RU2783846C1 - Application of an antibody to pd-1 in combination with famitinib for producing a medicinal product for treating tumours - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: presented are an application of an antibody to PD-1 in combination with famitinib for producing a medicinal product for treating tumours; a method for alleviating the adverse reaction caused by the antibody to PD-1 or an antigen-binding fragment thereof, including the administration of famitinib or a pharmacologically acceptable salt thereof in combination with the antibody to PD-1; a method for reducing the dose of the antibody to PD-11 or an antigen-binding fragment thereof or a dose of famitinib or a pharmaceutically acceptable salt thereof, as well as a pharmaceutical kit for treating a tumour or a cancer, containing famitinib or a pharmaceutically acceptable salt thereof and the antibody to PD-1.

EFFECT: group of inventions allows for effective application of combinations of the above antibody with famitinib for treating cancerous tumours and alleviating the side reaction in the form of a reactive capillary hyperplasia, which may occur when the antibody to PD-1 is used separately.

23 cl, 4 tbl, 3 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to the use of an anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of tumors.

PRIOR ART

In cancer, various genetic and epigenetic changes occur, resulting in new antigens that can be recognized by the immune system. The adaptive immune system, including T- and B-lymphocytes, has strong anti-cancer activity, significant functionality and high specificity in response to various tumor antigens. In addition, the immune system has significant flexibility and memory components. The successful use of all these properties of the adaptive immune system will make immunotherapy unique among all cancer treatments.

Cancer immunotherapy focuses on ways to enhance the immune response to tumors through adoptive transfer of activated effector cells, immunity against related antigens, or the provision of non-specific immunostimulants such as cytokines. In recent years, the development of inhibitors specific to the immune checkpoint pathway has emerged as a new immunotherapeutic treatment for cancer, such as ipilimumab (YERVOY®), an anti-CTLA antibody for the treatment of advanced melanoma (Hodi et al., 2010), nivolumab or pembrolizumab, specifically binding to the programmed death receptor (PD-1), and the like.

Anti-PD-1 antibodies specifically recognize and bind to PD-1 present on the surface of lymphocytes, block the PD-1/PD-L1 signaling pathway, thereby activating the effects of immune T cells to kill the tumor, and mobilize the body's immune system to eliminate the tumor. cells in the body. WO2015085847 discloses a novel anti-PD-1 antibody. An antibody to PD-1 is currently in clinical trials and has shown some antitumor effect.

In a multicenter, randomized, double-blind, placebo-controlled, phase II trial of advanced/metastatic colorectal adenoma for which standard second-line or higher chemotherapy with famitinib failed, the famitinib arm (25 mg once daily for 42 days) improved progression-free survival ( PFS) patients with advanced/metastatic colorectal cancer compared with the placebo group for 1.3 months (HR is 0.596, P is 0.0053). The objective remission rate (ORR) is 2.2%, the disease control rate (DCR) is 59.8%, the median survival (mOS) is 7.5 months, while the median survival for the placebo group is 7.6 months, and side effects reactions are under control. The structure is as follows:

Currently, several combination therapies based on an anti-PD-1 antibody and a VEGFR (vascular endothelial growth factor) inhibitor (such as sunitinib, sorafenib, etc.) are in phase II/III clinical trials and are suitable for the treatment of malignant liver cancer. (sorafenib in combination with an anti-PD-1 antibody) and metastatic renal cell carcinoma (sunitinib in combination with an anti-PD-1 antibody), respectively. Preliminary results show that the combination of two drugs shows superior effects compared to a single drug. However, there are no reports of the combination of famitinib and an anti-PD-1 antibody.

BRIEF DESCRIPTION OF THE INVENTION

Disclosed herein is the use of an anti-PD-1 antibody, or antigen-binding fragment thereof, in combination with famitinib, or a pharmaceutically acceptable salt thereof, to produce a medicament for the treatment of tumors.

The anti-PD-1 antibody is known, and preferably the light chain variable region of an anti-PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

The heavy chain variable region of an anti-PD-1 antibody contains HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively.

Among them, the CDR sequences mentioned above are shown in the following table:

Preferably, the anti-PD-1 antibody is a humanized antibody.

In some embodiments, the humanized antibody comprises a light chain variable region as shown in SEQ ID NO: 10, or a variant thereof, which variant preferably has 0 to 10 amino acid changes, more preferably the A43S amino acid change in the light chain variable region, having the sequence of SEQ ID NO: 10; and the humanized antibody comprises a heavy chain variable region as shown in SEQ ID NO: 9, or a variant thereof, which variant preferably has 0 to 10 amino acid changes, more preferably the G44R amino acid change in the heavy chain variable region having the sequence of SEQ ID NO:9.

The heavy and light chain variable region sequences of the aforementioned humanized antibody are as follows:

Heavy chain variable region

EVQLVESGGGLVQPGGSLRLSСAASGFTFSSYMMSWVRQAPGKGLEWATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSS

SEQ ID NO: 9;

Light chain variable region

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIK

SEQ ID NO: 10.

In other embodiments, the humanized antibody comprises a light chain as shown in SEQ ID NO: 8, or a variant thereof, which variant preferably has 0 to 10 amino acid changes, more preferably the A43S amino acid change in the light chain variable region; and the humanized antibody comprises a heavy chain as shown in SEQ ID NO: 7, or a variant thereof, which variant preferably has 0 to 10 amino acid changes, more preferably the G44R amino acid change in the heavy chain variable region.

In another embodiment, the humanized antibody comprises a light chain as shown in SEQ ID NO: 8 and a heavy chain as shown in SEQ ID NO: 7.

The sequences of the heavy and light chains of the humanized antibody are as follows: Heavy chain

ЕVQLVESGGGLVQPGGSLRLSСAASGFTFSSYMMSWVRQAPGKGLEWVATISGGGANTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARQLYYFDYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

SEQ ID NO: 7;

light chain

DIQMTQSPSSLSASVGDRVTITCLASQTIGTWLTWYQQKPGKAPKLLIYTATSLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQVYSIPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQRGDSKDSTYSLSSTLECSKADYSFEKHKVY

SEQ ID NO: 8.

An anti-PD-1 antibody or antigen-binding fragment thereof, in combination with famitinib or a pharmaceutically acceptable salt thereof, described in the present invention, has a synergistic effect.

In the use of the present invention, an anti-PD-1 antibody, or antigen-binding fragment thereof, is administered to a human subject at a dose, based on the patient's body weight, in the range of 0.1 to 10.0 mg/kg, which may be 0. 1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg /kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/ kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg, 4.8 mg/kg , 5.0 mg/kg, 5.2 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 5.8 mg/kg, 6.0 mg/kg, 6.2 mg/kg, 6.4 mg/kg, 6.6 mg/kg, 6.8 mg/kg, 7.0 mg/kg, 7.2 mg/kg, 7.4 mg/kg, 7.6 mg/kg, 7 .8 mg/kg, 8.0 mg/kg, 8.2 mg/kg, 8.4 mg/kg, 8.6 mg/kg, 8.8 mg/kg, 9.0 mg/kg, 9, 2 mg/kg, 9.4 mg/kg, 9.6 mg/kg, 9.8 mg/kg, 10.0 mg/kg, or any value between any two.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 10 to 300 mg, which may be 10.0 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg , 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, or any value between any two values, preferably 50 to 300 mg, most preferably 200 mg.

The anti-PD-1 antibody or antigen-binding fragment thereof according to the present invention is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks or once a month, preferably once every three weeks.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof of the present invention is administered at a dose in the range of 50 to 300 mg once every 2-3 weeks, more preferably 200 mg once every 2-3 weeks.

In the use of the present invention, famitinib, or a pharmaceutically acceptable salt thereof, is administered to a human subject at a dose, based on the patient's body weight, in the range of 0.1 to 10.0 mg/kg, which may be 0.1 mg/kg. kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg , 0.9 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3 .6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg, 4.8 mg/kg, 5, 0 mg/kg, 5.2 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 5.8 mg/kg, 6.0 mg/kg, 6.2 mg/kg, 6.4 mg/kg, 6.6 mg/kg, 6.8 mg/kg, 7.0 mg/kg, 7.2 mg/kg, 7.4 mg/kg, 7.6 mg/kg, 7.8 mg /kg, 8.0 mg/kg, 8.2 mg/kg, 8.4 mg/kg, 8.6 mg/kg, 8.8 mg/kg, 9.0 mg/kg, 9.2 mg/ kg, 9.4 mg/kg, 9.6 mg/kg, 9.8 mg/kg, 10.0 mg/kg, or any value between any two values.

In an alternative embodiment, famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose in the range of 0.1 to 100 mg, which may be 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg , 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg a value between any two values, preferably 1 to 20 mg.

The use according to the present invention, where famitinib or its pharmaceutically acceptable salt is administered at a frequency of once a day; once every two days; once every three days; once every four days; once every five days; once every six days; once a week; once a day three days a week; once a day four days a week; once a day five days a week.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose ranging from 10 to 300 mg, and famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose ranging from 0 .1 to 100 mg.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 10 to 300 mg once every 2-3 weeks, and famitinib or a pharmaceutically acceptable salt thereof is administered to the human subject. , at a dose ranging from 0.1 to 100 mg once a day.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 300 mg, and famitinib or a pharmaceutically acceptable salt thereof is administered to the human subject at a dose in the range of 1 up to 20 mg.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 300 mg once every 2-3 weeks and famitinib or a pharmaceutically acceptable salt thereof is administered to the human subject. , at a dose ranging from 1 to 20 mg once a day.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200 mg, and famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose in the range of 1 to 20 mg.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200 mg once every 2-3 weeks, and famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose in the range 1 to 20 mg once a day.

In an alternative embodiment, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200 mg once every 3 weeks, and famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose ranging from 1 up to 20 mg once a day.

In another aspect, in an alternative embodiment, in accordance with the use according to the present invention, the area under the pharmacokinetic curve (AUC) of famitinib or its pharmaceutically acceptable salt is increased by at least 15% (including 15%, 16%, 17%, 18% , 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or more), preferably at least 20% and most preferably by at least 25% compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone.

In an alternative embodiment, in accordance with the use according to the present invention, the C _max of famitinib or its pharmaceutically acceptable salt is increased by at least 15% (including 15%, 16%, 17%, 18%, 19%, 20%, 21% , 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% or higher), preferably at least 20% compared to the C _max of the same dose of famitinib or its pharmaceutical acceptable salt, which is administered separately.

In a preferred embodiment of the present invention, the anti-PD-1 antibody is administered by injection, such as subcutaneous or intravenous injection, and the anti-PD-1 antibody is formulated for injection prior to administration. A particularly preferred form for injection of the anti-PD-1 antibody is an injectable solution or an injectable lyophilized powder which contains the anti-PD-1 antibody, a buffer, a stabilizer and optionally a surfactant. The buffer may be one or more selected from the group consisting of acetate, citrate, succinate and phosphate. The stabilizer may be selected from saccharides or amino acids, preferably disaccharides such as sucrose, lactose, trehalose and maltose. The surfactant is selected from the group consisting of polyoxyethylene hydrogenated castor oil, glycerol fatty acid ester and polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, most preferably polysorbate 20 Most preferably, the anti-PD-1 antibody injectable formulation comprises anti-PD-1 antibody, acetate buffer, trehalose, and polysorbate 20.

Provided herein is the aforementioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of tumors.

The present disclosure provides the aforementioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug to reduce adverse drug reactions. Preferably, the adverse drug reactions are caused by an anti-PD-1 antibody or are caused by famitinib or a pharmaceutically acceptable salt thereof.

In an alternative embodiment, the adverse reaction described in accordance with the use according to the present invention is preferably an adverse reaction caused by an antibody to PD-1, and most preferably is a reactive capillary hyperplasia.

In some embodiments, the incidence of reactive capillary hyperplasia is no more than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11 %, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or less), preferably not more than 2.5% compared to the same dose of antibody to PD-1 (such as where the heavy and light chain sequences are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively), which is administered separately.

Provided herein is the aforementioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-PD-1 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. .

Provided herein is a method for treating tumors which comprises administering the aforementioned anti-PD-1 antibody and famitinib or a pharmaceutically acceptable salt thereof to a patient.

The present invention provides a method for reducing the dose of an anti-PD-1 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the aforementioned anti-PD-1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof. salt to the patient.

In other embodiments, when used in combination with an anti-PD-1 antibody, famitinib or a pharmaceutically acceptable salt thereof is administered in an amount of 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45% %, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5% dose given separately.

In other embodiments, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the anti-PD-1 antibody is administered in an amount of 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45% %, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10 to 50% of the dose administered separately.

Also provided herein is a method for reducing adverse reactions induced by an anti-PD-1 antibody or antigen-binding fragment thereof or famitinib or a pharmaceutically acceptable salt thereof, comprising administering famitinib or a pharmaceutically acceptable salt thereof in combination with the above anti-PD-1 antibody to a patient, and the reaction is preferably an anti-PD-1 antibody induced side reaction, and most preferably reactive capillary hyperplasia.

In an alternative embodiment, the adverse reaction described herein is preferably an anti-PD-1 antibody induced adverse reaction, and most preferably is reactive capillary hyperplasia.

In some embodiments, the incidence of reactive capillary hyperplasia is no more than 15% (including 15%, 14.5%, 14%, 13.5%, 13%, 12.5%, 12%, 11.5%, 11 %, 10.5%, 10%, 9.5%, 9%, 8.5%, 8%, 7.5%, 7%, 6.5%, 6%, 5.5%, 5%, 4%, 4.5%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1% or less), preferably not more than 2.5% compared to the same dose of antibody to PD-1 (eg, where the sequences of the heavy and light chains are shown in SEQ ID NO: 7 and SEQ ID NO: 8, respectively), which was administered separately.

Also provided herein is a pharmaceutical kit, or a pharmaceutical package, or a pharmaceutical combination that includes famitinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody.

The present invention also relates to the use of an anti-PD-L1 antibody or an anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of tumors.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose based on patient body weight ranging from 0.1 to 10.0 mg/kg, which can be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0 .7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1, 8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg /kg, 4.8 mg/kg, 5.0 mg/kg, 5.2 mg/kg, 5.4 mg/kg, 5.6 mg/kg, 5.8 mg/kg, 6.0 mg/ kg, 6.2 mg/kg, 6.4 mg/kg, 6.6 mg/kg, 6.8 mg/kg, 7.0 mg/kg, 7.2 mg/kg, 7.4 mg/kg , 7.6 mg/kg, 7.8 mg/kg, 8.0 mg/kg, 8.2 mg/kg, 8.4 mg/kg, 8.6 mg/kg, 8.8 mg/kg, 9.0 mg/kg, 9.2 mg/kg, 9.4 mg/kg, 9.6 mg/kg, 9.8 mg/kg, 10.0 mg/kg.

In another alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 700 mg, which may be 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg , 225 mg 230 mg 235 mg 240 mg 245 mg 250 mg 255 mg 260 mg 265 mg 270 mg 275 mg 280 mg 285 mg 290 mg 295 mg 300 mg 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg , 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 5 10 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg , 595 mg 600 mg 605 mg 610 mg 615 mg 620 mg 625 mg 630 mg 635 mg 640 mg 645 mg 650 mg 655 mg 660 mg 665 mg 670 mg 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, preferably 50 to 600 mg, most preferably 200 mg.

The anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof according to the present invention is administered at a frequency of once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

In an alternative embodiment, an anti-PD-L1 antibody or antigen-negative fragment thereof or an anti-CTAL-4 antibody or antigen-negative fragment thereof described herein is administered to a human subject at a dose of 50 to 600 mg once every 2-3 weeks , more preferably 200 mg once every 2-3 weeks.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 700 mg once every 2-3 weeks, and famitinib or its pharmaceutically acceptable salt is administered to a human subject at a dose in the range of 0.1 to 100 mg once a day.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 600 mg, and famitinib or a pharmaceutically acceptable salt thereof is administered to the subject, representing a person, at a dose in the range from 1 to 20 mg.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose in the range of 50 to 600 mg once every 2-3 weeks, and famitinib or its pharmaceutically acceptable salt is administered to a human subject at a dose in the range of 1 to 20 mg once a day.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof, or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200 mg, and famitinib or a pharmaceutically acceptable salt thereof is administered to the human subject in dose in the range of 1 to 20 mg.

In an alternative embodiment, the anti-PD-L1 antibody or antigen-binding fragment thereof or the anti-CTAL-4 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 200 mg once every 2-3 weeks and famitinib or a pharmaceutically acceptable salt thereof is administered. to a human subject at a dose in the range of 1 to 20 mg once a day.

In a preferred embodiment of the present invention, the anti-PD-L1 antibody or anti-CTAL-4 antibody is administered by injection, such as subcutaneous or intravenous injection, and the anti-PD-L1 antibody or anti-CTAL-4 antibody is formulated for injection prior to injection.

The present disclosure provides the aforementioned anti-PD-L1 antibody or anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug to reduce adverse drug reactions. Preferably, the adverse drug reactions are caused by an anti-PD-L1 antibody or an anti-CTAL-4 antibody, or are caused by famitinib or a pharmaceutically acceptable salt thereof.

Provided herein is the aforementioned anti-PD-L1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-PD-L1 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. .

Provided herein is the aforementioned anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof as a drug for reducing the dose of anti-CTAL-4 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. .

Provided herein is a method for treating tumors which comprises administering the aforementioned anti-PD-L1 antibody or anti-CTAL-4 antibody and famitinib or a pharmaceutically acceptable salt thereof to a patient.

Provided herein is a method for reducing the dose of an anti-PD-L1 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the aforementioned anti-PD-L1 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof. salt to the patient.

Provided herein is a method for reducing the dose of an anti-CTAL-4 antibody administered alone and/or the dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, the method comprising administering the aforementioned anti-CTAL-4 antibody in combination with famitinib or a pharmaceutically acceptable salt thereof. salt to the patient.

In an alternative embodiment, when used in combination with PD-L1, famitinib or a pharmaceutically acceptable salt thereof is administered in an amount of 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 75%, more preferably 75%, 50%, 25%, 12.5% of the dose, which is entered separately.

In an alternative embodiment, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the dose of anti-PD-L1 antibody is 10% to 100% (including 10%, 15%, 20%, 30%, 35%, 40%, 45% , 50%, 55%, 60%, 70%, 75%, 80%, 90%, 95%), preferably 10% to 50% of the dose administered separately.

In an alternative embodiment, when used in combination with an anti-CTAL-4 antibody, the dose of famitinib or a pharmaceutically acceptable salt thereof is 10% to 100%, preferably 10% to 75%, more preferably 75%, 50%, 25%, 12. 5% of the dose administered separately.

In an alternative embodiment, when used in combination with famitinib or a pharmaceutically acceptable salt thereof, the dose of anti-CTAL-4 antibody is 10% to 100%, preferably 10% to 50% of the dose administered alone.

Also provided herein is a pharmaceutical kit or pharmaceutical package that includes famitinib or a pharmaceutically acceptable salt thereof and an anti-PD-L1 antibody or an anti-CTAL-4 antibody.

In the use of the present invention, examples of tumors are selected without limitation from breast cancer (such as triple negative breast cancer), lung cancer, gastric cancer, colon cancer (such as rectal cancer, colorectal cancer), kidney cancer (such as renal -cell carcinoma), liver cancer (such as primary liver cancer, hepatocellular carcinoma, cholangiocarcinoma, metastatic liver cancer, secondary liver cancer), melanoma (such as metastatic melanoma), non-small cell lung cancer, urothelial cancer (such as bladder cancer, cancer ureter, urethral cancer), cervical cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, T-cell lymphoblastic leukemia, chronic myeloid leukemia, thyroid cancer, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute T-cell lymphoblastic leukemia, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryocyoblastic leukemia, acute megakaryoblastic leukemia, promyelocytic leukemia, erythroid leukemia, malignant lymphoma, multiple myeloma, plasmacytoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoblastic lymphoma, Burkitt's lymphoma, follicular lymphoma and myelodysplastic syndrome (MDS).

In an alternative embodiment, the tumor according to the use of the present invention is non-small cell lung cancer, thyroid cancer, breast cancer (such as triple negative breast cancer), melanoma (such as metastatic melanoma), kidney cancer, urothelial cancer (such such as bladder cancer, ureteral cancer, urethral cancer), cervical cancer, thyroid cancer, ovarian cancer (such as recurrent ovarian cancer), endometrial cancer, bowel cancer, or liver cancer.

In a preferred embodiment, the tumor patient has been treated with platinum-based drugs. For example, patients who have failed treatment with platinum-based drugs, or patients with intolerance to platinum-based drugs, or diseases that progressed or recurred during treatment or less than 6 months after treatment with platinum-based drugs.

In some embodiments, the implementation of the tumor in accordance with the use according to the present invention is a kidney cancer (renal cell carcinoma). Preferably the tumor is a progressive clear cell kidney cancer (mixed tumor, eg clear cell kidney cancer) diagnosed histologically or cytologically.

In a preferred embodiment, a patient with renal cell carcinoma according to the use of the present invention has previously been treated with interleukin-2 and/or anti-angiogenesis drugs and the treatment has failed.

In some embodiments, the tumor described in accordance with the use of the present invention is a urothelial cancer (such as bladder cancer, ureteral cancer, and urethral cancer). Preferably, the tumor is an incurable urothelial cancer (such as renal pelvis cancer, ureteral cancer, bladder cancer, and urethral cancer, as well as mixed cancers such as histologically subtype transitional cell carcinoma) diagnosed histologically or cytologically.

In a preferred embodiment, a patient with urothelial cancer in accordance with the use and according to the present invention was treated with drugs based on platinum. For example, patients who have failed treatment with platinum-based drugs, or patients with intolerance to platinum-based drugs, or diseases that have progressed or recurred during or after treatment with platinum-based drugs.

In some embodiments, the implementation of the tumor in accordance with the use of the present invention is cervical cancer. Preferably, the tumor is a progressive squamous cell carcinoma of the cervix, diagnosed histologically or cytologically.

In a preferred embodiment, treatment of a patient with cervical cancer using a previous 1st line or subsequent line system has failed.

In other embodiments, the tumor according to the use according to the present invention is ovarian cancer, preferably recurrent ovarian cancer and additionally recurrent epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer diagnosed histopathologically.

In a preferred embodiment, the patient with recurrent ovarian cancer was treated with platinum-based drugs. For example, patients who have failed treatment with platinum-based drugs, or patients with intolerance to platinum-based drugs, or diseases that progressed or recurred during treatment or less than 6 months after treatment with platinum-based drugs (4 or more treatments).

In some other embodiments, the implementation of the tumor in accordance with the use according to the present invention is endometrial cancer, preferably endometrial cancer diagnosed histopathologically. In a preferred embodiment, the patient with endometrial cancer has been treated with platinum-based drugs. For example, patients who have failed treatment with platinum-based drugs, or patients with intolerance to platinum-based drugs, or diseases that progressed or recurred during treatment or less than 6 months after treatment with platinum-based drugs (4 or more treatments).

The present disclosure also provides the use of famitinib or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disorder in which inhibition of TYRO3 and/or AXL and/or MER can be effective.

Also provided herein is a method for treating a disorder in which inhibition of TYRO3 and/or AXL and/or MER with famitinib or a pharmaceutically acceptable salt thereof can be effective, which comprises administering the aforementioned famitinib or a pharmaceutically acceptable salt thereof to a patient. In addition, in an alternative embodiment, famitinib or a pharmaceutically acceptable salt thereof may be used alone or in combination.

Additionally, in an alternative embodiment, famitinib or a pharmaceutically acceptable salt thereof may be administered alone or in combination.

Examples of disorders for which inhibition of TYRO3 (Tyro3 receptor tyrosine kinase inhibitor) and/or AXL (Ax1 tyrosine kinase receptor inhibitor) and/or MER (Mer tyrosine kinase receptor inhibitor) may be effective include, but are not limited to: lymphoblastic T -cell leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myeloid leukemia (AML), chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryocyoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, erythroid leukemia, malignant lymphoma multiple myeloma plasmacytoma Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoblastic lymphoma, Burkitt's lymphoma, follicular lymphoma, myelodysplastic syndrome (MDS), thrombotic disorders (such as myocardial infarction) rda, ischemic cerebral infarction, peripheral vascular disease, venous thromboembolism, etc.), etc.)

The pharmaceutically acceptable salt of famitinib in the present invention is selected from, but not limited to, methanesulfonate, maleate, tartrate, succinate, acetate, difluoroacetate, fumarate, citrate, benzenesulfonate, benzoate, naphthalenesulfonate, lactate, malaga, hydrochloride, hydrobromide, sulfate and phosphate, preferably malaga .

In some embodiments of the present invention, a pharmaceutically acceptable salt of famitinib is administered to a human subject at a dose calculated based on its free base form.

Unless otherwise indicated, the terms in this invention are defined as follows.

As used herein, "AUC" refers to the area enclosed by the pharmacokinetic curve of blood drug concentration versus time axis. This parameter is an important indicator for assessing the degree of absorption of the drug, reflecting the exposure profiles of the drug in vivo. Since blood drug concentration in pharmacokinetic studies can only be observed up to a certain time point t, AUC can be expressed in the following two ways: AUC (0-t) and AUC (0-∞), where AUC (0-t) is calculated from the area trapezoid, and AUC (0-∞) is calculated by the formula: AUC (0-∞)=AUC (0-t) + concentration at the end point / excretion rate at the end point. The AUC referred to herein refers to the patient's average steady-state AUC 0-24 after a single dose or multiple doses, preferably the patient's average steady-state AUC 0-24 after multiple doses (i.e., AUC _ss ).

In the present invention, "combination" refers to the mode of administration; this means that at least one dose of famitinib or a pharmaceutically acceptable salt thereof and at least one dose of an anti-PD-1 antibody or antigen-binding fragment thereof are administered within a defined period of time, both of which exhibit pharmacological effects. The time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours. Famitinib, or a pharmaceutically acceptable salt thereof, may be administered simultaneously or sequentially with the anti-PD-1 antibody or antigen-binding fragment thereof. This period of time includes those treatments in which famitinib or a pharmaceutically acceptable salt thereof is administered with an anti-PD-1 antibody or antigen-binding fragment thereof by the same or different routes of administration. The combined mode of administration of the present invention is selected from the group consisting of simultaneous administration, co-administration of separate dosage forms, and sequential administration of separate dosage forms. Overall survival (OS) refers to the period from an accidental point in time to death from any cause. For subjects who are still alive at the last control check, the last control check time is logged as censored data for the OS. For subjects that died before the control check, the last time that the subject could be confirmed alive is logged as censored data to the OS. OS with censored data is defined as the period from the time of the random grouping to the time of the censored data.

The objective remission rate (objective response rate, ORR) refers to the percentage of patients whose tumors are reduced to a certain level and remain so for a certain period of time, including cases of CR (complete remission) and PR (partial remission). The Solid Tumor Response Standard (RECIST 1.1 standard) was used to assess objective tumor remission. Subjects should have measurable tumor lesions at baseline. For the performance standard, efficacy can be divided into complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 1.1 standard.

The disease control rate (DCR) refers to the percentage of cases that show confirmed complete remission, partial remission, and stable disease (at least 8 weeks) compared to the number of patients for whom therapeutic efficacy can be assessed.

Complete remission (CR): All target lesions disappear and the shorter diameter of all pathological lymph nodes (including target and non-target nodules) should be reduced to less than 10 mm.

Partial remission (PR): The sum of target lesion diameters is reduced by at least 30% from baseline.

Progressive disease (PD): the sum of the diameters of all target lesions is increased by at least 20% compared to the minimum value of the sum of diameters (as a reference) measured during the entire experimental study (the sum of the diameters of all target lesions measured at baseline, will serve as a reference if this is the minimum value). In addition, the absolute sum of the diameters must be increased by at least 5 mm (development of one or more new lesions is also considered disease progression).

Stable disease (SD): The degree of reduction of the target lesions does not reach the PR, and the degree of increase does not reach the PD level, a state between PR and PD. The minimum value of the sum of the diameters can be used as a reference during the study.

"mpk": mg/kg.

The reagents, biological samples, or active agents used in the present invention are commercially available, for example, human PD-1 transgenic mice at 4-5 weeks of age were purchased from Cephrim B iosciences, Inc. Great Britain.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided to further describe the present invention, but are not intended to limit the scope of the disclosure.

Example 1:

Human PD-1 transgenic mice were used as experimental animals, and co-administration of anti-PD-1 antibodies and famitinib was evaluated in human PD-1 transgenic mice transplanted with C57 tumor from MC-38 (PD-L1) mouse colon cancer cells. ).

Compound A: an anti-PD-1 antibody with the heavy and light chain sequences shown in SEQ ID NO: 7 and SEQ ID NO: 8 of the present specification. 200 mg/each vial presented as 20 mg/ml for use.

Compound B: famitinib malate, which was prepared according to the method described in patent application WO2007085188.

Test report:

On day 7, MC38 cells (5×10 ⁵ ) were subcutaneously inoculated into 40 transgenic mice with human PD-1 (including male and female) from the right side. When the average tumor volume in mice reached about 100 mm ³ , 32 mice were selected and randomly divided into 4 groups, 8 mice in each group. After grouping, mice were given vehicle control, compound A by intraperitoneal injection, compound by gavage, and co-administration of both compounds according to the protocol. Tumor volume was measured twice a week, mice were weighed and data was recorded.

The results of this experiment show that the combination of anti-PD-1 antibody (3 mpk) and famitinib malaga (10 mpk) is superior to anti-PD-1 antibody or famitinib malaga alone. The weight of mice in each group was normal, indicating that there were no obvious side effects of the drug.

Example 2 Effect of famitinib malaga on the activity of TYRO3, AXL and MER kinases in vitro

Appropriate amounts of kinases and peptide substrates were separately mixed with different concentrations of famitinib malaga (1 nM, 3 nM, 10 nM, 30 nM, 100 nM, 300 nM, 1 µM, 3 µM, 10 µM) and incubated for 60 min at room temperature . Magnesium acetate and [gamma-33P]-ATP were added to initiate the reaction catalyzed by the kinase, and the reaction was carried out at room temperature for 40 minutes. After completion of the reaction, a 3% phosphoric acid solution was added to terminate the reaction. 10 µl of the reaction mixture was taken and added to the P30 filter membrane for filtration. The membrane was washed with 75 mM phosphate buffer 3 times and washed once with methanol to remove free [gamma-33P]-ATP. The protein was fixed and the membrane was dried. A liquid scintillation analyzer was used to determine the amount of peptide substrate by counting the amount of 33P.

(2) Test results

According to the inhibition-concentration curve, the IC50 value resulting from the fitting is shown in Table 1.

Example 3:

1. Antibodies and compounds to be tested

Compound A: its heavy and light chain sequences are shown in SEQ ID NO: 7 and SEQ ID NO: 8 of the present description. 200 mg/each vial presented as 20 mg/ml for use;

Compound B: famitinib malate, which was prepared according to the method described in patent application WO2007085188.

2. Criteria for inclusion in the study: patients with advanced kidney cancer, urothelial cancer, cervical cancer, recurrent ovarian cancer and endometrial cancer.

(1) For renal cell carcinoma: advanced clear cell renal cell carcinoma diagnosed histologically or cytologically (the group may include a mixed type tumor such as clear cell renal cell carcinoma as the dominant component); the primary tumor was surgically removed and treated with interleukin-2 and/or drugs directed against angiogenesis, but the treatment was unsuccessful;

(2) For urothelial cancer: incurable urothelial cancer diagnosed histologically or cytologically, including renal pelvis cancer, ureteral cancer, bladder cancer and urethral cancer. For mixed cancers, the primary histologic type should be the transitional cell carcinoma subtype; the disease progressed or relapsed after previous treatment with platinum-based regimens, with no more than 2 types of previous systemic regimens.

(3) For cervical cancer: advanced squamous cell carcinoma of the cervix, diagnosed histologically or cytologically; who has previously been treated with 1st or subsequent line systemic therapy without success;

(4) In recurrent ovarian cancer: recurrent ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed histopathologically, previously treated with a platinum-based regimen, and the disease progressed or relapsed during treatment or less than 6 months after treatment with platinum-based therapies (4 or more courses of treatment completed);

(5) For endometrial cancer: endometrial cancer diagnosed histopathologically, which was previously treated with at least a platinum-based regimen, and the disease progressed or recurred after or during treatment with therapy.

3. Dosing regimen:

Compound A: intravenous injection, 200 mg, once every 3 weeks, 1 cycle every 3 weeks; Compound B: 20 mg or 15 mg orally once a day.

4. Safety data

When Compound A was administered in combination with Compound B, no drug-related death was observed. Although the incidence of grade 3 or higher adverse reactions was 60%, they were all manageable. Toxic reactions were mainly associated with the administration of compound B, which was effectively controlled by adjusting the regimen or withholding the administration of compound B. The frequency of immune-related adverse reactions found by the investigators was low (13.8%), and they were essentially adverse reactions. low grade reactions. Grade 3 acute enteritis was observed in only one case, and adverse reactions of grade 2 or lower were observed in the rest. In addition, when the two drugs were co-administered, only 2 subjects (2.5%) developed reactive cutaneous capillary hyperplasia, the incidence being significantly lower than Compound A alone in the treatment of solid tumors (54.3%), suggesting that the side effects of Compound A can be reduced by co-administration with Compound B. The overall incidence of serious adverse reactions was low and only 2 (2.5%) subjects withdrew from treatment due to SAE (serious adverse reaction) . For this reason, the co-administration of compound A and compound B for the treatment of urinary system and gynecological tumors is safe.

5. Efficiency

Of the 80 subjects, 75 completed at least one efficacy evaluation, and 5 subjects could not be evaluated due to discontinuation or death prior to the first evaluation.

Among 25 subjects in the kidney cancer cohort, 23 subjects were evaluated for efficacy. 12 subjects showed partial remission (PR), 9 subjects showed stable disease (SD), and 2 subjects showed progressive disease (PD). The objective remission rate (ORR) was 52.2% and the disease control rate (DCR) was 91.3%. The ORR was higher than Compound B alone, 25 mg once daily, in the treatment of kidney cancer (36%).

Among 10 subjects in the urothelial cancer cohort, 9 subjects were evaluated for efficacy. 3 subjects showed partial remission (PR), 3 subjects showed stable disease (SD), and 3 subjects showed progressive disease (PD). The objective remission rate (ORR) was 33.3% and the disease control rate (DCR) was 66.7%.

24 subjects from the ovarian cancer cohort were evaluated for efficacy. 8 subjects showed partial remission (PR), 10 subjects showed stable disease (SD), and 7 subjects showed progressive disease (PD). The objective remission rate (ORR) was 33.3% and the disease control rate (DCR) was 75%.

Among 5 subjects in the endometrial cancer cohort, 4 subjects were evaluated for efficacy. 2 subjects showed partial remission (PR), 1 subject showed stable disease (SD), and 1 subject showed progressive disease (PD). The objective remission rate (ORR) was 50% and the disease control rate (DCR) was 75%.

Among 16 subjects in the cervical cancer cohort, 15 subjects were evaluated for efficacy. 8 subjects showed partial remission (PR), 5 subjects showed stable disease (SD), and 2 subjects showed progressive disease (PD). The objective remission rate (ORR) was 53.3% and the disease control rate (DCR) was 86.7%.

Overall, 75 of 80 subjects completed at least one efficacy evaluation, 33 subjects showed partial remission (PR), 27 subjects showed stable disease (SD), and 15 subjects showed progressive disease (PD). The objective remission rate (ORR) was 44.0% and the disease control rate (DCR) was 80.0%.

6. Pharmacokinetics

Among 12 subjects participating in the pharmacokinetic (PK) study, blood for PK was taken from 9 subjects.

The results showed that the amount of consumption of Compound B (when it was co-administered with Compound A) increased compared to the amount of consumption of Compound B administered alone, and the PK parameters of Compound B (including C _ss , min (stationary concentration), C _ss , max , AUC _ss ) were better than when administered alone.

7. Conclusion

For co-administration of Compound A and Compound B, tolerability is favorable, toxicity is controllable and acceptable. At the same time, co-administration can effectively reduce the occurrence of reactive capillary hyperplasia (a common side reaction caused by compound A) and provide favorable therapeutic effects.

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SEQUENCE LIST

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SUZHOU SUNCADIA BIOPHARMACEUTICALS CO., LTD.

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MEDICINE FOR THE TREATMENT OF TUMORS

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<---

Claims (25)

1. Use of an anti-PD-1 antibody or antigen-binding fragment thereof in combination with famitinib or a pharmaceutically acceptable salt thereof to produce a medicament for the treatment of tumors, wherein the light chain variable region of said anti-PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and the heavy chain variable region of an anti-PD-1 antibody contains HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively. 2. Use according to claim 1, wherein said anti-PD-1 antibody is a humanized antibody. 3. The use of claim 2, wherein said humanized antibody contains a light chain variable region as shown in SEQ ID NO: 10, or a variant thereof, and said variant having 0 to 10 amino acid changes; and wherein said humanized antibody comprises a heavy chain variable region as shown in SEQ ID NO: 9, or a variant thereof, and wherein said variant has 0 to 10 amino acid changes. 4. Use according to claim 3, where the specified variant of the variable region of the light chain of SEQ ID NO: 10 has an amino acid change A43S; and said heavy chain variable region variant of SEQ ID NO: 9 has the G44R amino acid change. 5. The use of claim. 2, where the specified humanized antibody contains a light chain, as shown in SEQ ID NO: 8, or a variant, and moreover, the specified variant has from 0 to 10 amino acid changes; and wherein said humanized antibody contains a heavy chain as shown in SEQ ID NO: 7, or a variant thereof, and said variant having 0 to 10 amino acid changes. 6. Use according to claim 5, where the specified variant of the variable region of the light chain of SEQ ID NO: 8 has an amino acid change A43S; and said heavy chain variable region variant of SEQ ID NO: 7 has the G44R amino acid change. 7. Use according to claim 5, wherein said humanized antibody comprises a light chain as shown in SEQ ID NO: 8 and a heavy chain as shown in SEQ ID NO: 7. 8. Use according to claim 1, wherein said tumor is selected from the group consisting of breast cancer, lung cancer, liver cancer, gastric cancer, colon cancer, kidney cancer, urothelial cancer, cervical cancer, ovarian cancer, endometrial cancer, melanoma , non-small cell lung cancer and thyroid cancer. 9. Use according to claim 8, wherein said tumor is non-small cell lung cancer, breast cancer, melanoma, liver cancer, urothelial cancer, cervical cancer, ovarian cancer, thyroid cancer, endometrial cancer, or kidney cancer. 10. Application according to any one of paragraphs. 1-9, wherein the area under the pharmacokinetic curve (AUC) of said famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15% compared to the AUC of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. 11. Use according to claim 10, wherein the AUC of said famitinib or a pharmaceutically acceptable salt thereof is increased by at least 20%. 12. Use according to claim 10, wherein the AUC of said famitinib or a pharmaceutically acceptable salt thereof is increased by at least 25%. 13. Application according to any one of paragraphs. 1-12, wherein the _Cmax of said famitinib or a pharmaceutically acceptable salt thereof is increased by at least 15% compared to the _Cmax of the same dose of famitinib or a pharmaceutically acceptable salt thereof administered alone. 14. Use according to claim 13, wherein the C _max of said famitinib or a pharmaceutically acceptable salt thereof is increased by at least 20%. 15. Use according to claim 1, wherein said anti-PD-1 antibody or antigen-binding fragment thereof is administered to a human subject at a dose of 10 to 300 mg once every 2-3 weeks. 16. Use according to claim 1, wherein said famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose of 0.1 mg to 100 mg once daily. 17. Use according to claim 16, wherein said famitinib or a pharmaceutically acceptable salt thereof is administered to a human subject at a dose of 1 mg to 20 mg once daily. 18. Application according to any one of paragraphs. 1-17, wherein said pharmaceutically acceptable famitinib salt is malate. 19. The use of claim. 8, where the incidence of reactive capillary hyperplasia is not more than 15% compared with the frequency caused by the same dose of antibodies to PD-1, as defined in any of paragraphs. 1-7, which is administered separately. 20. A method of reducing an adverse reaction caused by an anti-PD-1 antibody or antigen-binding fragment thereof, comprising administering famitinib or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody, wherein the light chain variable region of said anti-PD-1 antibody contains LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and the heavy chain variable region of an anti-PD-1 antibody contains HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein said adverse reaction is reactive capillary hyperplasia. 21. The method according to claim 20, wherein the incidence of reactive capillary hyperplasia is no more than 15%. 22. A method for reducing the dose of an anti-PD-1 antibody or antigen-binding fragment thereof, or a dose of famitinib or a pharmaceutically acceptable salt thereof administered alone, wherein the method comprises administering to a patient famitinib or a pharmaceutically acceptable salt thereof in combination with an anti-PD-1 antibody, wherein the variable region is light the chain of said anti-PD-1 antibody contains LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively, and the heavy chain variable region of the anti-PD-1 antibody contains HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively. 23. A pharmaceutical kit for the treatment of a tumor or cancer, comprising famitinib or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the light chain variable region of said anti-PD-1 antibody comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and the heavy chain variable region of the anti-PD-1 antibody contains HCDR1, HCDR2, and HCDR3, as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively.