CN118697865A - Drug combinations for treating lymphoma - Google Patents

Abstract

The application belongs to the field of biological medicine, and provides a pharmaceutical composition for treating lymphoma, which comprises an anti-LAG-3 antibody or an antigen binding fragment thereof and an anti-PD-1 antibody or an antigen binding fragment thereof. Kits for treating tumors comprising the pharmaceutical combinations are also provided. In addition, the application of the pharmaceutical combination in preparing medicaments for treating tumors and a method for treating tumors by using the pharmaceutical combination are also provided.

Description

Drug combinations for treating lymphoma

Technical Field

The present application belongs to the field of biomedicine, and specifically relates to a drug combination of an antibody binding to LAG-3 and an antibody binding to PD-1 and uses thereof.

Background Art

Lymphocyte activation gene-3 (LAG-3) belongs to the immunoglobulin superfamily and is mainly expressed on the surface of activated T cells, NK cells, B cells, plasmacytoid dendritic cells and other cells. LAG-3 has a variety of different ligands, including major histocompatibility complex-II molecule (MHC-II), fibronectin protein 1 (FGL1), galectin-3 and liver sinusoidal endothelial cell lectin (LSECtin). LAG-3 is an immune checkpoint receptor protein that can negatively regulate T cells and play an important role in maintaining the homeostasis of the body's immune system. However, there is increasing evidence that tumor cells express LAG-3 ligands, which bind to LAG-3 highly expressed on tumor infiltrating lymphocytes (TILs), resulting in T cell dysfunction or even exhaustion, leading to tumor cell immune escape and promoting tumor development.

PD-1 (Programmed death-1) is a key immune checkpoint receptor protein expressed by activated T lymphocytes and B lymphocytes. PD-1 binds to its ligands to mediate immunosuppression, and its ligands include PD-L1 and PD-L2. Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1, which can effectively block the binding of PD-1 to PD-L1 and shows good anti-tumor activity.

Anti-PD-1 antibody monotherapy still has certain limitations in the treatment of lymphoma, and other alternative therapies are needed.

SUMMARY OF THE INVENTION

In one aspect, the present application provides a drug combination, which includes an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is used to treat a tumor.

In another aspect, the present application also provides a method for treating a tumor in a subject, which comprises administering the pharmaceutical combination of the present application to the subject.

On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating a tumor in a subject. In addition, the present application also provides the use of the drug combination of the present application for treating a tumor in a subject. In some embodiments, the use includes administering the drug combination of the present application to a subject.

In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof of the present application.

On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in treating a tumor in a subject. In some embodiments, the use comprises administering the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application to the subject.

In another aspect, the present application provides use of the anti-LAG-3 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody or antigen-binding fragment thereof of the present application.

In another aspect, the present application provides use of the anti-PD-1 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-LAG-3 antibody or antigen-binding fragment thereof of the present application.

In some embodiments, in the methods and uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered sequentially and/or alternately.

In some embodiments, in the methods and uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg each time.

In some embodiments, in the methods and uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time.

In another aspect, the present application provides a kit for treating a tumor, comprising the drug combination of the present application. In some specific embodiments, the kit comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the anti-LAG-3 antibody or an antigen-binding fragment thereof and the anti-PD-1 antibody or an antigen-binding fragment thereof in combination to treat a tumor.

In some specific embodiments, the tumor is a lymphoma. In some specific embodiments, the tumor is a Hodgkin's lymphoma. In some specific embodiments, the tumor is a non-Hodgkin's lymphoma. In some specific embodiments, the tumor is a primary mediastinal large B-cell lymphoma.

DETAILED DESCRIPTION OF THE INVENTION

Drug combinations

In one aspect, the present application provides a pharmaceutical combination comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, the drug combination is packaged in the same kit, and the kit further includes instructions for using the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in combination to treat tumors. In other embodiments, the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in the drug combination are separately packaged in their own medicine boxes, and the medicine box further includes instructions for using the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment in combination to treat tumors.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is a lyophilized preparation. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is a lyophilized preparation.

In some embodiments, the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 60-1200 mg, 100-1000 mg, 100-800 mg, or 160-600 mg. In some embodiments, the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 550 mg, 560 mg, 580 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or a range formed by any of the foregoing values. In some embodiments, the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 160 mg, 200 mg, 300 mg and/or 600 mg. In some embodiments, the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 160 mg.

In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or its antigen-binding fragment is 10 mg, 20 mg, 30 mg, 40 mg, 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, In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg and/or 200 mg. In some embodiments, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg.

In some embodiments, the drug combination comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof at a unit dose of 60-1200 mg, 100-1000 mg, 100-800 mg, or 160-600 mg, and an anti-PD-1 antibody or an antigen-binding fragment thereof at a unit dose of 10-500 mg, 50-500 mg, 50-200 mg, or 100-200 mg. In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody or antigen-binding fragment thereof at a unit dose of 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 150 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 250 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 350 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 450 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 550 mg, 560 mg, 580 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, or a range formed by any of the foregoing values, and an anti-LAG-3 antibody or antigen-binding fragment thereof at a unit dose of 10 mg, 20 mg, 30 mg g, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 2 90mg, 3 In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof in a unit dose of 160 mg, 200 mg, 300 mg and/or 600 mg, and an anti-PD-1 antibody or an antigen-binding fragment thereof in a unit dose of 100 mg and/or 200 mg. In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof in a unit dose of 160 mg, 200 mg, 300 mg and/or 600 mg, and an anti-PD-1 antibody or an antigen-binding fragment thereof in a unit dose of 100 mg and/or 200 mg. In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof in a unit dose of 160 mg, and an anti-PD-1 antibody or an antigen-binding fragment thereof in a unit dose of 100 mg.

In some embodiments, the pharmaceutical composition comprises 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, In some embodiments, the pharmaceutical composition comprises 160-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination includes 600 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof.

In some embodiments, the drug combination includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination includes 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, the drug combination comprises 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof, or a range formed by any value thereof. In some embodiments, the drug combination includes 160-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination includes 600 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a daily dose. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is a once-daily dose.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof in the pharmaceutical combination is present in a uniform dose.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof in the drug combination is contained in a dosage for one treatment cycle, and each treatment cycle is 3 weeks (ie, 21 days).

In some embodiments, the amount of the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is a daily dose. In some embodiments, the amount of the anti-PD-1 antibody or its antigen-binding fragment in the pharmaceutical combination is a once-a-day dose.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof in the pharmaceutical combination is contained in a uniform dose.

In some embodiments, the content of the anti-PD-1 antibody or its antigen-binding fragment in the drug combination is a dose for one treatment cycle, and each treatment cycle is 3 weeks.

In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and comprises 160-800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle and includes 600 mg of an anti-LAG-3 antibody or antigen-binding fragment thereof.

In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof in a range formed by any of the above values. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle, which includes 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes an anti-LAG-3 antibody or an antigen-binding fragment thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10-800 mg, 50-500 mg, or 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle and includes 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg , 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or an anti-PD-1 antibody or an antigen-binding fragment thereof, or a range formed by any value thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 160-800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 100-200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration in a single treatment cycle, and includes 600 mg of an anti-LAG-3 antibody or an antigen-binding fragment thereof, and 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, in the drug combination, the mass ratio of anti-LAG-3 antibody or its antigen-binding fragment: anti-PD-1 antibody or its antigen-binding fragment is (0.1-50):1, (0.1-20):1, (0.5-10):1, (1-10):1, (1-5):1 or (3-5):1.

In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 10-800 mg, 50-500 mg, or 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-LAG-3 antibody or an antigen-binding fragment thereof is prepared to be suitable for administration to a patient at 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg , 320mg, 340mg, 360mg, 380mg, 400mg, 420mg, 440mg, 460mg, 480mg, 500mg, 520mg, 540mg, 560mg, 580mg, 600mg, 620mg, 640mg, 660mg, 680mg, 700mg, 720mg, 740mg, 760mg, 780mg, 800mg, 820mg, 840mg, 860mg, 8 A single dose or multiple doses of an anti-LAG-3 antibody or an antigen-binding fragment thereof of 80 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, or a range formed by any of the above values, and a pharmaceutical composition containing an anti-PD-1 antibody or an antigen-binding fragment thereof is prepared to be suitable for administering to a patient for 10 A single dose or multiple doses of an anti-PD-1 antibody or antigen-binding fragment thereof of 1 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or a range formed by any of the foregoing values. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 160-800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 100-200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient. In some embodiments, the pharmaceutical combination comprises a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprising the anti-LAG-3 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 600 mg of the anti-LAG-3 antibody or an antigen-binding fragment thereof to a patient, and the pharmaceutical composition comprising the anti-PD-1 antibody or an antigen-binding fragment thereof is prepared as a single dose or multiple doses suitable for administering 200 mg of the anti-PD-1 antibody or an antigen-binding fragment thereof to a patient.

In another aspect, the present application provides a kit for treating a tumor, the kit comprising a pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof, and instructions for using the pharmaceutical composition comprising an anti-LAG-3 antibody or an antigen-binding fragment thereof and the pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof in combination to treat the tumor.

In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or its antigen-binding fragment is a lyophilized preparation. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a liquid preparation or a solid preparation. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is an injection. In some specific embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation.

In some specific embodiments, the tumor is a lymphoma. In some specific embodiments, the tumor is a Hodgkin's lymphoma. In some specific embodiments, the tumor is a non-Hodgkin's lymphoma. In some specific embodiments, the tumor is a primary mediastinal large B-cell lymphoma.

use

The present application also provides a method for treating a tumor in a subject, which comprises administering to the subject a therapeutically effective amount of the pharmaceutical combination of the present application.

On the other hand, the present application also provides the use of the drug combination of the present application in the preparation of a drug for treating a tumor in a subject. In addition, the present application also provides the use of the drug combination of the present application for treating a tumor in a subject. In some embodiments, the use includes administering a therapeutically effective amount of the drug combination of the present application to the subject.

In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof of the present application.

On the other hand, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in the preparation of a medicament for treating a tumor in a subject. In addition, the present application also provides the use of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application in treating a tumor in a subject. In some embodiments, the use comprises administering to the subject a therapeutically effective amount of the anti-LAG-3 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment of the present application.

In another aspect, the present application provides use of the anti-LAG-3 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-PD-1 antibody or antigen-binding fragment thereof of the present application.

In another aspect, the present application provides use of the anti-PD-1 antibody or antigen-binding fragment thereof of the present application in the preparation of a medicament for treating a tumor in a subject, wherein the medicament is used in combination with the anti-LAG-3 antibody or antigen-binding fragment thereof of the present application.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof can be administered sequentially and/or alternately. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially. In some embodiments, in the methods or uses, the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, and then the anti-LAG-3 antibody or antigen-binding fragment thereof is administered.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, which can be administered sequentially and/or alternately. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, which can be administered sequentially. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition, and the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is administered first, and then the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is administered.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in the same or different dosing regimens. In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered in different dosing regimens.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 4 weeks. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160-800 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 600 mg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 160-800 mg anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 600 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 160-800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 160 mg, 200 mg, 300 mg, 400 mg, 600 mg, or 800 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 600 mg of the anti-LAG-3 antibody or antigen-binding fragment thereof.

In some embodiments, in the method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 4 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800 mg, 50-500 mg, or 100-200 mg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10 mg, 50 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg, or a range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 100-200 mg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 200 mg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered once every 3 weeks, each time at a dose of 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks, each time at a dose of 200 mg of the anti-PD-1 antibody or antigen-binding fragment thereof.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50 mg/kg, 0.1-40 mg/kg, 0.1-30 mg/kg, 0.1-20 mg/kg, 0.1-10 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg, 1-10 mg/kg, 3-50 mg/kg, 3-40 mg/kg, 3-30 mg/kg, 3-20 mg/kg, 3-10 mg/kg, 1-5 mg/kg, or 3-5 mg/kg per administration. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 0.1 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or a range formed by any of the above values. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 1-10 mg/kg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 3 mg/kg, 5 mg/kg or 10 mg/kg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 0.1-50 mg/kg, 0.1-40 mg/kg, 0.1-30 mg/kg, 0.1-20 mg/kg, 0.1-10 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg, 1-10 mg/kg, 3-50 mg/kg, 3-40 mg/kg, 3-30 mg/kg, 3-20 mg/kg, 3-10 mg/kg, 1-5 mg/kg, or 3-5 mg/kg. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1-10 mg/kg. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 1-10 mg/kg each time. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 3 mg/kg, 5 mg/kg or 10 mg/kg each time.

In some embodiments, in the method or use, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 0.1-50 mg/kg, 0.1-40 mg/kg, 0.1-30 mg/kg, 0.1-20 mg/kg, 0.1-10 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg, 1-10 mg/kg, 3-50 mg/kg, 3-40 mg/kg, 3-30 mg/kg, 3-20 mg/kg, 3-10 mg/kg, 1-5 mg/kg, or 3-5 mg/kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 0.1 mg/kg, 1 mg/kg, 1.5 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 3.5 mg/kg, 4 mg/kg, 4.5 mg/kg, 5 mg/kg, 5.5 mg/kg, 6 mg/kg, 6.5 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 20 mg/kg, 30 mg/kg, 40 mg/kg, 50 mg/kg, or a range formed by any of the above values. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 1-5 mg/kg each time. In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered at a dose of 2 mg/kg, 3 mg/kg or 5 mg/kg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 0.1-50 mg/kg, 0.1-40 mg/kg, 0.1-30 mg/kg, 0.1-20 mg/kg, 0.1-10 mg/kg, 1-50 mg/kg, 1-40 mg/kg, 1-30 mg/kg, 1-20 mg/kg, 1-10 mg/kg, 3-50 mg/kg, 3-40 mg/kg, 3-30 mg/kg, 3-20 mg/kg, 3-10 mg/kg, 1-5 mg/kg, or 3-5 mg/kg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, each time at a dose of 1-5 mg/kg. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 1-5 mg/kg each time. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 3 weeks at a dose of 2 mg/kg, 3 mg/kg or 5 mg/kg each time.

In some embodiments, in the methods or uses, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same or different treatment cycles, respectively. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, one treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof have the same treatment cycle, for example, one treatment cycle is every 3 weeks.

In some embodiments, in the methods or uses, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof are administered in each treatment cycle. In some embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof and anti-PD-1 antibodies or antigen-binding fragments thereof are administered once in each treatment cycle. In some embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof are administered on day 1 of each treatment cycle, and anti-PD-1 antibodies or antigen-binding fragments thereof are administered on day 1 of each treatment cycle. In some specific embodiments, every 3 weeks is a treatment cycle, and anti-LAG-3 antibodies or antigen-binding fragments thereof are administered once on day 1 of each treatment cycle, and anti-PD-1 antibodies or antigen-binding fragments thereof are administered once on day 1 of each treatment cycle.

In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 80-1800 mg, 120-1200 mg, 140-1000 mg, or 160-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 10-800 mg, 50-500 mg, or 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 160-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, and 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 600 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered in each treatment cycle, and 200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered in each treatment cycle. In some specific embodiments, in the method or use, every 3 weeks is a treatment cycle, 160-800 mg of anti-LAG-3 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle, and 100-200 mg of anti-PD-1 antibody or its antigen-binding fragment is administered on the first day of each treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 160 mg, 200 mg, 300 mg, 400 mg, 600 mg or 800 mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle. In some specific embodiments, in the methods or uses, one treatment cycle is 3 weeks, and 600 mg of anti-LAG-3 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle, and 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof is administered on day 1 of each treatment cycle.

In some embodiments, in the methods or uses, the dosing regimen (e.g., dosing cycle, dosing dose, and dose adjustment) of the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof 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, one treatment cycle of the anti-LAG-3 antibody or antigen-binding fragment thereof and/or the anti-PD-1 antibody or antigen-binding fragment thereof 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.

Anti-LAG-3 antibodies or antigen-binding fragments thereof

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: a heavy chain CDR1 (HCDR1) of the amino acid sequence of SEQ ID NO: 1 or 21, a HCDR2 of the amino acid sequence of SEQ ID NO: 2 or 22, a HCDR3 of the amino acid sequence of SEQ ID NO: 3 or 23, a light chain CDR1 (LCDR1) of the amino acid sequence of SEQ ID NO: 4 or 24, a LCDR2 of the amino acid sequence of SEQ ID NO: 5 or 25, and a LCDR3 of the amino acid sequence of SEQ ID NO: 6 or 26. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: a HCDR1 of the amino acid sequence of SEQ ID NO: 1, a HCDR2 of the amino acid sequence of SEQ ID NO: 2, a HCDR3 of the amino acid sequence of SEQ ID NO: 3, a LCDR1 of the amino acid sequence of SEQ ID NO: 4, a LCDR2 of the amino acid sequence of SEQ ID NO: 5, and a LCDR3 of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 21, HCDR2 of the amino acid sequence shown in SEQ ID NO: 22, HCDR3 of the amino acid sequence shown in SEQ ID NO: 23, LCDR1 of the amino acid sequence shown in SEQ ID NO: 24, LCDR2 of the amino acid sequence shown in SEQ ID NO: 25, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 26. The CDR sequences of the anti-LAG-3 antibody or antigen-binding fragment thereof are shown in Table 1.

Table 1. CDR sequences of anti-LAG-3 antibodies or antigen-binding fragments thereof

It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although Table 1 has shown CDR sequences, however, when referring to anti-LAG-3 antibodies or antigen-binding fragments thereof defined by specific CDR sequences, the scope of the anti-LAG-3 antibodies or antigen-binding fragments thereof encompasses anti-LAG-3 antibodies or antigen-binding fragments thereof defined by any numbering system (e.g., a combination of one or more of the AbM, Kabat, Chothia, IMGT, CCG or Contact definitions known in the art).

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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 set forth in SEQ ID NO: 7 or 27. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain variable region 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 set forth in SEQ ID NO: 8 or 28. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 8. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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 of SEQ ID NO:7 or 27, and a light chain variable region 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 of SEQ ID NO:8 or 28.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises: 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; and the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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 of SEQ ID NO:7, and a heavy chain variable region 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 of SEQ ID NO:7. The amino acid sequence shown in NO:8 has a light chain variable region 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.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region of the amino acid sequence set forth in SEQ ID NO: 27, and a light chain variable region of the amino acid sequence set forth in SEQ ID NO: 28. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof is set forth in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 28.

QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISSVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSS(SEQ ID NO:7);

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK(SEQ ID NO:8);

EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPA VKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDIDIDAWGQGTLVTVSS (SEQ ID NO: 27);

SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDDGGLFGSGTKVTVL (SEQ ID NO: 28).

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof may further comprise a constant region of an immunoglobulin, or a fragment, analog, 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 from a human immunoglobulin heavy chain, such as a heavy chain of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably a heavy chain of IgG1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence 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 of SEQ ID NO: 9 or 29. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence 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 of SEQ ID NO: 10 or 30. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain set forth in SEQ ID NO: 9. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the light chain region set forth in SEQ ID NO: 10.

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment 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 of SEQ ID NO:9 or 29, 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 of SEQ ID NO:10 or 30. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 9, and a light chain having an amino acid sequence as shown in SEQ ID NO: 10. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 29, and a light chain having an amino acid sequence as shown in SEQ ID NO: 30. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 9, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 29, and the amino acid sequence of the light chain is as shown in SEQ ID NO: 30.

Question NTKVDKRVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:9);

EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC(SEQ IDNO:10);

EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDIDIDAWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKV DKRVEPKSCD KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:29);

SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDGLFGSGTKVTVLRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC (SEQ ID NO:30).

Anti-PD-1 antibody or antigen-binding fragment thereof

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof described herein comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 16. The CDR sequences of the anti-PD-1 antibody or antigen-binding fragment thereof are shown in Table 2.

Table 2. CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof

HCDR1 GFAFSSYD SEQ ID NO:11 HCDR2 ISGGGRYT SEQ ID NO:12 HCDR3 ANRYGEAWFAY SEQ ID NO:13 LCDR1 QDINTY SEQ ID NO:14 LCDR2 RAN SEQ ID NO:15 LCDR3 LQYDEFPLT SEQ ID NO:16

It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although CDR regions are shown in Table 2, however, when it comes to defining anti-PD-1 antibodies or antigen-binding fragments thereof with specific CDR sequences, the scope of the anti-PD-1 antibodies or antigen-binding fragments thereof encompasses anti-PD-1 antibodies or antigen-binding fragments thereof defined by any numbering system (e.g., a combination of one or more of the definitions of AbM, Kabat, Chothia, IMGT, CCG or Contact, etc., which are well known in the art).

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence 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 of SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence 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 of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region as shown in SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region as shown in SEQ ID NO:18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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 of SEQ ID NO:17, and a light chain variable region 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 of SEQ ID NO:18.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a HCDR1 comprising the amino acid sequence of SEQ ID NO: 11, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 12, a HCDR3 comprising the amino acid sequence of SEQ ID NO: 13, a LCDR1 comprising the amino acid sequence of SEQ ID NO: 14, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 16; and the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region 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 of SEQ ID NO: 17, and a heavy chain variable region 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 of SEQ ID NO: 18. The amino acid sequence shown in NO:18 has a light chain variable region 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.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 17, and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 18. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 18.

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSS(SEQ ID NO:17);

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELK (SEQ ID NO: 18).

In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may further comprise a constant region of an immunoglobulin, or a fragment, analog, 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 from a human immunoglobulin heavy chain, such as a heavy chain of IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulins, preferably a heavy chain of IgG1. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a κ light chain or a λ light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that changes effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence 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 of SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence 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 of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence as shown in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment 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 of SEQ ID NO: 19, 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 of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO: 19, and a light chain having an amino acid sequence as shown in SEQ ID NO: 20. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 19, and the light chain amino acid sequence is as shown in SEQ ID NO: 20.

EVQLVESGGGLVQPGGSLRLSCAASGFAFSSYDMSWVRQAPGKGLDWVATISGGGRYTYYPDSVKGRFTISRDNSKNNLYLQMNSLRAEDTALYYCANRYGEAWFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKK VEPKSCDKTHT CPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGN VFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:19);

DIQMTQSPSSMSASVGDRVTFTCRASQDINTYLSWFQQKPGKSPKTLIYRANRLVSGVPSRFSGSGSGQDYTLTISSLQPEDMATYYCLQYDEFPLTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC (SEQ ID NO: 20).

In some other embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof of the present application is selected from: Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Zimberelimab, Balstilimab, geptanolimab, Lipustobart (LZM-100) of Livzon Pharmaceuticals, 009), Cemiplimab, Serplulimab, Prolgolimab, Pucotenlimab (HX008), Nofazinlimab, Finotonlimab, Dostarlimab, Cetrelimab, Qilu Pharmaceutical's QL1604, Spartalizumab, Retifanlimab, Sasanlimab, Shandong New Times Pharmaceutical's Rulonilimab (F520), or Shangjian Bio's Enlonstobart (SG001).

Pharmaceutical composition containing antibody or antigen-binding fragment thereof

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated for parenteral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated for intravenous, intramuscular, subcutaneous or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated for intravenous injection or infusion.

The anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into a suitable dosage form, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e., preparations suitable for injection, such as preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained-release preparations for oral or parenteral administration. In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into an injection (e.g., an injection solution or a lyophilized preparation for injection). In some specific embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can be formulated into a preparation suitable for intravenous injection (e.g., an injection solution or a lyophilized preparation for injection).

In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable carriers to prepare a suitable pharmaceutical composition.

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for parenteral administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular, subcutaneous or other parenteral administration, such as for injection or infusion. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous, intramuscular or subcutaneous administration. In some specific embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof can be formulated as a formulation for intravenous injection or infusion.

The anti-PD-1 antibody or its antigen-binding fragment can be formulated into a suitable dosage form, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (i.e., preparations suitable for injection, such as preparations suitable for intramuscular, intravenous, intraperitoneal, subcutaneous injection), granules, emulsions, suspensions, solutions, dispersions, and sustained-release preparations for oral or parenteral administration. In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be formulated into an injection (e.g., an injection solution or a lyophilized preparation for injection). In some specific embodiments, the anti-PD-1 antibody or its antigen-binding fragment can be formulated into a preparation suitable for intravenous injection (e.g., an injection solution or a lyophilized preparation for injection).

In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is formulated with one or more pharmaceutically acceptable carriers to prepare a suitable pharmaceutical composition.

Pharmaceutically acceptable carriers include, for example, excipients, diluents, encapsulating materials, fillers, buffers or other agents.

In some embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or antigen-binding fragment thereof is an aqueous injection. In some embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or antigen-binding fragment thereof is an aqueous injection. The aqueous injection includes but is not limited to an aqueous preparation that has not been lyophilized or an aqueous preparation reconstituted with a lyophilized powder.

In other embodiments, the pharmaceutical composition containing the anti-LAG-3 antibody or its antigen-binding fragment is a lyophilized preparation for injection. In other embodiments, the pharmaceutical composition containing the anti-PD-1 antibody or its antigen-binding fragment is a lyophilized preparation for injection. The lyophilized preparation for injection refers to a preparation prepared by a freeze-drying process of an aqueous solution, in which the substance is first frozen, and then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption (secondary drying process) until the amount of solvent is a value that no longer supports biological activity or chemical reaction. The lyophilized preparation of the present application can also be dried by other methods known in the art, such as spray drying and bubble drying.

Mode of administration

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

Each component in the drug combination of the present application can be administered independently of each other in various suitable routes, including but not limited to parenteral (e.g., by intravenous, intramuscular, topical or subcutaneous) route administration. In some embodiments, each component of the drug combination of the present application can be administered independently of each other by injection, such as intravenous or subcutaneous injection.

The pharmaceutical combination of the present application may further comprise an additional therapeutic agent. In some embodiments, the additional therapeutic agent may be a tumor therapeutic agent known in the art.

Tumor

The tumor described in the present application is a malignant tumor (ie, cancer); the malignant tumor refers to any malignant and/or invasive growth caused by abnormal cell growth.

In some embodiments, the tumor is a lymphoma. In some embodiments, the tumor is a newly treated, unresectable, refractory, advanced, recurrent and/or metastatic lymphoma. In some embodiments, the tumor is an unresectable lymphoma. In some embodiments, the tumor is a refractory lymphoma. In some embodiments, the tumor is an advanced lymphoma. In some embodiments, the tumor is a locally advanced lymphoma. In some embodiments, the tumor is a recurrent lymphoma. In some embodiments, the tumor is a metastatic lymphoma. In some embodiments, the tumor is a refractory, metastatic and/or recurrent lymphoma. In some embodiments, the tumor is a refractory and/or recurrent lymphoma. In some embodiments, the tumor is a metastatic and/or recurrent lymphoma. In some embodiments, the tumor is a metastatic and/or recurrent lymphoma.

In some embodiments, the tumor is Hodgkin's lymphoma. In some embodiments, the tumor is a newly treated, unresectable, refractory, advanced, recurrent and/or metastatic Hodgkin's lymphoma. In some embodiments, the tumor is an unresectable Hodgkin's lymphoma. In some embodiments, the tumor is a refractory Hodgkin's lymphoma. In some embodiments, the tumor is an advanced Hodgkin's lymphoma. In some embodiments, the tumor is a locally advanced Hodgkin's lymphoma. In some embodiments, the tumor is a recurrent Hodgkin's lymphoma. In some embodiments, the tumor is a metastatic Hodgkin's lymphoma. In some embodiments, the tumor is a refractory, metastatic and/or recurrent Hodgkin's lymphoma. In some embodiments, the tumor is a refractory and/or recurrent Hodgkin's lymphoma. In some embodiments, the tumor is a metastatic and/or recurrent Hodgkin's lymphoma. In some embodiments, the Hodgkin's lymphoma is a Hodgkin's lymphoma that has failed immune checkpoint inhibitor therapy. In some embodiments, the Hodgkin lymphoma is an advanced or locally advanced Hodgkin lymphoma that has failed immune checkpoint inhibitor therapy. In some embodiments, the Hodgkin lymphoma is refractory, metastatic, and/or recurrent Hodgkin lymphoma that has failed immune checkpoint inhibitor therapy. In some embodiments, the Hodgkin lymphoma is a Hodgkin lymphoma that is resistant to immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is an advanced or locally advanced Hodgkin lymphoma that is resistant to immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is a refractory, metastatic, and/or recurrent Hodgkin lymphoma that is resistant to immune checkpoint inhibitors. In some specific embodiments, the Hodgkin lymphoma is a refractory, metastatic, and/or recurrent Hodgkin lymphoma that has failed second-line systemic treatment and is resistant to immune checkpoint inhibitors.

In some embodiments, the tumor is a non-Hodgkin's lymphoma. In some embodiments, the tumor is a newly treated, unresectable, refractory, advanced, recurrent and/or metastatic non-Hodgkin's lymphoma. In some embodiments, the tumor is an unresectable non-Hodgkin's lymphoma. In some embodiments, the tumor is a refractory non-Hodgkin's lymphoma. In some embodiments, the tumor is an advanced non-Hodgkin's lymphoma. In some embodiments, the tumor is a locally advanced non-Hodgkin's lymphoma. In some embodiments, the tumor is a recurrent non-Hodgkin's lymphoma. In some embodiments, the tumor is a metastatic non-Hodgkin's lymphoma. In some embodiments, the tumor is a refractory, metastatic and/or recurrent non-Hodgkin's lymphoma. In some embodiments, the tumor is a refractory and/or recurrent non-Hodgkin's lymphoma. In some embodiments, the tumor is a metastatic and/or recurrent non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a non-Hodgkin's lymphoma that has failed immune checkpoint inhibitor treatment. In some embodiments, the non-Hodgkin's lymphoma is an advanced or locally advanced non-Hodgkin's lymphoma that has failed immune checkpoint inhibitor treatment. In some embodiments, the non-Hodgkin's lymphoma is a refractory, metastatic and/or recurrent non-Hodgkin's lymphoma that has failed immune checkpoint inhibitor treatment. In some embodiments, the non-Hodgkin's lymphoma is a non-Hodgkin's lymphoma that is resistant to immune checkpoint inhibitors. In some embodiments, the non-Hodgkin's lymphoma is an advanced or locally advanced non-Hodgkin's lymphoma that is resistant to immune checkpoint inhibitors. In some embodiments, the non-Hodgkin's lymphoma is a refractory, metastatic and/or recurrent non-Hodgkin's lymphoma that is resistant to immune checkpoint inhibitors. In some specific embodiments, the non-Hodgkin's lymphoma is a refractory, metastatic and/or recurrent non-Hodgkin's lymphoma that has failed second-line systemic treatment and is resistant to immune checkpoint inhibitors.

In some embodiments, the tumor is a primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a primary mediastinal large B-cell lymphoma that is initially treated, unresectable, refractory, advanced, recurrent and/or metastatic. In some embodiments, the tumor is an unresectable primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a refractory primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is an advanced primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a locally advanced primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a recurrent primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a metastatic primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is a refractory and/or recurrent primary mediastinal large B-cell lymphoma. In some embodiments, the tumor is metastatic and/or recurrent primary mediastinal large B-cell lymphoma.

In some embodiments, the subject with Hodgkin lymphoma has not been previously treated for Hodgkin lymphoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject with Hodgkin lymphoma has not previously received radiation therapy, chemotherapy, and/or immunotherapy to treat Hodgkin lymphoma. In some embodiments, the subject with Hodgkin lymphoma has not previously received systemic therapy to treat Hodgkin lymphoma.

In some embodiments, the subject with non-Hodgkin lymphoma has not been previously treated for non-Hodgkin lymphoma (e.g., lacks an effective treatment regimen). In some embodiments, the subject with non-Hodgkin lymphoma has not previously received radiation therapy, chemotherapy, and/or immunotherapy to treat non-Hodgkin lymphoma. In some embodiments, the subject with non-Hodgkin lymphoma has not previously received systemic therapy to treat non-Hodgkin lymphoma.

In some embodiments, the subject of the primary mediastinal large B-cell lymphoma has not been previously treated for primary mediastinal large B-cell lymphoma (e.g., lack of an effective treatment regimen). In some embodiments, the subject of the primary mediastinal large B-cell lymphoma has not previously received radiation therapy, chemotherapy, and/or immunotherapy to treat primary mediastinal large B-cell lymphoma. In some embodiments, the subject of the primary mediastinal large B-cell lymphoma has not previously received systemic therapy to treat primary mediastinal large B-cell lymphoma.

In some embodiments, the subject of Hodgkin's lymphoma has previously been treated for Hodgkin's lymphoma with one or more different anti-tumor therapies (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of Hodgkin's lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to treat Hodgkin's lymphoma (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of Hodgkin's lymphoma has previously received systemic therapy to treat Hodgkin's lymphoma (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of Hodgkin's lymphoma has previously received first-line therapy to treat Hodgkin's lymphoma (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of Hodgkin's lymphoma has previously received second-line therapy to treat Hodgkin's lymphoma (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of Hodgkin's lymphoma has previously received second-line systemic therapy to treat Hodgkin's lymphoma (e.g., treatment failed or was not applicable). In some specific embodiments, the subject of the Hodgkin lymphoma has previously received immunotherapy to treat the Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the Hodgkin lymphoma has previously received an immune checkpoint inhibitor to treat the Hodgkin lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of non-Hodgkin lymphoma has previously been treated with one or more different anti-tumor therapies for non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-Hodgkin lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-Hodgkin lymphoma has previously received systemic therapy to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-Hodgkin lymphoma has previously received first-line treatment to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of non-Hodgkin lymphoma has previously received second-line treatment to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with non-Hodgkin lymphoma has previously received second-line systemic therapy to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with non-Hodgkin lymphoma has previously received immunotherapy to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with non-Hodgkin lymphoma has previously received immune checkpoint inhibitors to treat non-Hodgkin lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously been treated with one or more different anti-tumor therapies for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received surgery, radiotherapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received systemic treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received first-line treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received second-line treatment for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received second-line systemic treatment for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received immunotherapy for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received immune checkpoint inhibitors for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the primary mediastinal large B-cell lymphoma has previously received anti-CD20 antibodies for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with primary mediastinal large B-cell lymphoma has previously received rituximab to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with primary mediastinal large B-cell lymphoma has previously received autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with primary mediastinal large B-cell lymphoma has previously received rituximab and autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the late or locally advanced Hodgkin's lymphoma has previously been treated for Hodgkin's lymphoma with one or more different anti-tumor therapies (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced Hodgkin's lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to treat Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced Hodgkin's lymphoma has previously received systemic therapy to treat Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced Hodgkin's lymphoma has previously received first-line treatment to treat Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced Hodgkin's lymphoma has previously received second-line treatment to treat Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced Hodgkin lymphoma has previously received second-line systemic therapy to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced Hodgkin lymphoma has previously received immunotherapy to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced Hodgkin lymphoma has previously received immune checkpoint inhibitors to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the late or locally advanced non-Hodgkin's lymphoma has previously been treated with one or more different anti-tumor therapies for non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced non-Hodgkin's lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy, and/or adjuvant chemotherapy to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced non-Hodgkin's lymphoma has previously received systemic therapy to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced non-Hodgkin's lymphoma has previously received first-line treatment to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced non-Hodgkin's lymphoma has previously received second-line treatment to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced non-Hodgkin's lymphoma has previously received second-line systemic therapy to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced non-Hodgkin's lymphoma has previously received immunotherapy to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced non-Hodgkin's lymphoma has previously received immune checkpoint inhibitors to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously been treated with one or more different anti-tumor therapies for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received surgical treatment, radiotherapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received systemic treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received first-line treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received second-line treatment for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received second-line systemic treatment for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received immunotherapy for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the late or locally advanced primary mediastinal large B-cell lymphoma has previously received immune checkpoint inhibitors for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced primary mediastinal large B-cell lymphoma has previously received an anti-CD20 antibody to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced primary mediastinal large B-cell lymphoma has previously received rituximab to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced primary mediastinal large B-cell lymphoma has previously received autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject with advanced or locally advanced primary mediastinal large B-cell lymphoma has previously received rituximab and autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously been treated for Hodgkin lymphoma with one or more different anti-tumor therapies (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received systemic therapy to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received first-line therapy to treat Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received second-line treatment for Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received second-line systemic treatment for Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received immunotherapy for Hodgkin lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent Hodgkin lymphoma has previously received immune checkpoint inhibitors for Hodgkin lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously been treated for non-Hodgkin's lymphoma with one or more different anti-tumor therapies (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received surgery, radiation therapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received systemic treatment to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received first-line treatment to treat non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received second-line treatment for non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received second-line systemic treatment for non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received immunotherapy for non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent non-Hodgkin's lymphoma has previously received immune checkpoint inhibitors for non-Hodgkin's lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously been treated with one or more different anti-tumor therapies for primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received surgery, radiotherapy, induction chemotherapy, concurrent chemotherapy and/or adjuvant chemotherapy to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received systemic treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received first-line treatment to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received second-line treatment for primary mediastinal large B-cell lymphoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received second-line systemic treatment for primary mediastinal large B-cell lymphoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received immunotherapy for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received immune checkpoint inhibitors for the treatment of primary mediastinal large B-cell lymphoma (e.g., treatment failure or inapplicability). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received an anti-CD20 antibody to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received rituximab to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable). In some specific embodiments, the subject of the refractory, metastatic and/or recurrent primary mediastinal large B-cell lymphoma has previously received rituximab and autologous hematopoietic stem cell transplantation to treat primary mediastinal large B-cell lymphoma (e.g., treatment failed or is not applicable).

In some embodiments, the Hodgkin lymphoma is a classical Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is a nodular lymphocyte-dominant Hodgkin lymphoma. In some embodiments, the Hodgkin lymphoma is a Hodgkin lymphoma selected from a nodular sclerosis type, a mixed cell type, a lymphocyte-enriched type, a lymphocyte-depleted type, or a lymphocyte-dominant type. In some embodiments, the Hodgkin lymphoma has a genetic change at 9p24.1. In some embodiments, the Hodgkin lymphoma expresses PD-L1 and/or PD-L2. In some embodiments, the Hodgkin lymphoma has been infected by Epstein-Barr virus (EBV). In some embodiments, the Hodgkin lymphoma is an advanced or locally advanced classical Hodgkin lymphoma that has failed to be treated with immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is a refractory, metastatic, and/or recurrent classical Hodgkin lymphoma that has failed to be treated with immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is an advanced or locally advanced classical Hodgkin lymphoma that is not suitable for treatment with immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is a refractory, metastatic, and/or relapsed classical Hodgkin lymphoma that is not suitable for treatment with immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is an advanced or locally advanced classical Hodgkin lymphoma that is resistant to immune checkpoint inhibitors. In some embodiments, the Hodgkin lymphoma is a refractory, metastatic, and/or relapsed classical Hodgkin lymphoma that is resistant to immune checkpoint inhibitors.

In some embodiments, the non-Hodgkin's lymphoma is T-cell non-Hodgkin's lymphoma (T-NHL) or B-cell non-Hodgkin's lymphoma (B-NHL). In some embodiments, the non-Hodgkin's lymphoma is aggressive non-Hodgkin's lymphoma or indolent non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), mantle cell lymphoma (MCL), Burkitt's lymphoma (BL), lymphoblastic lymphoma (LBL), cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, marginal zone lymphoma, NK/T-cell lymphoma and/or AIDS-related B-cell lymphoma.

In some embodiments, the immune checkpoint inhibitor is an antibody or antigen-binding fragment thereof against an immune checkpoint (e.g., PD-1, PD-L1, CTLA-4, or PD-L2), such as Nivolumab, Pembrolizumab, Toripalimab, Sintilimab, Camrelizumab, Tislelizumab, Balstilimab, Zimberelimab, Atezolizumab, Durvalumab, Avelumab, Envafolimab, Sugemalimab, Ipilimumab, or Tremelimumab.

Technical Effects

Generally, the use of the above-mentioned drug combination of the present application will help:

(1) Producing a better therapeutic effect in reducing tumor growth or even eliminating tumors compared to administering any of the drugs in the combination alone;

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

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

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

(5) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) in the patients treated;

(6) Providing a longer survival (e.g., median survival, progression-free survival, or overall survival) for the treated patients compared to standard chemotherapy;

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

(8) Compared with the administration of any drug in the combination alone, the combination has good anti-tumor activity and exhibits a more excellent anti-tumor synergistic effect.

The drug combination and treatment regimen of the present application have good efficacy in treating lymphoma, especially Hodgkin's lymphoma and non-Hodgkin's lymphoma (e.g., primary mediastinal large B-cell lymphoma and NK/T-cell lymphoma), and have beneficial effects in at least one of ORR, DCR, DOR, PFS, OS, tolerance and side effects.

Definition and Description

Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding commodity or its active ingredient.

As used herein, the term "pharmaceutical combination" refers to a combination of two or more active ingredients (including administration in the form of each active ingredient itself, or in the form of its respective pharmaceutically acceptable salt or ester derivatives, prodrugs or compositions) administered in any order. The active ingredients can be administered to a subject simultaneously as a single formulation, or sequentially in any order as a single formulation.

As used herein, the term "antibody" refers to an antigen binding protein having at least one antigen binding domain. The antibody and its fragment of the present application may be a whole antibody or any fragment thereof. Therefore, the antibody and its fragment of the present application include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof. Examples of antibody and its antigen binding fragment fragments include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' ₂ fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. The anti-LAG-3 antibodies and anti-PD-1 antibodies and their antigen binding fragments disclosed herein may be IgG1, IgG2, IgG3 or IgG4 isotypes. The term "isotype" refers to the antibody species encoded by the heavy chain constant region gene. The anti-LAG-3 antibodies and their antigen binding fragments and anti-PD-1 antibodies and their antigen binding fragments of the present application may be derived from any species, including but not limited to mice, rats, rabbits, primates, llamas and humans. The anti-LAG-3 antibody and its antigen-binding fragment and the anti-PD-1 antibody and its antigen-binding fragment of the present application can be a murine antibody, a chimeric antibody, a humanized antibody or a fully human antibody. Unless otherwise specified, the "antibody" of the present application includes the whole antibody and any antigen-binding fragment or single chain thereof. The conventional "whole antibody" is a glycoprotein comprising two heavy (H) chains and two light (L) chains, and the heavy chain and the light chain are connected by a disulfide bond. 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, namely complementarity determining regions (CDRs), and framework regions (FRs) with relatively conservative sequences. Each VH and VL is composed of three CDRs and four FRs, respectively, from the amino terminus to the carboxyl 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 those skilled in the art will appreciate, special "whole antibodies", such as nanobodies, have only heavy (H) chains and no light (L) chains.

An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., LAG-3 or PD-1). It has been demonstrated that the antigen-binding function of an antibody can be implemented by a fragment of the entire antibody. Examples encompassed by the term "antigen-binding fragment" of an antibody include: (i) Fab fragment: a monovalent fragment consisting of _VL , _VH , CL, and CH1 domains; (ii) F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) dAb fragment consisting of a VH domain (see Ward et al., Nature. 341: 544-546 (1989)); (vi) isolated complementarity determining regions (CDRs); and (vii) nanobodies, a heavy chain variable region comprising 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, VH and VL can be connected into a single protein chain by a recombinant method through a synthetic linker, wherein VL and VH are paired to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)). These single-chain antibodies are also encompassed in the term antigen-binding fragment. In addition, recombinant polypeptides, fusion proteins and immunoconjugates comprising the antigen-binding fragment are also encompassed in the term antigen-binding fragment.

A "chimeric antibody" is an antibody having at least a portion of a heavy chain variable region and at least a portion of a light chain variable region derived from one species; and at least a portion of a constant region derived from another species. For example, in one embodiment, a chimeric antibody may comprise a murine variable region and a human constant region.

"Humanized antibodies" are antibodies that contain complementary determining regions (CDRs) derived from non-human antibodies and framework regions and constant regions derived from human antibodies. For example, anti-LAG-3 antibodies and anti-PD-1 antibodies may contain CDRs derived from one or more murine antibodies and human framework regions and human constant regions. Exemplary humanized antibodies are provided herein. Additional anti-LAG-3 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be produced using any human framework sequence and are also included in the present application. Additional anti-PD-1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be produced using any human framework sequence and are also included in the present application. In one embodiment, framework sequences suitable for use in the present application include those that are structurally similar to the framework sequences provided herein. Additional modifications may be made in the framework region to improve the properties of the antibodies provided herein. Such additional framework modifications may include chemical modifications; point mutations to reduce immunogenicity or remove T cell epitopes; or revert mutations to residues in the original germline sequence. In some embodiments, such modifications include those corresponding to the mutations exemplified herein, including back mutations to the germline sequence. For example, in one embodiment, one or more amino acids in the human framework regions of the VH and/or VL of the humanized antibodies provided herein are backmutated to the corresponding amino acids in the parent murine antibody.

The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be compared that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be compared with the specific amino acid sequence shown in this article and introducing spaces if necessary to achieve the maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. The amino acid sequence alignment of identity can be carried out in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for comparing sequences, including any algorithm required to obtain the maximum alignment in the full length of the comparison sequence.

The term "treatment" generally refers to an operation to obtain a desired pharmacological and/or physiological effect. The effect may be preventive, in terms of completely or partially preventing a disease or its symptoms; and/or therapeutic, in terms of partially or completely stabilizing or curing a disease and/or side effects produced by the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of a disease, alleviating 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 state of a disease, extending the frequency and duration of symptom-free periods, and resolving or improving the prognosis of a disease.

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 disease or promotes disease regression, as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression 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 in humans, or by measuring the activity of the agent in in vitro assays.

The terms "administering," "dosing," or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

The routes of administration of the antibody or antigen-binding fragment thereof (e.g., anti-LAG-3 antibody or antigen-binding fragment thereof or anti-PD-1 antibody or antigen-binding fragment thereof) include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion. As used herein, the phrase "parenteral administration" refers to modes of administration other than enteral administration, which are usually performed by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, and in vivo electroporation. Administration can also be performed, for example, once, multiple times, and/or over one or more extended time periods.

The term "flat dose" is used to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). The flat dose is thus specified as an absolute amount of an agent (e.g., an anti-PD-1 antibody or antigen-binding fragment 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 antibody (e.g., 200 mg of an anti-PD-1 antibody or antigen-binding fragment thereof).

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

The term "pharmaceutical composition" refers to a mixture of the compound of the present application and a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present application to a subject. In this article, the terms "pharmaceutical composition" and "preparation" have the same meaning and can be used interchangeably.

As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "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.

As used herein, "combination" or "combined use" means that two or more compounds can be administered to a subject simultaneously, each as a single formulation, or sequentially in any order, each as a single formulation.

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

The term "recurrent" cancer is a cancer that regenerates in the original site or at a distant site after responding to initial treatment (eg, surgery). A "locally recurrent" cancer is a cancer that recurs after treatment in the same location as a previously treated cancer.

The term "metastatic" cancer refers to cancer that has spread from one part of the body to another part of the body.

The term "refractory" refers to a condition in which a subject or mammal has residual cancer cells in its body even after intensive treatment.

The term "first-line treatment" refers to the drug that can be selected first or standardly based on the patient's condition.

As used herein, "treatment failure" is defined as disease progression or recurrence during or after the last treatment.

The words “comprise”, “comprise” or “comprises” and their English variations such as comprises or comprising should be construed in an open, non-exclusive sense, ie, “including but not limited to”.

Herein, singular terms include plural referents and vice versa unless the context clearly dictates otherwise.

For the purpose of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. These publications are provided only because they are disclosed prior to the filing date of the present application. All statements regarding the dates of these documents or the representations of the contents of these documents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any reference to these publications herein does not constitute an admission that the publications are part of the common general knowledge in the art in any country.

Example

For the sake of clarity, the present application is further described with examples, but the examples do not limit the scope of the present application. All reagents used in the present application are commercially available and can be used without further purification.

The entire contents of WO2018069500A or CN110062766A patent application documents are incorporated herein. The heavy chain amino acid sequence of the anti-LAG-3 antibody in the following examples is shown in SEQ ID NO: 9 of the present application, and the light chain amino acid sequence is shown in SEQ ID NO: 10 of the present application.

The entire contents of the patent application document of CN106977602A are incorporated into this application. The heavy chain amino acid sequence of penpulimab in the following examples is shown in SEQ ID NO: 19 of this application, and the light chain amino acid sequence is shown in SEQ ID NO: 20 of this application.

Example 1: Clinical trial

1. Selection criteria

Patients who meet all of the following inclusion criteria can be enrolled in this trial:

(1) The subjects voluntarily participated in this study, signed the informed consent form (ICF), and had good compliance;

(2) Age: 18-75 years old (at the time of signing the ICF); ECOGPS score: 0-1 points; expected survival period is more than 3 months;

(3) Patients with advanced malignant tumors (including Hodgkin's lymphoma and non-Hodgkin's lymphoma) confirmed by cytology/histopathology;

1) For patients with relapsed or refractory Hodgkin lymphoma or NK/T cell lymphoma, the following criteria must be met:

Patients have received at least two lines of systemic treatment and are resistant to anti-PD-1/PD-L1 antibodies;

2) For patients with relapsed or refractory primary mediastinal large B-cell lymphoma, the following criteria must be met:

Patients who have relapsed after autologous hematopoietic stem cell transplantation (ASCT) or have not achieved complete remission (CR) or partial remission (PR) within 60 days after ASCT; if patients who have relapsed or are refractory after ASCT receive other interventions, they must have relapsed or become refractory after the last systemic treatment;

Patients who are not suitable for ASCT must be patients who have failed or relapsed after two or more lines of chemotherapy, and local radiotherapy is not considered the sole first-line treatment;

Patients had previously received rituximab treatment or were unable to receive rituximab treatment for any reason.

(4) The long diameter of lymph node lesions is greater than 15 mm or the long diameter of extranodal lesions is greater than 10 mm according to CT cross-sectional images;

(5) The major organs function normally, that is, they meet the following criteria:

1) Routine blood test standards (no blood transfusion and no use of hematopoietic stimulating factor drugs for correction within 7 days before screening):

a. Hemoglobin (HGB) ≥ 80 g/L;

b. Neutrophil absolute value (NEUT) ≥ 1.0 × 10 ⁹ /L;

c. Platelet count (PLT) ≥ 75 × 10 ⁹ /L; bone marrow involvement, PLT ≥ 50 × 10 ⁹ /L;

2) Biochemical examination must meet the following standards:

a. Serum total bilirubin (TBIL) ≤ 1.5 times the upper limit of normal (ULN);

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

ALT, AST ≤ 5 × ULN);

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

3) Coagulation function tests must meet the following criteria:

a) International normalized ratio (INR) ≤ 1.5 times ULN (not receiving anticoagulant therapy).

4) Thyroid function tests must meet the following criteria:

a) Thyroid stimulating hormone (TSH) ≤ ULN; if abnormal, triiodothyronine (T3) and tetraiodothyronine (T4) should be examined

Patients with normal T3 and T4 levels can be selected.

5) Cardiac ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ 50%.

(6) Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study and within 6 months after the end of the study; the serum pregnancy/urine pregnancy test should be negative within 7 days before study entry, and the subjects must be non-breastfeeding; male subjects should agree to use contraceptive measures during the study and within 6 months after the end of the study.

2. Experimental drugs

(1) Penpulimab injection (specification: 100 mg/10 mL/bottle): One treatment cycle is 3 weeks. The drug is administered by intravenous infusion at a dose of 200 mg of penpulimab on the first day of each treatment cycle.

(2) Anti-LAG-3 antibody injection (specification: 160 mg/8 mL/bottle): One treatment cycle is 3 weeks. The patient is given an intravenous infusion at a dose of 5 mg/kg, 10 mg/kg or 600 mg of anti-LAG-3 antibody once on the first day of each treatment cycle.

3. Treatment options

The infusion of penpulimab injection was performed first, and the anti-LAG-3 antibody injection was given at least 30 minutes later.

4. Adjustment of dosing regimen

Penpulimab Injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

Anti-LAG-3 antibody injection: Delayed medication is allowed, but the longest delay should not exceed 12 weeks.

5. Evaluation Criteria

The efficacy was evaluated according to the efficacy evaluation criteria revised by the 2014 Lugano conference.

The NCI-CTC AE 5.0 standard was used to judge the severity of adverse events.

6. End point indicators

Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), etc.

Adverse event rate: the occurrence of all adverse events (AEs), serious adverse events (SAEs), and treatment-related adverse events (TRAEs), as well as abnormal laboratory test indicators;

Pharmacokinetic/pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, receptor occupancy (RO), etc.

Detection of treatment-related biomarkers: such as the expression of PD-L1 and LAG-3 in tumor tissues.

7. Results

As of the data statistics date, the results showed that the combination of anti-LAG-3 antibodies and penpulimab can safely and effectively treat lymphoma and non-Hodgkin's lymphoma, significantly improve the clinical efficacy and survival benefits of patients, alleviate and control the patient's condition, slow down the progression of the disease, and prolong the patient's progression-free survival and overall survival. The specific results are as follows:

For relapsed or refractory Hodgkin's lymphoma, a total of 8 evaluable patients were included, of whom 5 patients achieved PR and 3 patients achieved SD, with an ORR of 62.5% and a DCR of 100%;

For relapsed or refractory primary mediastinal large B-cell lymphoma, a total of 2 patients were evaluable, both of whom achieved PR, with an ORR of 100% and a DCR of 100%.

8. Exemplary Results

Patient 1

1) Diagnosis: Hodgkin's lymphoma

2) Previous treatment: AVD regimen (doxorubicin, vinblastine, dacarbazine) combined with velocillin, ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine), anti-PD-1 monoclonal antibody, AVD regimen, GVD regimen (gemcitabine, vinorelbine, liposomal doxorubicin), sintilimab combined with decitabine, etc.;

3) Treatment regimen: 10 mg/kg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 2

1) Diagnosis: Hodgkin's lymphoma

2) Previous treatment: ABVD regimen, radiotherapy, etc.;

3) Treatment regimen: 600 mg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 3

1) Diagnosis: Hodgkin's lymphoma

2) Previous treatment: ABVD regimen, AVD regimen combined with tislelizumab, tislelizumab, etc.;

3) Treatment regimen: 600 mg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 4

1) Diagnosis: Hodgkin's lymphoma

2) Previous treatment: ABVD regimen, ICE regimen (ifosfamide, carboplatin, etoposide), autologous stem cell transplantation, radiotherapy, anti-PD-L1 monoclonal antibody, IE regimen (ifosfamide, etoposide) combined with sintilimab, sintilimab, etc.;

3) Treatment regimen: 600 mg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 5

1) Diagnosis: Hodgkin's lymphoma

2) Previous treatment: ABVD regimen, GVD regimen, GVD regimen combined with anti-PD-1 antibody, anti-PD-1 antibody, anti-PD-1/CD47 dual antibody, etc.;

3) Treatment regimen: 600 mg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 6

1) Diagnosis: Primary mediastinal large B-cell lymphoma

2) Previous treatment: R-CDOP regimen (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone), GVD regimen combined with carrelizumab, ICE regimen combined with brentuximab, etc.;

3) Treatment regimen: 5 mg/kg anti-LAG-3 antibody + 200 mg penicillin;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Patient 7

1) Diagnosis: Primary mediastinal large B-cell lymphoma

2) Previous treatment: R-CDOP regimen, R-CHP regimen (rituximab, cyclophosphamide, doxorubicin, prednisone) combined with brentuximab, ICE regimen combined with anti-PD-1 monoclonal antibody, anti-PD-1 monoclonal antibody, IE regimen combined with anti-PD-1 monoclonal antibody, etc.;

3) Treatment regimen: 600 mg anti-LAG-3 antibody + 200 mg penampalimab;

4) Treatment effect and evaluation: According to the efficacy evaluation criteria, the best treatment effect for patients so far is PR (partial remission).

Claims (13)

1. A pharmaceutical combination comprising an anti-LAG-3 antibody or antigen-binding fragment thereof and an anti-PD-1 antibody or antigen-binding fragment thereof, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof 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; or (b)

HCDR1 comprising the amino acid sequence shown in SEQ ID No. 21, HCDR2 comprising the amino acid sequence shown in SEQ ID No. 22, HCDR3 comprising the amino acid sequence shown in SEQ ID No. 23, LCDR1 comprising the amino acid sequence shown in SEQ ID No. 24, LCDR2 comprising the amino acid sequence shown in SEQ ID No. 25, and LCDR3 comprising the amino acid sequence shown in SEQ ID No. 26;

the anti-PD-1 antibody or antigen-binding fragment thereof comprises:

An HCDR1 comprising the amino acid sequence shown in SEQ ID NO. 11, an HCDR2 comprising the amino acid sequence shown in SEQ ID NO. 12, an HCDR3 comprising the amino acid sequence shown in SEQ ID NO. 13, an LCDR1 comprising the amino acid sequence shown in SEQ ID NO. 14, an LCDR2 comprising the amino acid sequence shown in SEQ ID NO. 15, and an LCDR3 comprising the amino acid sequence shown in SEQ ID NO. 16.

2. The pharmaceutical combination of claim 1, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises:

A heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 7, and a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 8; or (b)

A heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO.27, and a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 28.

3. The pharmaceutical combination of claim 1 or 2, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises:

A heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO. 9, and a light chain having an amino acid sequence at least 90% identical to the amino acid sequence shown in SEQ ID NO. 10; or (b)

A heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 29, and a light chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 30.

4. The pharmaceutical combination of any one of claims 1-3, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 17, and a light chain variable region having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 18.

5. The pharmaceutical combination of any one of claims 1-4, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 19, and a light chain having an amino acid sequence at least 90% identical to the amino acid sequence set forth in SEQ ID NO. 20.

6. The pharmaceutical combination of any one of claims 1-5, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is formulated as a formulation for parenteral administration; preferably, the anti-LAG-3 antibody or antigen-binding fragment thereof is formulated as a formulation for intravenous, intramuscular, or subcutaneous administration; and/or

The anti-PD-1 antibody or antigen-binding fragment thereof is formulated as a formulation for parenteral administration; preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is formulated for intravenous, intramuscular, or subcutaneous administration.

7. The pharmaceutical combination of any one of claims 1-6, wherein the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 60-1200mg, 100-1000mg, 100-800mg, or 160-600mg; preferably, the unit dose of the anti-LAG-3 antibody or antigen-binding fragment thereof is 160mg, 200mg, 300mg and/or 600mg; and/or

The unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 10-500mg, 50-200mg, or 100-200mg;

Preferably, the unit dose of the anti-PD-1 antibody or antigen-binding fragment thereof is 100mg and/or 200mg.

8. Use of a pharmaceutical combination according to any one of claims 1-7 for the manufacture of a medicament for the treatment of a tumor.

9. The use of claim 8, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof and the anti-PD-1 antibody or antigen-binding fragment thereof are administered sequentially or alternately.

10. The use of claim 8 or 9, wherein the tumor is a lymphoma, optionally the lymphoma is hodgkin's lymphoma or non-hodgkin's lymphoma, optionally the non-hodgkin's lymphoma is primary mediastinal large B-cell lymphoma.

11. The use according to any one of claims 8-10, wherein the lymphoma is refractory, metastatic and/or recurrent lymphoma.

12. The use of any one of claims 8-11, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; alternatively, the anti-LAG-3 antibody or antigen-binding fragment thereof is administered at a dose of 80-1800mg, 120-1200mg, 140-1000mg, or 160-800mg per time.

13. The use of any one of claims 8-12, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; alternatively, the anti-PD-1 antibody or antigen-binding fragment thereof is administered at a dose of 10-800mg, 50-500mg, or 100-200mg per time.