CN113018429A - Pharmaceutical composition for treating ovarian cancer - Google Patents

Abstract

The present application belongs to the field of biomedicine, relates to a drug combination for treating ovarian cancer, and specifically relates to a drug combination, a combined drug composition, a kit and the use thereof.

Description

Drug combination for ovarian cancer

technical field

The present application belongs to the field of biomedicine, and relates to a pharmaceutical combination, a combined pharmaceutical composition, a kit and the use thereof for the treatment of ovarian cancer.

Background technique

Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of protein tyrosine residues and play an important role in intracellular signal transduction. Proliferation, differentiation, migration and apoptosis are closely related. Many receptor tyrosine kinases are related to the formation of tumors, which can be divided into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptors according to the structure of their extracellular regions. body (VEGFR), fibroblast growth factor receptor (FGFR), etc.

PD-L1 (Programmed death-ligand 1), also known as CD247 and B7-H1, is a ligand of programmed death 1 (Programmed death, PD-1). PD-L1 is highly expressed on the surface of various tumor cells, and the malignancy and poor prognosis of tumors are closely related to the expression level of PD-L1. In the tumor microenvironment, PD-L1 on the surface of cancer cells inhibits the activation and proliferation of T cells by binding to PD-1 or CD80 on the surface of T cells, promotes effector T cells into an exhausted or unresponsive state, and induces T cell activation. Apoptosis stimulates the differentiation of helper T cells into regulatory T cells, thereby preventing the killing effect of T cells on tumor cells. Anti-PD-L1 antibodies can block the interaction of PD-L1 with PD-1 and CD80, so that the related negative regulatory signals cannot be initiated and transmitted, thereby avoiding the inhibition of effector T cell activity in the tumor microenvironment. , so that T cells can kill and inhibit tumor cells. Since anti-PD-L1 antibodies can directly act on tumor tissues, they have high specificity and safety.

The incidence of ovarian cancer ranks third among female reproductive system malignant tumors, and the mortality rate ranks first among gynecological malignant tumors. Globally, the incidence of ovarian cancer is 9.1/100,000 in developed countries and 5.0/100,000 in developing countries. In 2018, approximately 22,240 women in the United States developed ovarian cancer, and 14,070 patients died of ovarian cancer.

At present, the standard treatment of advanced ovarian cancer mainly includes comprehensive staging of ovarian cancer/cytoreductive surgery, and postoperative platinum-based first-line chemotherapy. Although the prognosis of ovarian cancer patients has been significantly improved over the past 20 years with the improvement of surgical skills and the clinical application of paclitaxel, platinum and many second-line chemotherapy drugs, the 5-year survival rate of advanced patients is still insufficient. 30%. Most patients with advanced disease eventually relapse after completing standard treatment. Clinically, according to the time of recurrence after receiving platinum-based chemotherapy, the recurrence after 6 months of chemotherapy is platinum-sensitive recurrence; the recurrence within 6 months of chemotherapy is platinum-resistant recurrence. But unfortunately, almost all platinum-sensitive patients will eventually develop platinum resistance. These patients have poor prognosis and short survival, which is the current research hotspot of ovarian cancer. However, the treatment options for platinum-resistant ovarian cancer are very limited. The available chemotherapeutic drugs include liposomal doxorubicin, gemcitabine, topotecan, etoposide, docetaxel, etc. The efficiency (ORR) is only about 10%-30%, and the median progression-free survival (PFS) is only 3-4 months. Therefore, it is particularly urgent to find new effective drugs to treat platinum-resistant patients clinically.

SUMMARY OF THE INVENTION

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

In another aspect, the present application provides a combined pharmaceutical composition for treating ovarian cancer, comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt.

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

Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 4; with SEQ ID NO: 2 or The heavy chain CDR2 region having at least 80% homology to the amino acid sequence shown in SEQ ID NO:5; the heavy chain having at least 80% homology to the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 CDR3 region; light chain CDR1 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:10; with the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:11 A light chain CDR2 region having at least 80% homology; a light chain CDR3 region having at least 80% homology with the amino acid sequence shown in SEQ ID NO:9 or SEQ ID NO:12. Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain CDR1 region selected from SEQ ID NO: 1 or SEQ ID NO: 4; a heavy chain CDR2 selected from SEQ ID NO: 2 or SEQ ID NO: 5 Region; selected from the heavy chain CDR3 region of SEQ ID NO:3 or SEQ ID NO:6; selected from the light chain CDR1 region of SEQ ID NO:7 or SEQ ID NO:10; selected from SEQ ID NO:8 or SEQ ID NO : the light chain CDR2 region of 11; selected from the light chain CDR3 region of SEQ ID NO:9 or SEQ ID NO:12. Further, the anti-PD-L1 antibody comprises: a heavy chain CDR1 region with the amino acid sequence shown in SEQ ID NO: 1, a heavy chain CDR2 region with the amino acid sequence shown in SEQ ID NO: 2, with The heavy chain CDR3 region with the amino acid sequence shown in SEQ ID NO:3; and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO:7, and the light chain CDR1 region with the amino acid sequence shown in SEQ ID NO:8. Chain CDR2 region, light chain CDR3 region having the amino acid sequence shown in SEQ ID NO:9. Further, the anti-PD-L1 antibody comprises the following amino acid sequence: a heavy chain variable region with at least 80% homology to the amino acid sequence shown in SEQ ID NO: 13 or SEQ ID NO: 14; and SEQ ID NO: The amino acid sequence shown in 15 or SEQ ID NO: 16 has a light chain variable region with at least 80% homology. Further, 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 , the variable light chain of hu5G11-hlgG1 or hu5G11-hlgg4 humanized antibodies.

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

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

Further, the present application provides a combined pharmaceutical composition, which comprises a pharmaceutical composition containing 600-2400 mg of anti-PD-L1 antibody provided in multiple doses and a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg of anti-PD-L1 antibody. Pharmaceutical composition of rotinib.

Further, the present application provides a combined pharmaceutical composition, which is a preparation suitable for administration in a single treatment cycle (eg, a treatment cycle of 21 days), including a drug containing 600-2400 mg of anti-PD-L1 antibody Compositions and pharmaceutical compositions containing 84-168 mg of anlotinib (eg, pharmaceutical compositions containing 1200 mg of anti-PD-L1 antibody and pharmaceutical compositions containing 168 mg of anlotinib).

Further, the application provides a combined pharmaceutical composition, which comprises a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5): 1, most preferably ( 7-14.5):1 anti-PD-L1 antibody and anlotinib. Among them, the anti-PD-L1 antibody and anlotinib can be packaged separately or together. And wherein, Anlotinib can be packaged in multiple equal parts (for example, 2 equal parts, 7 equal parts, 14 equal parts, 28 equal parts or more equal parts); anti-PD-L1 antibody can be in single equal parts or Multiple aliquots (eg, 2 aliquots, 4 aliquots or more) are packaged.

In another aspect, the present application also provides the use of the pharmaceutical combination of the present application, or the combined pharmaceutical composition of the present application, or the kit of the present application in preparing a medicament for treating ovarian cancer in a patient. The present application also provides a method of treating ovarian cancer, comprising administering an effective amount of the pharmaceutical combination of the present application, or the combined pharmaceutical composition of the present application, or the kit of the present application to a patient in need thereof. The present application also provides use of the pharmaceutical combination of the present application, or the combined pharmaceutical composition of the present application, or the kit of the present application for treating ovarian cancer in a patient.

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

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

In addition, the present application provides a kit for treating ovarian cancer, the kit comprising a pharmaceutical composition of an anti-PD-L1 antibody and a pharmaceutical composition of anlotinib, and instructions for treating ovarian cancer.

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

Detailed description of the invention

drug combination

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

In some embodiments of the present application, the pharmaceutical combination includes an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. In some embodiments of the present application, the pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof is a fixed combination. In some aspects, 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 pharmaceutical combination comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof is a non-fixed combination. In some aspects, 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.

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

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 complementarity determining region (CDR) of the 13C5 or 5G11 antibody, and is selected from the light chain complementarity determining region of the 13C5 or 5G11 antibody; an L1 antibody comprising a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 A variable light chain of a chimeric antibody; in one embodiment, the anti-PD-L1 antibody comprises a variable weight selected from the group consisting of hu13C5-hlgG1, hu13C5-hlgg4, hu5G11-hlgG1 or hu5G11-hlgg4 humanized antibody chain, and a variable light chain selected from the group consisting of hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1, or hu5G11-hIgG4 humanized antibodies; in one embodiment, the anti-PD-L1 antibody is selected from: 13C5, ch13C5- The HCDR1 sequence of hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS, the HCDR2 sequence is SISSGGSTYYPDSVKG, the HCDR3 sequence is GYDSGFAY, the LCDR1 sequence is ASQSVSTSSSSFMH, the LCDR2 sequence is YASNLES, and the LCDR3 sequence is QHSWEIPYT; 5G11, ch5G11-hIgG1, The HCDR1 sequence of 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;

ii) Anlotinib or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a pharmaceutical combination comprising a weight ratio of (0.35-29):1, preferably (3.5-29):1, more preferably (3.5-14.5):1, most preferably (7- 14.5): the anti-PD-L1 antibody of 1 and anlotinib or a pharmaceutically acceptable salt thereof. Wherein, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be packaged separately or together. And wherein, Anlotinib or a pharmaceutically acceptable salt thereof can be packaged in multiple aliquots (eg, 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).

Combination pharmaceutical composition

In another aspect, the present application provides a combined pharmaceutical composition for treating ovarian cancer, which comprises an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof; or, it comprises the aforementioned pharmaceutical combination.

In some embodiments of the present application, the combined 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.

In some embodiments of the present application, the combined 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 pharmaceutical composition of a pharmaceutically acceptable salt thereof. In some embodiments of the present application, the combination pharmaceutical composition is packaged in the same kit, and the kit further includes the combination therapy of PD-L1 antibody and Anlotinib or a pharmaceutically acceptable salt thereof Illustration of ovarian cancer.

In some embodiments of the present application, the combined pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises a drug containing 600-2400 mg of an anti-PD-L1 antibody Compositions and single doses are 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 single dose or multiple doses.

In some embodiments of the present application, the combined pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises an anti-PD-L1 antibody with a concentration of 10-60 mg/mL The anti-PD-L1 antibody pharmaceutical composition and the pharmaceutical composition of anlotinib in a single dose of 6 mg, 8 mg, 10 mg and/or 12 mg.

In some embodiments of the present application, the combined pharmaceutical composition comprising an anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof comprises an anti-PD-L1 antibody concentration of 10 mg/mL - L1 antibody pharmaceutical composition and pharmaceutical composition of Anlotinib in a single dose of 8 mg, 10 mg and/or 12 mg.

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

In some embodiments, there is provided a combined pharmaceutical composition for the treatment of ovarian cancer, comprising a weight ratio of (0.35-29): 1, preferably (3.5-29): 1, more preferably (3.5-14.5 ): 1, most preferably (7-14.5): 1 anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof. Wherein, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be packaged separately or together. And wherein, anlotinib can be packaged in multiple aliquots (eg, 2 aliquots, 7 aliquots, 14 aliquots, 28 aliquots or more).

Reagent test kit

In yet another aspect, the 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 a combination thereof Instructions for treating ovarian cancer; in some embodiments, a kit for treating ovarian cancer is provided, the kit comprising an anti-PD-L1 antibody pharmaceutical composition further comprising anlotinib or a pharmaceutically acceptable An acceptable salt pharmaceutical composition, and instructions for combined use to treat ovarian cancer; or, the kit includes the pharmaceutical combination or combined pharmaceutical composition of the present application, and instructions for combined use to treat ovarian cancer.

use

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

In some embodiments of the present application, in the above uses or methods of treatment, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof may be administered simultaneously, sequentially or at intervals.

In some embodiments of the present application, in the above-mentioned use or method of treatment, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are each administered in an interval administration 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, respectively. In some embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof are administered in different dosing regimens, respectively.

In some embodiments of the present application, the use or method of treatment, the anti-PD-L1 antibody may be weekly (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) ) applied once. In a specific embodiment, the anti-PD-L1 antibody is administered every 3 weeks. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 600-2400 mg per administration. In some embodiments, the anti-PD-L1 antibody is administered at a dose of 1200 mg each.

In some embodiments of the present application, the anlotinib or a pharmaceutically acceptable salt thereof may be administered at a dose of 6 mg, 8 mg, 10 mg or 12 mg once a day for 2 consecutive weeks and a dosing regimen of 1 week off Dosing. At this time, every 3 weeks is a dosing cycle.

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 dosing cycles, respectively. In some specific embodiments, the anti-PD-L1 antibody and anlotinib or a pharmaceutically acceptable salt thereof have the same dosing cycle, eg, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks for one dosing cycle.

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

In some embodiments of the present application, in the use or method of treatment, wherein the anti-PD-L1 antibody may comprise selected from the group consisting of 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 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 Doses up to 1200 mg are administered to patients.

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

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

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

Anti-PD-L1 antibody

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 the following amino acid sequence: at least 80% (for example, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% , 99% or 100%) homology to the heavy chain CDR1 region; at least 80% (eg 81%, 82%, 83%, 84%) with the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:5 , 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) with Derived heavy chain CDR2 region; at least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%, 87%) with the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:6 %, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the heavy chain CDR3 regions; At least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the light chain CDR1 region; with SEQ ID NO:8 or SEQ ID NO:8 The amino acid sequence shown in ID NO: 11 has at least 80% (eg 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92% , 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) homology to the light chain CDR2 region; with the amino acid shown in SEQ ID NO:9 or SEQ ID NO:12 Sequences have at least 80% (e.g. 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95% %, 96%, 97%, 98%, 99% or 100%) homology to the light chain CDR3 regions.

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

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

Each of the CDR regions described herein and the various variants described above can specifically recognize and bind to PD-L1, thereby effectively blocking the signaling between PD-L1 and PD-1.

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

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

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

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

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

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

In a specific embodiment, the anti-PD-L1 humanized monoclonal antibody provided in the present application comprises selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: : 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 10 One or more of ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO. 17, SEQ ID NO. 18, SEQ ID NO. 19, SEQ ID NO. 20, SEQ ID NO. 21 conservative substitution variants. The anti-PD-L1 humanized monoclonal antibody comprising the conservative substitution variant retains the ability to specifically recognize and bind to PD-L1.

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

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.

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

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 complementarity determining region (CDR) selected from a 13C5 or 5G11 antibody, and a light chain complementarity determining region selected from a 13C5 or 5G11 antibody. In one embodiment, the anti-PD-L1 antibody described herein comprises a variable heavy chain selected from the group consisting of ch5G11-hIgG1, ch5G11-hIgG4, ch13C5-hIgG1, ch13C5-hIgG4 chimeric antibodies, and selected from ch5G11- Variable light chains of 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 the group consisting of hu13C5-hlgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgg4 humanized antibody, and is selected from hu13C5 - Variable light chains of hIgG1, hu13C5-hlgG4, hu5G11-hlgG1 or hu5G11-hlgG4 humanized antibodies. Reference can be made to the description of the patent document WO2016022630 or CN107001463A: the HCDR1 sequence of 13C5, ch13C5-hIgG1, ch13C5-hIgG4, hu13C5-hIgG1 or hu13C5-hIgG4 is SYGMS (SEQ ID NO: 4), and the HCDR2 sequence is SISSGGSTYYPDSVKG (SEQ ID NO: 5 ), 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); 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), and the HCDR3 sequence is LGFYAMDY (SEQ ID NO: 2) :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).

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

Anlotinib

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

In some embodiments, the pharmaceutically acceptable salt that is anlotinib may be the hydrochloride or dihydrochloride. The doses of anlotinib or a pharmaceutically acceptable salt thereof referred to in this application, unless otherwise stated, are based on the molecular weight of the anlotinib free base.

Pharmaceutical composition of anti-PD-L1 antibody

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

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

In some embodiments of the present application, the pharmaceutical composition of the anti-PD-L1 antibody comprises one or more of buffers, isotonicity regulators, stabilizers and/or surfactants. In particular, the pharmaceutical composition of the anti-PD-L1 antibody comprises 1-150 mg/mL anti-PD-L1 antibody (eg monoclonal antibody), 3-50 mM buffer, 2-150 mg/mL isotonicity modifier/stabilizer and 0.01-0.8 mg/mL surfactant and pH about 4.5-6.8.

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

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

In some embodiments of the present application, the isotonicity modifier/stabilizer is about 20-150 mg/mL sucrose, preferably about 40-100 mg/mL sucrose, more preferably about 60 mg/mL on a w/v basis -80mg/mL of sucrose. In some embodiments, the sucrose is at a concentration of about 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, or 100 mg/mL. In some specific embodiments, the concentration of sucrose is about 60 mg/mL. In some specific embodiments, the concentration of sucrose is about 70 mg/mL. In some specific embodiments, the concentration of sucrose is about 80 mg/mL. In some specific embodiments, the concentration of sucrose is about 90 mg/mL.

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

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 on a w/v basis. In some embodiments, the concentration of the surfactant is about 0.05-0.6 mg/mL polysorbate 80, preferably about 0.1-0.4 mg/mL polysorbate 80, more preferably about 0.2-0.3 mg /mL of polysorbate 80, most preferably about 0.2 mg/mL of polysorbate 80. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL or 0.6 mg/mL; preferably Preferably, the content of polysorbate 80 in the pharmaceutical composition is about 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL or 0.5 mg/mL; more preferably, the content of polysorbate 80 in the pharmaceutical composition About 0.2 mg/mL, 0.3 mg/mL or 0.4 mg/mL; optimally, the polysorbate 80 content in the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the amount of polysorbate 80 in the pharmaceutical composition is about 0.1 mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.2 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.3 mg/mL. In other embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.4 mg/mL. In some embodiments, the polysorbate 80 content of the pharmaceutical composition is about 0.5 mg/mL.

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

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

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

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

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

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

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

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

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

In another specific embodiment of the present application, the pharmaceutical composition is a water-soluble injection, which includes but is not limited to a water-soluble preparation without lyophilization or a water-soluble preparation reconstituted with a lyophilized powder. In other aspects, the pharmaceutical composition is a lyophilized formulation. The lyophilized formulation refers to an aqueous solution that undergoes a lyophilization process to prepare a formulation. The lyophilized formulations of the present application may also be dried by other methods known in the art, such as spray drying and bubble drying.

Pharmaceutical composition of Anlotinib or a pharmaceutically acceptable salt thereof

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

In some embodiments of the present application, according to 2 weeks of administration and 1 week of rest, every 3 weeks is a dosing cycle, and the total amount of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition is administered in each cycle. Dosages include 84 to 168 mg. In some schemes, the total dose of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition comprises a range selected from 84 mg, 112 mg, 140 mg, 168 mg or any value formed above. In some schemes, the total dose of the anlotinib or its pharmaceutically acceptable salt pharmaceutical composition preferably includes 112 mg to 168 mg.

ovarian cancer

In some embodiments, the ovarian cancer is selected from Epithelial ovarian cancer, fallopian tube cancer and/or primary peritoneal cancer.

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

In some embodiments, the ovarian cancer is selected from relapsed 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.

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

In some embodiments, the ovarian cancer patient has disease progression after having previously received one, two, three, or four of cytotoxic therapy, targeted therapy, immunotherapy, radiation therapy, and/or hormonal therapy or relapse. In some embodiments, the patient with ovarian cancer has disease progression or recurrence after having previously received one, two, three, or four of chemotherapy, targeted therapy, immunotherapy, radiation therapy, and/or hormonal therapy , the chemotherapy includes but is not limited to cytotoxic therapy. In some embodiments, the ovarian cancer patient has at least prior platinum-containing chemotherapy for disease progression or relapse.

The cytotoxic treatment includes, but is not limited to, platinum (such as one of cisplatin, carboplatin, nedaplatin, dicycloplatin, picoplatin, oxaliplatin, meplatin, and lobaplatin) or several), taxanes (such as one or more of paclitaxel, paclitaxel albumin-bound, docetaxel), camptothecin, doxorubicin, mitoxantrone, irinotecan, topo Tecan, Etoposide, Teniposide, Bleomycin, Gemcitabine, 5-Fluorouracil, Leucovorin, Oxaliplatin, Hexamelamine, Capecitabine, Ifosfamide, Pemetrexed One or more of Troxet or Vinorelbine. Said targeted therapy includes, but is not limited to, PARP inhibitors (eg, olaparib, rucaparib, niraparib). The hormone therapy includes, but is not limited to, aromatase inhibitors, tamoxifen, fulvestrant, leuprolide, and megestrol acetate. The immunotherapy includes but is not limited to bevacizumab and pembrolizumab.

In some embodiments, the ovarian cancer patient is a patient who has failed prior platinum-containing drug therapy; in some embodiments, the ovarian cancer patient is a patient who has failed prior platinum-containing regimen therapy patient.

In some embodiments, the ovarian cancer patient is a patient who has failed at least one line of platinum therapy.

In some embodiments, the ovarian cancer patient is a patient who has received at least 1 or more lines of platinum therapy, and the patient has had disease recurrence or progression within 6 months after receiving the last platinum-containing therapy requiring discontinuation.

In some embodiments, the patient with ovarian cancer is a platinum-resistant patient.

In some embodiments, the ovarian cancer patient has received > 1 line of platinum-containing chemotherapy regimens after prior cytoreduction; optionally, at least 4 cycles of platinum-containing therapy.

In some embodiments, the patient with ovarian cancer is a platinum-resistant or refractory patient, including patients with disease progression or recurrence during prior platinum-containing chemotherapy regimen treatment or within ≤ 6 months after the end of platinum-containing therapy.

In some embodiments, the patient with ovarian cancer is a platinum-sensitive patient, and the patient has had disease progression or recurrence after at least 2 different platinum-containing chemotherapy regimens (the initial platinum-containing regimen) .

In some embodiments, the platinum-based regimen treatment includes, but is not limited to, one or more of cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, meplatin or lobaplatin Treatment.

In some embodiments, the ovarian cancer patient is a patient who has failed prior treatment with a taxane-containing drug; the taxane includes but is not limited to paclitaxel, paclitaxel albumin-bound, docetaxel one or more of the competitions.

In some embodiments, the patient with ovarian cancer has been previously treated with one or more of the following regimens, 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 Platinum and gemcitabine; 5-fluorouracil, leucovorin, and oxaliplatin; or capecitabine and oxaliplatin.

In some embodiments, the patient with ovarian cancer has been previously treated with one or more of the following regimens, including:

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

² ) Intravenous infusion of carboplatin AUC 5 combined with doxorubicin liposome 30mg/m2, repeated every 4 weeks, for a total of 3 to 6 cycles;

3) Docetaxel 60～75mg/m ² , intravenous infusion for 1 hour, carboplatin AUC 5～6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, for a total of 6 cycles;

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

5) Paclitaxel 80mg/ ^m2 intravenous infusion for 1 hour, on the 1st, 8th and 15th days, carboplatin AUC 5-6, intravenous infusion for 1 hour, on the 1st day, repeated every 3 weeks, a total of 6 cycles;

6) Paclitaxel 60mg/m2/week, intravenous infusion for 1 hour, carboplatin AUC ² /week, intravenous infusion for 30 minutes, a total of 18 weeks;

7) Docetaxel 60～75mg/m ² , intravenous infusion for 1 hour, carboplatin AUC 5～6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, for a total of 6 cycles;

8) Intravenous infusion of carboplatin AUC ⁵ combined with doxorubicin liposome 30mg/m2, repeated every 4 weeks, for a total of 6 cycles;

9) Paclitaxel 175mg/m ² , intravenous infusion for 3 hours, carboplatin AUC 5-6, intravenous infusion for 1 hour, bevacizumab 7.5mg/kg, intravenous infusion for 30-90 minutes, on the first day, every Repeated for 3 weeks for a total of 5 to 6 cycles, after which the bevacizumab monotherapy continued to be maintained for 12 cycles;

10) Paclitaxel 175mg/m ² , intravenous infusion for 3 hours, carboplatin AUC 6, intravenous infusion for 1 hour, on the first day. Repeated every 3 weeks for a total of 6 cycles, from the first day of the second cycle, bevacizumab 15mg/kg was administered intravenously for 30 to 90 minutes, repeated every 3 cycles, a total of 22 cycles;

11) Paclitaxel 135mg/m ² , intravenous infusion for 3 hours or 24 hours, on the first day, cisplatin 75-100mg/m ² intraperitoneal injection, on the second day, paclitaxel 60mg/m ² intraperitoneal injection, on the 8th day, every 3 Weekly repetition, a total of 6 cycles;

Or, 12) BEP regimen: bleomycin 30 units, once a week, etoposide 100 mg/m ² per day, 1-5 days, cisplatin 20 mg/m ² per day, 1-5 days, intravenous drip Note, repeat every 3 weeks.

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 relapsed or refractory ovarian cancer; optionally, the ovarian cancer The cancer is selected from platinum-resistant or platinum-sensitive ovarian cancer; optionally, the patient with ovarian cancer has previously undergone surgery, cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy or hormone therapy Disease progression or recurrence; optionally, the patient with ovarian cancer has previously received cisplatin, carboplatin, nedaplatin, bicycloplatin, picoplatin, oxaliplatin, meplatin, lobaplatin, camptothecin , doxorubicin, mitoxantrone, irinotecan, topotecan, etoposide, teniposide, paclitaxel or its albumin-bound form, bevacizumab, doxorubicin or its liposome , docetaxel, bleomycin, gemcitabine, 5-fluorouracil, leucovorin, oxaliplatin, hexamethylmelamine, capecitabine, ifosfamide, pemetrexed, or vinorelbine one or more of the treatments; optionally, the patient with ovarian cancer has previously received one or more of the following regimens, including: paclitaxel and carboplatin; carboplatin and doxorubicin; Cetaxel 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 patient with ovarian cancer has previously Received one or more of the following regimens, including: 1) Paclitaxel 175mg/m ² , intravenous infusion for 3 hours, carboplatin AUC 5-6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, A total of 3-6 cycles; 2) Carboplatin AUC 5 combined with doxorubicin liposome 30mg/ ^m2 intravenous drip, repeated every 4 weeks, a total of 3-6 cycles; 3) Docetaxel 60-75mg /m ² , intravenous infusion for 1 hour, carboplatin AUC 5-6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, a total of 6 cycles; 4) Paclitaxel 175 mg/m ² , intravenous infusion for 3 hours, Carboplatin AUC 5-6, intravenous infusion for 1 hour, on day 1, repeated every 3 weeks, for a total of 6 cycles; 5) Paclitaxel 80 mg/ ^m2 intravenous infusion for 1 hour, on days 1, 8, and 15, carboplatin AUC 5～6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, for a total of 6 cycles; 6) Paclitaxel 60mg/m2/week, intravenous infusion for 1 hour, carboplatin AUC ² /week, intravenous infusion 30 minutes, a total of 18 weeks; 7) Docetaxel 60-75mg/m ² , intravenous infusion for 1 hour, carboplatin AUC 5-6, intravenous infusion for 1 hour, on the first day, repeated every 3 weeks, a total of 6 Cycle; 8) Carboplatin AUC 5 combined with doxorubicin liposome 30mg/m ² intravenous infusion, repeated every 4 weeks, a total of 6 cycles; 9) Paclitaxel 175mg/m ² , intravenous infusion for 3 hours, carboplatin AUC5～6, intravenous infusion for 1 hour, bevacizumab 7.5mg/kg, intravenous infusion for 30-90 minutes, the first 10) Paclitaxel 175mg/m ² , intravenous infusion for 3 hours, carboplatin AUC 6, intravenous infusion Note 1 hour, day 1. Repeat every 3 weeks for a total of 6 cycles, from the first day of the second cycle, administer bevacizumab 15mg/kg, intravenous drip for 30-90 minutes, repeat every 3 cycles, for a total of 22 cycles; 11) Paclitaxel 135 mg/m ² , intravenous infusion for 3 hours or 24 hours, on day 1, cisplatin 75-100 mg/m ² intraperitoneal injection, on day 2, paclitaxel 60 mg/m ² intraperitoneal injection, on day 8, repeat every 3 weeks, A total of 6 cycles; or, 12) BEP regimen: bleomycin 30 units, once a week, etoposide 100 mg/m ² per day, 1-5 days, cisplatin 20 mg/m ² per day, 1- 5 days, intravenous infusion, repeat every 3 weeks.

way of administration

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

The components of the pharmaceutical compositions of the present application may each be administered independently, or some or all of them may be administered together by various routes as appropriate, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous route). In some embodiments, the components of the pharmaceutical combinations of the present application may each be administered independently, or some or all of them may be administered orally or by injection, eg, intravenously or intraperitoneally.

The components of the pharmaceutical compositions of the present application may each independently, or some or all of which may be taken together in a suitable dosage form, including, but not limited to, tablets, troches, pills, capsules (eg, hard capsules, soft capsules) , enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral use The dosage form of the sustained release formulation for administration.

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

The pharmaceutical combinations of the present application may also contain additional therapeutic agents. In one embodiment, the additional therapeutic agent may be a small cell cancer therapeutic agent known in the art.

dosing regimen

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 method for treating ovarian cancer in a patient, and the use for treating ovarian cancer in a patient.

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

In some embodiments of the present application, the dosing regimen includes: 1) the anti-PD-L1 antibody is administered once a day on days 1-7 of each dosing cycle; 2) Anlotinib or its pharmacy The above acceptable salts are administered continuously on days 1-28 of each dosing cycle.

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

In some embodiments of the present application, the dosing regimen includes: 1) the anti-PD-L1 antibody hu5G11-hIgG1 (ie hu5G11-hIgG1 in WO2016022630) is administered once on the first day of each dosing cycle; 2 ) Anlotinib dihydrochloride was administered continuously on days 1-14 of each dosing cycle.

In some embodiments of the present application, the anti-PD-L1 antibody is administered once on the 1st, 2nd, 3rd, 4th, 5th, 6th, or 7th day of each dosing cycle, preferably each dosing cycle Dosing once on day 1.

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

technical effect

The pharmaceutical combination or combined pharmaceutical composition of the present application has a good activity for treating ovarian cancer. The combination or combined use of a plurality of active ingredients exhibits superior antitumor effects compared with the case where they are used alone.

In general, use of the above-mentioned combination pharmaceutical compositions of the present application will help:

(1) produce better efficacy in reducing tumor growth or even eliminating tumors compared to administration of either drug in the combination alone;

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

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

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

(5) Provide longer survival (eg, median survival, progression-free survival, or overall survival) in the treated patient;

(6) Provide that the treated patient has a longer survival (eg, median survival, progression-free survival, or overall survival) compared to standard chemotherapy;

(7) Provide longer duration of disease remission (DOR); and/or effectively delay compounding time, thereby prolonging patient survival; and/or

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

Definition and Explanation

Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but 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 its corresponding trade or its active ingredient.

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. Accordingly, 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 can also include recombinant polypeptides, fusion proteins, and bispecific antibodies. The anti-PD-L1 antibodies and fragments thereof disclosed herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the species of antibody encoded by the heavy chain constant region genes. In one embodiment, the anti-PD-L1 antibodies and fragments thereof disclosed herein are of the IgG1 or IgG4 isotype. The PD-L1 antibodies and fragments thereof of the present application can be derived from any species including, but not limited to, mouse, rat, rabbit, primate, llama, and human. PD-L1 antibodies and fragments thereof can be chimeric antibodies, humanized antibodies, or fully human antibodies. In one embodiment, the anti-PD-L1 antibody is an antibody produced by a mouse-derived hybridoma cell line. Thus, in one embodiment, the anti-PD-L1 antibody is a murine antibody. In another embodiment, the anti-PD-L1 antibody is a chimeric antibody. In another embodiment, the chimeric antibody is a mouse-human chimeric antibody. In another embodiment, the antibody is a humanized antibody. In another embodiment, the antibody is derived from a murine antibody and is humanized.

A "humanized antibody" is an antibody that contains complementarity determining regions (CDRs) derived from a non-human antibody; and framework and constant regions derived from a human antibody. For example, the anti-PD-L1 antibodies provided herein can comprise CDRs derived from one or more murine antibodies as well as human framework and constant regions. Thus, in one embodiment, the humanized antibodies provided herein bind the same epitope on PD-L1 as the murine antibody from which the CDRs of the antibody are derived. Exemplary humanized antibodies are provided herein. Additional anti-PD-L1 antibodies or variants thereof comprising the heavy and light chain CDRs provided herein can be generated using any human framework sequences 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 those provided herein. Additional modifications can be made in the framework regions to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or to remove T cell epitopes; or reversion of mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including backmutations to germline sequences. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids in the parental murine antibody. For example, for the VH and VL of humanized 5G11 and humanized 13C5, several sites in the framework amino acids of the template human antibodies described above were backmutated to the corresponding amino acid sequences in the mouse 5G11 and 13C5 antibodies. In one embodiment, the amino acids at positions 53 and/or 60 and/or 67 of the light chain variable region are backmutated to the corresponding ones found at said positions in the mouse 5G11 or 13C5 light chain variable region amino acid. In another embodiment, the amino acids at positions 24 and/or 28 and/or 30 and/or 49 and/or 73 and/or 83 and/or 94 of the heavy chain variable region are backmutated to be in mouse 5G11 or the corresponding amino acid found at said position in the 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) is Tyr(Y); and the heavy chain variable region, wherein the amino acid at position 24 is mutated from Phe(F) to Val(V) and the amino acid at position 49 is mutated from Ala(A) to Gly(G), The amino acid at position 73 was mutated from Thr(T) to Asn(N), and the amino acid at position 83 was mutated from Thr(T) to Asn(N). In one embodiment, the humanized 13C5 antibody comprises a light chain variable region in which the amino acid at position 53 is mutated from Tyr(Y) to Lys(K); and a heavy chain variable region in which the amino acid at position 28 is mutated from Tyr(Y) to Lys(K); The amino acid is mutated from Thr(T) to Ile(I), the amino acid at position 30 is mutated from Ser(S) to Arg(R), the amino acid at position 49 is mutated from Ser(S) to Ala(A), and The amino acid at position 94 was mutated from Tyr (Y) to Asp (D). Additional or alternative backmutations can be made in the framework regions of the humanized antibodies provided herein to improve the properties of the antibodies. The present application also includes humanized antibodies that bind PD-L1 and comprise framework modifications corresponding to the exemplary modifications described herein relative to any suitable framework sequences, and otherwise improve the antibody Additional frame decorations for properties.

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

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

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

The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.

The term "effective amount" means (i) treatment or prevention of a particular disease, condition or disorder, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay herein The amount of a compound of the present application to be used for the onset of one or more symptoms of a particular disease, condition or disorder described in . The amount of an active substance (eg, an antibody or compound of the present application) that constitutes a "therapeutically effective amount" may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the elicitation of the therapeutic agent or combination of therapeutic agents in the individual. ability to respond. Effective amounts can also be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

The term "administering" means physically introducing a composition comprising a therapeutic agent to 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 (eg, anti-PD-L1 antibodies) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, eg, by injection or infusion. The phrase "parenteral administration" as used herein refers to modes of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, lymphatic Intratracheal, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion injection, and in vivo electroporation. In certain embodiments, the immune checkpoint inhibitor (eg, 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, eg, intranasal, vaginal, rectal, sublingual, or topical. Administration can also be performed, eg, once, multiple times, and/or over one or more extended periods of time.

Use of the term "dose" refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). For example, a 60kg person and a 100kg person will receive the same dose of antibody (eg, 240mg anti-PD-L1 antibody).

The term "weight-based dose" as referred to herein refers to a dose administered to a patient calculated based on the patient's weight. For example, when a patient with a body weight of 60 kg requires 3 mg/kg of anti-PD-L1 antibody, one can withdraw an appropriate amount of anti-PD-L1 antibody (ie, 180 mg) at one time from a fixed-dose formulation of anti-PD-L1 antibody.

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 , Buccal, Intranasal, Inhalation, Vaginal, Intraocular, Topical, Subcutaneous, Intralipid, Intraarticular, Intraperitoneal and Intrathecal. In some specific embodiments, administration is by oral route. The amount of anlotinib, or a pharmaceutically acceptable salt thereof, to be 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 administered may be 2 mg to 20 mg, and in some embodiments, the daily dose of anlotinib or a pharmaceutically acceptable salt thereof may be administered 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, and 16 mg. Anlotinib or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, anlotinib or a pharmaceutically acceptable salt thereof is administered once daily in an oral solid formulation.

The dosage regimen of anlotinib or a pharmaceutically acceptable salt thereof can be comprehensively determined according to the activity of the drug, the toxicity, and the patient's tolerance. Preferably, anlotinib or a pharmaceutically acceptable salt thereof is administered in spaced dosing. The said interval administration includes a dosing period and a withdrawal period, during which anlotinib or a pharmaceutically acceptable salt thereof can be administered once or more times per day. For example, the ratio in days between the administration period and the withdrawal period is 2:0.5-5, preferably 2:0.5-3, more preferably 2:0.5-2, more preferably 2:0.5-1. In some embodiments, the dosing is for 2 consecutive weeks and the drug is off for 2 weeks. In some embodiments, 2 consecutive weeks of dosing are administered for 1 week off. In some embodiments, 5 consecutive days of administration are administered for 2 days off. For example, anlotinib or a pharmaceutically acceptable salt thereof can be administered orally at a dose of 6 mg, 8 mg, 10 mg, or 12 mg once a day, continuously for 2 weeks, and then for 1 week off.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" includes salts of base ions with free acids or salts of acid ions with free bases, including, for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, Formate, acetate, trifluoroacetate, fumarate, oxalate, maleate, citrate, succinate, mesylate, benzenesulfonate or p-toluene Sulfonates, preferably hydrochloride, hydrobromide, sulfate, formate, acetate, trifluoroacetate, fumarate, maleate, mesylate, p-toluene Sulfonate, sodium salt, potassium salt, ammonium salt, amino acid salt, etc. In the present application, when a pharmaceutically acceptable salt is formed, the molar ratio of the free acid to the base ion is about 1:0.5 to 1:5, preferably 1:0.5, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7 or 1:8. In the present application, when a pharmaceutically acceptable salt is formed, the molar ratio of the free base to 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.

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.

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

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

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

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

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

The term "fixed combination" refers to the simultaneous administration of the active components (eg, anti-PD-L1 antibody and anlotinib) to a patient in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or formulation.

The term "non-fixed combination" refers to the simultaneous, concurrent or sequential administration of two or more active ingredients as separate entities (eg, pharmaceutical compositions, formulations) and without a specific time limit, wherein the active ingredients administered to the patient achieve a therapeutic effect. effective dose level. An example of a non-fixed combination is a cocktail therapy, eg the administration of 3 or more active ingredients. In non-fixed combinations, the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions. The "non-fixed combination" also includes the use of a combination between "fixed combination" or "fixed combination" with any one or more separate entities of the active ingredient.

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

As used herein, the term "combination pharmaceutical composition" refers to the simultaneous or sequential administration of two or more active ingredients (either as the respective active ingredients themselves, or their respective pharmaceutically acceptable salts) or derivatives such as esters, prodrugs or compositions). As used herein, the terms "combination pharmaceutical composition", "pharmaceutical composition" and "pharmaceutical combination" are used interchangeably.

The term "platinum-resistant" includes disease progression during treatment with previous platinum-based chemotherapy regimens, and disease progression or relapse within ≤6 months after the end of platinum-based therapy.

The term "platinum-sensitive" refers to disease progression or relapse ≥6 months after the completion of platinum-containing chemotherapy regimens; including disease progression or recurrence after at least 2 different platinum-containing regimens in previous chemotherapy regimens.

Detailed ways

For the sake of clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in this application were commercially available and used without further purification. In the examples, the anti-PD-L1 antibody was prepared according to the method described in WO2016022630. After affinity chromatography, an eluate containing the antibody was obtained according to a conventional antibody purification method.

Example 1 Clinical trial

1.1 Inclusion criteria

1) Understand and voluntarily sign the written informed consent;

2) Age ≥18 years old, female; ECOG score 0-1, expected survival period ≥3 months;

3) Histologically confirmed epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer;

4) The subject has received ≥1 line of platinum-based chemotherapy (at least 4 cycles of platinum-containing therapy) after tumor debulking before, and meets any of the following criteria:

Platinum-resistant or refractory patients, including patients with disease progression or relapse during previous platinum-containing chemotherapy regimens or within ≤6 months after the end of platinum-containing therapy;

For platinum-sensitive patients (ie, disease progression or relapse ≥6 months after the completion of platinum-containing chemotherapy regimens), disease progression or recurrence after at least 2 different platinum-containing chemotherapy regimens (including initial chemotherapy regimens) platinum-based regimens);

5) According to RECIST1.1 solid tumor evaluation criteria, it contains at least one measurable lesion;

6) Laboratory tests during the screening period meet the following conditions:

Blood routine: hemoglobin (HB) ≥ 90g/L; absolute neutrophil value (ANC) ≥ 1.5×10 ⁹ /L; platelets (PLT) ≥ 80×10 ⁹ /L;

Blood biochemistry: total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase AST ≤ 2.5ULN, if associated with liver metastases, ALT and AST≤5ULN; Serum muscle (Cr)≤1.5ULN or creatinine clearance (CCr)≥60mL/min;

Urine routine: urine protein < 2+ (when the baseline urine protein is ≥ 2+, 24-hour urine protein quantitative detection should be performed within 7 days, and only when the urine protein is < 1 g can be selected);

Coagulation function: INR and APTT≤1.5×ULN;

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

7. Women must meet one of the following conditions:

1) Surgical sterilization has been performed;

2) Menopausal persons who have stopped menstruating for at least 1 year;

3) To be fertile, the following conditions must be met;

Negative serum/urine pregnancy test result prior to first dose; consent to use an approved method of contraception throughout the study (eg: oral contraceptive, injectable contraceptive or implanted, barrier contraceptive, spermicide and contraception condoms, or intrauterine device), and the contraceptive method remained unchanged throughout the study.

1.2 Investigational drug & dosing schedule

Injection containing hu5G11-hIgG1: 1200mg anti-PD-L1 antibody injection diluted with normal saline to 250mL, the infusion time is 60±5min, after the infusion is completed, flush the tube with normal saline according to the routine requirements of the hospital, and administer once every 21 days.

Specifications: 100mg/10mL, 300mg/10mL.

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

Anlotinib Hydrochloride Capsules (active ingredient is Anlotinib Dihydrochloride): Anti-PD-L1 Antibody Injection Start infusion and take Anlotinib Hydrochloride Capsules on an empty stomach within ±5min each time, orally for 2 consecutive weeks Stop for 1 week, that is, 21 days as a treatment cycle.

Specifications: 12mg, 10mg, 8mg.

1.3 Evaluation Criteria

Disease status was determined according to RECIST 1.1/irRECIST. The RECIST 1.1 evaluation standard is the main evaluation standard, and the iRECIST evaluation standard is supplemented.

1.4 Endpoint indicators

21 days is a treatment cycle. In the first 18 cycles of the treatment period, imaging evaluations are performed every 42 days (2 cycles), and after 18 cycles, imaging evaluations are performed every 63 days (3 cycles).

progression-free survival (PFS);

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.

1.5 Data Results

Twenty-five of the 26 subjects underwent at least one efficacy evaluation, and 11 subjects were withdrawn from the group due to imaging evaluation progress, voluntary withdrawal, and aggravation of disease symptoms.

Among the 25 patients who had at least one response evaluation, 12 had a partial response (PR) and 12 had a stable (SD) response, resulting in an objective response rate (ORR) of 52.0%. , the disease control rate (DCR) was 96.0%, and the median progression-free survival was 7.03 months, which showed good efficacy compared with the historical data of platinum-resistant patients (PFS 3-4 months).

sequence listing

<110> Chia Tai Tianqing Pharmaceutical Group Nanjing Shunxin Pharmaceutical Co., Ltd.

Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

<120> Drug combinations for ovarian cancer

<130> 2020

<160> 21

<170> SIPOSequenceListing 1.0

<210> 1

<211> 5

<212> PRT

<213> Mus sp.

<400> 1

Thr Tyr Gly Val His

1 5

<210> 2

<211> 16

<212> PRT

<213> Mus sp.

<400> 2

Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met Ser

1 5 10 15

<210> 3

<211> 8

<212> PRT

<213> Mus sp.

<400> 3

Leu Gly Phe Tyr Ala Met Asp Tyr

1 5

<210> 4

<211> 5

<212> PRT

<213> Mus sp.

<400> 4

Ser Tyr Gly Met Ser

1 5

<210> 5

<211> 16

<212> PRT

<213> Mus sp.

<400> 5

Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys Gly

1 5 10 15

<210> 6

<211> 8

<212> PRT

<213> Mus sp.

<400> 6

Gly Tyr Asp Ser Gly Phe Ala Tyr

1 5

<210> 7

<211> 11

<212> PRT

<213> Mus sp.

<400> 7

Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala

1 5 10

<210> 8

<211> 7

<212> PRT

<213> Mus sp.

<400> 8

Tyr Ala Ala Asn Arg Tyr Thr

1 5

<210> 9

<211> 9

<212> PRT

<213> Mus sp.

<400> 9

Gln Gln Asp Tyr Thr Ser Pro Tyr Thr

1 5

<210> 10

<211> 14

<212> PRT

<213> Mus sp.

<400> 10

Ala Ser Gln Ser Val Ser Thr Ser Ser Ser Ser Ser Phe Met His

1 5 10

<210> 11

<211> 7

<212> PRT

<213> Mus sp.

<400> 11

Tyr Ala Ser Asn Leu Glu Ser

1 5

<210> 12

<211> 9

<212> PRT

<213> Mus sp.

<400> 12

Gln His Ser Trp Glu Ile Pro Tyr Thr

1 5

<210> 13

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 13

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr

20 25 30

Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

65 70 75 80

Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 14

<211> 116

<212> PRT

<213> Artificial Sequence

<400> 14

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala

85 90 95

Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 15

<211> 107

<212> PRT

<213> Artificial Sequence

<400> 15

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105

<210> 16

<211> 111

<212> PRT

<213> Artificial Sequence

<400> 16

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser

20 25 30

Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys

100 105 110

<210> 17

<211> 446

<212> PRT

<213> Artificial Sequence

<400> 17

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr

20 25 30

Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

65 70 75 80

Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 18

<211> 214

<212> PRT

<213> Artificial Sequence

<400> 18

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

1 5 10 15

Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp

20 25 30

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

35 40 45

Tyr Tyr Ala Ala Asn Arg Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly

50 55 60

Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Ile Ala Thr Tyr Phe Cys Gln Gln Asp Tyr Thr Ser Pro Tyr

85 90 95

Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala

100 105 110

Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly

115 120 125

Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala

130 135 140

Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln

145 150 155 160

Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser

165 170 175

Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr

180 185 190

Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser

195 200 205

Phe Asn Arg Gly Glu Cys

210

<210> 19

<211> 446

<212> PRT

<213> Artificial Sequence

<400> 19

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ile Phe Arg Ser Tyr

20 25 30

Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Gly Gly Ser Thr Tyr Tyr Pro Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Asp Cys Ala

85 90 95

Arg Gly Tyr Asp Ser Gly Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr

210 215 220

Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe

225 230 235 240

Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro

245 250 255

Glu Val Thr Cys Val Val Val Ala Val Ser His Glu Asp Pro Glu Val

260 265 270

Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr

275 280 285

Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val

290 295 300

Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

305 310 315 320

Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

325 330 335

Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

340 345 350

Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val

355 360 365

Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly

370 375 380

Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp

385 390 395 400

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

405 410 415

Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His

420 425 430

Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440 445

<210> 20

<211> 218

<212> PRT

<213> Artificial Sequence

<400> 20

Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Pro Gly

1 5 10 15

Gln Arg Ala Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Thr Ser

20 25 30

Ser Ser Ser Phe Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro

35 40 45

Lys Leu Leu Ile Lys Tyr Ala Ser Asn Leu Glu Ser Gly Val Pro Ala

50 55 60

Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Asn

65 70 75 80

Pro Val Glu Ala Asn Asp Thr Ala Asn Tyr Tyr Cys Gln His Ser Trp

85 90 95

Glu Ile Pro Tyr Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg

100 105 110

Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln

115 120 125

Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr

130 135 140

Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser

145 150 155 160

Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr

165 170 175

Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys

180 185 190

His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro

195 200 205

Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

210 215

<210> 21

<211> 442

<212> PRT

<213> Artificial Sequence

<400> 21

Gln Ile Thr Leu Lys Glu Ser Gly Pro Thr Leu Val Lys Pro Thr Gln

1 5 10 15

Thr Leu Thr Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Thr Tyr

20 25 30

Gly Val His Trp Ile Arg Gln Pro Pro Gly Lys Ala Leu Glu Trp Leu

35 40 45

Gly Val Ile Trp Arg Gly Val Thr Thr Asp Tyr Asn Ala Ala Phe Met

50 55 60

Ser Arg Leu Thr Ile Thr Lys Asp Asn Ser Lys Asn Gln Val Val Leu

65 70 75 80

Thr Met Asn Asn Met Asp Pro Val Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Arg Leu Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala

115 120 125

Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu

130 135 140

Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly

145 150 155 160

Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser

165 170 175

Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu

180 185 190

Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr

195 200 205

Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro

210 215 220

Cys Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val

290 295 300

Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Gln Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly

435 440

Claims (16)

1. Use of a pharmaceutical combination comprising an anti-PD-L1 antibody and aritinib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of ovarian cancer.

2. Use according to claim 1, wherein the pharmaceutical combination is a fixed combination or a non-fixed combination.

3. The use of claim 1 or 2, wherein the compositions are packaged in the same kit, and the kit further comprises PD-L1 antibody, erlotinib, or a pharmaceutically acceptable salt thereof, and instructions for use in combination to treat ovarian cancer.

4. Use according to any one of claims 1 to 3, wherein the period of administration of the pharmaceutical combination is 14 to 42 days; preferably, the administration period is 14 days, 21 days, 28 days, 35 days or 42 days; more preferably, the administration period is 21 days.

5. The use according to any one of claims 1 to 4, wherein 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 the administration of erlotinib, or a pharmaceutically acceptable salt thereof, is continued on days 1-7, days 7-14, days 1-14, or days 7-21 of each dosing cycle.

6. Use according to any one of claims 1 to 5, wherein the period of administration of the pharmaceutical combination is 21 days.

7. Use according to any one of claims 1 to 5, characterized in that:

1) the anti-PD-L1 antibody was administered once a day within days 1-7 of each dosing cycle; 2) the administration of the erlotinib or pharmaceutically acceptable salt thereof is continuous on days 1-28 of each dosing cycle; or,

1) anti-PD-L1 antibody was administered once on day 1 of each dosing cycle; 2) the administration of the erlotinib or pharmaceutically acceptable salt thereof is continuous on days 1-14 of each dosing cycle; or,

1) anti-PD-L1 antibody hu5G11-hIgG1 was administered once on day 1 of each dosing cycle; 2) anrotinib dihydrochloride is administered continuously on days 1-14 of each dosing cycle.

8. The use of any one of claims 1-7, wherein the anti-PD-L1 antibody and the nilotinib, or a pharmaceutically acceptable salt thereof, are administered simultaneously, sequentially or at intervals; or the anti-PD-L1 antibody and the nilotinib, or a pharmaceutically acceptable salt thereof, each in a pharmaceutical composition, which can be administered simultaneously, sequentially or at intervals.

9. The use according to any one of claims 1 to 8, wherein the anti-PD-L1 antibody and the erlotinib, or a pharmaceutically acceptable salt thereof, are each administered on the same or different dosing regimen.

10. The use of any one of claims 1-8, wherein the anti-PD-L1 antibody can be administered once weekly, every 2 weeks, every 3 weeks, or every 4 weeks; and/or said nilotinib or a pharmaceutically acceptable salt thereof may be administered once daily at a dose of 6mg, 8mg, 10mg, or 12mg for 2 weeks on a dosing schedule of 1 week off.

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

12. Use according to any one of claims 1 to 11, wherein the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer.

13. The use according to any one of claims 1 to 12, wherein the ovarian cancer is selected from recurrent and/or refractory ovarian cancer and/or advanced ovarian cancer.

14. The use according to any one of claims 1 to 13, wherein the ovarian cancer is selected from platinum-resistant or platinum-sensitive ovarian cancer.

15. The use of any one of claims 1-14, wherein the ovarian cancer is a KRAS and/or BRCA (e.g., BRCA1, BRCA2) mutated ovarian cancer.

16. The use according to any one of claims 1 to 15, wherein the ovarian cancer patient is an ovarian cancer patient who has previously undergone disease progression or recurrence following one, two, three or four of cytotoxic therapy, targeted therapy, immunotherapy, radiotherapy and/or hormonal therapy; or the patient with ovarian cancer has received a platinum-containing chemotherapy scheme more than or equal to 1 after the previous tumor reduction operation; optionally, the platinum-containing treatment is for at least 4 cycles.