination pharmaceutical composition of any one of claims 1-6, or the use of claims 7-11, or the kit of any one of claims 12 or 13, wherein the anti-PD-L1 antibody comprises the amino acid sequence: a heavy chain variable region having at least 80% homology to the amino acid sequence shown in SEQ ID NO. 13 or SEQ ID NO. 14; a light chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO. 15 or SEQ ID NO. 16.

18. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the anti-PD-L1 antibody comprises the amino acid sequence: comprising a variable heavy chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies.

19. The combination pharmaceutical composition according to any one of claims 1-6, or the use according to any one of claims 7-11, or the kit according to claim 12 or 13, wherein An Luoti ni is in free base form, or in the form of a pharmaceutically acceptable salt thereof.

20. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the driver gene positivity comprises one or more of EGFR mutation, ALK mutation, ROS1 mutation, KRAS mutation, c-MET mutation, HER-2 mutation, BRAF mutation, KIF5B mutation, RET mutation.

21. The combination pharmaceutical composition of any one of claims 1-6, or the use of any one of claims 7-11, or the kit of any one of claims 12 or 13, wherein the driver-positive lung cancer is non-small cell lung cancer that has received failed anti-VEGFR mab, antimetabolite, taxane, platinum and/or EGFR inhibitor treatment, BRAF mutation, KIF5B mutation, RET mutation and/or EGFR mutation.