WO2020249018A1

WO2020249018A1 - Combined pharmaceutical composition for treating driver-gene-positive lung cancer

Info

Publication number: WO2020249018A1
Application number: PCT/CN2020/095417
Authority: WO
Inventors: 于浩; 潘茂琼
Original assignee: 正大天晴药业集团南京顺欣制药有限公司; 正大天晴药业集团股份有限公司
Priority date: 2019-06-10
Filing date: 2020-06-10
Publication date: 2020-12-17
Also published as: CN113905761A

Abstract

Disclosed is a combined pharmaceutical composition for treating driver-gene-positive lung cancer, wherein the composition comprises an anti-PD-L1 antibody and anlotinib, and same has a good activity against driver-gene-positive lung cancer.

Description

Combined medicine composition for treating driver gene positive lung cancer

Technical field

This application belongs to the field of biomedicine, and relates to a combined pharmaceutical composition for treating driver gene-positive lung cancer.

Background technique

Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. They play an important role in intracellular signal transduction. They are involved in the regulation, signal transmission and development of normal cells, and are also related to tumor cells. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are related to the formation of tumors, and can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial cell growth factor receptor according to the structure of their extracellular region. Body (VEGFR), Fibroblast Growth Factor Receptor (FGFR), etc.

PD-L1 (Programmed death-ligand l), also known as CD247 and B7-H1, is a ligand of programmed death molecule l (Programmed death, PD-1). PD-L1 is highly expressed on the surface of a variety of tumor cells, and the degree of tumor malignancy and poor prognosis are closely related to the expression level of PD-L1. In the tumor microenvironment, PD-L1 on the surface of cancer cells binds to PD-1 or CD80 on the surface of T cells to inhibit the activation and proliferation of T cells, promote effector T cells into a state of exhaustion or anergy, and induce T cell growth. Apoptosis stimulates the differentiation of helper T cells into regulatory T cells, thereby preventing T cells from killing tumor cells. Anti-PD-L1 antibody can block the interaction of PD-L1 with PD-1 and CD80, so that related negative regulatory signals cannot be initiated and transmitted, thereby avoiding the inhibition of effector T cell activity in the tumor microenvironment , So that T cells can play the role of killing and inhibiting tumor cells. Because anti-PD-L1 antibody can directly act on tumor tissues, it has high specificity and safety.

Cancer is a major public health problem in many parts of the world. Among them, due to the high incidence and mortality of lung cancer, it has become the main cause of cancer deaths worldwide. In 2012, approximately 1.8 million people worldwide newly contracted lung cancer and caused 1.6 million deaths. Lung cancer is a common cause of death from cancer in men, and second only to breast cancer in women. Lung cancer driver genes mainly include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), MET gene receptor tyrosine kinase (MET ) And human epidermal growth factor receptor 2 (HER-2). Although the targeted therapy for driver genes has made great progress, there are still many problems. Therefore, it is necessary to develop other treatment modes besides targeted therapy and chemotherapy in order to further improve the treatment effect and improve the prognosis of patients.

WO2016022630 discloses a class of PD-L1 antibodies that have high affinity for PD-L1, can significantly inhibit the interaction of PD-L1 and PD-1 on the cell surface, and significantly promote the secretion of IL-2 and INF-γ by T cells .

Although there are many treatment options for patients with proliferative diseases (cancer), there is still a need for more effective therapeutic agents for clinical use, especially the combined use of more than one drug.

Summary of the invention

In one aspect, the present application provides a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer, which includes an anti-PD-L1 antibody and anlotinib.

Further, Anlotinib is in the form of a free base, or in the form of a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt of anlotinib may be hydrochloride or dihydrochloride.

Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; and SEQ ID NO: 2 or A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 5; a heavy chain with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6 CDR3 region; light chain CDR1 region that has at least 80% homology with the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; and the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 11 A light chain CDR2 region having at least 80% homology; 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. Furthermore, 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 selected from SEQ ID NO: 2 or SEQ ID NO: 5 Region; selected from SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or SEQ ID NO: 10 light chain CDR1 region; selected from SEQ ID NO: 8 or SEQ ID The light chain CDR2 region of NO: 11; the light chain CDR3 region of SEQ ID NO: 9 or SEQ ID NO: 12. Furthermore, the anti-PD-L1 antibody comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, and a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, having The heavy chain CDR3 region with the amino acid sequence shown in SEQ ID NO: 3; and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 7, and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 8 The chain CDR2 region has the light chain CDR3 region with the amino acid sequence shown in SEQ ID NO: 9. Furthermore, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14; and SEQ ID NO: 15 or SEQ ID NO: 16 has a light chain variable region with at least 80% homology. Furthermore, the anti-PD-L1 antibody comprises: a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4 , Hu5G11-hIgG1 or hu5G11-hIgG4 humanized variable light chain.

Further, the above-mentioned combination pharmaceutical composition of the present application is packaged in the same kit, and the kit also includes instructions for the combined use of PD-L1 antibody and anlotinib to treat driver-positive lung cancer.

Further, the present application provides a combined pharmaceutical composition, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anlotinib combination. The pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.

Further, this application provides a combination pharmaceutical composition, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg The pharmaceutical composition of Rotinib.

Further, the present application provides a combination pharmaceutical composition, which is a preparation suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), and includes a drug containing 600-2400 mg of anti-PD-L1 antibody The composition and the pharmaceutical composition containing 84-168 mg of anlotinib.

Further, the present application provides a combination pharmaceutical composition, which comprises 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 anti-PD-L1 antibody and Anlotinib. Among them, the anti-PD-L1 antibody and Anlotinib can be packaged separately or together. In addition, Anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more); the anti-PD-L1 antibody can be packaged in single or Multiple equal parts (for example, 2 equal parts, 4 equal parts or more) are packaged.

On the other hand, the application also provides the use of the combined pharmaceutical composition herein in the preparation of a medicament for the treatment of driver gene-positive lung cancer. Alternatively, the present application also provides a method for treating driver gene-positive lung cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the present application. The application also provides the use of the combined pharmaceutical composition of the application for the treatment of driver gene-positive lung cancer. The combined pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib.

On the other hand, this application also provides the use of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for the treatment of gene-positive lung cancer. Alternatively, the present application also provides a method for treating driver gene-positive lung cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject. The application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat driver gene-positive lung cancer. Alternatively, this application also provides a combination of anti-PD-L1 antibody and anlotinib for the treatment of driver gene-positive lung cancer.

Further, the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals. Furthermore, the anti-PD-L1 antibody is administered every week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg each time. Furthermore, the anlotinib is administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 weeks with a 1-week stop.

In addition, the present application provides a kit for the treatment of driver gene-positive lung cancer, the kit includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib Instructions for the treatment of driver gene-positive lung cancer in combination with Nicolas.

Further, the above-mentioned kit is a kit suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), and includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and 84-168 mg of An Luo The pharmaceutical composition of tinib.

Detailed description of the invention

In some embodiments of the present application, the combination pharmaceutical composition includes an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.

In some embodiments of the application, the combination pharmaceutical composition is packaged in the same kit, and the kit also includes instructions for the combined use of PD-L1 antibody and anlotinib to treat driver-positive lung cancer.

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg, and / Or a pharmaceutical composition of 12 mg anlotinib. The pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which includes a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody in multiple doses and a single dose of 6 mg , 8mg, 10mg and/or 12mg anlotinib pharmaceutical composition.

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which includes a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5 -14.5):1. The most preferred (7-14.5):1 anti-PD-L1 antibody and anlotinib. Among them, the anti-PD-L1 antibody and Anlotinib can be packaged separately or together. And wherein, Anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more).

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which includes an anti-PD-L1 antibody pharmaceutical composition and an anlotinib pharmaceutical composition, wherein the anti-PD-L1 The pharmaceutical composition of the antibody is prepared to be suitable for administering a single dose or multiple doses of 600-2400 mg of anti-PD-L1 antibody to the patient at the first administration, and the pharmaceutical composition of anlotinib is prepared to be suitable for continuous 14 A single dose of 6mg, 8mg, 10mg and/or 12mg of Anlotinib was given to the patient every day.

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which comprises an anti-PD-L1 antibody pharmaceutical composition with an anti-PD-L1 antibody concentration of 10-60 mg/mL and a single The dosage is 6mg, 8mg, 10mg and/or 12mg of the pharmaceutical composition of Anlotinib.

In some embodiments, there is provided a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer, which comprises an anti-PD-L1 antibody concentration of 10 mg/mL and a single dose of the anti-PD-L1 antibody pharmaceutical composition A pharmaceutical composition of 8mg and/or 10mg and/or 12mg anlotinib.

In some embodiments, a combination pharmaceutical composition for the treatment of driver gene-positive lung cancer is provided, which includes a pharmaceutical composition containing 1200 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 8 mg and/ Or a pharmaceutical composition of 10mg and/or 12mg Anlotinib.

On the other hand, the application also provides the use of the combined pharmaceutical composition in the preparation of a drug for the treatment of driver gene-positive lung cancer. The application also provides a method for treating driver gene-positive lung cancer, which comprises administering to a subject an effective amount of the combined pharmaceutical composition of the application. The application also provides the use of the combined pharmaceutical composition for the treatment of driver gene-positive lung cancer. In some embodiments, the combination pharmaceutical composition includes an anti-PD-L1 humanized monoclonal antibody and anlotinib.

On the other hand, this application also provides the use of anti-PD-L1 antibody and Anlotinib in the preparation of drugs for the treatment of gene-positive lung cancer. This application also provides a method for treating driver gene-positive lung cancer, including administering an effective amount of anti-PD-L1 antibody and anlotinib to the subject. The application also provides the use of the combination of anti-PD-L1 antibody and anlotinib to treat driver gene-positive lung cancer. The application also provides a combination of anti-PD-L1 antibody and anlotinib for the treatment of driver gene-positive lung cancer.

In another aspect, the present application provides a kit for treating driver gene-positive lung cancer. The kit includes a pharmaceutical composition of anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, as well as an anti-PD-L1 antibody and an anti-PD-L1 antibody. Instructions for the combined use of Rotinib in the treatment of driver gene-positive lung cancer.

In another aspect, the present application also provides an anti-PD-L1 antibody for the treatment of driver gene-positive lung cancer. The application also provides a method for treating driver gene-positive lung cancer, which comprises administering to a subject an effective amount of the anti-PD-L1 antibody of the application. The application also provides the use of anti-PD-L1 antibodies for the treatment of driver gene-positive lung cancer. The application also provides the use of the anti-PD-L1 antibody in the preparation of a medicine for treating lung cancer with positive driver genes.

Dosing/treatment plan of combined pharmaceutical composition

In one aspect, the present invention provides a combination pharmaceutical composition, which includes an anti-PD-L1 antibody and anlotinib.

In some embodiments of the present application, in the above use or treatment method, the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.

In some embodiments of the present application, in the above-mentioned use or treatment method, the anti-PD-L1 antibody and anlotinib are each administered at intervals. In some embodiments, the antibody and anlotinib are administered in the same or different dosing schedules. In some embodiments, the administration is performed in different dosing schedules.

In some embodiments of the application, in the use or treatment method, the anti-PD-L1 antibody may be weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks ( q4w) Apply once. 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 each time.

The anlotinib can be administered in a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 weeks with a 1-week stop.

In some embodiments, the anti-PD-L1 antibody and Anlotinib have the same or different treatment cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody and anlotinib have the same treatment cycle, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks is a treatment cycle.

In some embodiments of the present application, in the use or treatment method, 21 days is a treatment cycle, and the PD-L1 antibody is administered on the first day of each cycle, and the PD-L1 antibody is administered daily on days 1-14 of each cycle Anlotinib. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib is administered once a day on days 1-14 of each cycle.

In some embodiments of the present application, in the use or treatment method, wherein the anti-PD-L1 antibody may comprise selected from 0.01 to 40 mg/kg, 0.1 to 30 mg/kg, 0.1 to 20 mg/kg, 0.1 to 15 mg /kg, 0.1 to 10 mg/kg, 1 to 15 mg/kg, 1 to 20 mg/kg, 1 to 3 mg/kg, 3 to 10 mg/kg, 3 to 15 mg/kg, 3 to 20 mg/kg, 3 to 30 mg/kg , 10 to 20 mg/kg, or 15 to 20 mg/kg to the subject; or 60 mg to 2400 mg, 90 mg to about 1800 mg, 120 mg to 1500 mg, 300 mg to 900 mg, 600 mg to 900 mg, 300 mg to 1200 mg, 600 mg to 1200 mg , Or a dose of 900mg to 1200mg administered to the subject.

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

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

Pharmaceutical composition of anti-PD-L1 antibody

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

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

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

In some embodiments of the present application, the anti-PD-L1 antibody pharmaceutical composition is calculated in w/v, and the anti-PD-L1 monoclonal antibody concentration is about 5-150 mg/mL; preferably about 10-60 mg/mL; More preferably, it is about 10-30 mg/mL. In some specific solutions, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/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 60 mg/mL, more preferably about 10 mg/mL, about 20 mg/mL, or about 30 mg/mL. In some embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 10 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 30 mg/mL. In other embodiments, the mass volume concentration of anti-PD-L1 monoclonal antibody is about 60 mg/mL.

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

In some embodiments of the present application, in terms of w/v, the isotonicity regulator/stabilizer is about 20-150 mg/mL sucrose, preferably about 40-100 mg/mL sucrose, more preferably about 60 -80mg/mL of sucrose. In some specific solutions, the concentration of the sucrose is about 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL. In some specific embodiments, the concentration of the sucrose is about 60 mg/mL. In some specific embodiments, the concentration of the sucrose is about 70 mg/mL. In some specific embodiments, the concentration of the sucrose is about 80 mg/mL. In some specific embodiments, the concentration of the sucrose is about 90 mg/mL.

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

In some embodiments of the present application, in terms of w/v, the surfactant is about 0.01-0.8 mg/mL of polysorbate 80 or polysorbate 20. In some specific embodiments, the surfactant is about 0.05-0.6 mg/mL polysorbate 80, preferably about 0.1-0.4 mg/mL polysorbate 80, more preferably about 0.2-0.3 mg/mL Polysorbate 80 of about 0.2 mg/mL is most preferred. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, or 0.6 mg/mL; preferably Preferably, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL or 0.5 mg/mL; more preferably, the content of polysorbate 80 in the pharmaceutical composition It is about 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; optimally, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL. In some other embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.3 mg/mL. In other embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.4 mg/mL. In some embodiments, the content of polysorbate 80 in the pharmaceutical composition is about 0.5 mg/mL.

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

In some specific embodiments of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody with a mass volume concentration of about 20 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.1 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.0. In a specific embodiment of the present invention, the pharmaceutical composition comprises: (a) anti-PD-L1 monoclonal antibody with a mass volume concentration of about 20 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.1 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid, and adjust 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 with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust 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 with a mass volume concentration of about 50 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.3 mg/ml, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust 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 with a mass volume concentration of about 100 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.5 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody with a mass volume concentration of about 30 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust 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 with a mass volume concentration of about 60 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 10 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.

In a specific embodiment of the present application, the pharmaceutical composition comprises: (a) anti-PD-L1 antibody with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 70 mg/mL, ( c) Polysorbate 80 with a mass volume concentration of about 0.4 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional acetic acid, and adjust 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 monoclonal antibody with a mass volume concentration of about 10 mg/mL, (b) sucrose with a mass volume concentration of about 80 mg/mL, (c) Polysorbate 80 with a mass volume concentration of about 0.2 mg/mL, (d) histidine with a molar concentration of about 20 mM, (e) optional hydrochloric acid, and adjust the pH of the composition to about 5.5.

In another specific embodiment of the present application, the pharmaceutical composition is a water-soluble injection, and the water-soluble injection includes, but is not limited to, a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted by lyophilized powder. In other scenarios, the pharmaceutical composition is a lyophilized formulation. The freeze-dried preparation refers to a preparation prepared by an aqueous solution undergoing a freeze-drying process, in which the substance is first frozen, and 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 freeze-dried formulation of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.

Anlotinib pharmaceutical composition

In some embodiments of the application, a single dose of the pharmaceutical composition of anlotinib includes 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib.

In some embodiments of the present application, the total dose of the pharmaceutical composition of anlotinib administered in each cycle includes 84-168 mg according to a treatment cycle of administration for 2 weeks and stop for 1 week. In some of the schemes, the total dose of the pharmaceutical composition of Anlotinib includes a range selected from 84mg, 112mg, 140mg, 168mg or any of the above values. In some schemes, the total dose of the pharmaceutical composition of Anlotinib preferably includes 112 mg to 168 mg.

Anti-PD-L1 antibody

In some embodiments of the present application, the anti-PD-L1 antibody is an antibody in WO2016022630 or CN107001463A.

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

In some embodiments of the present 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; selected from SEQ ID NO: 2 or SEQ ID NO: 5 heavy chain CDR2 region; selected from SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or SEQ ID NO: 10 light chain CDR1 region; selected from SEQ ID NO: 3 or SEQ ID NO: 6 The light chain CDR2 region of ID NO: 8 or SEQ ID NO: 11; the light chain CDR3 region of SEQ ID NO: 9 or SEQ ID NO: 12.

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

The various CDR regions described herein and the various variants described above can specifically recognize and bind PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.

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

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

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

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

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

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

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided in the present application comprises a monoclonal antibody selected from 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, SEQID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, One of 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 Or multiple conservative substitution variants. The anti-PD-L1 humanized monoclonal antibody containing the conservative substitution variant retains the ability to specifically recognize and bind to 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 a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from a 13C5 or 5G11 antibody. In one embodiment, the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody, and a variable heavy chain selected from ch5G11- Variable light chain of hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody. In one embodiment, the anti-PD-L1 antibody described in the present application comprises a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable heavy chain selected from hu13C5 -Variable light chain of hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody. Reference can be made to the description of patent document WO2016022630 or CN107001463A: The HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5 ), HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), LCDR2 sequence is YASNLES (SEQ ID NO: 11), LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12); The HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 is TYGVH (SEQ ID NO:1), HCDR2 sequence is VIWRGVTTDYNAAFMS (SEQ ID NO: 2), and HCDR3 sequence is LGFYAMDNOY (SEQ ID NO:1) :3), the sequence of LCDR1 is KASQSVSNDVA (SEQ ID NO: 7), the sequence of LCDR2 is YAANRYT (SEQ ID NO: 8), and the sequence of LCDR3 is QQDYTSPYT (SEQ ID NO: 9).

In some embodiments of the present application, the anti-PD-L1 antibody in the drug combination may be selected from one or more. As used in this application, the term "plurality" can be more than one, for example, two, three, four, five or more. For example, in some embodiments of the present application, the anti-PD-L1 antibody is selected from the group consisting of a heavy chain variable region as shown in SEQ ID NO: 13 and a light chain variable region as shown in SEQ ID NO: 15 , Or selected from the heavy chain variable region shown in SEQ ID NO: 14 and the light chain variable region shown in SEQ ID NO: 16, or selected from a combination of the above. For another example, the anti-PD-L1 antibody is selected from the heavy chain amino acid sequence shown in SEQ ID NO: 17 and the light chain amino acid sequence shown in SEQ ID NO: 18, or selected from the amino acid sequence shown in SEQ ID NO: 19 The heavy chain amino acid sequence and the light chain amino acid sequence shown in SEQ ID NO: 20, or selected from the heavy chain amino acid sequence shown in SEQ ID NO: 21 and the light chain amino acid sequence shown in SEQ ID NO: 18, or It is selected from the combination of any of the above.

Anlotinib

As used in this application, the chemical name of the free base of anlotinib is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methyl Oxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

As used in this application, the anlotinib includes its non-salt form (for example, free base), and also includes its pharmaceutically acceptable salt, and the non-salt form or salt is included in the protection scope of this application. For example, the pharmaceutically acceptable salt of anlotinib may be hydrochloride or dihydrochloride. The dosage of anlotinib or its salt in this application, unless otherwise specified, is based on the molecular weight of anlotinib free base.

Driver positive lung cancer

In some embodiments of the present application, the driver gene-positive lung cancer is selected from driver gene-positive non-small cell lung cancer. In some embodiments, the driver gene-positive non-small cell lung cancer includes lung squamous cell 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 gene-positive lung cancer includes, but is not limited to, EGFR mutation (for example, EGFR-T790M), ALK mutation, ROS1 mutation, KRAS mutation, MET mutation, HER-2 mutation, BRAF mutation, KIF5B mutation, RET mutation Or any two or more of lung cancers with mutations.

In some embodiments, the driver gene-positive lung cancer is non-small cell lung cancer that has failed treatment with at least one platinum-based drug.

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

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

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

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

In some embodiments, the driver gene-positive lung cancer is lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more kinase inhibitors, and the driver gene-positive lung cancer includes but is not limited to EGFR One or more of mutations, ALK mutations, ROS1 mutations, KRAS mutations, MET mutations, HER-2 mutations, BRAF mutations, KIF5B mutations, and RET mutations.

In some embodiments, the driver gene-positive lung cancer is non-small cell lung cancer with EGFR gene mutation that has previously received at least one EGFR inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is EGFR gene mutation non-small cell lung cancer that has previously received at least one EGFR-TKI inhibitor (EGFR tyrosine kinase inhibitor) treatment failure; in some embodiments, the driver gene-positive lung cancer is previously received At least one EGFR inhibitor and at least one chemotherapeutic drug have failed to treat non-small cell lung cancer with mutations in the EGFR gene; in some embodiments, the driver gene-positive lung cancer is previously received at least one EGFR inhibitor and at least A platinum-based drug treatment failed non-small cell lung cancer with EGFR mutation. In some embodiments, the driver gene-positive lung cancer is an EGFR mutant non-small cell that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more EGFR tyrosine kinase inhibitors. Lung cancer.

In some embodiments, the driver gene-positive lung cancer is an EGFR-T790M mutation that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more EGFR-T790M tyrosine kinase inhibitors. Of non-small cell lung cancer.

In some embodiments, the driver gene-positive lung cancer is ALK-mutated non-small cell lung cancer that has previously received at least one ALK inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is in First received at least one ALK inhibitor treatment failure ALK mutant non-small cell lung cancer; in some embodiments, the driver gene positive lung cancer is previously received at least one ALK inhibitor and at least one chemotherapeutic drug Treatment failed ALK-mutated non-small cell lung cancer; in some embodiments, the driver gene-positive lung cancer is ALK-mutated non-small cell that has previously received at least one ALK inhibitor and at least one platinum-based drug treatment failure Lung cancer. In some embodiments, the driver gene-positive lung cancer is ALK-mutated non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and at least one ALK inhibitor treatment.

In some embodiments, the driver gene-positive lung cancer is a patient who has previously received platinum drugs, at least one other chemotherapeutic drug, and two or more ALK inhibitors including crizotinib. ALK mutant non-small cell lung cancer.

In some embodiments, the driver gene-positive lung cancer is ROS1 mutant non-small cell lung cancer that has previously received at least one ROS1 inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer is in ROS1 mutant non-small cell lung cancer that has received at least one ROS1 inhibitor treatment failure; in some embodiments, the driver gene-positive lung cancer has previously received at least one ROS1 inhibitor and at least one chemotherapeutic drug Treatment failure of ROS1 mutant non-small cell lung cancer; in some embodiments, the driver gene-positive lung cancer is a ROS1 mutant non-small cell that has previously received at least one ROS1 inhibitor and at least one platinum-based drug treatment failure Lung cancer. In some embodiments, the driver gene-positive lung cancer is ROS1 mutant non-small cell lung cancer that has previously received platinum drugs, at least one other chemotherapeutic drug, and one or more ROS1 inhibitors.

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

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

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

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

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

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

In some embodiments, the EGFR mutations include, but are not limited to, exon 19 deletion mutation 19DEL, exon 20 T790M mutation, exon 20 C797S mutation, exon 21 L858R mutation, and copy number amplified EGFR mutation One or more mutations in.

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

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

In some embodiments, the KRAS mutation includes but is not limited to one or more of exon 2 G12C mutation, exon 2 G12V mutation, exon 2 G12A mutation, and exon 3 G61H mutation.

In some embodiments, the BRAF mutation includes, but is not limited to, the mutation of exon 15 V600E.

In some embodiments of the present application, the Met gene mutations include but are not limited to exon 14 skipping mutations, Met gene amplification, and the Met gene mutations cause c-Met abnormalities.

In this application, the chemotherapeutic drugs (chemotherapy drugs) include but are not limited to alkylating agents, including but not limited to bendamustine, carmustine, chlorambucil, chlorambucil, rolazine Mustard, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, ifosfamide, dacarbazine, temozolomide), antimetabolites, including but not limited to azacitidine, cytarabine, 5 -Fluorouracil, 6-mercaptopurine, capecitabine, decitabine, gemcitabine, fluorouridine, fludarabine, nelarabine, hydroxyurea, methotrexate, pratroxa, pemetrexed , Pentostatin, trifluridine/dipiforin combination), plant alkaloid (including but not limited to camptothecin) and antitumor antibiotics, including but not limited to daunorubicin , Doxorubicin, epirubicin, idarubicin, valrubicin, bleomycin, mitoxantrone), topoisomerase inhibitors (Topoisomerase inhibitors, including but not limited to irinotecan, topological One or more of tecan, etoposide, teniposide), and mitotic inhibitors (including but not limited to paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel).

In some embodiments, the chemotherapeutic drugs include but are not limited to platinum drugs, fluoropyrimidine derivatives, camptothecins, taxanes, vinblastines, anthracyclines, antibiotics, podophyllum One or more of tumors and antimetabolites. Examples that can be cited include but are not limited to platinum drugs (such as oxaliplatin, miplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin) , Lobaplatin, triplatin tetranitrate, phenanthroplatin, picoplatin, satraplatin, lobaplatin), fluoropyrimidine derivatives (e.g. gemcitabine, capecitabine, amphibin Fluorouridine, tegafur, carmofur, trifluorouridine), taxanes (e.g. paclitaxel, albumin-bound paclitaxel and docetaxel, camptothecins (e.g. camptothecin, hydroxycamptothecin) , 9-aminocamptothecin, 7-ethylcamptothecin, irinotecan, topotecan), vinblastines (vinorelbine, vinblastine, vincristine, vindesine, vinflunine) , Vinblastine), anthracyclines (epirubicin, doxorubicin, doxorubicin, daunorubicin, pirarubicin, amrubicin, idarubicin, mitoxene Quinone, arubicin, valrubicin, zorubicin, picotanone, pirarubicin), cytarabine, mercaptoguanine, pemetrexed, carmustine, melphalan, Etoposide (etoposide), teniposide, mitomycin, ifosfamide, cyclophosphamide, azacitidine, methotrexate, bendamustine, liposomal adriamycin , Actinomycin D (Dactinomycin), Bleomycin, Pingyangmycin, Temozolomide, Ammine, Pelomycin, Eribulin, Plenabulin, Sapacitabine, Trix One or more of treosulfan, 153Sm-EDTMP, ticgio, L-asparaginase, pegasparaginase, and encequidar.

In some embodiments, the platinum-based drugs include but are not limited to cisplatin, carboplatin, nedaplatin, oxaliplatin, miplatin, bicycloplatin, picoplatin, satraplatin, phenanthroplatin, tetranitrotriazine One or more of platinum or lobaplatin. In some embodiments, the other chemotherapeutic drugs refer to chemotherapeutic drugs other than platinum drugs, including but not limited to gemcitabine, paclitaxel, docetaxel, vinorelbine, pemetrexed, etoposide, irinote Kang, or topotecan.

In some embodiments, the platinum-based drug and one other chemotherapeutic drug are selected from a combination 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 of the driver gene-positive lung cancer has previously received other drug treatment, and the other drug is selected from the group consisting of docetaxel and nedaplatin, pemetrexed and nedaplatin, pemetrexed One or more of carboplatin, pemetrexed, pemetrexed, carboplatin and bevacizumab, pemetrexed and bevacizumab, bevacizumab and osimertinib Kind of combination.

In some embodiments, the kinase inhibitor includes, but is not limited to, Brigatinib, Osimertinib, Dacomitinib, Gefitinib, Afatinib, Erlotinib (Eerlotinib), Necitumumab, Icotinib, Olmutinib, Alectinib, Crizotinib, Lorlatinib, Certinib, Omedinib, Cabozantinib, Dacomitinib , Dabrafenib, Elpercatinib, Vorolanib, Pontatinib, Sitravatinib, Lenvatinib, or dovitinib.

In some embodiments, the EGFR inhibitor includes, but is not limited to, Brigatinib, Osimertinib, Dacomitinib, Gefitinib, Afatinib, Erlotinib , Necitumumab, Icotinib, or Olmutinib. In some embodiments, the EGFR-T790M inhibitor includes Osimertinib.

In some embodiments, the ALK inhibitor includes but is not limited to Brigatinib, Alectinib, Crizotinib, Lorlatinib, or Certinib.

In some embodiments, the ROS1 inhibitor includes but is not limited to Brigatinib, Crizotinib, Lorlatinib, or Certinib.

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

In some embodiments, the HER-2 inhibitor includes, but is not limited to, Dacomitinib, or 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, Pontatinib, Sitravatinib, Lenvatinib, or Dovitinib.

In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is BRAF p.V600E mutation. In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene-positive is BRAF p.V600E mutation, and the driver gene-positive lung cancer patient has received one or more of the following protocols Treatment of: 1) docetaxel and nedaplatin, 2) pemetrexed and nedaplatin, 3) pemetrexed and carboplatin, 4) pemetrexed, 5) erlotinib.

In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is EGFR del mutation and/or EGFR-T790M mutation. In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene positive is EGFR del mutation and/or EGFR-T790M mutation, and the driver gene-positive lung cancer patient has received one of the following protocols Or any two or more treatments: 1) pemetrexed, carboplatin and bevacizumab, 2) pemetrexed and bevacizumab, 3) bevacizumab and osimertinib, 4) Gefitinib, 5) Osimertinib.

In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, and the driver gene-positive is KIF5B-RET fusion gene positive. In some embodiments, the driver gene-positive lung cancer is lung adenocarcinoma, the driver gene-positive is KIF5B-RET fusion gene positive, and the driver-gene-positive lung cancer patient has received one or two of the following protocols Treatment: 1) Pemetrexed and carboplatin, 2) Pemetrexed.

In some embodiments, the patient suffering from the driver gene-positive lung cancer has received anti-VEGFR monoclonal antibodies (e.g. bevacizumab), antimetabolites (e.g. pemetrexed), taxanes (e.g. Docetaxel), platinum drugs (e.g. nedaplatin and/or carboplatin) and/or EGFR inhibitors (e.g. afatinib, erlotinib, gefitinib and/or osimertinib) treatment Non-small cell lung cancer patients with failed BRAF mutation, KIF5B mutation, RET mutation and/or EGFR mutation (such as BRAF p.V600E mutation, EGFR del mutation and/or EGFR-T790M mutation, KIF5B-RET fusion gene mutation).

Application method

The following content does not limit the administration mode of the drug combination of this application.

The components of the pharmaceutical composition of the present application can be administered independently, or part or all of them can be administered by various suitable routes, including but not limited to oral or parenteral (by intravenous, intramuscular, topical or subcutaneous way). In some embodiments, the components of the pharmaceutical combination of the present application may be individually administered orally or by injection, such as intravenous injection or intraperitoneal injection.

The components of the combined pharmaceutical composition of the present application may be independent of each other, or part or all of them may be a suitable dosage form together, including but not limited to tablets, troches, pills, capsules (such as hard capsules, soft capsules). Capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or non- The dosage form of a sustained-release preparation for oral administration.

The components in the combined drug combination of the present application may each independently, or part or all of them together contain a pharmaceutically acceptable carrier and/or excipient.

The combined drug combination of the present application may also include additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a cancer therapeutic agent known in the art, preferably a lung cancer therapeutic agent.

Technical effect

Generally, using the above-mentioned combination pharmaceutical composition of the application will help:

(1) Compared with administering any of the drugs in the combination alone, it produces a better curative effect in reducing tumor growth or even eliminating tumors;

(2) Compared with the single administration of any drug in the combination, it provides a smaller amount of administration;

(3) Provide a well-tolerated treatment in patients, which has fewer adverse reactions and/or complications compared with any single drug administered;

(4) Provide a better disease control rate among the treated patients;

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

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

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

(8) Compared with administering any of the drugs in the combination alone, it has good driver gene-positive lung cancer inhibitory activity and exhibits a more excellent anti-tumor synergistic effect.

Definition and description

Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be regarded as uncertain or unclear without a special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

As used in the text, the term "combined pharmaceutical composition" refers to two or more active ingredients administered simultaneously or sequentially (administered in the form of the respective active ingredients themselves, or in their respective pharmaceutically acceptable salts). Or esters and other derivatives, prodrugs or compositions). In this context, the terms "combined pharmaceutical composition" and "drug combination" are used interchangeably.

As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, and 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 can also include recombinant polypeptides, fusion proteins and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be of IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the antibody species encoded by the heavy chain constant region genes. 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 present invention can be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-PD-L1 antibody and its fragments can be chimeric antibodies, humanized antibodies or fully human antibodies. In one embodiment, the anti-PD-L1 antibody is an antibody produced by a hybridoma cell line derived from a mouse. Therefore, 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.

A "humanized antibody" is an antibody that contains a complementarity determining region (CDR) derived from a non-human antibody; and a framework region and constant region derived from a human antibody. For example, the anti-PD-L1 antibodies provided herein can include CDRs derived from one or more murine antibodies, as well as human framework and constant regions. Therefore, in one embodiment, the humanized antibody provided herein binds to the same epitope on PD-L1 as the murine antibody from which the CDR of the antibody is derived. Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy chain CDRs and light chain CDRs provided herein can be produced using any human framework sequence and are also included in the present invention. In one embodiment, framework sequences suitable for use in this application include those framework sequences that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or revert mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to the germline sequence. For example, in one embodiment, one or more amino acids in the human framework region of the VH and/or VL of the humanized antibody provided herein are backmutated to the corresponding amino acid in the parent murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several positions of the framework amino acids of the template human antibody were backmutated to the corresponding amino acid sequences in mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acid at position 53 and/or 60 and/or 67 of the light chain variable region is backmutated to the corresponding one found at that position in the mouse 5G11 or 13C5 light chain variable region Amino acids. 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 backmutated to 5G11 Or the corresponding amino acid found at that position in the variable region of the 13C5 heavy chain. 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) Is Tyr(Y); and the heavy chain variable region, in which the amino acid at position 24 is mutated from Phe(F) to Val(V), and the amino acid at position 49 is mutated from Ala(A) to Gly(G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was 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 in which the amino acid at position 28 The amino acid 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 was mutated from Tyr (Y) to Asp (D). Additional or alternative back mutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies. The present invention also includes humanized antibodies that bind to PD-L1 and include framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequence, as well as other ways to improve the antibody Other frame modifications of characteristics.

The present application provides isolated antibodies or fragments thereof that bind PD-L1, wherein the antibodies can be produced by hybridomas selected from the group consisting of hybridomas referred to herein as 13C5, 5G11. Therefore, this application also includes hybridomas 13C5, 5G11, and any hybridomas that produce the antibodies disclosed herein. The invention also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The present invention also includes an expression vector containing the isolated polynucleotide, and a host cell containing the expression vector.

The term "isolated antibody" refers to an antibody that contains substantially no other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds PD-1 contains substantially no specific binding other than PD-1 Antibodies to other antigens). However, an 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 antibody may be substantially free of other cellular materials and/or chemical substances.

The term "monoclonal antibody" ("mAb") refers to an antibody molecule composed of a single molecule (ie, an antibody molecule whose basic sequence is substantially the same, and which exhibits a single binding specificity and affinity for a specific epitope ) Non-naturally occurring preparations. mAb is an example of an isolated antibody. The mAb can be produced by hybridoma technology, recombinant technology, transgenic technology or other technologies known to those skilled in the art.

The antibodies and antigen-binding fragments thereof disclosed herein are specific to PD-L1. In one embodiment, the antibody or fragments thereof are specific to PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but not to PD-L1 from any other mammal. In another embodiment, the antibody or fragments thereof do not bind to mouse PD-L1. The terms "human PD-L1", "hPD-L1" and "huPD-L1" etc. are used interchangeably herein, and refer to human PD-L1 and human PD-L1 variants or isoforms. "Specificity" means that the antibody and its fragments 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 is partially or completely stable or cures the disease and/or side effects due to the disease, and can be therapeutic. "Treatment" as used herein covers any treatment of a patient's disease, including: (a) inhibiting the symptoms of the disease, that is, preventing its development; or (b) alleviating the symptoms of the disease, that is, causing the disease or symptoms to degenerate.

The term "effective amount" means (i) treating a given disease, condition, or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) delaying what is described herein The amount of the compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder. The amount of the active substance (such as the antibody or compound of the present application) that constitutes a "therapeutically effective amount" may vary depending on factors such as the individual’s disease state, age, sex, and weight, and the therapeutic agent or combination of therapeutic agents triggers in the individual The ability to respond. The effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

The term "administering" refers to the physical introduction of a composition containing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. The route of administration of immune checkpoint inhibitors (for example, anti-PD-1 antibody or anti-PD-L1 antibody) includes 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 local administration that are usually performed by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, and intralymphatic , Intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspine, epidural and intrasternal injections and infusions , And electroporation in vivo. In certain embodiments, the immune checkpoint inhibitor (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) is administered by a non-parenteral route, and in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, for example, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, for example, once, multiple times, and/or over one or more extended periods of time.

Unless otherwise stated, the use of the term "dose" refers to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60 kg person and a 100 kg person will receive the same dose of antibody (e.g., 240 mg of anti-PD-1 antibody).

The term "weight-based dose" mentioned herein refers to the dose calculated based on the weight of the patient and administered to the patient. For example, when a patient with a weight of 60 kg needs 3 mg/kg of anti-PD-1 antibody, one can draw an appropriate amount of anti-PD-1 antibody (ie, 180 mg) from a fixed-dose preparation of anti-PD-1 antibody at one time.

Anlotinib can be administered by a variety of routes, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, and transdermal Inhalation, vaginal, intraocular, topical administration, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally. The amount of Anlotinib administered can 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 anlotinib may be 2 mg to 20 mg. In some embodiments, the daily dose of anlotinib 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. Anlotinib can be administered one or more times a day. In some embodiments, Anlotinib is administered as an oral solid formulation once a day.

The dosage regimen of Anlotinib can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug. Preferably, anlotinib is administered in an interval dosing manner. The interval administration includes an administration period and a drug withdrawal period, during which anlotinib can be administered once or multiple times a day. For example, the ratio of the administration period and the drug withdrawal period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1. In some embodiments, the administration is continued for 2 weeks and the drug is stopped for 2 weeks. In some embodiments, the administration is continued for 2 weeks and the drug is stopped for 1 week. In some embodiments, the drug is discontinued for 2 days for 5 consecutive days. For example, Anlotinib can be administered orally at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day for 2 weeks with a 1-week stop.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues, but not Many toxicity, irritation, allergic reactions or other problems or complications are commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts formed by alkali ions and free acids or salts formed by acid ions and free bases, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, methyl Acid salt, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluenesulfonate Acid salt, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate Acid salt, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In this application, when a pharmaceutically acceptable salt is formed, the molar 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.

In this context, the terms "subject" or "patient" or "subject" are used interchangeably. 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" should be understood to include within three standard deviations of the average value or within the standard tolerance range in a specific field. In certain embodiments, about should be understood as a variation not exceeding 0.5. "About" modifies all values listed thereafter. For example, "about 1, 2, 3" means "about 1", "about 2", "about 3".

As used herein, "combination" or "combination" 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 certain amount of medicine. For example, a box of medicines has seven capsules, and each capsule is a single dose; or each bottle of injection is a single dose. In this document, the terms "single dose" and "unit dose" have the same meaning and can be used interchangeably.

The term "multi-dose" consists of multiple single doses.

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

In this article, unless otherwise stated, the terms "comprise, include and contain (comprise, comprises and comprising)" or equivalents are open-ended expressions, meaning that in addition to the listed elements, components and steps, Cover other unspecified elements, components and steps.

For the purpose of description and disclosure, all patents, patent applications and other established publications are expressly incorporated herein by reference. These publications are only provided because their publication is earlier than the filing date of this application. All statements regarding the dates of these documents or the representation of the contents of these documents are based on the information available to the applicant and do not constitute any recognition of the correctness of the dates of these documents or the contents of these documents. Moreover, in any country, any reference to these publications in this article does not constitute an endorsement that the publication has become part of the common knowledge in the field.

Detailed ways

For the sake of clarity, examples are further used to illustrate the present invention, but the examples do not limit the scope of the application. All reagents used in this application are commercially available and can be used without further purification. The anti-PD-L1 antibody in the examples was prepared according to the method described in WO2016022630, and after affinity chromatography, an eluate containing the antibody was obtained according to a conventional antibody purification method.

Example 1 Clinical trial

1.1 Selection criteria

1. No gender limit, age ≥18 years old;

2. The ECOG score is 0 to 1, and the expected survival time is ≥12 weeks;

3. Histologically or cytologically diagnosed as driver gene-positive non-small cell lung cancer (including but not limited to EGFK/ALK/ROS-1/c-MET/RET/HER-2/BRAF-V600E, the detection method refers to clinical practice) , And subject to stage IIIB/IV as defined in the TNM staging system of the 8th edition of the IASLC;

4. Failure after standard treatment, definitions include but not limited to the following:

4.1 EGFR gene sensitive mutation positive: it needs to undergo at least one EGFR-TKI inhibitor treatment failure, and at least one chemotherapy regimen including platinum-containing dual-drug regimen has failed treatment; if there is a patient with EGFR-T790M mutation, it must have been accepted Can be selected after the third-generation EGFR inhibitor treatment fails;

4.2 Patients with positive ALK gene rearrangements must undergo treatment failure with ALK inhibitors and at least one chemotherapy regimen including platinum-containing dual-drug regimens. If patients have only received crizotinib treatment, they need to receive another A new generation of ALK inhibitor treatment failed.

4.3 Patients with positive ROS1 gene rearrangement must undergo ROS1 inhibitor treatment failure, and at least one chemotherapy regimen including platinum-containing dual-drug regimens has failed treatment;

4.4 Patients with positive gene mutations need to receive at least one chemotherapy regimen including platinum-containing dual-drug regimens for treatment failure;

5. According to RECIST 1.1, the curative effect evaluation standard for solid tumors, at least one measurable lesion;

6. The main organs function during the screening period are normal, that is, they meet the following criteria:

① Routine blood examination (no blood transfusion within 14 days):

●The absolute value of neutrophils (ANC)≥1.5×10 ⁹ /L;

●Platelet count (PLT) ≥75×10 ⁹ /L;

●Hemoglobin (Hb) ≥80g/L;

②Blood biochemical examination:

●Total bilirubin (TBIL)≤1.5×ULN;

●Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤3×ULN (for liver metastases, ≤5×ULN);

● Serum creatinine (Cr)≤1.5×ULN, and creatinine clearance (Ccr)≥50ml/min (according to the standard Cockcroft-Gault formula);

③Urine routine

●Urine protein <2+ (when baseline urine protein ≥ 2+, a 24-hour urine protein quantitative test within 7 days, only when urine protein <1g can be selected);

④Cagulation function

●INR and APTT≤1.5×ULN;

⑤ Heart function

●Left ventricular ejection fraction (LVEF) ≥50%;

7. Women must meet one of the following conditions:

① Surgical sterilization has been performed;

②Patients who have been menopausal, have menopause for at least 1 year;

③Have fertility and must meet the following conditions:

Serum/urinary pregnancy test results were negative before enrollment in this study; during the entire study period, agreed to adopt an approved method of contraception (for example: oral contraception, injection contraception or implanted, barrier-effect contraceptive method, spermicide And condoms, or intrauterine contraceptive devices), and the contraceptive method remained unchanged throughout the study period.

Males must meet one of the following conditions:

① Surgical sterilization has been performed;

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

1.2 Test drug

Anti-PD-L1 antibody injection hu5G11-hIgG1: 1200 mg of anti-PD-L1 antibody injection is diluted with normal saline to 250mL, the infusion time is 60±10min, after the infusion is completed, the normal saline flushing tube is performed according to the hospital's routine requirements, and it is given every 21 days The medicine is given once, that is, 21 days as a treatment cycle.

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

Anlotinib hydrochloride capsules (active ingredient is Anlotinib dihydrochloride): the starting dose is 12 mg. The anti-PD-L1 antibody injection was administered on an empty stomach within ±5min, and anlotinib hydrochloride capsules were taken on an empty stomach, one capsule per day, oral administration for 2 weeks and 1 week stop, ie 21 days is a treatment cycle.

For Anlotinib Hydrochloride Capsules, 3 dose levels are designed, starting dose 12mg, dose level 1 is 10mg, and dose level 2 is 8mg. Any subject who needs to reduce the dose of Anlotinib Hydrochloride Capsules will continue to receive reduced dose treatment in subsequent cycles.

Specifications: 12mg, 10mg, 8mg, or 6mg.

1.3 Evaluation criteria

Determine the disease status according to RECIST 1.1.

1.4 Efficacy evaluation

ORR (Objective Response Rate): The proportion of subjects whose disease has been assessed as CR (complete response) + PR (partial response);

PFS (Progress-Free Survival): Randomly enrolled until disease progression or death (whichever comes first);

OS (overall survival): the time from randomization to death from all causes. For subjects who were alive at the last follow-up, their OS was counted as data censored based on the last follow-up time. For subjects who are lost to follow-up, their OS is counted as data censorship based on the last confirmed survival time before loss to follow-up;

DCR (Disease Control Rate): The proportion of patients whose tumors have shrunk or stabilized for a certain period of time, including CR, PR and SD (stable disease) cases; or

Health-related quality of life (EORTC QLQ-C30 and EORTC QLQ-LC13): Observe the changes in clinical symptoms and objective examination results of tumor patients before and after treatment to score, and score the results of each area of the scale according to the requirements of the quality of life scale Recorded in EDC.

1.5 Results

1.6 Past treatment history of each patient

Patient 001 has previously received chemotherapy and targeted therapy:

化疗方案描述Description of chemotherapy regimen	治疗周期Treatment cycle
多西紫杉醇+奈达铂Docetaxel + Nedaplatin	33
培美曲塞+奈达铂Pemetrexed + Nidaplatin	11
培美曲塞+卡铂Pemetrexed + Carboplatin	66
培美曲塞Pemetrexed	3737

Targeted therapy drug: Erlotinib.

Patient 008 has previously received chemotherapy and targeted therapy:

化疗方案描述Description of chemotherapy regimen	治疗周期Treatment cycle
培美曲塞+卡铂+贝伐珠单抗Pemetrexed + carboplatin + bevacizumab	33
培美曲塞+贝伐珠单抗Pemetrexed + Bevacizumab	22
贝伐珠单抗+奥希替尼Bevacizumab + Osimertinib	---

Targeted therapy drugs: gefitinib and osimertinib.

024 patients have received chemotherapy in the past:

化疗方案描述Description of chemotherapy regimen	治疗周期Treatment cycle
培美曲塞+卡铂Pemetrexed + Carboplatin	44
培美曲塞Pemetrexed	66

In the above embodiment, the amount of anlotinib hydrochloride capsules is based on the weight of anlotinib free base contained therein, and each dosing cycle is 21 days, and C6, C14, and C17 indicate 6 administration cycles, 14 cycles and 17 cycles.

Claims

A combined pharmaceutical composition for treating driver gene-positive lung cancer, which includes an anti-PD-L1 antibody and anlotinib.
The combination pharmaceutical composition according to claim 1, wherein the combination pharmaceutical composition comprises an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition.
The combination pharmaceutical composition according to any one of claims 1 or 2, wherein the combination pharmaceutical composition is packaged in the same kit, and the kit further comprises a combination of PD-L1 antibody and anlotinib Instructions for using the treatment of driver-positive lung cancer.
The combination pharmaceutical composition according to any one of claims 1-3, wherein the combination pharmaceutical composition comprises a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, A pharmaceutical composition of 10mg and/or 12mg Anlotinib.
The combination pharmaceutical composition according to any one of claims 1-4, wherein the combination pharmaceutical composition comprises a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1. The most preferred (7-14.5):1 anti-PD-L1 antibody and anlotinib.
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 (for example, a treatment cycle of 21 days), including 600-2400 mg of anti-PD-L1 antibody pharmaceutical composition and 84-168 mg of anlotinib.
The use of the combination pharmaceutical composition according to any one of claims 1-6 in the preparation of a medicament for the treatment of driver gene-positive lung cancer.
The use of anti-PD-L1 antibody and anlotinib in the preparation of drugs for treating lung cancer with positive driving genes.
The use according to any one of claims 7 or 8, wherein the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.
The use according to any one of claims 7-9, wherein the anti-PD-L1 antibody is administered once every week, every 2 weeks, every 3 weeks, or every 4 weeks, preferably at 600-2400 mg each time Dosage administration.
The use according to any one of claims 7-10, wherein the anlotinib is administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 weeks with a 1-week stop .
A kit for the treatment of driver gene-positive lung cancer, the kit comprising an anti-PD-L1 antibody pharmaceutical composition and anlotinib pharmaceutical composition, and an anti-PD-L1 antibody and anlotinib combined use treatment driver Description of gene-positive lung cancer.
The kit according to claim 12, wherein the kit is a kit suitable for administration in a single treatment cycle (for example, a treatment cycle of 21 days), including a kit containing 600-2400 mg of anti-PD-L1 antibody Pharmaceutical composition and pharmaceutical composition containing 84-168 mg anlotinib.
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 any one of claims 12 or 13, wherein The anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; and SEQ ID NO: 2 or SEQ ID A heavy chain CDR2 region with at least 80% homology to the amino acid sequence shown in NO: 5; a heavy chain CDR3 region with 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 with the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; having at least the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 11 A light chain CDR2 region with 80% homology; a light chain CDR3 region with at least 80% homology with the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO: 12.
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 any one of claims 12 or 13, wherein 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; From SEQ ID NO: 3 or SEQ ID NO: 6 heavy chain CDR3 region; selected from SEQ ID NO: 7 or SEQ ID NO: 10 light chain CDR1 region; selected from SEQ ID NO: 8 or SEQ ID NO: 11 The CDR2 region of the light chain; the CDR3 region of the light chain selected from SEQ ID NO: 9 or SEQ ID NO: 12.
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 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 an amino acid sequence shown in SEQ ID NO: 2, and having a heavy chain CDR2 region shown in SEQ ID NO: The heavy chain CDR3 region with the amino acid sequence shown in 3; and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 7, and the light chain CDR2 region with the amino acid sequence shown in SEQ ID NO: 8, with The light chain CDR3 region of the amino acid sequence shown in SEQ ID NO: 9.
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 The -L1 antibody comprises the following amino acid sequence: a heavy chain variable region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14; and SEQ ID NO: 15 or SEQ ID NO: The amino acid sequence shown in 16 has a light chain variable region with at least 80% homology.
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 any one of claims 12 or 13, wherein The anti-PD-L1 antibody comprises the following amino acid sequence: it comprises a variable heavy chain selected from a humanized antibody of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4, and a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4 , Hu5G11-hIgG1 or hu5G11-hIgG4 humanized variable light chain.
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 anlotinib In the form of a free base, or in the form of a pharmaceutically acceptable salt thereof.
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 any one of claims 12 or 13, wherein The positive driver gene includes one or more of EGFR mutation, ALK mutation, ROS1 mutation, KRAS mutation, c-MET mutation, HER-2 mutation, BRAF mutation, KIF5B mutation, and RET mutation.
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 any one of claims 12 or 13, wherein The driver gene-positive lung cancer is a BRAF mutation, KIF5B mutation, RET mutation and/or EGFR mutation that has received anti-VEGFR monoclonal antibodies, antimetabolites, taxanes, platinum drugs, and/or EGFR inhibitors. Of non-small cell lung cancer.