Pharmaceutical composition for treating ovarian cancer

Abstract

The invention belongs to the field of biological medicine, and relates to a pharmaceutical composition for treating ovarian cancer, in particular to a pharmaceutical composition, a combined pharmaceutical composition, a kit and application thereof.

Description

[0001] This application is a divisional application of the invention patent application with the invention name “Drug combination for treating ovarian cancer”, the application date is December 24, 2020, and the application number is 202011549093.5. Technical Field

[0002] The present application belongs to the field of biomedicine and relates to drug combinations, combined drug compositions, kits and their uses for treating ovarian cancer. Background Art

[0003] Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues. They play a crucial role in intracellular signal transduction, participating in the regulation, signaling, and development of normal cells. They are also closely associated with the proliferation, differentiation, migration, and apoptosis of tumor cells. Many receptor tyrosine kinases are associated with tumor formation. Based on the structure of their extracellular domains, they can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), and others.

[0004] PD-L1 (Programmed death-ligand 1), also known as CD247 and B7-H1, is a ligand for programmed death 1 (PD-1). PD-L1 is highly expressed on the surface of various tumor cells, and tumor malignancy and poor prognosis are closely correlated with PD-L1 expression levels. Within the tumor microenvironment, PD-L1 on cancer cells binds to PD-1 or CD80 on T cells, inhibiting T cell activation and proliferation, promoting effector T cell exhaustion or anergy, inducing T cell apoptosis, and stimulating helper T cells to differentiate into regulatory T cells, thereby preventing T cells from killing tumor cells. Anti-PD-L1 antibodies can block the interaction between PD-L1, PD-1, and CD80, preventing the initiation and transmission of related negative regulatory signals. This prevents the inhibition of effector T cell activity in the tumor microenvironment, allowing T cells to fully exert their functions of killing and suppressing tumor cells. Because they can act directly on tumor tissue, anti-PD-L1 antibodies have high specificity and safety.

[0005] Ovarian cancer ranks third in incidence among female reproductive system malignancies and has the highest mortality rate among gynecological malignancies. Globally, the incidence rate in developed countries is 9.1 per 100,000 women, while in developing countries it is 5.0 per 100,000. In 2018, an estimated 22,240 women in the United States were diagnosed with ovarian cancer, and 14,070 died from the disease.

[0006] Currently, the standard treatment for advanced ovarian cancer mainly includes comprehensive ovarian cancer staging surgery / tumor cell reduction surgery, and postoperative platinum-based first-line chemotherapy. Although the prognosis of ovarian cancer patients has improved significantly over the past 20 years with the improvement of surgical skills and the clinical application of paclitaxels, platinums, and numerous second-line chemotherapy drugs, the 5-year survival rate of patients with advanced disease is still less than 30%. Most patients with advanced disease eventually experience disease recurrence after completing standard treatment. Clinically, depending on the time of recurrence after the patient receives platinum-containing chemotherapy, recurrence occurring more than 6 months after the end of chemotherapy is considered platinum-sensitive recurrence; recurrence occurring within 6 months after the end of chemotherapy is considered platinum-resistant recurrence. Unfortunately, almost all platinum-sensitive patients will eventually develop platinum resistance. These patients have a poor prognosis and a short survival period, which is a current research hotspot in ovarian cancer. Treatment options for platinum-resistant ovarian cancer are very limited. Available chemotherapy drugs include liposomal doxorubicin, gemcitabine, topotecan, etoposide, and docetaxel. However, the objective response rate (ORR) of these single-agent chemotherapy regimens is only approximately 10%-30%, and the median progression-free survival (PFS) is only 3-4 months. Therefore, the clinical search for new and effective drugs to treat platinum-resistant patients is particularly urgent. SUMMARY OF THE INVENTION

[0007] In one aspect, the present application provides a drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0008] On the other hand, the present application provides a combination pharmaceutical composition for treating ovarian cancer, which includes an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0009] Furthermore, anlotinib is in the form of a free base or a pharmaceutically acceptable salt thereof. For example, the pharmaceutically acceptable salt of anlotinib may be a hydrochloride or a dihydrochloride.

[0010] Furthermore, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region that is at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 region that is at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region that is at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region that is at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region that is at least 80% homologous to the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region that is at least 80% homologous to 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 region selected from SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region selected from SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region selected from SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region selected from SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region selected from 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 set forth in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 3; and a light chain CDR1 region having the amino acid sequence set forth in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence set forth in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence set forth in SEQ ID NO: 9. Furthermore, the anti-PD-L1 antibody comprises the following amino acid sequences: a heavy chain variable region having at least 80% homology to the amino acid sequence set forth in SEQ ID NO: 13 or SEQ ID NO: 14; and a light chain variable region having at least 80% homology to the amino acid sequence set forth in SEQ ID NO: 15 or SEQ ID NO: 16.Furthermore, the anti-PD-L1 antibody comprises: a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable light chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody.

[0011] Furthermore, the above-mentioned combination pharmaceutical composition of the present application is packaged in the same kit, which also includes instructions for the combined use of PD-L1 antibody and anlotinib to treat ovarian cancer.

[0012] Furthermore, the present application provides a combination pharmaceutical composition comprising a pharmaceutical composition containing 600-2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition containing anlotinib in a single dose of 6 mg, 8 mg, 10 mg, and / or 12 mg. The pharmaceutical composition containing the anti-PD-L1 antibody is a single dose or multiple doses.

[0013] Furthermore, the present application provides a combination pharmaceutical composition, which includes a pharmaceutical composition containing 600 to 2400 mg of anti-PD-L1 antibody provided in multiple doses and a pharmaceutical composition containing a single dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib.

[0014] Furthermore, the present application provides a combination pharmaceutical composition, which is a preparation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), comprising a pharmaceutical composition containing 600 to 2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition containing 84 to 168 mg of anlotinib (e.g., a pharmaceutical composition containing 1200 mg of an anti-PD-L1 antibody and a pharmaceutical composition containing 168 mg of anlotinib).

[0015] Furthermore, the present application provides a combination pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1. The anti-PD-L1 antibody and anlotinib can be packaged separately or together. Furthermore, anlotinib can be packaged in multiple aliquots (e.g., 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots, or more); and the anti-PD-L1 antibody can be packaged in a single aliquot or multiple aliquots (e.g., 2 aliquots, 4 aliquots, or more).

[0016] In another aspect, the present application further provides the use of the drug combination, or the combination pharmaceutical composition, or the kit of the present application in the preparation of a medicament for treating ovarian cancer in a patient. The present application further provides a method for treating ovarian cancer, comprising administering an effective amount of the drug combination, or the combination pharmaceutical composition, or the kit of the present application to a patient in need thereof. The present application further provides the use of the drug combination, or the combination pharmaceutical composition, or the kit of the present application in treating ovarian cancer in a patient.

[0017] On the other hand, the present application also provides the use of an anti-PD-L1 antibody and anlotinib in combination to prepare a drug for treating ovarian cancer. Alternatively, the present application also provides a method for treating ovarian cancer, comprising administering an effective amount of an anti-PD-L1 antibody and anlotinib to a subject. The present application also provides the use of an anti-PD-L1 antibody and anlotinib in combination to treat ovarian cancer. Alternatively, the present application also provides a combination of an anti-PD-L1 antibody and anlotinib for treating ovarian cancer.

[0018] Furthermore, the anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially, or intermittently. Furthermore, the anti-PD-L1 antibody is administered weekly, every two weeks, every three weeks, or every four weeks; preferably, the anti-PD-L1 antibody is administered at a dose of 600 to 2400 mg each time. Furthermore, anlotinib is administered once daily at a dose of 6 mg, 8 mg, 10 mg, or 12 mg for two consecutive weeks followed by one week off.

[0019] In addition, the present application provides a kit for treating ovarian cancer, which includes a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, as well as instructions for treating ovarian cancer.

[0020] Furthermore, the above kit is a kit suitable for administration within a single treatment cycle (e.g., a treatment cycle of 21 days), comprising a pharmaceutical composition containing 600 to 2400 mg of an anti-PD-L1 antibody and a pharmaceutical composition containing 84 to 168 mg of anlotinib. Detailed Description of the Invention

[0022] Drug combinations

[0023] In one aspect, the present application provides a drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments of the present application, the drug combination comprises an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof is a fixed combination. In some embodiments, the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition. In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof is a non-fixed combination. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in the non-fixed combination are each in the form of a pharmaceutical composition.

[0025] In some embodiments of the present application, the drug combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises:

[0026] i) In one embodiment, the anti-PD-L1 antibody is an antibody in WO2016022630 or CN107001463A. Further, the anti-PD-L1 antibody is selected from the heavy chain complementary determining region (CDR) of 13C5 or 5G11 antibody, and the light chain complementary determining region selected from 13C5 or 5G11 antibody; In one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibody, and a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, c h13C5-hIgG1, ch13C5-hIgG4 chimeric antibody variable light chain; In one embodiment, the anti-PD-L1 antibody comprises a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable heavy chain selected from hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody. Variable light chain; In one embodiment, the anti-PD-L1 antibody is selected from: 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4, the HCDR1 sequence is SYGMS, the HCDR2 sequence is SISSGGSTYYPDSVKG, the HCDR3 sequence is GYDSGFAY, the LCDR1 sequence is ASQSVSTSSSSFMH, the LCDR2 sequence is YASNLES, LCD The R3 sequence is QHSWEIPYT; the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 is TYGVH, the HCDR2 sequence is VIWRGVTTDYNAAFMS, the HCDR3 sequence is LGFYAMDY, the LCDR1 sequence is KASQSVSNDVA, the LCDR2 sequence is YAANRYT, and the LCDR3 sequence is QQDYTSPYT;

[0027] ii) anlotinib or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, a pharmaceutical combination is provided, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1. The anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be packaged separately or together. Furthermore, anlotinib or a pharmaceutically acceptable salt thereof can be packaged in multiple equal portions (e.g., 2 equal portions, 7 equal portions, 14 equal portions, 28 equal portions, or more equal portions).

[0029] Combination drug composition

[0030] On the other hand, the present application provides a combination pharmaceutical composition for treating ovarian cancer, which includes an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; or, it includes the aforementioned drug combination.

[0031] In some embodiments of the present application, the combination pharmaceutical composition includes an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; or, it includes the above-mentioned anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments of the present application, the combination pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises an anti-PD-L1 antibody pharmaceutical composition and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments of the present application, the combination pharmaceutical composition is packaged in the same kit, which also includes instructions for the combined use of the PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof to treat ovarian cancer.

[0033] In some embodiments of the present application, the combination pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises a pharmaceutical composition containing 600-2400 mg of an anti-PD-L1 antibody and a single dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the anti-PD-L1 antibody is a single dose or multiple doses.

[0034] In some embodiments of the present application, the combination pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof includes an anti-PD-L1 antibody pharmaceutical composition having an anti-PD-L1 antibody concentration of 10-60 mg / mL and a pharmaceutical composition having a single dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib.

[0035] In some embodiments of the present application, the combination pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof includes an anti-PD-L1 antibody pharmaceutical composition having an anti-PD-L1 antibody concentration of 10 mg / mL and a pharmaceutical composition having a single dose of 8 mg, 10 mg and / or 12 mg of anlotinib.

[0036] In some embodiments, a combination pharmaceutical composition for treating ovarian cancer is provided, comprising a pharmaceutical composition containing 1200 mg of an anti-PD-L1 antibody provided in multiple doses and a pharmaceutical composition containing a single dose of 8 mg and / or 10 mg of anlotinib or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, a combination pharmaceutical composition for treating ovarian cancer is provided, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof in a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1. The anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be packaged separately or together. Anlotinib can be packaged in multiple equal parts (e.g., 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts, or more).

[0038] Reagent test kit

[0039] In another aspect, the present application provides a kit for treating ovarian cancer, the kit comprising an anti-PD-L1 antibody pharmaceutical composition and anlotinib or a pharmaceutically acceptable salt thereof, and instructions for combined use to treat ovarian cancer; in some embodiments, a kit for treating ovarian cancer is provided, the kit comprising an anti-PD-L1 antibody pharmaceutical composition, which further contains anlotinib or a pharmaceutically acceptable salt thereof, and instructions for combined use to treat ovarian cancer; or, the kit comprises the drug combination or combination pharmaceutical composition of the present application, and instructions for combined use to treat ovarian cancer.

[0040] use

[0041] In another aspect, the present application also provides the use of the drug combination, or the combined pharmaceutical composition, or the kit of the present application in the preparation of a medicament for treating ovarian cancer in a patient. The present application also provides a method for treating ovarian cancer in a patient, comprising administering an effective amount of the drug combination, or the combined pharmaceutical composition, or the kit of the present application to a patient in need thereof. The present application also provides the use of the drug combination, or the combined pharmaceutical composition, or the kit of the present application in treating ovarian cancer in a patient. The drug combination, or the combined pharmaceutical composition, or the kit is as described above.

[0042] In some embodiments of the present application, in the above-mentioned uses or treatment methods, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially or intermittently.

[0043] In some embodiments of the present application, in the above-mentioned uses or treatment methods, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each administered in an intermittent manner. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered in the same or different dosing regimens. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered in different dosing regimens.

[0044] In some embodiments of the present application, the use or treatment method, the anti-PD-L1 antibody can be administered once a week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). 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 to 2400 mg each time. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1200 mg each time.

[0045] In some embodiments of the present application, anlotinib or a pharmaceutically acceptable salt thereof can be administered at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once daily for 2 consecutive weeks followed by 1 week of rest. In this case, one administration cycle is 3 weeks.

[0046] In some embodiments of the present application, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof have the same or different administration cycles. In some specific embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof have the same administration cycle, for example, every 1 week, every 2 weeks, every 3 weeks or every 4 weeks as one administration cycle.

[0047] In some embodiments of the present application, in the dosing regimen of the drug combination or combination pharmaceutical composition, or in the use or treatment method, a 21-day dosing cycle is defined as one cycle, and the PD-L1 antibody is administered on the first day of each dosing cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each cycle. In a specific embodiment, the PD-L1 antibody is administered once on the first day of each cycle, and anlotinib or a pharmaceutically acceptable salt thereof is administered once daily on days 1 to 14 of each cycle.

[0048] In some embodiments of the present application, in the use or treatment method, the anti-PD-L1 antibody may be administered at a dose 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; or administered to a patient at a dose of 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 900 mg to 1200 mg.

[0049] In some embodiments of the use or treatment method, 21 days is a dosing cycle, 1200 mg of PD-L1 antibody is administered on the first day of each cycle, and 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib or a pharmaceutically acceptable salt thereof is administered daily on days 1 to 14 of each cycle.

[0050] In some embodiments of the present application, in one treatment cycle every three weeks, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered to the subject at a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, and most preferably (7-14.5):1, wherein the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered in a single dose and multiple doses, respectively.

[0051] In yet another aspect, the present application further provides an anti-PD-L1 antibody for treating ovarian cancer. The present application further provides a method for treating ovarian cancer, comprising administering an effective amount of the anti-PD-L1 antibody of the present application to a patient. The present application further provides the use of the anti-PD-L1 antibody for treating ovarian cancer. The present application further provides the use of the anti-PD-L1 antibody in the preparation of a medicament for treating ovarian cancer.

[0052] Anti-PD-L1 antibodies

[0053] In some embodiments of the present application, the anti-PD-L1 antibody is the antibody in WO2016022630. Further, in some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous to the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) homologous to the amino acid sequence of SEQ ID NO:5; a heavy chain CDR3 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) homologous to the amino acid sequence of SEQ ID NO:3 or SEQ ID NO:6; a light chain CDR1 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous to the amino acid sequence of SEQ ID NO: 10; a light chain CDR2 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous to the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 11; The amino acid sequence shown in NO:12 has a light chain CDR3 region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homologous.

[0054] 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; a heavy chain CDR2 region selected from SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region selected from SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region selected from SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region selected from SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region selected from SEQ ID NO: 9 or SEQ ID NO: 12.

[0055] In some embodiments of the present application, the anti-PD-L1 antibody described herein comprises: a heavy chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 2, and a heavy chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 3; and a light chain CDR1 region having the amino acid sequence shown in SEQ ID NO: 7, a light chain CDR2 region having the amino acid sequence shown in SEQ ID NO: 8, and a light chain CDR3 region having the amino acid sequence shown in SEQ ID NO: 9.

[0056] Each CDR region described herein and its various variants described above can specifically recognize and bind to PD-L1, thereby effectively blocking the signal transduction between PD-L1 and PD-1.

[0057] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) homologous to the amino acid sequence of SEQ ID NO: 13 or SEQ ID NO: 14; and a light chain variable region that is at least 80% (e.g., 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) homologous to the amino acid sequence of SEQ ID NO: 15 or SEQ ID NO: 16.

[0058] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: 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.

[0059] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region as shown in SEQ ID NO: 14; and a light chain variable region as shown in SEQ ID NO: 16.

[0060] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO: 17; and a light chain amino acid sequence as shown in SEQ ID NO: 18.

[0061] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO: 19; and a light chain amino acid sequence as shown in SEQ ID NO: 20.

[0062] In some embodiments of the present application, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain amino acid sequence as shown in SEQ ID NO: 21; and a light chain amino acid sequence as shown in SEQ ID NO: 18.

[0063] In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided herein comprises one or more conservative substitution variants 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, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, and SEQ ID NO. 21. The anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.

[0064] In some embodiments of the present application, the anti-PD-L1 antibody may be an IgG1 or IgG4 antibody.

[0065] In some embodiments of the present application, the anti-PD-L1 antibody is an IgG1 antibody. In some embodiments, the anti-PD-L1 antibody is a glycosylated IgG1 antibody.

[0066] In some embodiments of the present application, the anti-PD-L1 antibody is a humanized antibody. In some embodiments of the present application, the anti-PD-L1 antibody is a humanized monoclonal antibody.

[0067] In some embodiments of the present application, the anti-PD-L1 antibody is an antibody in WO2016022630. Further, in some embodiments of the present application, the anti-PD-L1 antibody comprises a heavy chain complementary determining region (CDR) selected from 13C5 or 5G11 antibodies, and a light chain complementary determining region selected from 13C5 or 5G11 antibodies. In one embodiment, the anti-PD-L1 antibody described herein comprises a variable heavy chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and a variable light chain selected from ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies. In one embodiment, the anti-PD-L1 antibody described herein comprises a variable heavy chain selected from a hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody, and a variable light chain selected from a hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 humanized antibody. Reference may be made to the records of patent documents WO2016022630 or CN107001463A: the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5), the HCDR3 sequence is GYDSGFAY (SEQ ID NO: 6), the LCDR1 sequence is ASQSVSTSSSSFMH (SEQ ID NO: 10), the LCDR2 sequence is YASNLES (SEQ ID NO: 11), and the LCDR3 sequence is QHSWEIPYT (SEQ ID NO: 12). NO:12); the HCDR1 sequence of 5G11, ch5G11-hIgG1, ch5G11-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 is TYGVH (SEQ ID NO:1), the HCDR2 sequence is VIWRGVTTDYNAAFMS (SEQ ID NO:2), the HCDR3 sequence is LGFYAMDY (SEQ ID NO:3), the LCDR1 sequence is KASQSVSNDVA (SEQ ID NO:7), the LCDR2 sequence is YAANRYT (SEQ ID NO:8), and the LCDR3 sequence is QQDYTSPYT (SEQ ID NO:9).

[0068] In some embodiments of the present application, the anti-PD-L1 antibody in the drug combination can be selected from one or more. As used herein, the term "multiple" 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 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 a heavy chain variable region as shown in SEQ ID NO: 14 and a light chain variable region as shown in SEQ ID NO: 16, or a combination thereof. For another example, the anti-PD-L1 antibody is selected from a heavy chain amino acid sequence as shown in SEQ ID NO: 17 and a light chain amino acid sequence as shown in SEQ ID NO: 18, or a heavy chain amino acid sequence as shown in SEQ ID NO: 19 and a light chain amino acid sequence as shown in SEQ ID NO: 20, or a heavy chain amino acid sequence as shown in SEQ ID NO: 21 and a light chain amino acid sequence as shown in SEQ ID NO: 18, or a combination thereof.

[0069] Anlotinib

[0070] 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-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, which has the following structural formula:

[0071]

[0072] In some embodiments, the pharmaceutically acceptable salt of anlotinib may be hydrochloride or dihydrochloride. The dosage of anlotinib or its pharmaceutically acceptable salts involved in this application, unless otherwise specified, is based on the molecular weight of anlotinib free base.

[0073] Pharmaceutical compositions of anti-PD-L1 antibodies

[0074] In some embodiments of the present application, a single dose of the anti-PD-L1 antibody pharmaceutical composition comprises 300 mg or 600 mg of the anti-PD-L1 antibody.

[0075] In some embodiments of the present application, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody is 600 to 2400 mg. In some embodiments, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody is selected from 600 mg, 900 mg, 1200 mg, 1500 mg, 1800 mg, 2100 mg, 2400 mg, or a range formed by any of the above values. In some embodiments, the total dose of the pharmaceutical composition of the anti-PD-L1 antibody is preferably 600 to 2100 mg, or 900 mg to 1500 mg.

[0076] In some embodiments of the present application, the pharmaceutical composition of the anti-PD-L1 antibody comprises 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 of an anti-PD-L1 antibody (e.g., a monoclonal antibody), 3-50 mM buffer, 2-150 mg / mL of an isotonicity regulator / stabilizer, and 0.01-0.8 mg / mL of a surfactant, and has a pH of about 4.5-6.8.

[0077] In some embodiments of the present application, the concentration of the anti-PD-L1 antibody pharmaceutical composition is calculated by mass / volume (w / v), and the anti-PD-L1 monoclonal antibody concentration is about 5-150 mg / mL; preferably about 10-60 mg / mL; more preferably about 10-30 mg / mL. In some specific embodiments, the anti-PD-L1 monoclonal antibody mass volume concentration 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 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL or about 120 mg / mL, preferably about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / 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 anti-PD-L1 monoclonal antibody has a mass volume concentration of about 10 mg / mL. In other embodiments, the anti-PD-L1 monoclonal antibody has a mass volume concentration of about 30 mg / mL. In other embodiments, the anti-PD-L1 monoclonal antibody has a mass volume concentration of about 60 mg / mL.

[0078] In some embodiments of the present application, the buffer is a histidine salt buffer. The histidine salt buffer concentration is about 5-30mM, preferably about 10-25mM, more preferably about 10-20mM, and most preferably about 10-15mM. In some embodiments, the histidine salt buffer concentration is about 5mM, about 10mM, about 15mM, about 20mM, about 25mM, or about 30mM. In some embodiments, the histidine salt buffer concentration is about 10mM. In other embodiments, the histidine salt buffer concentration is about 15mM. In other embodiments, the histidine salt buffer concentration is about 20mM. Wherein, the histidine salt buffer comprises histidine and hydrochloric acid.

[0079] In some embodiments of the present application, calculated in w / v, the isotonic regulator / stabilizer is about 20-150mg / mL of sucrose, preferably about 40-100mg / mL of sucrose, more preferably about 60-80mg / mL of sucrose. In some embodiments, the concentration of the sucrose is about 40mg / mL, 50mg / mL, 60mg / mL, 70mg / mL, 80mg / mL, 90mg / mL or 100mg / mL. In some embodiments, the concentration of the sucrose is about 60mg / mL. In some embodiments, the concentration of the sucrose is about 70mg / mL. In some embodiments, the concentration of the sucrose is about 80mg / mL. In some embodiments, the concentration of the sucrose is about 90mg / mL.

[0080] In some embodiments of the present application, the surfactant is selected from polysorbate 80, polysorbate 20, and poloxamer 188; preferably polysorbate 80 or polysorbate 20; more preferably polysorbate 80. In some embodiments, the concentration of the surfactant is about 0.05-0.6 mg / mL, preferably about 0.1-0.4 mg / mL, and more preferably about 0.2-0.3 mg / mL, calculated on a w / v basis.

[0081] In some embodiments of the present application, the concentration of the surfactant is about 0.01-0.8 mg / mL of polysorbate 80 or polysorbate 20, calculated on a w / v basis. In some specific embodiments, the concentration of the surfactant is about 0.05-0.6 mg / mL of polysorbate 80, preferably about 0.1-0.4 mg / mL of polysorbate 80, more preferably about 0.2-0.3 mg / mL of polysorbate 80, and most preferably about 0.2 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition contains polysorbate 80 at a content of 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, the pharmaceutical composition contains polysorbate 80 at a content of about 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, or 0.5 mg / mL; more preferably, the pharmaceutical composition contains polysorbate 80 at a content of about 0.2 mg / mL, 0.3 mg / mL, or 0.4 mg / mL; and most preferably, the pharmaceutical composition contains polysorbate 80 at a content of about 0.2 mg / mL. In some embodiments, the pharmaceutical composition contains polysorbate 80 at a content of about 0.1 mg / mL. In other embodiments, the pharmaceutical composition contains polysorbate 80 at a content of about 0.2 mg / mL. In some embodiments, the pharmaceutical composition contains polysorbate 80 at a content of about 0.3 mg / mL. In other embodiments, the pharmaceutical composition comprises about 0.4 mg / mL of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.5 mg / mL of polysorbate 80.

[0082] In some embodiments of the present application, the pH 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; and most preferably 5.5. In some embodiments, the pH 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 solution of the pharmaceutical composition is about 5.0. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 5.2. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 5.4. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 5.5. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 5.6. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 5.8. In some embodiments, the pH of the aqueous solution of the pharmaceutical composition is about 6.0.

[0083] In some specific embodiments of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of about 20 mg / mL, (b) sucrose at a mass volume concentration of about 70 mg / mL, (c) polysorbate 80 at a mass volume concentration of about 0.1 mg / mL, (d) histidine at a molar concentration of about 20 mM, and (e) optionally an appropriate amount of hydrochloric acid to 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 monoclonal antibody at a mass volume concentration of about 20 mg / mL, (b) sucrose at a mass volume concentration of about 70 mg / mL, (c) polysorbate 80 at a mass volume concentration of about 0.1 mg / mL, (d) histidine at a molar concentration of about 20 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to about 5.0.

[0084] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of approximately 10 mg / mL, (b) sucrose at a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg / mL, (d) histidine at a molar concentration of approximately 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0085] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of approximately 50 mg / mL, (b) sucrose at a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.3 mg / ml, (d) histidine at a molar concentration of approximately 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0086] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody having a mass volume concentration of approximately 100 mg / mL, (b) sucrose having a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 having a mass volume concentration of approximately 0.5 mg / mL, (d) histidine having a molar concentration of approximately 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0087] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of approximately 30 mg / mL, (b) sucrose at a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg / mL, (d) histidine at a molar concentration of approximately 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0088] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of approximately 60 mg / mL, (b) sucrose at a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg / mL, (d) histidine at a molar concentration of approximately 10 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0089] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 antibody at a mass volume concentration of approximately 10 mg / mL, (b) sucrose at a mass volume concentration of approximately 70 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.4 mg / mL, (d) histidine at a molar concentration of approximately 20 mM, and (e) an appropriate amount of acetic acid, and the pH of the composition is adjusted to approximately 6.5.

[0090] In another specific embodiment of the present application, the pharmaceutical composition comprises: (a) an anti-PD-L1 monoclonal antibody at a mass volume concentration of approximately 10 mg / mL, (b) sucrose at a mass volume concentration of approximately 80 mg / mL, (c) polysorbate 80 at a mass volume concentration of approximately 0.2 mg / mL, (d) histidine at a molar concentration of approximately 20 mM, and (e) optionally an appropriate amount of hydrochloric acid to adjust the pH of the composition to approximately 5.5.

[0091] In another specific embodiment of the present application, the pharmaceutical composition is a water-soluble injection, which includes but is not limited to a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted from a lyophilized powder. In other embodiments, the pharmaceutical composition is a lyophilized preparation. The lyophilized preparation refers to an aqueous solution that undergoes a lyophilization process to prepare a preparation. The lyophilized preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubbling drying.

[0092] Pharmaceutical composition of anlotinib or its pharmaceutically acceptable salt

[0093] In some embodiments of the present application, a single dose of the anlotinib or pharmaceutically acceptable salt thereof pharmaceutical composition comprises 6 mg, 8 mg, 10 mg, or 12 mg of anlotinib or pharmaceutically acceptable salt thereof.

[0094] In some embodiments of the present application, the dosage is 2 weeks on and 1 week off, with every 3 weeks being one dosage cycle, and the total dose of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition administered in each cycle includes 84 to 168 mg. In some embodiments, the total dose of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition includes a range selected from 84 mg, 112 mg, 140 mg, 168 mg or any of the above values. In some embodiments, the total dose of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition preferably includes 112 mg to 168 mg.

[0095] Ovarian cancer

[0096] In some embodiments, the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, and / or primary peritoneal cancer.

[0097] In some embodiments, the ovarian cancer includes but is not limited to ovarian epithelial cell carcinoma (ovarian carcinoma), malignant germ cell tumor, sex cord stromal tumor. In some embodiments, according to the histological type, the ovarian cancer includes but is not limited to serous ovarian cancer, mucinous ovarian cancer, endometrioid carcinoma, clear cell carcinoma.

[0098] In some embodiments, the ovarian cancer is selected from recurrent or refractory ovarian cancer. In some embodiments, the ovarian cancer is selected from platinum-resistant or platinum-sensitive ovarian cancer. In some embodiments, the ovarian cancer is selected from advanced ovarian cancer.

[0099] In some embodiments, the ovarian cancer includes but is not limited to ovarian cancer with KRAS or BRCA (eg, BRCA1, BRCA2) mutations; in some embodiments, the ovarian cancer is ovarian cancer with BRCA1 and / or BRCA2 mutations.

[0100] In some embodiments, the ovarian cancer patient has previously received one, two, three, or four of the following: cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy, and / or hormonal therapy, and the disease has progressed or recurred. In some embodiments, the ovarian cancer patient has previously received one, two, three, or four of the following: chemotherapy, including but not limited to cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy, and / or hormonal therapy, and the disease has progressed or recurred. In some embodiments, the ovarian cancer patient has previously received at least one platinum-containing chemotherapy, and the disease has progressed or recurred.

[0101] The cytotoxic therapy includes but is not limited to platinums (e.g., one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, and lobaplatin), taxanes (e.g., one or more of paclitaxel, paclitaxel albumin-bound, and docetaxel), camptothecin, doxorubicin, mitoxantrone, irinotecan, topotecan, etoposide, teniposide, bleomycin, gemcitabine, 5-fluorouracil, leucovorin, oxaliplatin, hexamethylpyrimidine, capecitabine, ifosfamide, pemetrexed, or vinorelbine. The targeted therapy includes but is not limited to PARP inhibitors (e.g., olaparib, rucaparib, and niraparib). The hormonal therapy includes but is not limited to aromatase inhibitors, tamoxifen, fulvestrant, leuprorelin, and megestrol acetate. The immunotherapy includes but is not limited to bevacizumab and pembrolizumab.

[0102] In some embodiments, the ovarian cancer patient is a patient who has previously failed treatment with a platinum-containing drug; in some embodiments, the ovarian cancer patient is a patient who has previously failed treatment with a platinum-containing regimen.

[0103] In some embodiments, the ovarian cancer patient has failed at least one line of platinum therapy.

[0104] In some embodiments, the ovarian cancer patient has received at least one line of platinum-based therapy, and the disease relapses or progresses within 6 months of discontinuation of the last platinum-based therapy.

[0105] In some embodiments, the ovarian cancer patient is a platinum-resistant patient.

[0106] In some embodiments, the ovarian cancer patient has previously received ≥1 line of platinum-containing chemotherapy after cytoreductive surgery; optionally, at least 4 cycles of platinum-containing treatment.

[0107] In some embodiments, the ovarian cancer patient is a platinum-resistant or refractory patient, including patients whose disease progressed or recurred during previous treatment with a platinum-containing chemotherapy regimen or within 6 months after completion of platinum-containing treatment.

[0108] In some embodiments, the ovarian cancer patient is a platinum-sensitive patient, and the patient has previously received at least two different platinum-containing chemotherapy regimens with disease progression or recurrence (including the initial platinum-containing treatment regimen).

[0109] In some embodiments, the platinum-based regimen includes but is not limited to one or more of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, or lobaplatin.

[0110] In some embodiments, the ovarian cancer patient is a patient who has previously failed treatment with a taxane-containing drug; the taxanes include but are not limited to one or more of paclitaxel, albumin-bound paclitaxel, and docetaxel.

[0111] In some embodiments, the patient with ovarian cancer has previously received one or more of the following regimens: paclitaxel and carboplatin; carboplatin and doxorubicin; docetaxel and carboplatin; paclitaxel, carboplatin, and bevacizumab; bleomycin, etoposide, and cisplatin; etoposide and carboplatin; carboplatin and doxorubicin; carboplatin, gemcitabine, and bevacizumab; cisplatin and gemcitabine; 5-fluorouracil, leucovorin, and oxaliplatin; or capecitabine and oxaliplatin.

[0112] In some embodiments, the ovarian cancer patient has previously received one or more of the following treatment regimens, including:

[0113] 1) Paclitaxel 175 mg / m 2 , intravenous infusion for 3 hours, carboplatin AUC 5-6, intravenous infusion for 1 hour, day 1, repeated every 3 weeks, for a total of 3-6 cycles;

[0114] 2) Carboplatin AUC 5 combined with liposomal doxorubicin 30 mg / m 2 Intravenous drip, repeated every 4 weeks, for a total of 3 to 6 cycles;

[0115] 3) Docetaxel 60–75 mg / m 2 , intravenous drip for 1 hour, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks for a total of 6 cycles;

[0116] 4) Paclitaxel 175 mg / m 2 , intravenous drip for 3 hours, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks for a total of 6 cycles;

[0117] 5) Paclitaxel 80 mg / m 2 Intravenous infusion for 1 hour on days 1, 8, and 15; carboplatin AUC 5-6, intravenous infusion for 1 hour on day 1, repeated every 3 weeks for 6 cycles;

[0118] 6) Paclitaxel 60 mg / m 2 / week, 1 hour intravenous infusion, carboplatin AUC 2 / week, 30 minutes intravenous infusion, for a total of 18 weeks;

[0119] 7) Docetaxel 60–75 mg / m 2 , intravenous drip for 1 hour, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks for a total of 6 cycles;

[0120] 8) Carboplatin AUC 5 combined with liposomal doxorubicin 30 mg / m 2 Intravenous drip, repeated every 4 weeks, for a total of 6 cycles;

[0121] 9) Paclitaxel 175 mg / m 2 , intravenous infusion for 3 hours, carboplatin AUC 5-6, intravenous infusion for 1 hour, bevacizumab 7.5 mg / kg, intravenous infusion for 30-90 minutes, on the first day, repeated every 3 weeks for a total of 5-6 cycles, after which bevacizumab monotherapy is continued as maintenance therapy for 12 cycles;

[0122] 10) Paclitaxel 175 mg / m 2 , intravenous infusion for 3 hours, carboplatin AUC 6, intravenous infusion for 1 hour, day 1. Repeat every 3 weeks for a total of 6 cycles, starting from day 1 of cycle 2, bevacizumab 15 mg / kg is given by intravenous infusion for 30-90 minutes, repeated every 3 cycles for a total of 22 cycles;

[0123] 11) Paclitaxel 135 mg / m 2 Intravenous drip for 3 hours or 24 hours, day 1, cisplatin 75-100 mg / m 2 Intraperitoneal injection, day 2, paclitaxel 60 mg / m 2 intraperitoneal injection, on day 8, repeated every 3 weeks for a total of 6 cycles;

[0124] Alternatively, 12) BEP regimen: bleomycin 30 units once a week and etoposide 100 mg / m2 / day 2 , cisplatin 20 mg / m2 per day on days 1 to 5 2 , on days 1 to 5, intravenous drip, repeated every 3 weeks.

[0125] In some embodiments, the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; optionally, the ovarian cancer is selected from recurrent or refractory ovarian cancer; optionally, the ovarian cancer is selected from platinum-resistant or platinum-sensitive ovarian cancer; optionally, the patient with ovarian cancer has previously received surgical treatment, cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy or hormone therapy and the disease progresses or relapses; optionally, the patient with ovarian cancer has previously received cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, miplatin, lobaplatin, camptothecin, doxorubicin, mitoxantrone, irinotecan, topotecan, etoposide, teniposide, paclitaxel or its albumin-bound form, bevacizumab, doxorubicin or its liposome, docetaxel, bleomycin, One or more of gemcitabine, 5-fluorouracil, leucovorin, oxaliplatin, hexamethylmelamine, capecitabine, ifosfamide, pemetrexed or vinorelbine; optionally, the ovarian cancer patient has previously received one or more of the following treatments, including: paclitaxel and carboplatin; carboplatin and doxorubicin; docetaxel and carboplatin; paclitaxel, carboplatin and bevacizumab; bleomycin, etoposide and cisplatin; etoposide and carboplatin; carboplatin and doxorubicin; carboplatin, gemcitabine and bevacizumab; cisplatin and gemcitabine; 5-fluorouracil, leucovorin and oxaliplatin; or capecitabine and oxaliplatin; optionally, the ovarian cancer patient has previously received one or more of the following treatments, including: 1) paclitaxel 175 mg / m 2 , intravenous drip for 3 hours, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks, for a total of 3-6 cycles; 2) carboplatin AUC 5 combined with doxorubicin liposome 30mg / m 2 Intravenous drip, repeated every 4 weeks for 3 to 6 cycles; 3) Docetaxel 60 to 75 mg / m 2 , intravenous drip for 1 hour, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks, for a total of 6 cycles; 4) paclitaxel 175 mg / m 2 , intravenous drip for 3 hours, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks, for a total of 6 cycles; 5) paclitaxel 80 mg / m 2 Intravenous drip for 1 hour on days 1, 8, and 15; carboplatin AUC 5-6, intravenous drip for 1 hour on day 1, repeated every 3 weeks for 6 cycles; 6) paclitaxel 60 mg / m 2 / week, intravenous drip for 1 hour, carboplatin AUC 2 / week, intravenous drip for 30 minutes, for a total of 18 weeks; 7) docetaxel 60-75 mg / m 2 , intravenous drip for 1 hour, carboplatin AUC 5-6, intravenous drip for 1 hour, day 1, repeated every 3 weeks, for a total of 6 cycles; 8) carboplatin AUC 5 combined with doxorubicin liposome 30 mg / m 2Intravenous drip, repeated every 4 weeks for 6 cycles; 9) Paclitaxel 175 mg / m 2 , intravenous drip for 3 hours, carboplatin AUC5-6, intravenous drip for 1 hour, bevacizumab 7.5 mg / kg, intravenous drip for 30-90 minutes, on the first day, repeated every 3 weeks for a total of 5-6 cycles, and then bevacizumab monotherapy continued for 12 cycles; 10) paclitaxel 175 mg / m 2 , intravenous drip for 3 hours, carboplatin AUC 6, intravenous drip for 1 hour, day 1. Repeat every 3 weeks for a total of 6 cycles, bevacizumab 15 mg / kg is given on day 1 of the second cycle, intravenous drip for 30-90 minutes, repeated every 3 cycles for a total of 22 cycles; 11) paclitaxel 135 mg / m 2 Intravenous drip for 3 hours or 24 hours, day 1, cisplatin 75-100 mg / m 2 Intraperitoneal injection, day 2, paclitaxel 60 mg / m 2 Intraperitoneal injection, on day 8, repeated every 3 weeks for 6 cycles; or, 12) BEP regimen: bleomycin 30 units once a week, etoposide 100 mg / m2 per day 2 , cisplatin 20 mg / m2 per day on days 1 to 5 2 , on days 1 to 5, intravenous drip, repeated every 3 weeks.

[0126] Administration

[0127] The following does not limit the administration method of the drug combination of the present application.

[0128] The components of the pharmaceutical composition of the present application can be administered independently, or some or all of them together, by various suitable routes, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). In some embodiments, the components of the pharmaceutical combination of the present application can be administered independently, or some or all of them together, orally or by injection, such as intravenous or intraperitoneal injection.

[0129] The components of the pharmaceutical composition of the present application can be each independently, or some or all of them together can be in the form of suitable dosage forms, including, but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and sustained-release preparations for oral or parenteral administration.

[0130] The components of the pharmaceutical combination of the present application may each independently, or some or all of them may contain a pharmaceutically acceptable carrier and / or excipient.

[0131] The pharmaceutical combination of the present application may further comprise an additional therapeutic agent. In one embodiment, the additional therapeutic agent may be a small cell cancer therapeutic agent known in the art.

[0132] Dosage regimen

[0133] The dosing regimens described herein are also applicable to the uses described herein for preparing a medicament for treating ovarian cancer in a patient, the methods for treating ovarian cancer in a patient, and the uses for treating ovarian cancer in a patient.

[0134] In some embodiments of the present application, the dosing cycle of the dosing regimen is 14 to 42 days; in some embodiments, the dosing cycle is 14 days, 21 days, 28 days, 35 days or 42 days; in some embodiments, the dosing cycle is 21 days.

[0135] In some embodiments of the present application, the dosing regimen comprises: 1) administering the anti-PD-L1 antibody once a day within the 1st to 7th day of each dosing cycle; 2) administering anlotinib or a pharmaceutically acceptable salt thereof continuously from the 1st to the 28th day of each dosing cycle.

[0136] In a specific embodiment, each 21 days is a dosing cycle, and the dosing regimen includes: 1) administering the anti-PD-L1 antibody once on the first day of each dosing cycle; 2) administering anlotinib or a pharmaceutically acceptable salt thereof continuously on days 1 to 14 of each dosing cycle.

[0137] In some embodiments of the present application, the dosing regimen comprises: 1) the anti-PD-L1 antibody hu5G11-hIgG1 (i.e., hu5G11-hIgG1 in WO2016022630) is administered once on the first day of each dosing cycle; 2) anlotinib dihydrochloride is administered continuously on days 1 to 14 of each dosing cycle.

[0138] In some embodiments of the present application, the anti-PD-L1 antibody is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each dosing cycle, preferably once on day 1 of each dosing cycle.

[0139] In some embodiments of the present application, anlotinib or a pharmaceutically acceptable salt thereof is continuously administered on days 1-7, 7-14, 1-14, or 7-21 of each dosing cycle, preferably continuously administered on days 1-14 of each dosing cycle.

[0140] Technical Effects

[0141] The drug combination or combined pharmaceutical composition of the present application has good activity in treating ovarian cancer. The combination or combined use of multiple active ingredients shows excellent anti-tumor effects compared to the use of any of the active ingredients alone.

[0142] Generally, the use of the above-mentioned combination pharmaceutical composition of the present application will help:

[0143] (1) Produce a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering either drug alone;

[0144] (2) provide for administration of a smaller amount of the drug than would be possible with either drug alone;

[0145] (3) provide a treatment that is well tolerated by patients and has fewer adverse effects and / or complications than either drug given alone;

[0146] (4) provide better disease control rates among treated patients;

[0147] (5) provide longer survival (e.g., median survival, progression-free survival, or overall survival) in treated patients;

[0148] (6) provide longer survival (e.g., median survival, progression-free survival, or overall survival) for treated patients compared to standard chemotherapy;

[0149] (7) Provide a longer duration of disease remission (DOR); and / or effectively delay the time of compounding, thereby prolonging the patient's survival; and / or

[0150] (8) Compared with the administration of any drug in the combination alone, it has good inhibitory activity against ovarian cancer and exhibits a more excellent anti-tumor synergistic effect.

[0151] Definition and Description

[0152] Unless otherwise indicated, the following terms used in this application have the following meanings. A particular term, unless specifically defined, should not be construed as undefined or unclear, but rather should be understood according to its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commercial product or its active ingredient.

[0153] As used herein, the term "antibody" refers to a binding protein having at least one antigen binding domain. The antibodies and fragments thereof of the present application may be whole antibodies or any fragments thereof. Therefore, the antibodies and fragments of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof, as well as immunoconjugates. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab)' fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. Antibodies and fragments thereof may also include recombinant polypeptides, fusion proteins and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein may be IgG1, IgG2, IgG3 or IgG4 isotypes. The term "isotype" refers to the type of antibody encoded by the heavy chain constant region gene. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are IgG1 or IgG4 isotypes. The PD-L1 antibodies and fragments thereof of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. PD-L1 antibodies and fragments thereof can be chimeric, humanized, 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. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.

[0154] "Humanized antibodies" are antibodies that contain complementary determining regions (CDRs) derived from non-human antibodies; and framework regions and constant regions derived from human antibodies. For example, the anti-PD-L1 antibodies provided herein may comprise CDRs derived from one or more murine antibodies and human framework regions and constant regions. Thus, in one embodiment, the humanized antibodies provided herein bind to the same epitope on PD-L1 as the murine antibodies from which the CDRs of the antibodies are 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 this application. In one embodiment, framework sequences suitable for use in this application include those that are structurally similar to the framework sequences provided herein. Additional modifications may be made in the framework region 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 reverting 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 antibodies provided herein are back-mutated to the corresponding amino acids in the parent murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites of the framework amino acids of the above-mentioned template human antibodies are back-mutated to the corresponding amino acid sequences in mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and / or 60 and / or 67 of the light chain variable region are back-mutated to the corresponding amino acids found at the positions in the mouse 5G11 or 13C5 light chain variable region. In another embodiment, the amino acids at positions 24 and / or 28 and / or 30 and / or 49 and / or 73 and / or 83 and / or 94 of the heavy chain variable region are back-mutated to the corresponding amino acids found at the positions in the mouse 5G11 or 13C5 heavy chain variable region. In one embodiment, the humanized 5G11 antibody comprises a light chain variable region in which the amino acid at position 60 is mutated from Ser (S) to Asp (D), and the amino acid at position 67 is mutated from Ser (S) to Tyr (Y); and a heavy chain variable region in which the amino acid at position 24 is mutated from Phe (F) to Val (V), the amino acid at position 49 is mutated from Ala (A) to Gly (G), the amino acid at position 73 is mutated from Thr (T) to Asn (N), and the amino acid at position 83 is mutated from Thr (T) to Asn (N).In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr (Y) to Lys (K); and a heavy chain variable region in which the amino acid at position 28 is mutated from Thr (T) to Ile (I), the amino acid at position 30 is mutated from Ser (S) to Arg (R), the amino acid at position 49 is mutated from Ser (S) to Ala (A), and the amino acid at position 94 is mutated from Tyr (Y) to Asp (D). Additional or alternative back mutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibody. The present application also includes the following 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 framework modifications that otherwise improve antibody properties.

[0155] The present application provides an isolated antibody or fragment thereof that binds to PD-L1, wherein the antibody is produced by a hybridoma selected from the group consisting of hybridomas referred to herein as 13C5 and 5G11. Therefore, the present application also includes hybridomas 13C5, 5G11, and any hybridoma that produces the antibodies disclosed herein. The present application also provides isolated polynucleotides encoding the antibodies and fragments thereof provided herein. The present application also includes expression vectors comprising the isolated polynucleotides, and host cells comprising the expression vectors.

[0156] The term "monoclonal antibody" ("mAb") refers to a non-naturally occurring preparation of an antibody molecule of single molecular composition (i.e., an antibody molecule whose primary sequence is substantially identical and which exhibits a single binding specificity and affinity for a particular epitope). mAbs are an example of an isolated antibody. mAbs can be produced by hybridoma technology, recombinant technology, transgenic technology, or other techniques known to those skilled in the art.

[0157] The antibodies and antigen-binding fragments thereof disclosed herein are specific for PD-L1. In one embodiment, the antibodies or fragments thereof are specific for PD-L1. In one embodiment, the antibodies and fragments provided herein bind to human or primate PD-L1, but do not bind to PD-L1 from any other mammal. In another embodiment, the antibodies 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 variants or isoforms of human PD-L1. "Specific for" means that the antibodies and fragments thereof bind to PD-L1 with greater affinity than any other target.

[0158] The term "treat" generally refers to obtaining a desired pharmacological and / or physiological effect. This effect can be therapeutic in terms of partial or complete stabilization or cure of a disease and / or side effects caused by the disease. As used herein, "treat" encompasses any treatment of a patient's disease, including: (a) suppressing the symptoms of the disease, i.e., arresting its progression; or (b) relieving the symptoms of the disease, i.e., causing regression of the disease or its symptoms.

[0159] The term "effective amount" means an amount of the compound of the present invention that (i) treats or prevents a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of active substance (e.g., an antibody or compound of the present invention) that constitutes a "therapeutically effective amount" may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual. The effective amount can also be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.

[0160] The term "administer" means that a composition comprising a therapeutic agent is physically introduced into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration of immune checkpoint inhibitors (e.g., anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to a mode of administration other than enteral and topical administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardial, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (e.g., anti-PD-L1 antibody) is administered by a non-parenteral route, in certain embodiments, orally. Other non-parenteral routes include topical, epidermal or mucosal routes of administration, e.g., intranasally, vaginally, rectally, sublingually or topically. Administration can also be performed, e.g., once, multiple times, and / or over one or more extended periods of time.

[0161] The term "dose" is used to refer 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 would receive the same dose of antibody (e.g., 240 mg of anti-PD-L1 antibody).

[0162] The term "weight-based dose" mentioned herein refers to a dose administered to a patient calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 3 mg / kg of an anti-PD-L1 antibody, one can withdraw an appropriate amount of the anti-PD-L1 antibody (i.e., 180 mg) from the fixed-dose formulation of the anti-PD-L1 antibody at one time.

[0163] Anlotinib or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, by inhalation, vaginal, intraocular, by topical administration, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal. In some specific embodiments, it is administered orally. The amount of anlotinib or a pharmaceutically acceptable salt thereof administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof can be 2 mg to 20 mg. In some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and 16 mg. Anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more daily. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily as an oral solid dosage form.

[0164] The dosage regimen of anlotinib or a pharmaceutically acceptable salt thereof can be determined comprehensively based on the activity, toxicity, and patient tolerance of the drug. Preferably, anlotinib or a pharmaceutically acceptable salt thereof is administered in an intermittent manner. The intermittent administration includes a dosing period and a rest period. During the dosing period, anlotinib or a pharmaceutically acceptable salt thereof can be administered once or multiple times a day. For example, the ratio of the dosing period to the rest period in days is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, and even more preferably 2:0.5-1. In some embodiments, the drug is administered for 2 consecutive weeks and then rested for 2 weeks. In some embodiments, the drug is administered for 2 consecutive weeks and then rested for 1 week. In some embodiments, the drug is administered for 5 consecutive days and then rested for 2 days. For example, anlotinib or a pharmaceutically acceptable salt thereof can be administered orally once daily at a dose of 6 mg, 8 mg, 10 mg, or 12 mg for 2 consecutive weeks and then rested for 1 week.

[0165] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0166] The term "pharmaceutically acceptable salt" includes salts formed by alkaline ions and free acids or salts formed by acid ions and free bases, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, methanesulfonate, benzenesulfonate or p-toluenesulfonate, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free acid to the alkaline 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 the present application, when forming a pharmaceutically acceptable salt, the molar ratio of the free base to the acid 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.

[0167] The term "patient" or "subject" is a mammal. In some embodiments, the patient or subject is a mouse. In some embodiments, the patient or subject is a human.

[0168] The term "about" should be understood to include within three standard deviations of the mean or within the standard tolerance range for a particular field. In certain embodiments, about should be understood to mean a variation of no more than 0.5. "About" modifies all subsequent listed values. For example, "about 1, 2, 3" means "about 1," "about 2," "about 3."

[0169] As used herein, "combination" or "combined use" means that two or more active substances can be administered to a patient simultaneously, each as a single formulation, or sequentially in any order, each as a single formulation.

[0170] The term "single dose" refers to the smallest packaging unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, each capsule is a single dose; or each bottle of injection is a single dose.

[0171] The term "multiple doses" consists of a plurality of single doses.

[0172] The term "pharmaceutical combination" refers to the simultaneous, concurrent or sequential use of two or more active ingredients in combination.

[0173] The term "fixed combination" means that the active ingredients (e.g., anti-PD-L1 antibody and anlotinib) are administered to a patient simultaneously in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

[0174] The term "non-fixed combination" refers to two or more active ingredients that are administered to a patient as independent entities (e.g., pharmaceutical compositions, formulations) simultaneously, concurrently or sequentially and without specific time limits, wherein the active ingredients administered to the patient reach a therapeutically effective level. An example of a non-fixed combination is cocktail therapy, e.g., administration of three or more active ingredients. In a non-fixed combination, the individual active ingredients may be packaged, sold or administered as completely independent pharmaceutical compositions. The "non-fixed combination" also includes the combined use of "fixed combinations" with each other, or a "fixed combination" with any one or more independent entities of the active ingredients.

[0175] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients or their combination of active ingredients of the present invention and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present invention or their combination of active ingredients to a patient.

[0176] As used herein, the term "combination pharmaceutical composition" refers to a combination of two or more active ingredients (administered as each active ingredient itself, or as a pharmaceutically acceptable salt or ester derivative, prodrug, or combination thereof) that are administered simultaneously or sequentially. The terms "combination pharmaceutical composition," "pharmaceutical composition," and "drug combination" are used interchangeably herein.

[0177] The term "platinum-resistant" includes disease progression during previous treatment with a platinum-containing chemotherapy regimen and disease progression or recurrence within 6 months after the completion of platinum-containing treatment.

[0178] The term "platinum-sensitive" refers to disease progression or recurrence ≥6 months after the completion of a platinum-containing chemotherapy regimen; this includes disease progression or recurrence after at least two different platinum-containing chemotherapy regimens. DETAILED DESCRIPTION

[0179] For the sake of clarity, the present application is further illustrated by examples, but the examples do not limit the scope of the present 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. After affinity chromatography, the eluate containing the antibody was obtained according to conventional antibody purification methods.

[0180] Example 1 Clinical Trial

[0181] 1.1 Inclusion Criteria

[0182] 1) Understand and voluntarily sign the written informed consent;

[0183] 2) Age ≥18 years, female; ECOG score 0-1, expected survival time ≥3 months;

[0184] 3) histologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer;

[0185] 4) The subject has received ≥1 line of platinum-containing chemotherapy (at least 4 cycles of platinum-containing treatment) after cytoreductive surgery and meets any of the following criteria:

[0186] Patients with platinum-resistant or refractory disease, including those whose disease progressed or relapsed during previous platinum-containing chemotherapy or within 6 months after completion of platinum-containing treatment;

[0187] If the patient is platinum-sensitive (i.e., the disease progresses or relapses ≥ 6 months after the end of a platinum-containing chemotherapy regimen), the patient should have previously received at least two different platinum-containing chemotherapy regimens after which the disease progressed or relapsed (including the initial platinum-containing treatment regimen);

[0188] 5) Contain at least one measurable lesion according to RECIST1.1 solid tumor evaluation criteria;

[0189] 6) Laboratory tests during the screening period must meet the following conditions:

[0190] Blood test: Hemoglobin (HB) ≥ 90 g / L; absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L; platelet (PLT) ≥80×10 9 / L;

[0191] Blood biochemistry: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT)

[0192] and aspartate aminotransferase AST ≤ 2.5 ULN. If accompanied by liver metastasis, ALT and AST ≤ 5 ULN; serum creatinine (Cr) ≤ 1.5 ULN or creatinine clearance (CCr) ≥ 60 mL / min;

[0193] Urinalysis: urine protein <2+ (if the baseline urine protein is ≥2+, a 24-hour urine protein quantitative test should be performed within 7 days, and patients will be selected only when the urine protein is <1g);

[0194] Coagulation function: INR and APTT ≤ 1.5 × ULN;

[0195] Cardiac function: left ventricular ejection fraction (LVEF) ≥50%;

[0196] 7. Women must meet one of the following conditions:

[0197] 1) Surgical sterilization has been performed;

[0198] 2) Postmenopausal women, who have stopped menstruating for at least 1 year;

[0199] 3) Have reproductive capacity and meet the following conditions;

[0200] The serum / urine pregnancy test result is negative before the first medication; agree to use an approved method of contraception (such as oral contraception, injection contraception or implantable, barrier contraception, spermicide and condoms, or intrauterine contraceptive device) throughout the study, and the contraceptive method remains unchanged throughout the study.

[0201] 1.2 Investigational Drugs and Dosage Regimens

[0202] Injection containing hu5G11-hIgG1: 1200 mg of anti-PD-L1 antibody injection is diluted to 250 mL with normal saline. The infusion time is 60±5 minutes. After the infusion is completed, the tube is flushed with normal saline according to the hospital's routine requirements. The drug is administered once every 21 days.

[0203] Specifications: 100mg / 10mL, 300mg / 10mL.

[0204] The anti-PD-L1 antibody hu5G11-hIgG1 comprises a heavy chain variable region sequence as shown in SEQ ID NO: 13 and a light chain variable region sequence as shown in SEQ ID NO: 15. The heavy chain amino acid sequence of hu5G11-hIgG1 is shown in SEQ ID NO: 17, and the light chain amino acid sequence is shown in SEQ ID NO: 18.

[0205] Anlotinib Hydrochloride Capsules (active ingredient is anlotinib dihydrochloride): Take one anlotinib hydrochloride capsule on an empty stomach within ±5 minutes after the start of infusion of anti-PD-L1 antibody injection. Take orally for 2 weeks and rest for 1 week, that is, 21 days as a treatment cycle.

[0206] Specifications: 12mg, 10mg, 8mg.

[0207] 1.3 Evaluation Criteria

[0208] Disease status was determined according to RECIST 1.1 / irRECIST, with RECIST 1.1 as the primary evaluation criteria and iRECIST as a supplement.

[0209] 1.4 Endpoint indicators

[0210] One treatment cycle was 21 days. During the first 18 cycles of treatment, imaging assessment was performed every 42 days (2 cycles). After 18 cycles, imaging assessment was performed every 63 days (3 cycles).

[0211] progression-free survival (PFS);

[0212] Anti-tumor efficacy indicators: objective response rate (ORR) = (complete response (CR) + partial response (PR)), disease control rate (DCR = CR + PR + stable disease (SD)), progression-free survival (PFS), overall survival (OS), etc.

[0213] 1.5 Data Results

[0214] Among the 26 subjects, 25 underwent at least one efficacy evaluation, and 11 subjects were removed from the group due to progression of imaging assessment, voluntary withdrawal, worsening of disease symptoms, etc.

[0215] Among the 25 patients who underwent at least one efficacy evaluation, 12 achieved partial remission (PR) as the best efficacy evaluation, and 12 achieved stable disease (SD) as the best efficacy evaluation. The objective response rate (ORR) was 52.0%, the disease control rate (DCR) was 96.0%, and the median progression-free survival was 7.03 months, which showed excellent efficacy compared with the historical data of platinum-resistant patients (PFS 3-4 months).

Claims

1. Use of an anti-PD-L1 antibody in the preparation of a medicament for a combination therapy for treating ovarian cancer, wherein the medicament is administered in combination with anlotinib to treat ovarian cancer.

2. Use of anlotinib in the preparation of a medicament for a combination therapy for treating ovarian cancer, wherein the medicament is administered in combination with an anti-PD-L1 antibody to treat ovarian cancer.

3. Use of anti-PD-L1 antibodies in the preparation of drugs for use in combination with anlotinib in the treatment of ovarian cancer.

4. Use of anlotinib in the preparation of a medicament for treating ovarian cancer in combination with an anti-PD-L1 antibody.

5. The use according to any one of claims 1 to 4, characterized in that The anti-PD-L1 antibody and anlotinib are each in the form of a pharmaceutical composition and are administered simultaneously, sequentially or intermittently.

6. The use according to any one of claims 1 to 5, characterized in that The anti-PD-L1 antibody pharmaceutical composition includes a pharmaceutical composition containing 600 to 2400 mg of the anti-PD-L1 antibody.

7. The use according to any one of claims 1 to 6, characterized in that The anlotinib pharmaceutical composition includes a pharmaceutical composition containing a single dose of 6 mg, 8 mg, 10 mg and / or 12 mg of anlotinib.

8. The use according to any one of claims 1 to 7, characterized in that The anti-PD-L1 antibody is administered once per cycle; or the anti-PD-L1 antibody is administered once on day 1, 2, 3, 4, 5, 6, or 7 of each dosing cycle; and / or anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on days 1-7, 7-14, 1-14, or 7-21 of each dosing cycle.

9. The use according to any one of claims 1 to 8, characterized in that The administration cycle of the drug combination is 21 days.

10. The use according to any one of claims 1 to 9, characterized in that: 1) Anti-PD-L1 antibody is administered once a day on the 1st to 7th day of each dosing cycle; 2) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on the 1st to 28th day of each dosing cycle; or, 1) Anti-PD-L1 antibody is administered once on the first day of each dosing cycle; 2) Anlotinib or a pharmaceutically acceptable salt thereof is administered continuously on the 1st to 14th days of each dosing cycle; or, 1) The anti-PD-L1 antibody hu5G11-hIgG1 was administered once on the first day of each dosing cycle; 2) Anlotinib dihydrochloride was administered continuously on days 1-14 of each dosing cycle.

11. The use according to any one of claims 1 to 10, wherein the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof can be administered simultaneously, sequentially or intermittently; or the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each in the form of a pharmaceutical composition and can be administered simultaneously, sequentially or intermittently.

12. The use according to any one of claims 1 to 11, characterized in that The anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered in the same or different dosing regimens.

13. The use according to any one of claims 1 to 12, characterized in that The anti-PD-L1 antibody can be administered once a week, every 2 weeks, every 3 weeks, or every 4 weeks; and / or the anlotinib or a pharmaceutically acceptable salt thereof can be administered once a day at a dose of 6 mg, 8 mg, 10 mg or 12 mg, for 2 consecutive weeks and 1 week off.

14. The use according to any one of claims 1 to 13, characterized in that The anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 5; a heavy chain CDR3 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 6; a light chain CDR1 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 10; a light chain CDR2 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO: 11; and a light chain CDR3 region that is at least 80% homologous to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO:

12.

15. The use according to any one of claims 1 to 14, characterized in that The ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

16. The use according to any one of claims 1 to 15, wherein the ovarian cancer is selected from recurrent and / or refractory ovarian cancer and / or advanced ovarian cancer.

17. The use according to any one of claims 1 to 16, wherein the ovarian cancer is selected from platinum-resistant or platinum-sensitive ovarian cancer.

18. The use according to any one of claims 1 to 17, wherein the ovarian cancer is ovarian cancer with KRAS and / or BRCA (such as BRCA1, BRCA2) mutations.

19. The use according to any one of claims 1 to 18, characterized in that The ovarian cancer patient is an ovarian cancer patient whose disease progresses or relapses after previously receiving one, two, three or four of cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy and / or hormonal therapy; or the ovarian cancer patient has previously received ≥1 line of platinum-containing chemotherapy after cytoreductive surgery; optionally, the platinum-containing treatment is for at least 4 cycles.

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