Pharmaceutical composition for treating bone and soft tissue tumors

Abstract

The invention belongs to the field of biological medicines, particularly provides a pharmaceutical composition containing an anti-CD47 antibody and a tyrosine kinase inhibitor for treating bone and soft tissue tumors, and further provides a kit containing the pharmaceutical composition. In addition, the use of the anti-CD47 antibody in the preparation of a medicament for the treatment of bone and soft tissue tumors in combination with a tyrosine kinase inhibitor and a method of treating bone and soft tissue tumors are provided.

Description

Technical Field

[0001] This application belongs to the field of biomedicine, and specifically relates to a pharmaceutical combination of an anti-CD47 antibody and a tyrosine kinase inhibitor and its use. Background Art

[0002] CD47 is a transmembrane glycoprotein widely expressed among multiple species and various tissues. It is also known as integrin-associated protein and is a member of the immunoglobulin superfamily. The inhibitory receptor signal regulatory protein α (SIRPα) is one of the ligands of CD47, and CD47 binds to the NH2-terminal IgV-like domain of SIRPα. SIRPα is mainly expressed in myeloid-derived cells, including macrophages, granulocytes, DC cells, mast cells, and their precursors, including hematopoietic stem cells. CD47 expression and / or activity have been implicated in many diseases and disorders. A number of different studies have shown that almost all tumor cells and tumor tissues highly express CD47. The high expression of CD47 on the surface of tumor cells binds to SIRPα on the surface of macrophages, releasing a "don't eat me" signal, which results in macrophages in the tumor tissue infiltration area not only coexisting harmoniously with tumor cells, but also promoting tumor angiogenesis, inhibiting the function of effector T cells, and promoting the amplification and growth of tumor cells. Currently, drugs targeting the CD47-SIRPα axis, such as anti-CD47 antibodies, have entered clinical trials.

[0003] Tyrosine kinases are a group of enzymes that catalyze the phosphorylation of tyrosine residues in proteins and play an important role in intracellular signal transduction. They are involved in the regulation of normal cells, signal transmission, and development, and are also closely related to the proliferation, differentiation, migration, and apoptosis of tumor cells. Many receptor tyrosine kinases are associated with tumor formation and can be classified into epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), etc. according to the different structures of their extracellular regions. Anlotinib is a quinoline derivative tyrosine kinase inhibitor that acts as a multi-target tyrosine kinase inhibitor (TKI) in affecting tumor angiogenesis and proliferation signal transduction. Document WO2008112407 discloses a quinoline derivative tyrosine kinase inhibitor 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine and its preparation method in Example 24.

[0004] Bone and soft tissue tumors are mesenchymal-derived tumors with many subtypes, and sarcomatous lesions have a high degree of malignancy and poor prognosis, posing a huge challenge to clinical treatment. Summary of the Invention

[0006] In one aspect, the present application provides a pharmaceutical combination for treating bone and soft tissue tumors, which comprises an anti-CD47 antibody or an antigen-binding portion thereof, and a tyrosine kinase inhibitor.

[0007] In another aspect, the present application provides the use of an anti-CD47 antibody or an antigen-binding portion thereof, and optionally a tyrosine kinase inhibitor, in the preparation of a medicament for treating bone and soft tissue tumors.

[0008] In another aspect, the present application provides a method for treating bone and soft tissue tumors in a subject, which comprises administering an anti-CD47 antibody or an antigen-binding portion thereof to the subject, and optionally administering a tyrosine kinase inhibitor to the subject.

[0009] In some embodiments, in the said use or method, the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor can be administered simultaneously, successively or alternately.

[0010] In some embodiments, the anti-CD47 antibody or an antigen-binding portion thereof is administered once every 1 week, 2 weeks, 3 weeks or 4 weeks.

[0011] In some embodiments, the tyrosine kinase inhibitor is administered once or more times a day.

[0012] In another aspect, the present application provides a kit, which comprises the pharmaceutical combination of the present application. In some specific embodiments, the kit comprises an anti-CD47 antibody or an antigen-binding portion thereof and a tyrosine kinase inhibitor, and instructions for combining the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor for treating bone and soft tissue tumors.

[0013] In some embodiments, the bone and soft tissue tumors are advanced, recurrent, metastatic and / or failed in first-line treatment.

[0014] In some embodiments, the bone and soft tissue tumors are bone tumors. In some specific embodiments, the bone and soft tissue tumors are chondrogenic tumors, osteogenic tumors or chordoma-derived tumors. In some more specific embodiments, the bone and soft tissue tumors are dedifferentiated chondrosarcoma, osteosarcoma or chordoma.

[0015] In some embodiments, the bone and soft tissue tumors are soft tissue tumors. In some specific embodiments, the bone and soft tissue tumors are adipocytic tumors. In some more specific embodiments, the bone and soft tissue tumors are dedifferentiated liposarcoma or pleomorphic liposarcoma. DETAILED DESCRIPTION OF THE INVENTION

[0017] Drug combination

[0018] In one aspect, the present application provides a drug combination for treating bone and soft tissue tumors, which comprises an anti-CD47 antibody or an antigen-binding portion thereof and a tyrosine kinase inhibitor.

[0019] In some embodiments, the drug combination is packaged in the same kit, and the kit further comprises instructions for the combined use of the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor to treat bone and soft tissue tumors. In other embodiments, the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor in the drug combination are separately packaged in respective cartridges, and the cartridges further comprise instructions for the combined use of the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor to treat tumors.

[0020] In some embodiments, the anti-CD47 antibody or an antigen-binding portion thereof and the tyrosine kinase inhibitor are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is an injection solution. In some specific embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is a lyophilized preparation. In some embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor is a suspension. In some specific embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor is a capsule.

[0021] In some embodiments, the unit dose of the anti-CD47 antibody or its antigen-binding portion in the drug combination is 50-500 mg, 100-500 mg, 100-400 mg, or 100-200 mg. In some embodiments, the unit dose of the anti-CD47 antibody or its antigen-binding portion in the drug combination is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, or a range formed by any of the above values. In some embodiments, the unit dose of the anti-CD47 antibody or its antigen-binding portion in the drug combination is 100 mg or 200 mg. In some embodiments, the unit dose of the anti-CD47 antibody or its antigen-binding portion in the drug combination is 200 mg.

[0022] In some embodiments, the unit dose of the tyrosine kinase inhibitor in the drug combination is 6-20 mg, 6-16 mg, 6-12 mg, or 8-12 mg. In some embodiments, the unit dose of the tyrosine kinase inhibitor in the drug combination is 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, or a range formed by any of the above values. In some embodiments, the unit dose of the tyrosine kinase inhibitor in the drug combination is 8 mg - 12 mg. In some embodiments, the unit dose of the tyrosine kinase inhibitor in the drug combination is 8 mg, 10 mg, or 12 mg.

[0023] In some embodiments, the drug combination comprises an anti-CD47 antibody or an antigen-binding portion thereof in a unit dose of 50 - 500 mg, 100 - 500 mg, 100 - 400 mg, or 100 - 200 mg, and a tyrosine kinase inhibitor in a unit dose of 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg. In some embodiments, the drug combination comprises an anti-CD47 antibody or an antigen-binding portion thereof in a unit dose of 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, or any range formed by the above values, and a tyrosine kinase inhibitor in a unit dose of 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, or any range formed by the above values. In some embodiments, the drug combination comprises an anti-CD47 antibody or an antigen-binding portion thereof in a unit dose of 100 mg or 200 mg, and a tyrosine kinase inhibitor in a unit dose of 8 - 12 mg. In some embodiments, the drug combination comprises an anti-CD47 antibody or an antigen-binding portion thereof in a unit dose of 200 mg, and a tyrosine kinase inhibitor in a unit dose of 8 mg, 10 mg, or 12 mg.

[0024] In some embodiments, the pharmaceutical combination comprises 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg of an anti-CD47 antibody or an antigen-binding portion thereof. In some embodiments, the pharmaceutical combination comprises 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, or an anti-CD47 antibody or an antigen-binding portion thereof within a range formed by any of the foregoing values. In some embodiments, the pharmaceutical combination comprises 1200 - 1800 mg of an anti-CD47 antibody or an antigen-binding portion thereof. In some embodiments, the pharmaceutical combination comprises 1200 mg, 1500 mg, 1600 mg, or 1800 mg of an anti-CD47 antibody or an antigen-binding portion thereof.

[0025] In some embodiments, the pharmaceutical combination comprises 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg of a tyrosine kinase inhibitor. In some embodiments, the pharmaceutical combination comprises 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, or a tyrosine kinase inhibitor within a range formed by any of the foregoing values. In some embodiments, the pharmaceutical combination comprises 8 - 12 mg of a tyrosine kinase inhibitor. In some embodiments, the pharmaceutical combination comprises 8 mg, 10 mg, or 12 mg of a tyrosine kinase inhibitor.

[0026] In some embodiments, the drug combination comprises 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg of an anti - CD47 antibody or an antigen - binding portion thereof, and 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg of a tyrosine kinase inhibitor. In some embodiments, the drug combination comprises 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, or an anti - CD47 antibody or an antigen - binding portion thereof within the range formed by any of the above values, and 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, or a tyrosine kinase inhibitor within the range formed by any of the above values. In some embodiments, the drug combination comprises 1200 - 1800 mg of an anti - CD47 antibody or an antigen - binding portion thereof, and 8 - 12 mg of a tyrosine kinase inhibitor. In some embodiments, the drug combination comprises 1200 mg, 1500 mg, 1600 mg, or 1800 mg of an anti - CD47 antibody or an antigen - binding portion thereof, and 8 mg, 10 mg, or 12 mg of a tyrosine kinase inhibitor.

[0027] In some embodiments, in the drug combination, the content of the anti - CD47 antibody or an antigen - binding portion thereof is a daily dose. In some embodiments, in the drug combination, the content of the anti - CD47 antibody or an antigen - binding portion thereof is a once - daily dose.

[0028] In some embodiments, in the drug combination, the content of the anti - CD47 antibody or an antigen - binding portion thereof is a fixed dose.

[0029] In some embodiments, in the drug combination, the content of the tyrosine kinase inhibitor is a daily dose. In some embodiments, in the drug combination, the content of the tyrosine kinase inhibitor is a once - daily dose.

[0030] In some embodiments, in the drug combination, the content of the tyrosine kinase inhibitor is a fixed dose.

[0031] In some embodiments, the drug combination comprises a pharmaceutical composition comprising an anti-CD47 antibody or an antigen-binding portion thereof and a pharmaceutical composition comprising a tyrosine kinase inhibitor, wherein the pharmaceutical composition comprising the anti-CD47 antibody or an antigen-binding portion thereof is prepared to be suitable for administering a single dose or multiple doses of 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof to a patient, and the pharmaceutical composition comprising the tyrosine kinase inhibitor is prepared to be suitable for administering a single dose or multiple doses of 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg of the tyrosine kinase inhibitor to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition comprising an anti-CD47 antibody or an antigen-binding portion thereof and a pharmaceutical composition comprising a tyrosine kinase inhibitor, wherein the pharmaceutical composition comprising the anti-CD47 antibody or an antigen-binding portion thereof is prepared to be suitable for administering a single dose or multiple doses of 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, or a single dose or multiple doses of the anti-CD47 antibody or an antigen-binding portion thereof within a range formed by any of the above values to a patient, and the pharmaceutical composition comprising the tyrosine kinase inhibitor is prepared to be suitable for administering a single dose or multiple doses of 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, or a single dose or multiple doses of the tyrosine kinase inhibitor within a range formed by any of the above values to a patient. In some embodiments, the drug combination comprises a pharmaceutical composition comprising an anti-CD47 antibody or an antigen-binding portion thereof and a pharmaceutical composition comprising a tyrosine kinase inhibitor, wherein the pharmaceutical composition comprising the anti-CD47 antibody or an antigen-binding portion thereof is prepared to be suitable for administering a single dose or multiple doses of 1200 - 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof to a patient, and the pharmaceutical composition comprising the tyrosine kinase inhibitor is prepared to be suitable for administering a single dose or multiple doses of 8 - 12 mg of the tyrosine kinase inhibitor to a patient.In some embodiments, the drug combination comprises a pharmaceutical composition containing an anti-CD47 antibody or an antigen-binding portion thereof and a pharmaceutical composition containing a tyrosine kinase inhibitor, wherein the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is prepared to be suitable for administering a single dose or multiple doses of 1200 mg, 1500 mg, 1600 mg or 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof to a patient, and the pharmaceutical composition containing the tyrosine kinase inhibitor is prepared to be suitable for administering a single dose or multiple doses of 8 mg, 10 mg or 12 mg of the tyrosine kinase inhibitor to a patient.

[0032] In another aspect, the present application provides a kit, which comprises the drug combination of the present application. In some embodiments, the kit comprises a pharmaceutical composition containing an anti-CD47 antibody or an antigen-binding portion thereof and a pharmaceutical composition containing a tyrosine kinase inhibitor, and instructions for using the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof and the pharmaceutical composition containing the tyrosine kinase inhibitor in combination for treating bone and soft tissue tumors.

[0033] In some embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof in the kit is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is an injection solution. In some specific embodiments, the pharmaceutical composition containing the anti-CD47 antibody or an antigen-binding portion thereof is a freeze-dried preparation. In some embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor in the kit is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor is a suspension. In some specific embodiments, the pharmaceutical composition containing the tyrosine kinase inhibitor is a capsule.

[0034] In some embodiments, the bone and soft tissue tumor is a bone tumor. In some specific embodiments, the bone and soft tissue tumor is a chondrogenic tumor, an osteogenic tumor or a chordoma-derived tumor. In some more specific embodiments, the bone and soft tissue tumor is a dedifferentiated chondrosarcoma, osteosarcoma or chordoma.

[0035] In some embodiments, the bone and soft tissue tumor is a soft tissue tumor. In some specific embodiments, the bone and soft tissue tumor is an adipocytic tumor. In some more specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma or a pleomorphic liposarcoma.

[0036] Use or method

[0037] The present application also provides the use of the anti-CD47 antibody or its antigen-binding portion of the present application, and optionally the tyrosine kinase inhibitor of the present application, in the preparation of a medicament for the treatment of bone and soft tissue tumors. On the other hand, the present application also provides the use of the anti-CD47 antibody or its antigen-binding portion of the present application in the preparation of a medicament for the combined use with a tyrosine kinase inhibitor for the treatment of bone and soft tissue tumors. On the other hand, the present application also provides a method for treating bone and soft tissue tumors in a subject, which comprises administering to the subject the anti-CD47 antibody or its antigen-binding portion of the present application, and optionally, administering to the subject the tyrosine kinase inhibitor of the present application. On the other hand, the present application also provides a method for treating bone and soft tissue tumors in a subject, which comprises administering to the subject a therapeutically effective amount of the anti-CD47 antibody or its antigen-binding portion of the present application, and optionally, further administering to the subject a therapeutically effective amount of the tyrosine kinase inhibitor of the present application.

[0038] In some embodiments, in the said use or method, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor can be administered simultaneously, successively or alternately. In some embodiments, in the said use or method, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor are each in the form of a pharmaceutical composition and can be administered simultaneously, successively or alternately.

[0039] In some embodiments, in the said use or method, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor are administered according to the same or different dosing regimens. In some embodiments, in the said use or method, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor are administered according to different dosing regimens.

[0040] In some embodiments, in the use or method, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week (q1w), once every 2 weeks (q2w), once every 3 weeks (q3w), or once every 4 weeks (q4w). In a specific embodiment, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered at a dose of 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered at a dose of 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, or a dose within the range formed by any of the above values each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered at a dose of 1200 - 1800 mg each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered at a dose of 1200 mg, 1500 mg, 1600 mg, or 1800 mg each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, at a dose of 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg of the anti-CD47 antibody or its antigen-binding portion each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, at a dose of 1200 - 1800 mg of the anti-CD47 antibody or its antigen-binding portion each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks, at a dose of 1200 mg, 1500 mg, 1600 mg, or 1800 mg of the anti-CD47 antibody or its antigen-binding portion each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, at a dose of 1200 - 1800 mg of the anti-CD47 antibody or its antigen-binding portion each time. In some embodiments, the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, at a dose of 1200 mg, 1500 mg, 1600 mg, or 1800 mg of the anti-CD47 antibody or its antigen-binding portion each time.

[0041] In some embodiments, in the use or method, the tyrosine kinase inhibitor is administered once or more times per day. In a specific embodiment, the tyrosine kinase inhibitor is administered once per day. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg each time. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 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, or a dose within the range formed by any of the above values each time. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 8 - 12 mg each time. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 8 mg, 10 mg, or 12 mg each time. In some embodiments, the tyrosine kinase inhibitor is administered once or more times per day at a dose of 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg of the tyrosine kinase inhibitor each time. In some embodiments, the tyrosine kinase inhibitor is administered once or more times per day at a dose of 8 - 12 mg of the tyrosine kinase inhibitor each time. In some embodiments, the tyrosine kinase inhibitor is administered once or more times per day at a dose of 8 mg, 10 mg, or 12 mg of the tyrosine kinase inhibitor each time. In some embodiments, the tyrosine kinase inhibitor is administered once per day at a dose of 8 - 12 mg of the tyrosine kinase inhibitor each time. In some embodiments, the tyrosine kinase inhibitor is administered once per day at a dose of 8 mg, 10 mg, or 12 mg of the tyrosine kinase inhibitor each time.

[0042] In some embodiments, in the use or method, the anti-CD47 antibody or antigen-binding portion thereof is administered at a dose of 0.5-70 mg / kg, 0.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, 25-35 mg / kg, or 15-35 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 50 mg / kg, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, or a dose within the range formed by any of the above values each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered at a dose of 15-35 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered at a dose of 20 mg / kg, 25 mg / kg, or 30 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at a dose of 0.5-70 mg / kg, 0.5-40 mg / kg, 15-40 mg / kg, 15-30 mg / kg, 25-35 mg / kg, or 15-35 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at a dose of 15-35 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered once every 1 week, at a dose of 15-35 mg / kg each time. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is administered once every 1 week, at a dose of 20 mg / kg, 25 mg / kg, or 30 mg / kg each time.

[0043] In some embodiments, in the described use or method, the tyrosine kinase inhibitor is administered each time at a dose of 0.01 - 5 mg / kg, 0.05 - 2 mg / kg, 0.1 - 1 mg / kg, 0.1 - 0.5 mg / kg, or 0.1 - 0.3 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered each time at a dose of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.11 mg / kg, 0.12 mg / kg, 0.13 mg / kg, 0.14 mg / kg, 0.15 mg / kg, 0.16 mg / kg, 0.17 mg / kg, 0.18 mg / kg, 0.19 mg / kg, 0.2 mg / kg, 0.21 mg / kg, 0.22 mg / kg, 0.23 mg / kg, 0.24 mg / kg, 0.25 mg / kg, 0.26 mg / kg, 0.27 mg / kg, 0.28 mg / kg, 0.29 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 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or a dose within the range formed by any of the above values. In some embodiments, the tyrosine kinase inhibitor is administered each time at a dose of 0.1 - 0.3 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered each time at a dose of 0.15 mg / kg, 0.2 mg / kg, or 0.25 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered once or more times per day, each time at a dose of 0.01 - 5 mg / kg, 0.05 - 2 mg / kg, 0.1 - 1 mg / kg, 0.1 - 0.5 mg / kg, or 0.1 - 0.3 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered once or more times per day, each time at a dose of 0.1 - 0.3 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered once per day, each time at a dose of 0.1 - 0.3 mg / kg. In some embodiments, the tyrosine kinase inhibitor is administered once per day, each time at a dose of 0.15 mg / kg, 0.2 mg / kg, or 0.25 mg / kg.

[0044] In some embodiments, in the described use or method, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor have the same or different treatment cycles respectively. In some specific embodiments, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor have the same treatment cycle, for example, one treatment cycle every 1 week, every 2 weeks, every 3 weeks or every 4 weeks. In some specific embodiments, the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor have the same treatment cycle, for example, one treatment cycle every 3 weeks.

[0045] In some embodiments, in the described use or method, one treatment cycle is every 3 weeks, and the anti-CD47 antibody or its antigen-binding portion is administered in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the anti-CD47 antibody or its antigen-binding portion is administered 1, 2 or 3 times in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the anti-CD47 antibody or its antigen-binding portion is administered 3 times in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the anti-CD47 antibody or its antigen-binding portion is administered once on the 1st day, the 8th day and the 15th day of each treatment cycle respectively.

[0046] In some embodiments, in the described use or method, one treatment cycle is every 3 weeks, and the tyrosine kinase inhibitor is administered in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the tyrosine kinase inhibitor is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 times in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the tyrosine kinase inhibitor is administered 14 times in each treatment cycle. In some specific embodiments, one treatment cycle is every 3 weeks, and the tyrosine kinase inhibitor is administered once every day for the first 14 days of each treatment cycle.

[0047] In some embodiments, in the use or method, each treatment cycle is 3 weeks, and an anti-CD47 antibody or an antigen-binding portion thereof and a tyrosine kinase inhibitor are administered in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and the anti-CD47 antibody or an antigen-binding portion thereof is administered 1, 2, or 3 times in each treatment cycle, and the tyrosine kinase inhibitor is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 times in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and the anti-CD47 antibody or an antigen-binding portion thereof is administered 3 times in each treatment cycle, and the tyrosine kinase inhibitor is administered 14 times in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and the anti-CD47 antibody or an antigen-binding portion thereof is administered 1 time on the 1st, 8th, and 15th days of each treatment cycle, and the tyrosine kinase inhibitor is administered 1 time on each of the first 14 days of each treatment cycle.

[0048] In some specific embodiments, in the use or method, each treatment cycle is 3 weeks, and 60 - 3000 mg, 200 - 1800 mg, 600 - 1800 mg, or 1200 - 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof is administered 1, 2, or 3 times in each treatment cycle, and 6 - 20 mg, 6 - 16 mg, 6 - 12 mg, or 8 - 12 mg of the tyrosine kinase inhibitor is administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 times in each treatment cycle. In some specific embodiments, in the use or method, each treatment cycle is 3 weeks, and 1200 - 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof is administered 3 times in each treatment cycle, and 8 - 12 mg of the tyrosine kinase inhibitor is administered 14 times in each treatment cycle. In some specific embodiments, each treatment cycle is 3 weeks, and 1200 mg, 1500 mg, 1600 mg, or 1800 mg of the anti-CD47 antibody or an antigen-binding portion thereof is administered 1 time on the 1st, 8th, and 15th days of each treatment cycle, and 8 mg, 10 mg, or 12 mg of the tyrosine kinase inhibitor is administered 1 time on each of the first 14 days of each treatment cycle.

[0049] In some embodiments, in the use or method, the administration regimen (e.g., administration cycle, administration dose, and dose adjustment) of the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, a treatment cycle of the anti-CD47 antibody or its antigen-binding portion can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

[0050] Anti-CD47 antibody or its antigen-binding portion

[0051] In some embodiments, the anti-CD47 antibody or its antigen-binding portion described in the present application comprises: a heavy chain CDR1 (HCDR1) having the amino acid sequence shown in SEQ ID NO: 1 or 7, an HCDR2 having the amino acid sequence shown in SEQ ID NO: 2 or 8, an HCDR3 having the amino acid sequence shown in SEQ ID NO: 3 or 9, a light chain CDR1 (LCDR1) having the amino acid sequence shown in SEQ ID NO: 4 or 10, an LCDR2 having the amino acid sequence shown in SEQ ID NO: 5 or 11, and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 6 or 12. In some embodiments, the anti-CD47 antibody or its antigen-binding portion described in the present application comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 1, an HCDR2 having the amino acid sequence shown in SEQ ID NO: 2, an HCDR3 having the amino acid sequence shown in SEQ ID NO: 3, an LCDR1 having the amino acid sequence shown in SEQ ID NO: 4, an LCDR2 having the amino acid sequence shown in SEQ ID NO: 5, and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 6. In some embodiments, the anti-CD47 antibody or its antigen-binding portion described in the present application comprises: an HCDR1 having the amino acid sequence shown in SEQ ID NO: 7, an HCDR2 having the amino acid sequence shown in SEQ ID NO: 8, an HCDR3 having the amino acid sequence shown in SEQ ID NO: 9, an LCDR1 having the amino acid sequence shown in SEQ ID NO: 10, an LCDR2 having the amino acid sequence shown in SEQ ID NO: 11, and an LCDR3 having the amino acid sequence shown in SEQ ID NO: 12. Exemplary CDR sequences of the anti-CD47 antibody or its antigen-binding portion are shown in Table 1.

[0052] Table 1. CDR Sequences of the Anti-CD47 Antibody or Its Antigen-Binding Portion

[0053]

[0054] Those skilled in the art should understand that, unless otherwise specified, the "CDR" or "complementary determining region" of a given antibody or its region (such as the variable region) should be understood to cover the complementary determining regions defined by any known scheme. Although Table 1 has shown the CDR sequences, however, when it comes to defining an anti-CD47 antibody or its antigen-binding portion with a specific CDR sequence, the scope of the anti-CD47 antibody or its antigen-binding portion covers the anti-CD47 antibody or its antigen-binding portion defined by the CDR sequences defined by any numbering system (such as the combination of one or more of the definitions known in the art, such as AbM, Kabat, Chothia, IMGT, or Contact, etc.).

[0055] In some embodiments, the anti-CD47 antibody or its antigen-binding portion comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 13, 15 or 16, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO: 14 or 17.

[0056] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6; and the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:13, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:14.

[0057] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6; and the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:14.

[0058] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises: an HCDR1 comprising the amino acid sequence shown in SEQ ID NO:7, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:8, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:9, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:10, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:11, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:12; and, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region having an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to the amino acid sequence shown in SEQ ID NO:17.

[0059] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:13, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:14. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region having the amino acid sequence shown in SEQ ID NO:17. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO:13, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:14. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO:15, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:14. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO:16, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:17.

[0060] QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIEWVRQAPGQGLEWMGRIDPANDKTKYAQKFQ GRVTMTGDTSTNTVYMELSSLRSEDTAVYYCARPGLRRYYSMDYWGQGTLVTVSS(SEQ ID NO:13);

[0061] DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRYTGVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLTFGQGTKLEIK(SEQ ID NO:14);

[0062] QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIEWVRQAPGQGLEWMGRIDPANDKTKYAQKFQ GRVTMTGDTSTNTVYMELSSLRSEDTAVYYCTRPGLRRYYSMDYWGQGTLVTVSS(SEQ ID NO:15);

[0063] QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGEFIPGSDTTNYAQKFQ GRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDYWGQGTLVTVSS(SEQ ID NO:16);

[0064] DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLHWYQQKPGKAPKLWIYTTSTLASGVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWTFGQGTKLEIK(SEQ ID NO:17).

[0065] In some embodiments, the anti-CD47 antibody or its antigen-binding portion may further comprise a constant region of an immunoglobulin, or a fragment, analogue, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as the heavy chains of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably the heavy chain of IgG4. In some embodiments, the light chain constant region is derived from a human immunoglobulin light chain, such as the κ light chain or λ light chain of human immunoglobulins, preferably the κ light chain. In some embodiments, the constant region may comprise any modification described in the text, such as insertions, deletions, substitutions or chemical modifications of amino acids. In some embodiments, the constant region comprises mutations that alter effector functions. In some embodiments, any amino acid residue of the constant region may be replaced with an amino acid residue of any allotype.

[0066] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 18, 20 or 21, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence shown in SEQ ID NO: 19 or 22. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 18 and a light chain having the amino acid sequence shown in SEQ ID NO: 19. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 20 and a light chain having the amino acid sequence shown in SEQ ID NO: 19. In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 21 and a light chain having the amino acid sequence shown in SEQ ID NO: 22. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO: 18 and the amino acid sequence of the light chain is as shown in SEQ ID NO: 19. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO: 20 and the amino acid sequence of the light chain is as shown in SEQ ID NO: 19. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-CD47 antibody or antigen-binding portion thereof is as shown in SEQ ID NO: 21 and the amino acid sequence of the light chain is as shown in SEQ ID NO: 22.

[0067] QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIEWVRQAPGQGLEWMGRIDPANDKTKYAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCARPGLRRYYSMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:18);

[0068] DIQMTQSPSSLSASVGDRVTITCKASENVVSYVSWYQQKPGKAPKLLIYGASNRYTGVPSRFIGSGSSTDFTLTISSLQPEDFATYYCGQSYSYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:19);

[0069] QVQLVQSGAEVKKPGASVKVSCKVSGFNIEDDYIEWVRQAPGQGLEWMGRIDPANDKTKYAQKFQGRVTMTGDTSTNTVYMELSSLRSEDTAVYYCTRPGLRRYYSMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:20);

[0070] QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGEFIPGSDTTNYAQKFQGRVTITADISTSTAYMELSSLRSEDTAVYYCARGGLRRMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQID NO:21);

[0071] DIQMTQSPSSLSASVGDRVTITCRASSSVSSTYLHWYQQKPGKAPKLWIYTTSTLASGVPSRFSGSGSGTSYTLTISSLQPEDFATYYCQQFSESTWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:22).

[0072] Tyrosine kinase inhibitor

[0073] In some embodiments, the tyrosine kinase inhibitor described in the present application is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0074]

[0075] As used in the present application, the chemical name of the compound of formula I is 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine.

[0076] The compound of formula I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted into the free base form of the compound of formula I in vivo. For example, pharmaceutically acceptable salts of the compound of formula I are within the scope of the present application and can be produced from different organic and inorganic acids by methods well known in the art.

[0077] In some embodiments, it is administered in the form of the hydrochloride salt of the compound of formula I. In some embodiments, it is administered in the form of the monohydrochloride salt of the compound of formula I. In some embodiments, it is administered in the form of the dihydrochloride salt of the compound of formula I. In some embodiments, it is administered in the crystalline form of the hydrochloride salt of the compound of formula I. In some specific embodiments, it is administered in the crystalline form of the dihydrochloride salt of the compound of formula I.

[0078] In the present application, whenever anlotinib is involved, it refers to the compound of formula I. Anlotinib hydrochloride is the hydrochloride salt of the compound of formula I.

[0079] In the present application, the dose of anlotinib or its salt, unless otherwise specified, is calculated based on the molecular weight of the free base form of anlotinib.

[0080] Pharmaceutical composition and administration mode

[0081] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into a preparation for parenteral administration. In some specific embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into a preparation for intravenous, intramuscular or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into a preparation for intravenous or intramuscular administration. In some specific embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into a preparation for intravenous injection or infusion.

[0082] The anti-CD47 antibody or antigen-binding portion thereof can be formulated into suitable dosage forms, including but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, syrups, injections (i.e., preparations suitable for injection, such as intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions, and dosage forms of sustained-release preparations for oral or non-oral administration. In some specific embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into an injection (for example, an injection solution or a freeze-dried preparation for injection). In some specific embodiments, the anti-CD47 antibody or antigen-binding portion thereof can be formulated into a preparation suitable for intravenous injection.

[0083] In some embodiments, the anti-CD47 antibody or antigen-binding portion thereof is formulated together with one or more pharmaceutically acceptable carriers to form a suitable pharmaceutical composition.

[0084] In some embodiments, in the pharmaceutical composition containing the anti-CD47 antibody or antigen-binding portion thereof, the unit dose of the anti-CD47 antibody or antigen-binding portion thereof is 50 - 500 mg, 100 - 500 mg, 100 - 400 mg or 100 - 200 mg, such as 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg or a range formed by any of the above values.

[0085] In a specific embodiment, the pharmaceutical composition containing an anti-CD47 antibody or an antigen-binding portion thereof is a water-soluble injection solution. The water-soluble injection solution includes, but is not limited to, a water-soluble preparation without lyophilization or a water-soluble preparation reconstituted from a lyophilized powder.

[0086] In other embodiments, the pharmaceutical composition containing an anti-CD47 antibody or an antigen-binding portion thereof is a lyophilized preparation. The lyophilized preparation refers to a preparation prepared by subjecting an aqueous solution to a lyophilization process, in which the substance is first frozen and then the solvent amount is reduced first by sublimation (primary drying process) and then by desorption (secondary drying process) until the solvent amount reaches a value that no longer supports biological activity or chemical reactions. The lyophilized preparations of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.

[0087] In some embodiments, in the pharmaceutical composition containing an anti-CD47 antibody or an antigen-binding portion thereof, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 1-100 mg / mL, 5-80 mg / mL, 10-80 mg / mL, 10-60 mg / mL, 20-60 mg / mL, 40-60 mg / mL or 45-55 mg / mL. In some specific embodiments, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 1 mg / mL, 5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL or 100 mg / mL. In some embodiments, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 10 mg / mL. In some embodiments, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 20 mg / mL. In some embodiments, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 50 mg / mL. In some embodiments, the concentration of the anti-CD47 antibody or an antigen-binding portion thereof is 100 mg / mL.

[0088] In some embodiments, the tyrosine kinase inhibitor can be formulated into a preparation for gastrointestinal administration. In some specific embodiments, the tyrosine kinase inhibitor can be formulated into a preparation for oral, sublingual, rectal or other gastrointestinal administration. In some specific embodiments, the tyrosine kinase inhibitor can be formulated into a preparation for oral administration.

[0089] The tyrosine kinase inhibitor can be formulated into suitable dosage forms, including but not limited to, tablets, lozenges, pills, capsules (such as hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, syrups, injections (i.e., preparations suitable for injection, such as intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersants, and dosage forms of sustained-release preparations for oral or non-oral administration. In some specific embodiments, the tyrosine kinase inhibitor can be formulated into a suspension. In some specific embodiments, the tyrosine kinase inhibitor can be formulated into a capsule. In some specific embodiments, the tyrosine kinase inhibitor can be formulated into a preparation suitable for oral administration.

[0090] In some embodiments, the tyrosine kinase inhibitor is formulated with one or more pharmaceutically acceptable carriers to form a suitable pharmaceutical composition.

[0091] Bone and soft tissue tumors

[0092] In some embodiments, the bone and soft tissue tumors are untreated, unresectable, refractory, recurrent, metastatic, and / or advanced bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are unresectable bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are refractory bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are recurrent bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are metastatic bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are advanced bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are locally advanced bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are recurrent and / or metastatic bone and soft tissue tumors. In some embodiments, the bone and soft tissue tumors are refractory, metastatic, and / or recurrent bone and soft tissue tumors.

[0093] In some embodiments, the main body of the bone and soft tissue tumors has not been previously treated for bone and soft tissue tumors. In some embodiments, the main body of the bone and soft tissue tumors has not previously received radiotherapy, chemotherapy, and / or immunotherapy for treating bone and soft tissue tumors. In some embodiments, the main body of the bone and soft tissue tumors has not previously received systemic treatment for treating bone and soft tissue tumors.

[0094] In some embodiments, the main body of the bone and soft tissue tumor has been previously treated with one or more different anti-tumor therapies for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously undergone surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously received systemic treatment for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously received first-line treatment for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously received chemotherapy for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously received first-line chemotherapy for the bone and soft tissue tumor. In some specific embodiments, the main body of the bone and soft tissue tumor has previously received first-line chemotherapy for the bone and soft tissue tumor and relapsed during or within 6 months after adjuvant chemotherapy. In some specific embodiments, the main body of the bone and soft tissue tumor has failed first-line chemotherapy and is not suitable for re-receiving first-line chemotherapy.

[0095] In some embodiments, the chemotherapy previously received by the main body of the bone and soft tissue tumor includes, but is not limited to, one or more of platinum-based chemotherapy, taxane-based chemotherapy, antimetabolite chemotherapy, camptothecin chemotherapy, nitrogen mustard chemotherapy, anthracycline chemotherapy, vinca alkaloid chemotherapy, podophyllotoxin chemotherapy, and hormonal chemotherapy. In some specific embodiments, the chemotherapy is anthracycline chemotherapy.

[0096] In some embodiments, the bone and soft tissue tumor is a bone tumor or a soft tissue tumor.

[0097] In some specific embodiments, the bone and soft tissue tumor is a chondrogenic tumor, an osteogenic tumor, a chordoma-derived tumor, and / or an adipocytic tumor. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated chondrosarcoma, a high-grade osteosarcoma, a chordoma, a dedifferentiated liposarcoma, and / or a pleomorphic liposarcoma.

[0098] In some embodiments, the bone and soft tissue tumor is a newly diagnosed, unresectable, refractory, recurrent, metastatic, and / or advanced osteosarcoma. In some embodiments, the bone and soft tissue tumor is an unresectable osteosarcoma. In some embodiments, the bone and soft tissue tumor is a refractory osteosarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent osteosarcoma. In some embodiments, the bone and soft tissue tumor is a metastatic osteosarcoma. In some embodiments, the bone and soft tissue tumor is an advanced osteosarcoma. In some embodiments, the bone and soft tissue tumor is a locally advanced osteosarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic osteosarcoma. In some embodiments, the bone and soft tissue tumor is a refractory, metastatic, and / or recurrent osteosarcoma.

[0099] In some embodiments, the bone and soft tissue tumor is an osteosarcoma that has been treated with one or more different anti-tumor therapies. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma that has received surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma that has received systemic treatment. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma that has received first-line treatment. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma that has previously received chemotherapy. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma that has previously received first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma in which first-line treatment has failed. In some specific embodiments, the bone and soft tissue tumor is an osteosarcoma in which first-line chemotherapy has failed. In some specific embodiments, the bone and soft tissue tumor is an advanced osteosarcoma in which first-line chemotherapy has failed. In some specific embodiments, the bone and soft tissue tumor is an advanced high-grade osteosarcoma in which first-line chemotherapy has failed.

[0100] In some embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that is newly diagnosed, unresectable, refractory, recurrent, metastatic, and / or advanced. In some embodiments, the bone and soft tissue tumor is an unresectable de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a refractory de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a metastatic de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is an advanced de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a locally advanced de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a refractory, metastatic, and / or recurrent de-differentiated chondrosarcoma.

[0101] In some embodiments, the bone and soft tissue tumor is an untreated de-differentiated chondrosarcoma. In some embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has been treated with one or more different anti-tumor therapies. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has received surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has received systemic treatment. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has received first-line treatment. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has previously received chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma that has received first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a de-differentiated chondrosarcoma in which first-line treatment has failed. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic de-differentiated chondrosarcoma in which first-line treatment has failed.

[0102] In some embodiments, the bone and soft tissue tumor is a primary, unresectable, refractory, recurrent, metastatic, and / or advanced chordoma. In some embodiments, the bone and soft tissue tumor is an unresectable chordoma. In some embodiments, the bone and soft tissue tumor is a refractory chordoma. In some embodiments, the bone and soft tissue tumor is a recurrent chordoma. In some embodiments, the bone and soft tissue tumor is a chordoma. In some embodiments, the bone and soft tissue tumor is an advanced chordoma. In some embodiments, the bone and soft tissue tumor is a locally advanced chordoma. In some embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic chordoma. In some embodiments, the bone and soft tissue tumor is a refractory, metastatic, and / or recurrent chordoma.

[0103] In some embodiments, the bone and soft tissue tumor is an untreated chordoma. In some embodiments, the bone and soft tissue tumor is a chordoma that has been treated with one or more different anti-tumor therapies. In some specific embodiments, the bone and soft tissue tumor is a chordoma that has received surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy. In some specific embodiments, the bone and soft tissue tumor is a chordoma that has received systemic treatment. In some specific embodiments, the bone and soft tissue tumor is a chordoma that has received first-line treatment. In some specific embodiments, the bone and soft tissue tumor is a chordoma that has received chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a chordoma that has previously received first-line chemotherapy. In some embodiments, the bone and soft tissue tumor is a chordoma in which first-line treatment has failed. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic chordoma in which first-line treatment has failed.

[0104] In some embodiments, the bone and soft tissue tumor is a primary, unresectable, refractory, recurrent, metastatic, and / or advanced dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is an unresectable dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a refractory dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a metastatic dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is an advanced dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a locally advanced dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic dedifferentiated liposarcoma. In some embodiments, the bone and soft tissue tumor is a refractory, metastatic, and / or recurrent dedifferentiated liposarcoma.

[0105] In some embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has been treated with one or more different anti-tumor therapies. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has undergone surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has undergone systemic treatment. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has undergone first-line treatment. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has previously undergone chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma that has undergone first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma with failed first-line treatment. In some specific embodiments, the bone and soft tissue tumor is a dedifferentiated liposarcoma with failed first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic dedifferentiated liposarcoma with failed first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic dedifferentiated liposarcoma with failed first-line anthracycline chemotherapy.

[0106] In some embodiments, the bone and soft tissue tumor is a newly diagnosed, unresectable, refractory, recurrent, metastatic, and / or advanced pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is an unresectable pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a refractory pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a metastatic pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is an advanced pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a locally advanced pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic pleomorphic liposarcoma. In some embodiments, the bone and soft tissue tumor is a refractory, metastatic, and / or recurrent pleomorphic liposarcoma.

[0107] In some embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has been treated with one or more different anti-tumor therapies. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has undergone surgical treatment, radiotherapy, chemotherapy, and / or immunotherapy. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has undergone systemic treatment. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has undergone first-line treatment. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has previously undergone chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma that has undergone first-line chemotherapy. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma in which first-line treatment has failed. In some specific embodiments, the bone and soft tissue tumor is a pleomorphic liposarcoma in which first-line chemotherapy has failed. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic pleomorphic liposarcoma in which first-line chemotherapy has failed. In some specific embodiments, the bone and soft tissue tumor is a recurrent and / or metastatic pleomorphic liposarcoma in which first-line anthracycline chemotherapy has failed.

[0108] Technical effect

[0109] Generally, using the drug combinations of the present application described above will help to:

[0110] (1) produce better efficacy in reducing tumor growth or even eliminating the tumor compared to administering any one of the drugs in the combination alone;

[0111] (2) provide a lower dosage compared to administering any one of the drugs in the combination alone;

[0112] (3) provide a well-tolerated treatment in patients, with fewer adverse reactions and / or complications compared to any one of the drugs administered alone;

[0113] (4) provide a better disease control rate among the patients being treated;

[0114] (5) provide a longer survival period (e.g., median survival, progression-free survival, or overall survival) in the patients being treated;

[0115] (6) provide a longer survival period (e.g., median survival, progression-free survival, or overall survival) in the patients being treated compared to standard chemotherapy;

[0116] (7) provide a longer duration of disease remission (DOR); and / or

[0117] (8) has good anti-tumor activity and exhibits more excellent anti-tumor synergistic effects compared to administering any one of the drugs in the combination alone.

[0118] The pharmaceutical combination and treatment regimen of the present application have good therapeutic effects in the treatment of bone and soft tissue tumors, especially dedifferentiated chondrosarcoma, osteosarcoma, chordoma, dedifferentiated liposarcoma, and / or pleomorphic liposarcoma. It has beneficial effects in at least one aspect of ORR, DCR, DOR, PFS, OS, safety, and tolerance.

[0119] Definition and description

[0120] Unless otherwise specified, the following terms used in the present application have the following meanings. A particular term should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning in the art. When a trade name appears in the present application, it is intended to refer to its corresponding product or its active ingredient.

[0121] As used in the text, the term "pharmaceutical combination" refers to a combination of two or more active ingredients (including administered in the form of their respective active ingredients themselves, or in the form of their respective pharmaceutically acceptable salts, esters, or other derivatives, prodrugs, or compositions) administered simultaneously or sequentially. The active ingredients can be administered to a subject simultaneously as separate single formulations, or sequentially in any order as separate single formulations, or all or part of the active ingredients can be formulated in a single formulation and administered to the subject simultaneously.

[0122] As used herein, the term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. Examples of antibodies and their antigen-binding portions include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' 2Fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv), and other antigen-binding portions known in the art. The anti-CD47 antibodies or antigen-binding portions thereof disclosed herein can be of the IgG1, IgG2, IgG3, or IgG4 isotype. The term "isotype" refers to the class of antibodies encoded by the heavy-chain constant region genes. The anti-CD47 antibodies or antigen-binding portions thereof of the present application can be derived from any species, including but not limited to mice, rats, rabbits, primates, camels, and humans. The anti-CD47 antibodies or antigen-binding portions thereof of the present application can be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies. A conventional "whole antibody" is a glycoprotein comprising two heavy (H) chains and two light (L) chains, which are linked by disulfide bonds. Each heavy chain consists of a heavy-chain variable region (VH) and a heavy-chain constant region (CH). The heavy-chain constant region consists of three domains, namely CH1, CH2, and CH3. Each light chain consists of a light-chain variable region (VL) and a light-chain constant region (CL). The light-chain constant region consists of one domain, CL. The VH and VL regions can also be divided into hypervariable regions, i.e., complementarity-determining regions (CDRs), and relatively conserved framework regions (FRs). Each VH and VL is respectively composed of three CDRs and four FRs, from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as is known to those skilled in the art, special "whole antibodies", such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0123] The "antigen-binding portion" of an antibody refers to one or more portions of the antibody that retain the function of specifically binding an antigen (e.g., CD47). It has been demonstrated that the antigen-binding function of an antibody can be implemented by portions of the whole antibody. Examples encompassed by the term "antigen-binding portion" of an antibody include: (i) Fab fragment: consisting of V L 、V H, a monovalent fragment consisting of the CL and CH1 domains; (ii) an F(ab')2 fragment, a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain; (vi) an isolated complementarity-determining region (CDR); and (vii) a nanobody, a heavy-chain variable region containing a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, recombinant methods can be used to link VH and VL into a single protein chain through a synthetic linker, where VL and VH pair to form a monovalent molecule (referred to as a single-chain Fv (scFv)), and these single-chain antibodies are also encompassed by the term antigen-binding portion. In addition, recombinant polypeptides, fusion proteins, and immunoconjugates containing this antigen-binding portion are also encompassed by the term antigen-binding portion.

[0124] A "chimeric antibody" is an antibody that has at least a portion of the heavy-chain variable region and at least a portion of the light-chain variable region derived from one species; and at least a portion of the constant region derived from another species. For example, in one embodiment, a chimeric antibody can comprise murine variable regions and human constant regions.

[0125] A "humanized antibody" is an antibody that contains complementarity-determining regions (CDRs) derived from a non-human antibody and framework regions and constant regions derived from a human antibody. For example, an anti-CD47 antibody can comprise CDRs derived from one or more murine antibodies and human framework regions and human constant regions. Exemplary humanized antibodies are provided herein. Additional anti-CD47 antibodies or variants thereof containing the HCDRs and LCDRs provided herein can be generated using any human framework sequence and are also included in this application. In one embodiment, framework sequences suitable for use in this application include those that are structurally similar to the framework sequences provided herein. Additional modifications can be made in the framework region to improve the properties of the antibodies provided herein. Such additional framework modifications can include chemical modifications; point mutations to reduce immunogenicity or 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 reversion mutations to the germline sequence. For example, in one embodiment, one or more amino acids in the human framework region of the VH and / or VL of the humanized antibodies provided herein are reverted to the corresponding amino acids in the parental murine antibody.

[0126] The term "identity", also known as concordance. The "percent identity (%)" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues of the specific amino acid sequence shown herein, after aligning the sequence to be aligned with the specific amino acid sequence shown herein and introducing gaps if necessary to achieve the maximum percent sequence identity, and without considering any conservative substitutions as part of the sequence identity. Amino acid sequence alignments for identity can be performed in a variety of ways within the art, such as with BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithms needed to obtain the maximum alignment over the full length of the compared sequences.

[0127] The term "treatment" generally refers to an operation that achieves the desired pharmacological and / or physiological effect. This effect can be prophylactic according to the complete or partial prevention of a disease or its symptoms; and / or therapeutic according to the partial or complete stabilization or cure of a disease and / or the side effects resulting from the disease. "Treatment" as used herein encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, alleviating the symptoms of a disease, reducing any direct or indirect pathological consequences of a disease, preventing the metastasis of a disease, slowing the progression of a disease, improving or alleviating the condition of a disease, increasing the frequency and duration of asymptomatic periods, and regressing or improving the prognosis of a disease.

[0128] A "therapeutically effective amount" or "therapeutically effective dose" is any amount of a drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes the regression of a disease, as demonstrated by a decrease in the severity of the disease symptoms, an increase in the frequency and duration of disease-free symptoms, or the prevention of damage or disability caused by the affliction of the disease. The ability of a therapeutic agent to promote the regression of a disease can be evaluated using a variety of methods known to skilled practitioners, such as in human subjects during clinical trials, in animal model systems predictive of efficacy for humans, or by measuring the activity of the agent in in vitro assays.

[0129] The term "administer" or "administering" means physically introducing a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0130] Routes of administration of an antibody or antigen-binding portion thereof (e.g., an anti-CD47 antibody or antigen-binding portion thereof) include intravenous, intramuscular, intraperitoneal, intraspinal, or other parenteral routes of administration, such as by injection or infusion. The phrase "parenteral administration" as used herein refers to a mode of administration other than enteral administration, typically by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion, as well as in vivo electroporation. Administration can also be carried out, for example, once, multiple times, and / or over one or more extended time periods.

[0131] The application of the term "fixed dose" means a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed dose is specified as an absolute amount of a medicament (e.g., an anti-CD47 antibody or antigen-binding portion thereof), rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person will receive the same dose of an antibody (e.g., 1200 mg of an anti-CD47 antibody or antigen-binding portion thereof).

[0132] The term "pharmaceutically acceptable" pertains to those compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0133] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients of the present application or their pharmaceutical combinations and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds or their pharmaceutical combinations of the present application to a subject. In this context, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

[0134] In this context, the terms "subject", "patient", or "subject" are used interchangeably. A "subject", "patient", or "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the terms "subject", "patient", or "subject" are mammals. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0135] As used herein, "administered in combination" or "used in combination" means that two or more active substances can be administered to a subject simultaneously as separate single formulations, or in any order as separate single formulations sequentially, or all or part of the active ingredients can be formulated in a single formulation and administered to the subject simultaneously.

[0136] The term "single dose" refers to the smallest packaging unit containing a certain amount of a drug. For example, if a box of medicine contains seven tablets, then one tablet is a single dose; or a vial of injection is a single dose. The term "multiple doses" consists of multiple single doses. "Unit dose" refers to the dose of the active ingredient contained in the smallest packaging unit containing a certain amount of a drug. For example, the dose of the antibody contained in a vial of antibody injection is the unit dose.

[0137] The term "first-line treatment" refers to the treatment with drugs that can be selected first or as a standard option according to the patient's condition.

[0138] The term "high grade" refers to bone tumors with a histological grade (G) of G2 or higher in the American Joint Committee on Cancer (AJCC) bone tumor staging system (eighth edition) (excluding lymphoma and myeloma).

[0139] The words "comprise", "comprises" or "comprising" and their English variants such as comprises or comprising should be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0140] As used herein, "about" means within the error range acceptable to a person of ordinary skill in the art for a particular value, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can represent within 1 standard deviation or more than 1 standard deviation in accordance with the practice in the art. Alternatively, "about" can represent a range of up to ±5%, such as fluctuating within a range of ±2%, ±1% or ±0.5% of the given specific numerical value. When a specific value is given in this application or claim, unless otherwise stated, the meaning of "about" should be considered to be within the acceptable error range of that specific value. In this article, unless otherwise stated, all values of drug doses, times, step parameters or conditions are defaulted to be modified by "about".

[0141] In this article, unless the context clearly dictates otherwise, singular terms cover plural referents and vice versa.

[0142] For purposes of description and disclosure, all patents, patent applications, and other identified publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosures predated the filing date of the present application. All statements as to the dates of these documents or the representation of the content thereof are based on the information available to the applicant and do not constitute any admission as to the dates of these documents or the correctness of the content thereof. Moreover, in any country, any reference in this application to these publications does not constitute an admission that such publication is part of the common general knowledge in the art.

[0143] The present application also provides the following exemplary embodiments, but is not limited thereto:

[0144] Embodiment 1. A pharmaceutical combination for treating bone and soft tissue tumors, comprising (i) an anti-CD47 antibody or an antigen-binding portion thereof and (ii) a tyrosine kinase inhibitor.

[0145] Embodiment 2. Use of an anti-CD47 antibody or an antigen-binding portion thereof, and optionally a tyrosine kinase inhibitor, in the preparation of a medicament for treating bone and soft tissue tumors.

[0146] Embodiment 3. Use of an anti-CD47 antibody or an antigen-binding portion thereof in the preparation of a medicament for treating bone and soft tissue tumors in combination with a tyrosine kinase inhibitor.

[0147] Embodiment 4. A method for treating bone and soft tissue tumors in a subject, the method comprising administering to the subject an anti-CD47 antibody or an antigen-binding portion thereof, and optionally, administering to the subject a tyrosine kinase inhibitor.

[0148] Embodiment 5. The pharmaceutical combination according to Embodiment 1, the use according to Embodiment 2 or 3, or the method according to Embodiment 4, wherein the anti-CD47 antibody or an antigen-binding portion thereof comprises:

[0149] (1) HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6; or

[0150] (2) An HCDR1 comprising the amino acid sequence shown in SEQ ID NO:7, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO:8, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO:9, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO:10, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO:11, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO:12.

[0151] Embodiment 6. The pharmaceutical combination, use or method according to any one of Embodiments 1-5, wherein the anti-CD47 antibody or its antigen-binding portion comprises:

[0152] (1) A heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:13, and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:14;

[0153] (2) A heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:14; or

[0154] (3) A heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:17.

[0155] Embodiment 7. The pharmaceutical combination, use or method according to any one of Embodiments 1-6, wherein the anti-CD47 antibody or its antigen-binding portion comprises:

[0156] (1) A heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:18, and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:19;

[0157] (2) A heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:20, and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:19; or

[0158] (3) A heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:21, and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:22.

[0159] Embodiment 8. The pharmaceutical combination, use or method according to any one of Embodiments 1-7, wherein the tyrosine kinase inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof,

[0160]

[0161] Embodiment 9. The pharmaceutical combination, use or method according to Embodiment 8, wherein the pharmaceutically acceptable salt of the compound of Formula I is the hydrochloride salt of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropanamine, preferably the dihydrochloride salt.

[0162] Embodiment 10. The pharmaceutical combination, use or method according to any one of Embodiments 1-9, wherein the anti-CD47 antibody or its antigen-binding portion is formulated for administration by a parenteral route; preferably, the anti-CD47 antibody or its antigen-binding portion is formulated for intravenous or intramuscular administration.

[0163] Embodiment 11. The pharmaceutical combination, use or method according to any one of Embodiments 1-10, wherein the tyrosine kinase inhibitor is formulated for oral administration.

[0164] Embodiment 12. The pharmaceutical combination, use or method according to any one of Embodiments 1-11, wherein the bone and soft tissue tumor is advanced, recurrent, metastatic and / or has failed first-line treatment.

[0165] Embodiment 13. The pharmaceutical combination, use or method according to any one of Embodiments 1-12, wherein the bone and soft tissue tumor is a bone tumor, preferably a chondrogenic tumor, an osteogenic tumor or a chordoma-derived tumor, more preferably a dedifferentiated chondrosarcoma, an osteosarcoma or a chordoma.

[0166] Embodiment 14. The pharmaceutical combination, use or method according to any one of Embodiments 1-12, wherein the bone and soft tissue tumor is a soft tissue tumor, preferably an adipocytic tumor, more preferably a dedifferentiated liposarcoma or a pleomorphic liposarcoma.

[0167] Embodiment 15. The pharmaceutical combination, use or method according to any one of Embodiments 1-14, wherein the anti-CD47 antibody or its antigen-binding portion and the tyrosine kinase inhibitor can be administered simultaneously, sequentially or alternately.

[0168] Embodiment 16. The pharmaceutical combination, use or method according to any one of Embodiments 1-15, wherein the anti-CD47 antibody or its antigen-binding portion is administered once every 1 week, once every 2 weeks, once every 3 weeks or once every 4 weeks.

[0169] Embodiment 17. The pharmaceutical combination, use or method according to any one of Embodiments 1-16, wherein the anti-CD47 antibody or its antigen-binding portion is administered each time in a dose of 60-3000 mg, 200-1800 mg, 600-1800 mg or 1200-1800 mg.

[0170] Embodiment 18. The pharmaceutical composition, use or method according to any one of Embodiments 1-17, wherein the tyrosine kinase inhibitor is administered once or more times a day.

[0171] Embodiment 19. The pharmaceutical combination, use or method according to Embodiments 1-18, wherein the tyrosine kinase inhibitor is administered each time in a dose of 6 mg - 20 mg, 6 mg - 16 mg, 6 mg - 12 mg or 8 mg - 12 mg.

[0172] Embodiment 20. A kit, which comprises the pharmaceutical combination according to any one of Embodiments 1-19.

[0173] Embodiment 21. Use of an anti-CD47 antibody in the preparation of a product for treating bone and soft tissue tumors, the product comprising a vial containing a fixed dose of the anti-CD47 antibody or its antigen-binding portion.

[0174] Embodiment 22. The use according to Embodiment 21, wherein the anti-CD47 antibody comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

[0175] Embodiment 23. The use according to Embodiment 21 or 22, wherein the anti-CD47 antibody comprises: a heavy chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:13, and a light chain variable region having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO:14.

[0176] Embodiment 24. The use according to any one of Embodiments 21-23, wherein the anti-CD47 antibody comprises: a heavy chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 18, and a light chain having an amino acid sequence with at least 95% identity to the amino acid sequence shown in SEQ ID NO: 19.

[0177] Embodiment 25. The use according to any one of Embodiments 21-24, wherein the fixed dose is 1200-1800 mg, preferably 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg or 1800 mg.

[0178] Embodiment 26. The use according to any one of Embodiments 21-25, wherein the treatment comprises administering to the subject one or more fixed doses of the anti-CD47 antibody.

[0179] Embodiment 27. The use according to any one of Embodiments 21-26, wherein the treatment comprises administering a fixed dose of the anti-CD47 antibody to the subject once every 1 week, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0180] Embodiment 28. The use according to any one of Embodiments 21-27, wherein the bone and soft tissue tumor is advanced, recurrent, metastatic, and / or has failed first-line treatment.

[0181] Embodiment 29. The use according to any one of Embodiments 21-28, wherein the bone and soft tissue tumor is a bone tumor, preferably a chondrogenic tumor, an osteogenic tumor or a chordoma-derived tumor, more preferably a dedifferentiated chondrosarcoma, osteosarcoma or chordoma.

[0182] Embodiment 30. The use according to any one of Embodiments 21-28, wherein the bone and soft tissue tumor is a soft tissue tumor, preferably an adipocytic tumor, more preferably a dedifferentiated liposarcoma or a pleomorphic liposarcoma.

[0183] Embodiment 31. The use according to any one of Embodiments 21-30, wherein the treatment comprises administering other therapeutic agents to the patient.

[0184] Embodiment 32. The use according to Embodiment 31, wherein the other therapeutic agent is a tyrosine kinase inhibitor.

[0185] Embodiment 33. The use according to Embodiment 32, wherein the tyrosine kinase inhibitor is a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0186] Example

[0187] For clarity, the present disclosure is further illustrated by examples, which, however, do not limit the scope of the present disclosure.

[0188] A vector containing the gene encoding the heavy chain of the anti-CD47 antibody (SEQ ID NO: 18) and the gene encoding the light chain (SEQ ID NO: 19) was transfected into CHO cells. The CHO cells were cultured, and then the cell culture supernatant was purified by standard purification methods to obtain the anti-CD47 antibody used in the following examples, which has a heavy chain variable region shown in SEQ ID NO: 13 and a light chain variable region shown in SEQ ID NO: 14.

[0189] Example 1: Clinical Trial

[0190] 1. Inclusion Criteria

[0191] Only those who meet all of the following inclusion criteria can be enrolled in this trial:

[0192] (1) The subject voluntarily joins this study, signs the informed consent form (ICF), and has good compliance;

[0193] (2) Age: 18 - 75 years old (at the time of signing the ICF); ECOG PS score: 0 - 1 (amputees can be 2); the predicted survival period exceeds 12 weeks; (3) The enrolled patients meet the following criteria:

[0194] 1) Subjects with high-grade osteosarcoma have failed at least one line of first-line chemotherapy and are not suitable for re-accepting the first-line chemotherapy regimen, or have progressed within 6 months after the end of the first-line treatment;

[0195] 2) Subjects with dedifferentiated liposarcoma or pleomorphic liposarcoma have failed at least one line of first-line chemotherapy for recurrent / metastatic lesions or have relapsed during or within 6 months after adjuvant chemotherapy after surgery (regarded as failure of the first-line treatment);

[0196] 3) Subjects with chordoma and dedifferentiated chondrosarcoma have failed first-line treatment or have not received front-line systemic treatment;

[0197] Note: Perioperative chemotherapy for osteosarcoma subjects is regarded as first-line chemotherapy; treatment failure refers to the recurrence and progression of the disease confirmed by imaging.

[0198] (4) The number of front-line treatment lines received by the subject: ≤ 2 lines;

[0199] (5) According to the RECIST 1.1 standard, it is confirmed that there is at least one measurable lesion;

[0200] (6) The main organ functions are within the following standards within 7 days before treatment:

[0201] 1) Blood routine examination criteria (no blood transfusion and no use of hematopoietic stimulating factor drugs for correction within 7 days before screening):

[0202] a. Hemoglobin (HGB) ≥ 100 g / L;

[0203] b. Absolute neutrophil count (NEUT) ≥ 1.5×10 9 / L;

[0204] c. Platelet count (PLT) ≥ 90×10 9 / L.

[0205] 2) Biochemical examination should meet the following criteria:

[0206] a. Total serum bilirubin (TBIL) ≤ 1.5 times the upper limit of normal value (ULN);

[0207] b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN (if there is liver metastasis: ALT,

[0208] AST ≤ 5×ULN);

[0209] c. Serum creatinine (CR) ≤ 1.5×ULN or creatinine clearance rate (CCR) ≥ 60 mL / min (Cockcroft Gault formula);

[0210] 3) Doppler ultrasound assessment: Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal value (50%).

[0211] (7) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine device, contraceptive pill or condom) during the study period and within 6 months after the end of the study; the serum pregnancy / urine pregnancy test should be negative within 7 days before study enrollment, and the subject must be non-lactating; male subjects should agree to use contraceptive measures during the study period and within 6 months after the end of the study period.

[0212] 2. Test drugs

[0213] 3.1 Anti-CD47 antibody injection: Provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., specification: 200 mg / 4 mL / vial;

[0214] 3.2 Anlotinib hydrochloride capsules: Provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., specifications are 8 mg, 10 mg and 12 mg (calculated according to C 23 H 22 FN 3 O 3 count).

[0215] 3. Treatment regimen

[0216] The anti-CD47 antibody injection is intravenously infused on the first day of each week (days 1, 8, and 15 of each treatment cycle) at a dose of 1200 mg or 1800 mg of the anti-CD47 antibody, and each treatment cycle is 3 weeks.

[0217] Anlotinib hydrochloride capsules are taken on an empty stomach every 2 weeks per cycle at a dose of 12 mg, with a 1-week rest in the third week, and each treatment cycle is 3 weeks.

[0218] 4. Adjustment of the dosing regimen

[0219] Anti-CD47 antibody injection: Delayed administration is allowed, but the maximum delay cannot exceed 12 weeks.

[0220] Anlotinib hydrochloride capsules: Delayed administration or dose adjustment can be made. For subjects who need to delay administration due to adverse reactions and still cannot resume use after more than 6 weeks, permanent discontinuation can be considered.

[0221] 5. Evaluation criteria

[0222] The RECIST 1.1 and iRECIST criteria are used to determine the disease status.

[0223] The NCI-CTC AE 5.0 criteria are used to judge the severity of adverse events.

[0224] 6. Trial results

[0225] As of the data statistics, the overall safety of the drug is good. Two osteosarcoma patients (Table 2) had partial remission (PR), and it was found that the combined drug composition of this application has clinical benefits.

[0226] Table 2. Treatment status of enrolled patients

[0227]

[0228]

[0229] Note: "--" represents that the data has not been obtained yet.

Claims

1. A pharmaceutical combination for treating bone and soft tissue tumors, comprising (i) an anti-CD47 antibody or an antigen-binding portion thereof and (ii) a tyrosine kinase inhibitor.

2. Use of an anti-CD47 antibody or an antigen-binding portion thereof in the preparation of a medicament for use in combination with a tyrosine kinase inhibitor in the treatment of bone and soft tissue tumors.

3. The pharmaceutical combination according to claim 1 or the use according to claim 2, wherein: The anti-CD47 antibody or antigen-binding portion thereof comprises: (1) a HCDR1 comprising the amino acid sequence of SEQ ID NO:1, a HCDR2 comprising the amino acid sequence of SEQ ID NO:2, a HCDR3 comprising the amino acid sequence of SEQ ID NO:3, a LCDR1 comprising the amino acid sequence of SEQ ID NO:4, a LCDR2 comprising the amino acid sequence of SEQ ID NO:5, and a LCDR3 comprising the amino acid sequence of SEQ ID NO:6; or (2) HCDR1 comprising the amino acid sequence shown in SEQ ID NO:7, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:8, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:9, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:10, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:11, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

12.

4. The pharmaceutical combination or use according to any one of claims 1 to 3, wherein The anti-CD47 antibody or antigen-binding portion thereof comprises: (1) a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 13, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 14; (2) a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 15, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 14; or (3) a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

17.

5. The pharmaceutical combination or use according to any one of claims 1 to 4, wherein The anti-CD47 antibody or antigen-binding portion thereof comprises: (1) a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19; (2) a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:20, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence set forth in SEQ ID NO:19; or (3) a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:21, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO:

22.

6. The pharmaceutical combination or use according to any one of claims 1 to 5, wherein: The tyrosine kinase inhibitor is a compound of formula I or a pharmaceutically acceptable salt thereof, Wherein, the pharmaceutically acceptable salt of the compound of formula I is the hydrochloride of 1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yl)oxy-6-methoxyquinolin-7-yl]oxy]methyl]cyclopropylamine, preferably the dihydrochloride.

7. The pharmaceutical combination or use according to any one of claims 1 to 6, wherein: The bone and soft tissue tumor is a bone tumor, preferably a cartilage-derived tumor, an osteogenic tumor or a notochord-derived tumor, more preferably a dedifferentiated chondrosarcoma, an osteosarcoma or a chordoma; or The bone and soft tissue tumor is a soft tissue tumor, preferably a fat cell tumor, and more preferably a dedifferentiated liposarcoma or a pleomorphic liposarcoma. A kit comprising the pharmaceutical combination according to any one of claims 1 to 7.

9. Use of an anti-CD47 antibody in the preparation of a product comprising a vial containing a fixed dose of an anti-CD47 antibody or an antigen-binding portion thereof for treating bone and soft tissue tumors; The anti-CD47 antibody comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:1, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:2, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:3, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:

6.

10. The use according to claim 9, wherein The treatment comprises administering to the patient another therapeutic agent; preferably a tyrosine kinase inhibitor, more preferably a compound of formula I or a pharmaceutically acceptable salt thereof,

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