PD-1 / il-2r bispecific antibody fusion protein, and use and usage method thereof

Abstract

The present invention relates to a PD-1 / IL-2R bispecific antibody fusion protein for treating tumors (such as solid tumors or hematologic tumors), or a pharmaceutical composition or pharmaceutical combination containing same, and a use and usage method thereof.

Description

PD-1 / IL-2R bispecific antibody fusion protein and its uses and methods of use Technical Field

[0001] The present invention relates to the field of medicine. Specifically, the present invention relates to a PD-1 / IL-2R bispecific antibody fusion protein for treating tumors (e.g., solid tumors or hematological tumors), or a pharmaceutical composition or drug combination comprising the same, as well as their uses and methods of use. Background Art

[0002] Malignant tumors pose a major threat to human health and well-being. It is estimated that nearly 10 million people died from cancer worldwide in 2020. Effective drug treatments can help patients achieve longer survival and improved quality of life. Currently available drug treatments include chemotherapy drugs, targeted therapies, and immunotherapies. Furthermore, genetic recombination technology has led to a booming development of genetically engineered protein drugs, including cytokines and therapeutic humanized monoclonal antibodies.

[0003] However, due to the lack of fundamental metabolic differences between tumor cells and normal cells, anti-tumor drugs cannot completely avoid damage to normal tissues. Moreover, although immunotherapy (IO) has achieved some benefits in the treatment of some tumors, the clinical needs for tumors resistant to immunotherapy and cold tumors are still urgently needed to be addressed. For a specific anti-tumor drug, it is necessary to carefully design and determine the dosage regimen to exert the expected efficacy and have acceptable side effects. Inappropriate dosage regimens (including route of administration, dosage level and frequency of administration, etc.) will affect clinical efficacy. For example, excessively high doses may even lead to unacceptable side effects, reducing patient compliance and quality of life. On the other hand, toxic side effects also limit the application of second-line treatment for tumors. Patients who have experienced side effects of anti-tumor drugs are usually more difficult to tolerate second-line treatment for tumors, especially in the case of superimposed toxicity.

[0004] Therefore, the optimization of the dosing regimen is particularly critical for anti-tumor drugs. On the one hand, anti-tumor drugs should be considered based on the upper limit of safety. On the other hand, they should achieve the killing of tumor cells as much as possible under conditions that normal cells can tolerate, obtain good clinical benefits and provide a longer survival period, while improving the quality of life and increasing patient compliance. In particular, for a specific anti-tumor drug, it is necessary to comprehensively consider various influencing factors and carefully design and determine the dosing regimen. There is still an unmet need in this field to provide safe and effective anti-tumor drug treatments.

[0005] In addition, the biological behavior of most tumors is not dominated by a single signal transduction pathway, but multiple signal transduction pathways work together, which results in limited therapeutic effects of most anticancer drugs. In addition, anticancer drugs are often accompanied by significant adverse reactions. Therefore, the combination of drugs with different mechanisms of action to enhance anticancer effects and / or reduce side effects is one of the hot spots in anticancer drug research and development. For example, pembrolizumab is approved by the U.S. Food and Drug Administration (FDA) for use in combination with chemotherapy agents, such as in combination with pemetrexed and platinum chemotherapy drugs or in combination with carboplatin and paclitaxel as first-line treatment for metastatic non-squamous non-small cell lung cancer, in combination with platinum chemotherapy drugs and fluorouracil as first-line treatment for metastatic head and neck squamous cell carcinoma or unresectable recurrent head and neck squamous cell carcinoma, and in combination with lenvatinib for the treatment of advanced endometrial cancer. Palbociclib is FDA-approved for the treatment of hormone receptor (HR)-positive, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in postmenopausal women in combination with an aromatase inhibitor or fulvestrant. Bevacizumab is approved by the National Medical Products Administration (NMPA) for the treatment of metastatic colorectal cancer in combination with fluorouracil and for the treatment of unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer in combination with platinum chemotherapy.

[0006] While there is a demand for combination drug regimens and products targeting different signaling pathways, given the complexity of tumorigenesis and the unpredictable nature of drug interactions, combining anticancer drugs with different mechanisms of action does not necessarily produce beneficial effects. Therefore, discovering effective anticancer combination drug regimens and products remains a major challenge in the pharmaceutical field.

[0007] Therefore, the present invention aims to provide a PD-1 / IL-2R bispecific antibody fusion protein or a pharmaceutical composition or drug combination comprising the same, as well as their uses or methods, that can effectively treat tumors such as solid tumors or hematological tumors, thereby providing patients with more treatment options and meeting clinical needs. Summary of the Invention

[0008] Summary of the Invention

[0009] The present inventors unexpectedly discovered that by administering the PD-1 / IL-2R bispecific antibody fusion protein of the present invention, particularly according to the dosing regimen of the present invention, encouraging therapeutic effects were obtained in patients with tumors (including solid tumors and hematological tumors), and the protein was well tolerated, providing longer survival and / or improved quality of life, with an acceptable and controllable safety profile.

[0010] The present inventors also unexpectedly found that administering the PD-1 / IL-2R bispecific antibody fusion protein according to the dosing regimen of the present invention can produce beneficial effects in treating tumors resistant to immunotherapy (IO) and cold tumors, and the safety profile is acceptable and controllable.

[0011] The present inventors have also surprisingly discovered that a drug combination comprising the PD-1 / IL-2R bispecific antibody fusion protein of the present invention is effective in treating tumors such as cancer, particularly advanced cancer. Cancers that can be treated with the drug combination of the present invention include, for example, intestinal cancer (including rectal cancer, colon cancer, and colorectal cancer), melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), hepatocellular carcinoma, lymphoma, renal cell carcinoma, esophageal squamous cell carcinoma, gastric and gastroesophageal junction adenocarcinoma, pancreatic cancer, breast cancer, ovarian cancer, and the like.

[0012] Therefore, in a first aspect, provided is a use of the PD-1 / IL-2R bispecific antibody fusion protein of the present invention for treating tumors such as solid tumors or hematological tumors.

[0013] In a second aspect, a method of treating a tumor, such as a solid tumor or a blood tumor, in an individual is provided, the method comprising administering the PD-1 / IL-2R bispecific antibody fusion protein of the present invention to the individual in need thereof.

[0014] In a third aspect, a PD-1 / IL-2R bispecific antibody fusion protein of the present invention is provided for use in treating tumors such as solid tumors or hematological tumors.

[0015] In a fourth aspect, provided is a use of the PD-1 / IL-2R bispecific antibody fusion protein of the present invention in the preparation of a medicament for treating tumors such as solid tumors or hematological tumors.

[0016] In a fifth aspect, a pharmaceutical composition is provided, comprising the PD-1 / IL-2R bispecific antibody fusion protein of the present invention and one or more pharmaceutically acceptable excipients.

[0017] In a sixth aspect, a kit is provided, comprising the PD-1 / IL-2R bispecific antibody fusion protein of the present invention and instructions for using the fusion protein to treat tumors such as solid tumors or hematological tumors.

[0018] In another aspect, a pharmaceutical combination for treating tumors such as solid tumors or hematological tumors is provided, wherein the pharmaceutical combination comprises the PD-1 / IL-2R bispecific antibody fusion protein of the present invention as a first active ingredient and a second active ingredient.

[0019] In another aspect, there is provided use of the pharmaceutical combination of the present invention in the preparation of a medicament.

[0020] In another aspect, a method of treating a tumor (including a solid tumor or a hematological tumor), such as cancer, by administering the pharmaceutical combination of the present invention is provided.

[0021] In another aspect, a single-dose administration unit is provided, which comprises a single therapeutically effective amount of the PD-1 / IL-2R bispecific antibody fusion protein of the present invention.

[0022] In other aspects, the present invention also provides a drug combination for use in treating tumors (including solid tumors or hematological tumors) such as cancer. In another aspect, a kit comprising the drug combination of the present invention and instructions for using the drug combination for treating tumors such as solid tumors or hematological tumors is also provided. Various variations of the aspects of the present invention are also included in the present invention, as long as they do not deviate from the purpose of the present invention.

[0023] Detailed Description of the Invention

[0024] Interleukin-2 (IL-2) is one of the earliest approved therapies for anti-tumor treatment. However, its safety is poor and may cause a variety of serious toxic reactions including vascular leak syndrome (VLS), pulmonary edema, hypotension and cardiotoxicity. In addition, due to the effect of IL-2 on T regs It has effects on both target and effector T cells. How to guide them to exert the desired immune regulatory effect has also brought great challenges to the anti-tumor application of IL-2 therapy. In recent years, the breakthrough progress of immune checkpoint inhibitors (ICI) therapy represented by CTLA-4 and PD-1 has brought new development ideas for IL-2. Compared with traditional chemotherapy and radiotherapy, ICI therapy can provide patients with more lasting clinical benefits. However, most patients show primary or secondary resistance to ICI after treatment. It is inferred that this is to some extent due to the exhaustion of tumor antigen-specific T cells, which is characterized by multi-checkpoint expression and impaired cytokine secretion and activity. IL-2 acts as an inhibitor of tumor-specific CD8 + IL-2 is an important cytokine for T cells and is complementary to ICI in terms of mechanism. Multiple studies have confirmed that IL-2 can reverse T cell exhaustion in preclinical models.

[0025] The PD-1 / IL-2R bispecific antibody fusion protein of the present invention can simultaneously block the PD-1 / PD-L1 pathway and activate the IL-2 pathway, thereby achieving simultaneous PD-1 blockade and IL-2 delivery, with great potential to address the clinical needs of immunotherapy (IO) resistance and cold tumors. The fusion protein of the present invention has demonstrated good anti-tumor activity in multiple tumor-bearing pharmacological models, including a PD-1 resistance and metastasis model (B16F10).

[0026] The present inventors, through carefully designed Phase Ia, Phase Ib, and Phase II clinical trials, comprehensively considered preclinical efficacy results as well as pharmacokinetics, pharmacodynamics, immunogenicity, and toxicology in human subjects, and determined the uses and methods of the PD-1 / IL-2R bispecific antibody fusion protein of the present invention for treating tumors, such as solid tumors or hematological tumors, and determined suitable optimized dosing regimens (including combination administration).

[0027] Specifically, the present invention provides the following embodiments:

[0028] Embodiment 1. Use of a PD-1 / IL-2R bispecific antibody fusion protein for treating solid tumors or hematological tumors, wherein the PD-1 / IL-2R bispecific antibody fusion protein comprises: (a) a first monomer comprising an IL-2 mutant protein fused to an Fc fragment, optionally via or without a linker, wherein the IL-2 mutant protein has T3A+N88R+S130R mutations and IL15B'C' loop region AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3); and (b) a second monomer comprising one heavy chain and one light chain of an antibody that specifically binds to PD-1.

[0029] Embodiment 2. The use according to embodiment 1, wherein the IL-2 mutant protein comprises or consists of the following amino acid sequence:

[0030] The amino acid sequence of SEQ ID NO: 4; or

[0031] An amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4 and has T3A+N88R+S130R mutations and an amino acid sequence of IL15B'C' loop AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence set forth in SEQ ID NO: 3).

[0032] Embodiment 3. The use according to embodiment 1, wherein the linker comprises (GGGGS)n, wherein n is an integer of at least 1, such as 1, 2, 3 or 4, such as SEQ ID NO: 5.

[0033] Embodiment 4. The use according to any one of Embodiments 1 to 3, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises an Fc fragment, and the Fc fragment and the Fc fragment fused to the IL-2 mutant protein are Fc fragments of IgG1, IgG2, IgG3 or IgG4, for example, human IgG1 Fc.

[0034] Embodiment 5. The use according to embodiment 4, wherein the Fc fragment has a mutation that binds to an Fcγ receptor, such as L234A / L235A mutation or L234A / L235E / G237A.

[0035] Embodiment 6. The use according to embodiment 4 or 5, wherein the Fc fragment of the first monomer comprises a Knob mutation, and the antibody heavy chain Fc fragment of the second monomer comprises a Hole mutation, or the Fc fragment of the first monomer comprises a Hole mutation, and the antibody heavy chain Fc fragment of the second monomer comprises a Knob mutation, for example, the Hole mutation is Y349C, T366S, L368A, Y407V mutation, and / or the Knob mutation is T366W and S354C mutation.

[0036] Embodiment 7. The use according to embodiment 6, wherein

[0037] The Fc fragment of the first monomer comprises or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:6, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO:6;

[0038] or

[0039] The antibody heavy chain Fc fragment of the second monomer comprises or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO: 12, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 12.

[0040] Embodiment 8. The use according to any one of embodiments 1 to 6, wherein the first monomer comprises:

[0041] The amino acid sequence shown in SEQ ID NO: 7; or

[0042] An amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 7 and, in an IL-2 mutant protein, comprises T3A+N88R+S130R mutations and IL15B'C' loop region AGDASIH, and / or comprises S354C / T366W in the Fc fragment, and optionally L234A / L235A mutations relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3).

[0043] Embodiment 9. The use according to any one of Embodiments 1 to 7, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises HCDR1, HCDR2, and HCDR3, and the light chain of the antibody that specifically binds to PD-1 comprises LCDR1, LCDR2, and LCDR3, wherein the amino acid sequences of the HCDR1, HCDR2, and HCDR3 are as follows: SEQ ID NOs: 9, 10, and 11, respectively, and the amino acid sequences of the LCDR1, LCDR2, and LCDR3 are as follows: SEQ ID NOs: 16, 17, and 18, respectively.

[0044] Embodiment 10. The use according to embodiment 9, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises a heavy chain variable region VH, and the light chain of the antibody that specifically binds to PD-1 comprises a light chain variable region VL, wherein the VH comprises or consists of an amino acid sequence as shown in SEQ ID NO: 8, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical thereto, and the VL comprises or consists of an amino acid sequence as shown in SEQ ID NO: 15, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical thereto.

[0045] Embodiment 11. The use according to embodiment 9 or 10, wherein the heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence comprising a Hole mutation that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 14; and the light chain comprises or consists of the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 20.

[0046] Embodiment 12. The use according to embodiment 1, wherein

[0047] The first monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 7;

[0048] The heavy chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 14;

[0049] The light chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 20.

[0050] Embodiment 13. The use according to any of the preceding embodiments, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen: a dosage level of 0.2 μg / kg to 3 mg / kg body weight, for example, 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight or a range consisting of any two thereof.

[0051] Embodiment 14. The use according to any one of the preceding embodiments, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen: once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W) at a dose of 0.2 μg / kg to 3 mg / kg body weight, for example 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2

[00145] In some embodiments, the fusion protein is administered at a dosage of 30 μg / kg, 0.1-3 mg / kg, 0.1-2 mg / kg, 0.6-3 mg / kg, 0.6-2 mg / kg, 1-3 mg / kg or 1-2 mg / kg body weight; wherein the fusion protein is administered for one or more treatment cycles of three weeks for weekly or three-weekly administration and four weeks for biweekly administration.

[0052] Embodiment 15. The use according to any one of the preceding embodiments, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen:

[0053] 1-3 mg / kg body weight or 1-2 mg / kg body weight administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles of three weeks for weekly or three-week administration and four weeks for biweekly administration;

[0054] Preferably, 0.3, 0.6, 1 or 2 mg / kg body weight is administered once every two weeks (Q2W), wherein the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is four weeks; or

[0055] 0.6, 1, 1.5, 2 or 3 mg / kg body weight is administered once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is three weeks.

[0056] Embodiment 16. The use according to any of the preceding embodiments, wherein when the single dose is ≥0.6 mg / kg body weight, a dose of the fusion protein of ≤200 μg / kg body weight is administered by injection, preferably intravenous injection, as an initial dose 7±1 days before the first single dose.

[0057] Embodiment 17. The use according to embodiment 16, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 0.2-200 μg / kg body weight on day 1, and a normal dose of 0.6-3 mg / kg body weight once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W) starting from day 8±1.

[0058] Embodiment 18. The use according to embodiments 16-17, wherein the initial dose is 2-200 μg / kg body weight, preferably 30-200 μg / kg body weight, more preferably 30-150 μg / kg body weight, most preferably 30-100 μg / kg body weight.

[0059] Embodiment 19. The use according to embodiment 17 or 18, wherein the normal dose is a dose of 0.6-3 mg / kg, or 0.6-2 mg / kg, or 1-3 mg / kg, or 1-2 mg / kg of body weight administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), and wherein the normal dose of the fusion protein is administered for one or more treatment cycles of three weeks for weekly or three-week administration and four weeks for biweekly administration.

[0060] Embodiment 20. The use according to any one of embodiments 17 to 19, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 30-100 μg / kg body weight on day 1, and a normal dose of 0.6-3 mg / kg, such as 0.6-2 mg / kg, such as 1-3 mg / kg, such as 1-2 mg / kg body weight once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is three weeks for weekly or three-weekly administration and four weeks for biweekly administration.

[0061] Embodiment 21. The use according to any one of embodiments 17-20, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen:

[0062] An initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, or 2 mg / kg body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is four weeks; or

[0063] An initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, 1.5, 2 or 3 mg / kg body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is three weeks.

[0064] Embodiment 22. Use according to any one of embodiments 14-21, wherein, when there is more than one treatment cycle, the treatment cycles may be continuous or intermittent.

[0065] Embodiment 23. The use according to any one of the preceding embodiments, wherein the solid tumor or blood tumor is selected from intestinal cancer (including rectal cancer, colon cancer, colorectal cancer), melanoma, lung cancer (such as non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer), breast cancer (such as triple-negative breast cancer), pancreatic cancer, bile duct cancer, ovarian cancer, cervical cancer, uterine cancer, head and neck cancer (such as head and neck squamous cell carcinoma), liver cancer (such as hepatocellular carcinoma), kidney cancer (such as renal cell carcinoma), gastric cancer, lymphoma, leukemia or multiple myeloma;

[0066] Preferably, the solid tumor or blood tumor is selected from colorectal cancer, melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), breast cancer, pancreatic cancer, bile duct cancer, ovarian cancer, cervical cancer, head and neck cancer (such as head and neck squamous cell carcinoma), hepatocellular carcinoma, renal cell carcinoma and lymphoma;

[0067] More preferably, the solid tumor or blood tumor is selected from colorectal cancer, melanoma and non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer).

[0068] Embodiment 24. The use according to any one of the preceding embodiments, wherein the solid or hematological tumor is advanced, recurrent, metastatic or unresectable, for which standard therapy has failed or is intolerant to standard therapy.

[0069] Embodiment 25. The use according to any one of the preceding embodiments, wherein the solid tumor or hematological tumor is selected from:

[0070] Melanoma, such as cutaneous melanoma, acral melanoma, mucosal melanoma, or melanoma of unknown primary, particularly those that have failed or are intolerant to standard therapy, are advanced, recurrent, metastatic, or unresectable; such as unresectable locally advanced or metastatic melanoma that has progressed or recurred after prior treatment with an immune checkpoint inhibitor, or unresectable locally advanced or metastatic melanoma that has not been treated with a systemic immune checkpoint inhibitor;

[0071] Colorectal cancer, preferably advanced, recurrent, metastatic or unresectable colorectal cancer that has failed or is intolerant to standard treatment, especially colorectal cancer with normal mismatch repair genes (pMMR) and / or microsatellite stable (MSS); and

[0072] Non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer, especially advanced, recurrent, metastatic or unresectable non-small cell lung cancer with no known driver gene mutations and failure or intolerance to standard treatment.

[0073] Embodiment 26. A method for treating a solid tumor or a hematological tumor in an individual, the method comprising administering to the individual in need thereof an effective amount of a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of embodiments 1-12.

[0074] Embodiment 27. The method according to embodiment 26, wherein the PD-1 / IL-2R bispecific antibody fusion protein is administered by injection, preferably intravenous injection, according to the dosing regimen as defined in any one of embodiments 13-22.

[0075] Embodiment 28. The method according to embodiment 26, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen:

[0076] An initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, or 2 mg / kg body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is four weeks; or

[0077] An initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, 1.5, 2 or 3 mg / kg body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is three weeks.

[0078] Embodiment 29. The method according to any one of embodiments 26-28, wherein the solid tumor or hematological tumor is as defined in any one of embodiments 23-25.

[0079] Embodiment 30. A pharmaceutical composition for treating solid tumors or hematological tumors, comprising the PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of Embodiments 1-12, wherein the pharmaceutical composition is administered by injection, preferably intravenous injection, according to the dosing regimen as defined in any one of Embodiments 13-22. Preferably, the pharmaceutical composition is used to treat solid tumors or hematological tumors as defined in any one of Embodiments 23-25.

[0080] The present invention also provides the following embodiments:

[0081] Embodiment 31. A pharmaceutical combination for treating solid tumors or blood tumors, comprising:

[0082] (i) a first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein, comprising: (a) a first monomer comprising an IL-2 mutant protein fused to an Fc fragment, optionally via or without a linker, wherein the IL-2 mutant protein has T3A+N88R+S130R mutations and IL15B'C' loop region AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3); and (b) a second monomer comprising one heavy chain and one light chain of an antibody that specifically binds to PD-1; and

[0083] (ii) a second active ingredient, which is bevacizumab.

[0084] Embodiment 32. The pharmaceutical combination according to embodiment 31, wherein the IL-2 mutant protein comprises or consists of the following amino acid sequence:

[0085] The amino acid sequence of SEQ ID NO: 4; or

[0086] An amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4 and has T3A+N88R+S130R mutations and an amino acid sequence of IL15B'C' loop AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence set forth in SEQ ID NO: 3).

[0087] Embodiment 33. The drug combination according to embodiment 31, wherein the linker comprises (GGGGS)n, wherein n is an integer of at least 1, such as 1, 2, 3 or 4, such as SEQ ID NO: 5.

[0088] Embodiment 34. The drug combination according to any one of Embodiments 31 to 33, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises an Fc fragment, and the Fc fragment and the Fc fragment fused to the IL-2 mutant protein are Fc fragments of IgG1, IgG2, IgG3 or IgG4, for example, human IgG1 Fc.

[0089] Embodiment 35. The pharmaceutical combination according to embodiment 34, wherein the Fc fragment has a mutation that binds to an Fcγ receptor, such as L234A / L235A mutation or L234A / L235E / G237A.

[0090] Embodiment 36. The drug combination according to embodiment 34 or 35, wherein the Fc fragment of the first monomer comprises a Knob mutation, and the antibody heavy chain Fc fragment of the second monomer comprises a Hole mutation, or the Fc fragment of the first monomer comprises a Hole mutation, and the antibody heavy chain Fc fragment of the second monomer comprises a Knob mutation, for example, the hole mutation is Y349C, T366S, L368A, Y407V mutation, and / or the Knob mutation is T366W and S354C mutation.

[0091] Embodiment 37. The pharmaceutical combination according to embodiment 36, wherein

[0092] The Fc fragment of the first monomer comprises or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:6, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO:6;

[0093] or

[0094] The antibody heavy chain Fc fragment of the second monomer comprises or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO: 12, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 12.

[0095] Embodiment 38. The pharmaceutical combination according to any one of embodiments 31-36, wherein the first monomer comprises:

[0096] The amino acid sequence shown in SEQ ID NO: 7; or

[0097] An amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 7 and, in an IL-2 mutant protein, comprises T3A+N88R+S130R mutations and IL15B'C' loop region AGDASIH, and / or comprises S354C / T366W in the Fc fragment, and optionally L234A / L235A mutations relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3).

[0098] Embodiment 39. The drug combination according to any one of Embodiments 31-37, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises HCDR1, HCDR2 and HCDR3, and the light chain of the antibody that specifically binds to PD-1 comprises LCDR1, LCDR2 and LCDR3, wherein the amino acid sequences of the HCDR1, HCDR2 and HCDR3 are as follows: SEQ ID NO: 9, 10 and 11, respectively, and the amino acid sequences of the LCDR1, LCDR2 and LCDR3 are as follows: SEQ ID NO: 16, 17 and 18, respectively.

[0099] Embodiment 40. The drug combination according to embodiment 39, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises a heavy chain variable region, VH, and the light chain of the antibody that specifically binds to PD-1 comprises a light chain variable region, VL, wherein the VH comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 8, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical thereto, and the VL comprises or consists of an amino acid sequence as set forth in SEQ ID NO: 15, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical thereto.

[0100] Embodiment 41. The drug combination according to embodiment 39 or 40, wherein the heavy chain comprises or consists of the amino acid sequence shown in SEQ ID NO: 14, or an amino acid sequence comprising a Hole mutation that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 14; and the light chain comprises or consists of the amino acid sequence shown in SEQ ID NO: 20, or an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 20.

[0101] Embodiment 42. The pharmaceutical combination according to embodiment 31, wherein

[0102] The first monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 7;

[0103] The heavy chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 14;

[0104] The light chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 20.

[0105] Embodiment 43. The pharmaceutical combination according to any one of embodiments 31-42, wherein the first active ingredient is for administration by injection, such as intravenous infusion; and the second active ingredient is for administration by injection, such as intravenous infusion.

[0106] Embodiment 44. The pharmaceutical combination according to any one of embodiments 31-42, wherein the first active ingredient is administered by injection, preferably intravenous injection, according to the dosing regimen defined in any one of embodiments 13-22; and the second active ingredient is administered by intravenous infusion at a dose of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle, for one or more treatment cycles.

[0107] Embodiment 45. The pharmaceutical combination according to embodiment 44,

[0108] The first active ingredient is used for injection, preferably intravenous administration, as follows: a dose of 0.6-3 mg / kg, for example 0.6-2 mg / kg, for example 1-3 mg / kg, for example 1-2 mg / kg body weight once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W), for one or more treatment cycles, one treatment cycle is three weeks; or an initial dose of 30-100 μg / kg body weight on day 1, and a normal dose of 0.6-3 mg / kg, for example 0.6-2 mg / kg, for example 1-3 mg / kg, for example 1-2 mg / kg body weight once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, one treatment cycle is three weeks; and

[0109] The second active ingredient is administered by intravenous infusion at a dose of 5-15 mg / kg body weight (e.g., 5, 7.5, 10, 12.5, 15 mg / kg body weight or a range consisting of any two thereof), administered once every two weeks, with every four weeks being a treatment cycle, or administered once every three weeks, with every three weeks being a treatment cycle, for one or more treatment cycles.

[0110] Embodiment 46. The pharmaceutical combination according to any one of embodiments 31-42, wherein

[0111] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0112] The second active ingredient is administered by intravenous infusion at a dosage of 5 mg / kg to 15 mg / kg body weight, administered once every two weeks, with four weeks as a treatment cycle, or administered once every three weeks, with three weeks as a treatment cycle.

[0113] Embodiment 47. A pharmaceutical combination according to any one of Embodiments 31-46, wherein the solid tumor or blood tumor is selected from intestinal cancer (including rectal cancer, colon cancer, colorectal cancer), melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), hepatocellular carcinoma, renal cell carcinoma, lymphoma or other advanced solid tumors.

[0114] Embodiment 48. The pharmaceutical combination according to embodiment 47, wherein the solid tumor is colorectal cancer, preferably advanced colorectal cancer, more preferably advanced colorectal cancer that has failed standard treatment;

[0115] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0116] The second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg to 15 mg / kg body weight, administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg to 10 mg / kg body weight (e.g., 5 mg / kg or 7.5 mg / kg body weight), administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle; in particular, 7.5 mg / kg, administered once every three weeks (Q3W).

[0117] Embodiment 49. The pharmaceutical combination according to embodiment 47, wherein the solid tumor is melanoma, preferably advanced melanoma, more preferably advanced melanoma that has not undergone immunotherapy or advanced melanoma that has failed previous immunotherapy;

[0118] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0119] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg or 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle.

[0120] Embodiment 50. The pharmaceutical combination according to embodiment 47, wherein the solid tumor is non-small cell lung cancer, such as squamous or non-squamous non-small cell lung cancer (preferably advanced non-squamous non-small cell lung cancer, more preferably advanced non-squamous non-small cell lung cancer that has failed or is intolerant to standard treatment), hepatocellular carcinoma (preferably advanced hepatocellular carcinoma, more preferably advanced hepatocellular carcinoma that has not been systemically treated), or renal cell carcinoma (preferably advanced renal cell carcinoma, more preferably advanced renal cell carcinoma that has failed or is intolerant to standard treatment);

[0121] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0122] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 10 mg / kg to 15 mg / kg body weight (for example, 10 mg / kg body weight, 12.5 mg / kg body weight or 15 mg / kg body weight), administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle.

[0123] Embodiment 51. The pharmaceutical combination according to embodiment 47, wherein the solid tumor is lymphoma or other solid tumors, preferably lymphoma or other advanced solid tumors that have failed or are intolerant to standard treatment;

[0124] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0125] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg or 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle.

[0126] Embodiment 52. A pharmaceutical combination for treating melanoma, comprising:

[0127] (i) a first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of Embodiments 1-12 or Embodiments 31-42; and

[0128] (ii) a second active ingredient, which is dacarbazine.

[0129] Embodiment 53. The pharmaceutical combination according to embodiment 52, wherein the first active ingredient is for administration by injection, such as intravenous infusion, for example, by injection, preferably intravenous injection according to the dosage regimen defined in any one of embodiments 13-22; and the second active ingredient is administered by injection, such as intravenous infusion, intravenous push injection, arterial infusion or arterial push injection.

[0130] Embodiment 54. The pharmaceutical combination according to embodiment 53, wherein

[0131] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0132] The second active ingredient, dacarbazine, is administered by intravenous or arterial infusion, and when administered by intravenous or arterial infusion, the dosage of dacarbazine is 2.5-6 mg / kg body weight or 200-400 mg / m 2 Body surface area, once daily for 5-10 consecutive days, followed by a break, with a treatment cycle of 3-6 weeks, or a dose of 650-1450 mg / m 2 body surface area, administered every 4-6 weeks, with each treatment cycle consisting of 4-6 weeks; when administered by intravenous or arterial bolus, the dose of dacarbazine is 200-400 mg / m 2 , administered once a day for 5 consecutive days, then stopped, with each 3-4 weeks as a treatment cycle.

[0133] Embodiment 55. The pharmaceutical combination according to any one of embodiments 52-54, wherein the melanoma is an advanced melanoma that has not been systemically treated; the second active ingredient dacarbazine is administered by intravenous infusion at a dose of 850 mg / m 2 body surface area, administered once every four weeks, with four weeks as a treatment cycle; or for intravenous infusion, the dosage is 650-1050 mg / m 2 Body surface area (e.g. 850 mg / m 2Body surface area), administered once every three weeks (one treatment cycle); or for intravenous injection, the dose is 200-300 mg / m 2 Body surface area (e.g. 250 mg / m 2 Body surface area), once a day for 5 consecutive days, then suspend the administration, and every four weeks is a treatment cycle; or for intravenous push administration, the dosage is 200-300mg / m 2 Body surface area (e.g. 250 mg / m 2 The drug was administered once a day for 5 consecutive days, and then the drug was suspended. Every three weeks was a treatment cycle.

[0134] Embodiment 56. A pharmaceutical combination for treating non-small cell lung cancer, comprising:

[0135] (i) a first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of Embodiments 1-12 or Embodiments 31-42; and

[0136] (ii) a second active ingredient, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0137] in

[0138] W is O; Z is O; G is CR; a is 0; c is 1; b is 1; R is H or C 1-6 alkyl;

[0139] yes

[0140] R1, R2, R3 are each independently selected from H, halogen and C 1-6 alkoxy;

[0141] R4 and R5 are each independently selected from H or C 1-6 alkyl;

[0142] R6 is H.

[0143] Embodiment 57. The pharmaceutical combination according to embodiment 56, wherein the second active ingredient is anlotinib or a pharmaceutically acceptable salt thereof, such as anlotinib dihydrochloride.

[0144] Embodiment 58. The pharmaceutical combination according to embodiment 55 or 57, wherein the first active ingredient is for administration by injection, such as intravenous infusion, for example, by injection, preferably intravenous injection according to the dosage regimen defined in any one of embodiments 13-22; and the second active ingredient is for oral administration.

[0145] Embodiment 59. The pharmaceutical combination according to embodiment 58, wherein

[0146] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0147] The second active ingredient is for oral administration, with a dosage of 8 mg to 12 mg, once a day, for 2 consecutive weeks, followed by 1 week of rest, with one treatment cycle consisting of three weeks.

[0148] Embodiment 60. The drug combination according to any one of Embodiments 56-59, wherein the non-small cell lung cancer is advanced non-small cell lung cancer, preferably advanced non-small cell lung cancer that has failed or is intolerant to standard treatment; the second active ingredient (e.g., anlotinib dihydrochloride) is for oral administration, with a dosage of 12 mg (when the second active ingredient is a pharmaceutically acceptable salt of anlotinib, such as dihydrochloride, calculated as anlotinib), once a day for 2 consecutive weeks, followed by 1 week of rest, and each three weeks as a treatment cycle.

[0149] Embodiment 61. The pharmaceutical combination according to any one of embodiments 31-60, comprising the first active ingredient and the second active ingredient as the only active ingredients.

[0150] Embodiment 62. The pharmaceutical combination according to any one of Embodiments 31 to 61, wherein the pharmaceutical combination is in the form of a kit or a pack, wherein the kit or pack comprises: a pharmaceutical composition comprising a first active ingredient; a pharmaceutical composition comprising a second active ingredient; and instructions for use, wherein the instructions for use describe methods for administering the two pharmaceutical compositions.

[0151] Embodiment 63. Use of the pharmaceutical combination of any one of Embodiments 31-61 in the preparation of a medicament.

[0152] Embodiment 64. A method for treating cancer, comprising administering the pharmaceutical combination of any one of embodiments 31-61, wherein the first active ingredient and the second active ingredient are administered simultaneously in a single pharmaceutical composition or administered simultaneously or separately in separate pharmaceutical compositions.

[0153] In various aspects or embodiments of the present disclosure, the PD-1 / IL-2R bispecific antibody fusion protein of the present invention comprises: (a) a first monomer comprising an IL-2 mutant protein fused to an Fc fragment, optionally via a linker or not; and (b) a second monomer comprising one heavy chain and one light chain of an antibody that specifically binds to PD-1.

[0154] In some embodiments, the IL-2 mutant protein comprises, relative to wild-type IL-2 (preferably human IL-2, more preferably IL-2 comprising the sequence of SEQ ID NO: 3): (i) N88D; N88R; N88R+S130R; F42A+N88R+S127E; F42A+N88R+S127E; or K35E+N88R+S127E; and (ii) the B'C' loop region is replaced with the IL15 B'C' loop region AGDASIH (SEQ ID NO: 25) or AQSKNFH (SEQ ID NO: 26); and optionally (iii) T3A.

[0155] In some embodiments, the IL-2 mutant protein has T3A+N88R+S130R mutations and IL15B'C' loop region substitution (i.e., the B'C' loop region sequence is replaced with AGDASIH (SEQ ID NO: 25)) relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3).

[0156] In some embodiments, the IL-2 mutant protein comprises or consists of the following amino acid sequence: the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-2 mutant protein comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 and comprises the T3A+N88R+S130R mutations and the IL15B 'C' loop region AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence set forth in SEQ ID NO: 3).

[0157] In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein comprises or consists of: (a) a first monomer comprising or consisting of an IL-2 mutant protein of the present invention fused to an Fc fragment, optionally fused via a linker or not; and (b) a second monomer comprising or consisting of an antibody or fragment thereof that specifically binds to PD-1, preferably, the fragment comprises or consists of one heavy chain and one light chain of the anti-PD-1 antibody.

[0158] In some embodiments, the molecular format of the PD-1 / IL-2R bispecific antibody fusion protein is shown in FIG1 .

[0159] In some embodiments, the heavy chain of the anti-PD-1 antibody comprises an Fc fragment.

[0160] In some embodiments, the linker can be selected from the following linker sequences: (GS)n, (GSGGS)n, (GGGGS)n, and (GGGS)n, wherein n is an integer of at least 1, such as 1, 2, 3 or 4. Preferably, the linker comprises (G4S)2, i.e., GGGGSGGGGS (SEQ ID NO: 5).

[0161] In some embodiments, the Fc fragment is an IgG1, IgG2, IgG3, or IgG4 Fc fragment. In some embodiments, the Fc fragment is a human IgG Fc, such as a human IgG1 Fc, a human IgG2 Fc, or a human IgG4 Fc. In some embodiments, the Fc fragment comprises or consists of the amino acid sequence of SEQ ID NO: 24, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity thereto.

[0162] In some embodiments, the Fc fragment has a mutation that reduces binding to Fcγ receptors, such as L234A / L235A mutations or L234A / L235E / G237A. In some embodiments, the Fc fragment comprises or consists of the amino acid sequence of SEQ ID NO: 23 or is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical thereto. In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 23 and has the L234A / L235A mutation.

[0163] In some embodiments, the Fc fragment may include a mutation that facilitates dimerization of the first monomer and the second monomer. Preferably, based on the Knob-in-Hole technology, corresponding Knob mutations and Hole mutations are introduced into the first monomer and the second monomer. In some embodiments, the Fc fragment of the first monomer includes a Knob mutation, and the antibody heavy chain Fc fragment of the second monomer includes a Hole mutation, or the Fc fragment of the first monomer includes a Hole mutation, and the antibody heavy chain Fc fragment of the second monomer includes a Knob mutation. In some embodiments, the Knob mutation includes T366W. In some embodiments, the hole mutation includes T366S, L368A and Y407V. In some embodiments, the Knob mutation and the Hole mutation in the first monomer and the second monomer further include a cysteine ​​mutation (for example, one monomer includes Y349C and the other monomer includes S354C), thereby forming a non-natural disulfide bond.

[0164] In some embodiments, in the PD-1 / IL-2R bispecific antibody fusion protein,

[0165] a) one Fc-region polypeptide comprises the mutation T366W and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or

[0166] b) one Fc-region polypeptide comprises the mutations T366W and Y349C and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and S354C, or

[0167] c) one Fc-region polypeptide comprises the mutations T366W and S354C and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C.

[0168] In some embodiments, an Fc region comprises or consists of the following sequence:

[0169] (i) the amino acid sequence shown in SEQ ID NO: 6, or

[0170] (ii) an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 6; or

[0171] (ii) an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 6 and comprises S354C / T366W;

[0172] Optionally, the Fc region further comprises L234A / L235A mutations.

[0173] In some embodiments, the further Fc region comprises or consists of the following sequence:

[0174] (i) the amino acid sequence shown in SEQ ID NO: 12, or

[0175] (ii) an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 12; or

[0176] (ii) an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 12 and comprises Y349C / T366S / L368A / Y407V;

[0177] Optionally, the Fc region further comprises L234A / L235A mutations.

[0178] In some embodiments, the IL-2 mutant protein fused to the Fc fragment comprises or consists of the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the IL-2 mutant protein fused to the Fc fragment comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the IL-2 mutant protein fused to the Fc fragment comprises an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, and comprises T3A+N88R+S130R mutations and IL15B'C' loop AGDASIH relative to wild-type IL-2 (e.g., the amino acid sequence shown in SEQ ID NO: 3) in the IL-2 mutant protein, and / or comprises S354C / T366W in the Fc fragment, and optionally L234A / L235A mutations.

[0179] In some embodiments, the second monomer comprises an antibody or antigen-binding fragment thereof that specifically binds to PD-1, such as an antibody fragment selected from the group consisting of Fab, Fab', Fab'-SH, Fv, single-chain antibody (e.g., scFv), (Fab')2, single-domain antibody such as VHH, dAb (domain antibody), or linear antibody or half antibody, as long as it can specifically bind to PD-1.

[0180] In some embodiments, the second monomer comprises or consists of a heavy chain and a light chain of an antibody that specifically binds to PD-1. In some embodiments, the heavy chain comprises the heavy chain variable region VH of an antibody that specifically binds to PD-1, and the light chain comprises the light chain variable region VL of an antibody that specifically binds to PD-1.

[0181] In some embodiments, the heavy chain variable region VH comprises the three complementarity determining regions HCDR1, HCDR2, and HCDR3 contained in VH as set forth in SEQ ID NO: 8. In some embodiments, the light chain variable region VL comprises the three complementarity determining regions LCDR1, LCDR2, and LCDR3 contained in VL as set forth in SEQ ID NO: 15. In some embodiments, the heavy chain variable region comprises the HCDR1, HCDR2, and HCDR3 of an antibody that specifically binds to PD-1, as set forth in the following amino acid sequences: SEQ ID NOs: 9, 10, and 11, respectively. In some embodiments, the light chain variable region comprises the LCDR1, LCDR2, and LCDR3 of the following amino acid sequences: SEQ ID NOs: 16, 17, and 18, respectively.

[0182] In some embodiments, the VH comprises or consists of the amino acid sequence of SEQ ID NO: 8, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto. In some embodiments, the VL comprises or consists of the amino acid sequence of SEQ ID NO: 15, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0183] In some embodiments, the second monomer comprises a heavy chain variable region VH and a light chain variable region VL of an antibody that specifically binds to PD-1, comprising the three complementarity determining regions HCDR1, HCDR2, and HCDR3 contained in VH as shown in SEQ ID NO: 8, and the three complementarity determining regions LCDR1, LCDR2, and LCDR3 contained in VL as shown in SEQ ID NO: 15.

[0184] In some embodiments, the second monomer comprises HCDR1, HCDR2, HCDR3 as shown in the following amino acid sequences: SEQ ID NOs: 9, 10, and 11, respectively, and LCDR1, LCDR2, and LCDR3 as shown in the following amino acid sequences: SEQ ID NOs: 16, 17, and 18, respectively, of an antibody that specifically binds to PD-1.

[0185] In some embodiments, the second monomer comprises the following VH and VL of an antibody that specifically binds to PD-1: a VH comprising, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, or consisting of said amino acid sequence, and a VL comprising, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto, of the amino acid sequence shown in SEQ ID NO: 15.

[0186] In some embodiments, the heavy chain comprises a heavy chain constant region. In some embodiments, the light chain comprises a light chain constant region. In some embodiments, the second monomer comprises a heavy chain constant region and / or a light chain constant region. In some embodiments, the heavy chain constant region HC is a heavy chain constant region of (human) IgG1, IgG2, IgG3 or IgG4, preferably a heavy chain constant region of human IgG1, for example, a heavy chain constant region of IgG1 with L234A & L235A (LALA) mutations. In some embodiments, a Knob into hole mutation is introduced into the heavy chain constant region, for example, a mutation of S354C and T366W is introduced to obtain an antibody heavy chain constant region comprising a Knob mutation, and / or a mutation of Y349C & T366S & L368A & Y407V is introduced to obtain an antibody heavy chain constant region comprising a Hole mutation. In some embodiments, the light chain constant region is a lambda or kappa light chain constant region.

[0187] In some embodiments, the heavy chain constant region comprises, or consists of, an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from SEQ ID NO: 21; or comprises, or consists of, an amino acid sequence selected from SEQ ID NO: 21. In some embodiments, the heavy chain constant region comprising a Hole mutation comprises, or consists of, an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from SEQ ID NO: 13; or comprises, or consists of, an amino acid sequence selected from SEQ ID NO: 13. In some embodiments, the light chain constant region comprises or consists of an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from SEQ ID NO: 19; or comprises or consists of an amino acid sequence selected from SEQ ID NO 19.

[0188] In some embodiments, the second monomer comprises a heavy chain and a light chain of an antibody that specifically binds to PD-1. In some embodiments, the heavy chain comprises, or consists of, a heavy chain variable region and a heavy chain constant region (e.g., a heavy chain constant region comprising a Hole mutation) of an antibody that specifically binds to PD-1. In some embodiments, the light chain comprises, or consists of, a light chain variable region and a light chain constant region of an antibody that specifically binds to PD-1.

[0189] In some embodiments, the second monomer comprises a heavy chain and a light chain of an antibody that specifically binds to PD-1, wherein the heavy chain comprises, or consists of, the amino acid sequence of SEQ ID NO: 14, or an amino acid sequence comprising a Hole mutation and having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto (optionally further comprising L234A / L235A mutations); and the light chain comprises, or consists of, the amino acid sequence of SEQ ID NO: 20, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity thereto.

[0190] In some embodiments of the present invention, the antibody or antigen-binding fragment thereof against PD-1 contained in the second monomer is the anti-PD-1 antibody or antigen-binding fragment thereof disclosed in WO2017024465A1. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises one or more CDRs (preferably 3 CDRs, i.e., HCDR1, HCDR2H, and HCDR3; or LCDR1, LCDR2, and LCDR3, more preferably 6 CDRs, i.e., HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3) of the anti-PD-1 antibody or antigen-binding fragment thereof disclosed in WO2017024465A1, or comprises the VH and / or VL of the anti-PD-1 antibody or antigen-binding fragment thereof disclosed in WO2017024465A1, or comprises the heavy chain and / or light chain of the antibody.

[0191] In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein of the present invention comprises:

[0192] (a) a first monomer comprising or consisting of an IL-2 mutein of the present invention fused to an Fc fragment via a linker; and

[0193] (b) a second monomer comprising or consisting of a heavy chain and a light chain of an anti-PD-1 antibody;

[0194] wherein the first monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 7;

[0195] The heavy chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 14;

[0196] The light chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO: 20.

[0197] In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein of the present invention is an immunoconjugate disclosed in WO2023 / 045977A1, in particular in the claims, and the entire content of the patent application (including term definitions) is incorporated herein in its entirety. The PD-1 / IL-2R bispecific antibody fusion protein of the present invention is preferably the immunoconjugates 3010, 2061, 2063, 2132, 2149, 2213, 2214, 2219 disclosed in WO2023 / 045977A1, and particularly preferably the immunoconjugate 2149 disclosed in WO2023 / 045977A1 ​​(also referred to herein as "PD-1 / IL-2R bispecific antibody fusion protein 2149" or "2149").

[0198] Fusion protein 2149 is a recombinant IgG1-Fc fusion protein bispecific molecule that targets PD-1 and IL-2 receptors. It consists of 1030 amino acids and is composed of the following:

[0199] (a) a first monomer consisting of an IL-2 mutein of the present invention fused to an Fc fragment via a linker; and

[0200] (b) a second monomer consisting of a heavy chain and a light chain of an anti-PD-1 antibody;

[0201] in

[0202] The first monomer consists of the amino acid sequence shown in SEQ ID NO:7;

[0203] The heavy chain of the second monomer consists of the amino acid sequence shown in SEQ ID NO: 14;

[0204] The light chain of the second monomer consists of the amino acid sequence shown in SEQ ID NO:20;

[0205] The heavy chain and light chain of the first monomer and the anti-PD-1 antibody are connected by 9 pairs of intrachain disulfide bonds and 4 pairs of interchain disulfide bonds, and a schematic diagram of their structure is shown in Figure 1.

[0206] In fusion protein 2149, the anti-PD-1 heavy chain is γ1 type, consisting of 450 amino acids, the anti-PD-1 light chain is κ type, consisting of 214 amino acids, and the IL2 chain is an Fc fusion protein, consisting of 366 amino acids. Fusion protein 2149 contains two N-glycosylation sites, one at asparagine position 300 of the anti-PD-1 heavy chain and the other at asparagine position 216 of the IL2 chain. The molecular formula of fusion protein 2149 is C 5006 H 7796 N 1334 O 1554 S 38(disulfide bonds are in oxidized state), the theoretical molecular weight is 115.4 kDa (G0F / G0F glycoform), and the theoretical extinction coefficient is 1.31 (mg / ml) -1 cm -1 .

[0207] Herein, the terms "PD-1 / IL-2R bispecific antibody fusion protein of the present invention" and "fusion protein of the present invention" are used interchangeably to refer to those defined herein.

[0208] Herein, when referring to a "fusion protein", unless otherwise specified, it also covers a pharmaceutical composition or pharmaceutical preparation comprising the fusion protein.

[0209] Therefore, when referring to the 2149 molecule, unless otherwise specified, it encompasses both the 2149 molecule itself and the pharmaceutical composition or pharmaceutical formulation containing the same.

[0210] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be administered by any suitable route, preferably by parenteral administration, such as injection. For example, the fusion protein of the present invention (e.g., 2149) can be administered by intravenous injection (e.g., intravenous infusion, intravenous push injection), intramuscular injection, intratumoral injection, etc. Preferably, the fusion protein of the present invention (e.g., 2149) is administered by intravenous injection.

[0211] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: the dosage level is 0.2 μg / kg to 3 mg / kg body weight, for example, 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight or a range consisting of any two thereof. For example, the fusion protein of the present invention (e.g., 2149) can be administered by injection, preferably intravenous injection, according to the following dosage regimen: a dosage level of 0.2 μg / kg to 3 mg / kg, 0.2 μg / kg to 2.5 mg / kg, 0.2 μg / kg to 2 mg / kg, 0.2 μg / kg to 1.5 mg / kg, 0.2 μg / kg to 1 mg / kg, 2 μg / kg to 3 mg / kg, 2 μg / kg to 2.5 mg / kg, 2 μg / kg to 2mg / kg, 2μg / kg to 1.5mg / kg, 2μg / kg to 1mg / kg, 10μg / kg to 3mg / kg, 10μg / kg to 2.5mg / kg, 10μg / kg to 2mg / kg, 10μg / kg to 1.5mg / kg, 10μg / kg to 1mg / kg, 30μg / kg to 3mg / kg, 30μg / kg to 2.5mg / kg, 30μg / kg to 2mg / kg, 30μg / kg to 1.5mg / kg, 30μg / kg to 1mg / kg, 0.1mg / kg to 3mg / kg, 0.1mg / kg to 2.5mg / kg, 0.1mg / kg to 2mg / kg, 0.1mg / kg to 1.5mg / kg, 0.1mg / kg to 1mg / kg, 0.3mg / kg to 3mg / kg, 0.3mg / kg to 2.5mg / kg, 0.3mg / kg to 2mg / kg, 0.3mg / kg to 1 0.5 mg / kg, 0.3 mg / kg to 1 mg / kg, 0.6 mg / kg to 3 mg / kg, 0.6 mg / kg to 2.5 mg / kg, 0.6 mg / kg to 2 mg / kg, 0.6 mg / kg to 1.5 mg / kg, 0.6 mg / kg to 1 mg / kg, 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 2 mg / kg, 1 mg / kg to 1.5 mg / kg body weight.

[0212] In a further embodiment, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: a dose of 0.2 μg / kg to 3 mg / kg body weight, for example, 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight, or a range consisting of any two thereof, once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W); wherein the fusion protein is administered for one or more treatment cycles, the treatment cycle being three weeks for weekly or three-week administration and four weeks for biweekly administration.For example, the fusion protein of the present invention (e.g., 2149) can be administered by injection, preferably intravenous injection, according to the following dosage regimen: dosage levels of 0.2 μg / kg to 3 mg / kg, 0.2 μg / kg to 2.5 mg / kg, 0.2 μg / kg to 2 mg / kg, 0.2 μg / kg to 1.5 mg / kg, 0.2 μg / kg to 1 mg / kg, 2 μg / kg to 3 mg / kg, 2 μg / kg to 2.5 mg / kg, 2 μg / kg to 2 mg / kg, 2 μg / kg to 1.5 mg / kg. 5mg / kg, 2μg / kg to 1mg / kg, 10μg / kg to 3mg / kg, 10μg / kg to 2.5mg / kg, 10μg / kg to 2mg / kg, 10μg / kg to 1.5mg / kg, 10μg / kg to 1mg / kg, 30μg / kg to 3mg / kg, 30μg / kg to 2.5mg / kg, 30μg / kg to 2mg / kg, 30μg / kg to 1.5mg / kg, 30μg / kg to 1mg / kg, 0.1mg / kg to 3mg / kg, 0.1mg / kg to 2.5mg / kg, 0.1mg / kg to 2mg / kg, 0.1mg / kg to 1.5mg / kg, 0.1mg / kg to 1mg / kg, 0.3mg / kg to 3mg / kg, 0.3mg / kg to 2.5mg / kg, 0.3mg / kg to 2mg / kg, 0.3mg / kg to 1.5mg / kg, 0.3mg / kg to 1mg / kg, 0.6mg / kg to 3mg / kg, 0.6mg / kg g to 2.5 mg / kg, 0.6 mg / kg to 2 mg / kg, 0.6 mg / kg to 1.5 mg / kg, 0.6 mg / kg to 1 mg / kg, 1 mg / kg to 3 mg / kg, 1 mg / kg to 2.5 mg / kg, 1 mg / kg to 2 mg / kg, 1 mg / kg to 1.5 mg / kg body weight, wherein the fusion protein is administered for one or more treatment cycles of three weeks for weekly or three-weekly administration and four weeks for biweekly administration.

[0213] In a further embodiment, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: a dose of 30 μg / kg to 3 mg / kg body weight, e.g., 30 μg / kg-3 mg / kg, 0.1-3 mg / kg, or 0.1-2 mg / kg, or 0.6-3 mg / kg, or 0.6-2 mg / kg, or 1-3 mg / kg, or 1-2 mg / kg body weight, once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W); wherein the fusion protein is administered for one or more treatment cycles, the treatment cycle being three weeks for weekly or three-week administration and four weeks for biweekly administration.

[0214] Preferably, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 0.6-3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q2W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks for weekly or three-week administration and four weeks for biweekly administration. For example, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 0.6-3 mg / kg body weight is administered once a week (QW), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks. Alternatively, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 0.6-3 mg / kg body weight is administered once every two weeks (Q2W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is four weeks. Alternatively, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: 0.6-3 mg / kg body weight once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles of three weeks.

[0215] Additionally preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 1-3 mg / kg body weight or 1-2 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks for weekly or three-week administration and four weeks for biweekly administration. For example, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 1-2 mg / kg body weight is administered once a week (QW), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks. Alternatively, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: 1-2 mg / kg body weight is administered once every two weeks (Q2W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is four weeks. Alternatively, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: 1-2 mg / kg body weight once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles of three weeks.

[0216] Still further preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: 0.3, 0.6, 1 or 2 mg / kg body weight once a week (Q2W), wherein the fusion protein is administered for one or more treatment cycles, each of which is four weeks.

[0217] Still further preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: 0.6, 1, 1.5, 2 or 3 mg / kg body weight once every three weeks (Q3W) for one or more treatment cycles, wherein the treatment cycle is three weeks.

[0218] Still further preferably, the fusion protein of the present invention (eg, 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: 3 mg / kg body weight once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles of three weeks.

[0219] When the single dose of the fusion protein of the present invention (e.g., 2149) is ≥0.6 mg / kg body weight (i.e., normal dose or therapeutic dose), a low dose of the fusion protein is administered by injection, preferably intravenous injection, 7±1 days before the first single dose as an initial dose, and the initial dose is 2-50% of the single dose (normal dose or therapeutic dose). Preferably, the initial dose is about 2%, 3.33%, 5%, 6.67%, 10%, 15%, 16.67%, 20%, 25%, 30%, 33.3%, 35%, 40%, 45% or 50% of the single dose (normal dose or therapeutic dose) or a range consisting of any two of them. In particular, the initial dose is 0.2 μg / kg-1 mg / kg, 0.2 μg / kg-0.6 mg / kg, 0.2 μg / kg-0.3 mg / kg, 0.2 μg / kg-0.2 mg / kg, 0.2 μg / kg-0.1 mg / kg body weight. The initial dose is usually administered 6, 7 or 8 days before the first normal dose or therapeutic dose, preferably 7 days before the first normal dose or therapeutic dose.

[0220] In some embodiments, when the single dose of the fusion protein of the present invention (e.g., 2149) is ≥0.6 mg / kg body weight, a dose of ≤200 μg / kg body weight of the fusion protein is administered by injection, preferably intravenous injection, 7±1 days before the first single dose as an initial dose. Preferably, the initial dose is administered 7 days before the first single dose.

[0221] In a further embodiment, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 0.2-200 μg / kg body weight is administered on day 1, and a normal dose of 0.6-3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1. Preferably, the normal dose is administered starting from day 8.

[0222] Preferably, the initial dose is 2-200 μg / kg body weight, preferably 30-200 μg / kg body weight, more preferably 30-150 μg / kg body weight, most preferably 30-100 μg / kg body weight. For example, the initial dose is 100 μg / kg body weight.

[0223] Additionally preferably, the normal dose is a dose of 0.6-3 mg / kg body weight administered once per week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), for example, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight, or a range consisting of any two of these. For example, the normal dose can be a dose of 0.6-3 mg / kg, 0.6-2.5 mg / kg, 0.6-2 mg / kg, 0.6-1.5 mg / kg, 0.6-1 mg / kg, 1-3 mg / kg, 1-2.5 mg / kg, 1-2 mg / kg, 1-1.5 mg / kg body weight. Preferably, the normal dose is 0.6-3mg / kg, or 0.6-2.5mg / kg, or 0.6-2mg / kg, or 1-3mg / kg, or 1-2.5mg / kg, or 1-2mg / kg body weight administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W). The normal dose administers one or more treatment cycles of three weeks and four weeks for biweekly administration.

[0224] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 30-100 μg / kg body weight on day 1, and a normal dose of 0.6-3 mg / kg, e.g., 0.6-2 mg / kg, e.g., 1-3 mg / kg, e.g., 1-2 mg / kg body weight once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, wherein the treatment cycle is three weeks for administration once a week or once every three weeks and four weeks for administration once every two weeks. Preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: an initial dose of 30-100 μg / kg body weight is administered on day 1, and a normal dose of 0.6-3 mg / kg, preferably 0.6-2 mg / kg, more preferably 1-2 mg / kg body weight is administered once a week (QW) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks. Additionally preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: an initial dose of 30-100 μg / kg body weight is administered on day 1, and a normal dose of 0.6-3 mg / kg, preferably 0.6-2 mg / kg, more preferably 1-2 mg / kg body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, and the treatment cycle is four weeks. Still further preferably, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 30-100 μg / kg body weight is administered on day 1, and a normal dose of 0.6-3 mg / kg, preferably 0.6-2 mg / kg, more preferably 1-2 mg / kg body weight is administered once every three weeks (QW) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, each of which is three weeks. Preferably, the normal dose is administered starting from day 8.

[0225] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, or 2 mg / kg body weight is administered once every two weeks (Q2W) starting on day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, each of which is four weeks. Preferably, the normal dose is administered starting on day 8.

[0226] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenously, according to the following dosing regimen: an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, 1.5, 2, or 3 mg / kg body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, each of which is three weeks. Preferably, the normal dose is administered starting from day 8.

[0227] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 1.5 mg / kg body weight is administered once every three weeks (Q3W) starting on day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, each of which is three weeks. Preferably, the normal dose is administered starting on day 8.

[0228] In some embodiments, the fusion protein of the present invention (e.g., 2149) is administered by injection, preferably intravenous injection, according to the following dosing regimen: an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 3 mg / kg body weight is administered once every three weeks (Q3W) starting on day 8±1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, each of which is three weeks. Preferably, the normal dose is administered starting on day 8.

[0229] It will be appreciated that the normal dose is usually administered on the 8th day after the initial dose, but may be administered earlier or later due to various reasons, such as inconvenience to the patient.

[0230] It will also be understood that when there is more than one treatment cycle, the treatment cycles may be continuous or intermittent (eg, with medication suspended for a period of time for various reasons).

[0231] The fusion protein of the present invention (e.g., 2149) can be formulated into a form suitable for administration, particularly a form suitable for injection (injection preparation), such as a solution, an emulsion, a suspension, a concentrate, a lyophilized powder (reconstituted with an injection solvent such as water for injection, normal saline, glucose injection, etc. before use), etc., for example, can be formulated by methods known in the art. Preferably, the fusion protein of the present invention (e.g., 2149) is formulated into a form for administration with the dosage regimen described herein. In some embodiments, the fusion protein of the present invention is in the form of a sterile injection solution, preferably containing 0.5-150 mg / ml of the fusion protein, preferably 0.5-100 mg / mL, such as 0.5-50 mg / ml or 1-20 mg / ml, such as about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg / ml. It will be appreciated that, if desired, the injection solution may be diluted to a desired concentration using a suitable injection vehicle to adapt to the dosage regimen of the present invention. In some embodiments, the fusion protein of the present invention is in the form of a sterile lyophilized powder that can be reconstituted to a desired concentration using a suitable injection vehicle prior to use to adapt to the dosage regimen of the present invention.

[0232] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be used to treat solid tumors or blood tumors, selected from intestinal cancer (including rectal cancer, colon cancer, colorectal cancer), melanoma, lung cancer (e.g., non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer), breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, bile duct cancer, ovarian cancer, cervical cancer, uterine cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), gastric cancer, lymphoma, leukemia, or multiple myeloma.

[0233] Preferably, the fusion protein of the present invention (e.g., 2149) can be used to treat solid tumors or hematologic malignancies, wherein the solid tumors or hematologic malignancies are selected from colorectal cancer, melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), breast cancer, pancreatic cancer, bile duct cancer, ovarian cancer, cervical cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), and lymphoma. More preferably, the solid tumors or hematologic malignancies are selected from colorectal cancer, melanoma, and non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer).

[0234] In some embodiments, the melanoma is selected from the group consisting of cutaneous melanoma, acral melanoma, mucosal melanoma, and melanoma of unknown primary.

[0235] In some embodiments, the non-small cell lung cancer is selected from squamous and non-squamous non-small cell lung cancer, such as lung squamous cell carcinoma or lung adenocarcinoma.

[0236] In other embodiments, the hematological tumor is selected from lymphoma, leukemia and multiple myeloma, in particular lymphoma.

[0237] In some embodiments, the solid or hematological tumor is advanced, recurrent, metastatic, or unresectable, for which standard therapy has failed or is intolerant to standard therapy.

[0238] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be used to treat melanoma, such as cutaneous melanoma, acral melanoma, mucosal melanoma, or melanoma of unknown primary, particularly those that have failed or are intolerant to standard treatment, are advanced, recurrent, metastatic, or unresectable; for example, unresectable locally advanced or metastatic melanoma that has progressed or recurred after previous treatment with an immune checkpoint inhibitor, or unresectable locally advanced or metastatic melanoma that has not been treated with systemic immune checkpoint inhibitors. Preferably, the fusion protein of the present invention (eg, 2149) is used for the treatment of melanoma by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg of body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks for weekly or three-week administration and four weeks for biweekly administration. Additionally, preferably, the fusion protein of the present invention (eg, 2149) is used for the treatment of melanoma by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 1 mg / kg of body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is four weeks. Still further preferably, the fusion protein of the present invention (e.g., 2149) is used to treat melanoma by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 3 mg / kg body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, each treatment cycle being three weeks.

[0239] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be used to treat colorectal cancer, preferably advanced, recurrent, metastatic or unresectable colorectal cancer that has failed or is intolerant to standard treatment, in particular colorectal cancer with normal mismatch repair genes (pMMR) and / or microsatellite stability (MSS). Preferably, the fusion protein of the present invention (e.g., 2149) is injected, preferably intravenously, for the treatment of colorectal cancer according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 0.1-3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks for administration once a week or once every three weeks and four weeks for administration once every two weeks. In addition, preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of colorectal cancer by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 1 mg / kg of body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is four weeks. Still in addition, preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of colorectal cancer by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 3 mg / kg of body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks.

[0240] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be used to treat non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer, in particular, non-small cell lung cancer without known driver gene mutations, failure of standard treatment or intolerance, advanced, recurrent, metastatic or unresectable non-small cell lung cancer. Preferably, the fusion protein of the present invention (e.g., 2149) is injected, preferably intravenously, for the treatment of non-small cell lung cancer according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 0.6-3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks for administration once a week or once every three weeks and four weeks for administration once every two weeks. Additionally preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of non-small cell lung cancer by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 1 mg / kg of body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is four weeks. Still additionally preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of non-small cell lung cancer by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg, is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 3 mg / kg of body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks.

[0241] In some embodiments, the fusion protein of the present invention (e.g., 2149) can be used to treat lymphoma, particularly late stage, recurrent or metastatic lymphoma, lymphoma that standard treatment has failed or is not tolerated to standard treatment, or unresectable lymphoma. Preferably, the fusion protein of the present invention (e.g., 2149) is injected, preferably intravenously, for the treatment of lymphoma according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg is administered on day 1, and a normal dose of 1-3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks for administration once a week or once every three weeks and four weeks for administration once every two weeks. In addition, preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of melanoma by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 1 mg / kg of body weight is administered once every two weeks (Q2W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is four weeks. Still further preferably, the fusion protein of the present invention (e.g., 2149) is used for the treatment of melanoma by injection, preferably intravenous injection, according to the following regimen: an initial dose of 30-100 μg / kg, preferably 100 μg / kg is administered on day 1, and a normal dose of 1-3 mg / kg, preferably 3 mg / kg of body weight is administered once every three weeks (Q3W) starting from day 8±1, wherein the normal dose is administered for one or more treatment cycles, and the treatment cycle is three weeks.

[0242] In a second aspect, a method of treating a solid tumor or a hematological tumor in an individual is provided, the method comprising administering to an individual in need thereof a PD-1 / IL-2R bispecific antibody fusion protein of the present invention, wherein the PD-1 / IL-2R bispecific antibody fusion protein is as defined herein. In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein is administered according to a dosing regimen as described herein. In some embodiments, the solid tumor or hematological tumor is as defined herein.

[0243] In a third aspect, a PD-1 / IL-2R bispecific antibody fusion protein of the present invention is provided for use in treating a solid tumor or a hematological tumor, wherein the PD-1 / IL-2R bispecific antibody fusion protein is as defined herein. In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein is administered according to a dosing regimen as described herein. In some embodiments, the solid tumor or hematological tumor is as defined herein.

[0244] In a fourth aspect, the present invention provides a use of the PD-1 / IL-2R bispecific antibody fusion protein in the preparation of a drug for treating solid tumors or blood tumors, wherein the PD-1 / IL-2R bispecific antibody fusion protein is as defined herein. In some embodiments, the drug is in a form suitable for injection (injection preparation), such as a solution, emulsion, suspension, concentrate, lyophilized powder (reconstituted with an injection solvent such as water for injection, normal saline, glucose injection, etc. before use), etc. In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein is administered according to a dosing regimen as described herein. In some embodiments, the drug is in the form of a formulation that can be administered or delivered by injection, preferably intravenous injection, according to the dosing regimen of the present invention. In some embodiments, the drug is administered according to a dosing regimen as described herein. In some embodiments, the solid tumor or blood tumor is as defined herein.

[0245] In a fifth aspect, a pharmaceutical composition is provided, which comprises a PD-1 / IL-2R bispecific antibody fusion protein of the present invention and one or more pharmaceutically acceptable excipients, wherein the PD-1 / IL-2R bispecific antibody fusion protein is as defined herein. In some embodiments, the pharmaceutical composition is in a form suitable for injection (injection preparation), such as a solution, an emulsion, a suspension, a concentrate, a lyophilized powder (reconstituted with an injection solvent such as water for injection, normal saline, glucose injection, etc. before use), etc. In some embodiments, the PD-1 / IL-2R bispecific antibody fusion protein is administered according to a dosing regimen as described herein. In some embodiments, the pharmaceutical composition is in the form of a formulation that can be administered or delivered by injection, preferably intravenous injection, in the dosing regimen of the present application. In some embodiments, the pharmaceutical composition is administered according to a dosing regimen as described herein. In some embodiments, the solid tumor or hematological tumor is as defined herein.

[0246] In some embodiments, a single-dose administration unit is provided, which comprises a single therapeutically effective amount of a fusion protein of the present invention (e.g., 2149). In some embodiments, the single-dose administration unit is administered by injection, preferably by intravenous injection. In some embodiments, the single-dose administration unit is in a form suitable for injection (injection preparation), such as a solution, an emulsion, a suspension, a concentrate, a lyophilized powder (reconstituted with an injection solvent such as water for injection, normal saline, glucose injection, etc. before use), etc. Preferably, the single-dose administration unit is in the form of an injectable solution or a lyophilized powder injection.

[0247] In some embodiments, a single dosage unit of the present invention comprises 10 μg to 300 mg of the fusion protein, for example, 10 μg, 200 μg, 800 μg, 1 mg, 1.5 mg, 3 mg, 10 mg, 12 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, or a range consisting of any two thereof. For example, the dosage unit comprises 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-100 mg, 1-50 mg, 1-25 mg, 1-12 mg, 3-300 mg, 3-250 mg, 3-200 mg, 3-150 mg, 3-100 mg, 3-50 mg, 3-25 mg, 3-12 mg, 10-300 mg, 10-2 50mg, 10-200mg, 10-150mg, 10-100mg, 10-50mg, 10-25mg, 10-12mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-100mg, 100-300mg, 100-250mg, 100-200mg, 100-150mg of the fusion protein.

[0248] In some embodiments, a single-dose administration unit of the present invention provides a fusion protein of the present invention (e.g., 2149) at a dose of 0.2 μg / kg to 3 mg / kg body weight to a patient. Preferably, a single-dose administration unit of the present invention is capable of providing a patient with any dosage level as described herein, such as any dosage level defined in any one of Embodiments 13-22. For example, a single-dose administration unit of the present invention is capable of providing a patient with a fusion protein of the present invention (e.g., 2149) at a dose level of 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight, or a range consisting of any two thereof.

[0249] In a sixth aspect, a kit is provided, comprising a PD-1 / IL-2R bispecific antibody fusion protein of the present invention and instructions for using the fusion protein to treat solid tumors or hematological tumors, wherein the PD-1 / IL-2R bispecific antibody fusion protein is as defined herein. In some embodiments, the kit is configured to administer or deliver the PD-1 / IL-2R bispecific antibody fusion protein by injection, preferably intravenous injection, according to the dosing regimen of the present application. In some embodiments, the solid tumor or hematological tumor is as defined herein.

[0250] In another aspect, a kit is provided comprising one or more single-dose administration units of the present invention and instructions for administering the one or more single-dose administration units according to a dosing regimen as defined herein, for example, a dosing regimen as defined in any one of Embodiments 13 to 22. Preferably, the kit is for use in treating solid tumors or hematological tumors.

[0251] It will be understood that the fusion protein of the present invention can also be used in combination with one or more other active agents or therapies for the purposes described herein, and the other active agents or therapies may have the same or different pharmacological effects as the fusion protein of the present invention. The fusion protein of the present invention can be administered simultaneously with, before, or after the other active agent or therapy, and the fusion protein of the present invention and the other active agent can be administered in the same or different dosage forms and by the same or different routes of administration. The administration regimen of the other active agent or therapy can be determined by the participating physician. The various aspects, embodiments, and features described herein for the PD-1 / IL-2R bispecific antibody fusion protein of the present invention are also applicable to the first active ingredient in the pharmaceutical combination of the present invention.

[0252] In a seventh aspect, the present invention provides a pharmaceutical combination comprising:

[0253] (i) a first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein, comprising: (a) a first monomer comprising an IL-2 mutant protein fused to an Fc fragment, optionally via a linker or not; and (b) a second monomer comprising one heavy chain and one light chain of an antibody that specifically binds to PD-1; and

[0254] (ii) a second active ingredient, which is bevacizumab.

[0255] In some embodiments, the first active ingredient is a PD-1 / IL-2R bispecific antibody fusion protein as defined herein, for example as defined in the aforementioned embodiments 1-12 or 31-42.

[0256] The dosage of the PD-1 / IL-2R bispecific antibody fusion protein (e.g., immunoconjugate 2149) can vary depending on the route of administration, the disease being treated, the patient's age, weight, and overall health condition, and concomitant medications. Those skilled in the relevant art can readily determine the effective therapeutic amount in practice based on the specific circumstances of the individual in need of treatment. For example, when administered intravenously, the PD-1 / IL-2R bispecific antibody fusion protein (e.g., immunoconjugate 2149) can be administered at a dose of 0.2 μg / kg to 1 mg / kg body weight, for example, 0.2, 0.5, 1, 2, 4, 6, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 μg / kg body weight or 1 mg / kg body weight, administered once a week (QW), with one treatment cycle every three weeks; or 1 mg / kg body weight The dosage is from 1 mg / kg to 3 mg / kg body weight, for example, 1 mg / kg body weight, 1.5 mg / kg body weight, 2 mg / kg body weight, 2.5 mg / kg body weight, 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or the dosage is from 1 mg / kg to 3 mg / kg body weight, for example, 1 mg / kg body weight, 1.5 mg / kg body weight, 2 mg / kg body weight, 2.5 mg / kg body weight, 3 mg / kg body weight, administered once every two weeks (Q2W), and every four weeks is a treatment cycle; or the dosage is from 1 mg / kg to 3 mg / kg body weight, for example, 1 mg / kg body weight, 1.5 mg / kg body weight, 2 mg / kg body weight, 2.5 mg / kg body weight, 3 mg / kg body weight, administered once every three weeks (Q3W), and every three weeks is a treatment cycle.In one embodiment, the PD-1 / IL-2R bispecific antibody fusion protein (e.g., immunoconjugate 2149) is administered by intravenous infusion on day 1 at a dose of 0.2 μg / kg to 1 mg / kg (e.g., 20, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 μg / kg or 1 mg / kg), preferably an initial dose of 100 μg / kg to 1 mg / kg, and 2 mg / kg on day 8±1. g body weight maintenance dose, administered once every two weeks; or intravenous infusion, 0.2 μg / kg body weight to 1 mg / kg body weight (e.g., 20, 40, 60, 80, 100, 150, 200, 250, 300, 350, 400, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 μg / kg body weight or 1 mg / kg body weight) on day 1, preferably an initial dose of 100 μg / kg body weight to 1 mg / kg body weight, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is administered on day 8±1, and a maintenance dose is administered once every three weeks.

[0257] The second active ingredient, bevacizumab, is used for intravenous infusion administration, with a dosage of 5 mg / kg to 15 mg / kg body weight (for example, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15 mg / kg body weight), administered once every two weeks, with every four weeks being a treatment cycle, or administered once every three weeks, with every three weeks being a treatment cycle; preferably, the second active ingredient, bevacizumab, is used for intravenous infusion administration, with a dosage of 5 mg / kg, 7.5 mg / kg, 10 mg / kg or 15 mg / kg body weight, administered once every two weeks, with every four weeks being a treatment cycle, or administered once every three weeks, with every three weeks being a treatment cycle.

[0258] Bevacizumab has been approved by the National Medical Products Administration (NMPA) for the treatment of recurrent glioblastoma. It has also been approved by the NMPA for combination with fluorouracil for the treatment of metastatic colorectal cancer and for combination with platinum chemotherapy agents for the treatment of unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer. In addition, bevacizumab can enhance dendritic cell maturation and promote lymphocyte migration into tumors, suggesting that bevacizumab may enhance IL-2-mediated anti-tumor immune responses.

[0259] In one embodiment, the bevacizumab is bevacizumab sold under the trade name Tavastin or Avastin.

[0260] The drug combination of the seventh aspect is used to treat solid tumors, wherein the solid tumors are selected from colorectal cancer, melanoma, non-squamous non-small cell lung cancer, hepatocellular carcinoma, lymphoma and other solid tumors. Preferably, the solid tumor is in the late stage.

[0261] In one embodiment, the solid tumor is colorectal cancer, particularly advanced colorectal cancer, more particularly advanced colorectal cancer that has failed standard treatment;

[0262] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0263] The second active ingredient is used for intravenous infusion administration, with a dosage of 5 mg / kg to 15 mg / kg body weight, administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion administration, with a dosage of 5 mg / kg to 10 mg / kg body weight (for example, 5 mg / kg or 7.5 mg / kg body weight), administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle.

[0264] In one embodiment, the solid tumor is melanoma, preferably advanced melanoma, more preferably advanced melanoma that has not undergone immunotherapy or advanced melanoma that has failed previous immunotherapy;

[0265] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0266] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg or 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle.

[0267] In one embodiment, the solid tumor is non-squamous non-small cell lung cancer (preferably advanced non-squamous non-small cell lung cancer, more preferably advanced non-squamous non-small cell lung cancer that has failed or is intolerant to standard treatment), hepatocellular carcinoma (preferably advanced hepatocellular carcinoma, more preferably advanced hepatocellular carcinoma that has not been systemically treated), or renal cell carcinoma (preferably advanced renal cell carcinoma, more preferably advanced renal cell carcinoma that has failed or is intolerant to standard treatment);

[0268] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0269] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 10 mg / kg to 15 mg / kg body weight (for example, 10 mg / kg body weight, 12.5 mg / kg body weight or 15 mg / kg body weight), administered once every two weeks, with every four weeks as a treatment cycle, or administered once every three weeks, with every three weeks as a treatment cycle.

[0270] In one embodiment, the solid tumor is lymphoma or other solid tumors, preferably lymphoma or other advanced solid tumors that have failed or are intolerant to standard treatment;

[0271] The first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, with one treatment cycle of three weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, with one treatment cycle of four weeks; or at a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, with one treatment cycle of three weeks; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0272] The second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg to 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle; preferably, the second active ingredient is used for intravenous infusion, with a dosage of 5 mg / kg, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg or 15 mg / kg body weight, once every two weeks, with every four weeks as a treatment cycle, or once every three weeks, with every three weeks as a treatment cycle.

[0273] The seventh aspect also includes a method for treating solid tumors with the drug combination described above, which comprises administering the first active ingredient and the second active ingredient in the same or different pharmaceutical compositions simultaneously or separately at the dosage and dosage regimen described above.

[0274] The seventh aspect also includes the use of the above-mentioned drug combination for treating solid tumors.

[0275] The seventh aspect also includes the use of the above-mentioned drug combination in the preparation of a pharmaceutical product for treating solid tumors.

[0276] In an eighth aspect, the present invention provides a pharmaceutical combination comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is the PD-1 / IL-2R bispecific antibody fusion protein described above, and the second active ingredient is dacarbazine. Specific embodiments, preferred embodiments, administration methods, and dosages of the PD-1 / IL-2R bispecific antibody fusion protein are as described herein, for example, as defined in Embodiments 1-64 above.

[0277] The chemical structure of dacarbazine is

[0278] Dacarbazine is approved as an injection for the treatment of malignant melanoma and can be used as an intravenous infusion, intravenous push, intra-arterial infusion, or intra-arterial push.

[0279] When administered by intravenous or arterial infusion, dacarbazine is administered at a dose of 2.5-6 mg / kg body weight or 200-400 mg / m 2 Body surface area, once daily for 5-10 consecutive days, followed by a break, with a treatment cycle of 3-6 weeks, or a dose of 650-1450 mg / m 2 body surface area, administered every 4-6 weeks, with each treatment cycle consisting of 4-6 weeks; when administered by intravenous or arterial bolus, the dose of dacarbazine is 200-400 mg / m 2 , administered once a day for 5 consecutive days, then stopped, with each 3-4 weeks as a treatment cycle.

[0280] The drug combination of the eighth aspect is used for treating melanoma, particularly advanced melanoma, more particularly advanced melanoma that has not been treated with systemic therapy.

[0281] In one embodiment, the first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dose of 0.2 μg / kg to 1 mg / kg of body weight, administered once a week, with one treatment cycle every three weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once a week, with one treatment cycle every three weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once every two weeks, with one treatment cycle every four weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once every three weeks, with one treatment cycle every three weeks. Treatment cycle; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0282] The second active ingredient, dacarbazine, is administered by intravenous or arterial infusion, and when administered by intravenous or arterial infusion, the dosage of dacarbazine is 2.5-6 mg / kg body weight or 200-400 mg / m 2 Body surface area, once daily for 5-10 consecutive days, followed by a break, with a treatment cycle of 3-6 weeks, or a dose of 650-1450 mg / m 2 body surface area, administered every 4-6 weeks, with each treatment cycle consisting of 4-6 weeks; when administered by intravenous or arterial bolus, the dose of dacarbazine is 200-400 mg / m 2 , administered once a day for 5 consecutive days, then stopped, with each 3-4 weeks as a treatment cycle.

[0283] In a preferred embodiment, the second active ingredient, dacarbazine, is administered by intravenous infusion at a dose of 850 mg / m 2 body surface area, administered once every four weeks, with four weeks as a treatment cycle; or for intravenous infusion, the dosage is 650-1050 mg / m 2 Body surface area (e.g. 850 mg / m 2 Body surface area), once every three weeks, with each three-week treatment cycle; or for intravenous injection, the dosage is 200-300 mg / m 2 Body surface area (e.g. 250 mg / m 2Body surface area), once a day for 5 consecutive days, then suspend the administration, and each four-week treatment cycle; or for intravenous push administration, the dosage is 200-300 mg / m 2 Body surface area (e.g. 250 mg / m 2 The drug was administered once a day for 5 consecutive days, and then the drug was suspended. Every three weeks was a treatment cycle.

[0284] The eighth aspect also includes a method for treating melanoma, particularly advanced melanoma, and more particularly advanced melanoma that has not been systemically treated, using the drug combination described above, the method comprising administering the first active ingredient and the second active ingredient simultaneously or separately in the same or different pharmaceutical compositions at the dosage and dosage regimen described above.

[0285] The eighth aspect also includes use of the above-mentioned drug combination for treating melanoma, particularly advanced melanoma, and more particularly advanced melanoma that has not been treated systematically.

[0286] The eighth aspect also includes the use of the above-mentioned drug combination for preparing a pharmaceutical product for treating melanoma, especially advanced melanoma, more especially advanced melanoma that has not received systemic treatment.

[0287] In a ninth aspect, the present invention provides a drug combination comprising a first active ingredient and a second active ingredient, wherein the first active ingredient is the PD-1 / IL-2R bispecific antibody fusion protein described above, and the second active ingredient is a compound disclosed in WO2008 / 112407 and its equivalent patents or patent applications (e.g., Chinese patents ZL200880007358.X, ZL201310454117.2, ZL 201610147579.3), or a pharmaceutically acceptable salt thereof. The entire contents of the patents or patent applications (including term definitions) are incorporated herein. Specific embodiments, preferred embodiments, modes of administration, and dosages of the PD-1 / IL-2R bispecific antibody fusion protein are as described herein, for example, as defined in Embodiments 1-64 above.

[0288] In one embodiment, the second active ingredient is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0289] in

[0290] W is O; Z is O; G is CR; a is 0; c is 1; b is 1; R is H or C 1-6 alkyl;

[0291] yes

[0292] R1, R2, R3 are each independently selected from H, halogen and C 1-6 alkoxy;

[0293] R4 and R5 are each independently selected from H or C 1-6 alkyl;

[0294] R6 is H.

[0295] In a preferred embodiment, the second active ingredient is anlotinib or a pharmaceutically acceptable salt thereof, in particular anlotinib dihydrochloride

[0296] Anlotinib is a novel multi-target tyrosine kinase inhibitor that effectively inhibits kinases such as VEGFR, PDGFR, FGFR, and c-Kit, demonstrating anti-angiogenesis and tumor growth inhibition. Anlotinib dihydrochloride, as an oral formulation, has been approved by the National Medical Products Administration (NMPA) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer whose disease has progressed or recurred after at least two prior lines of systemic chemotherapy.

[0297] The compound of formula (II) or a pharmaceutically acceptable salt thereof (e.g., anlotinib dihydrochloride) can be formulated into a suitable dosage form, such as tablets, capsules, powders, solutions, emulsions, suspensions, lyophilized powders reconstituted with an injection vehicle (e.g., glucose injection, sodium chloride injection, water for injection, etc.) shortly before use, etc. The compound of formula (II) or a pharmaceutically acceptable salt thereof can be administered by any suitable route, preferably orally.

[0298] The compound of formula (II) or a pharmaceutically acceptable salt thereof (e.g., anlotinib dihydrochloride) can be varied according to the route of administration, the disease being treated, the age, weight, and overall health of the patient, and concomitant medications. Those skilled in the relevant art can easily determine the effective therapeutic amount thereof in practice according to the specific circumstances of the individual in need of treatment. For example, the compound of formula (II) or a pharmaceutically acceptable salt thereof (e.g., anlotinib dihydrochloride) is used for oral administration, with a dosage of 8 mg to 12 mg, such as 8 mg, 9 mg, 10 mg, 11 mg, or 12 mg, administered once daily for 2 consecutive weeks, followed by 1 week of discontinuation, with each three weeks being a treatment cycle.

[0299] In one embodiment, the first active ingredient is for administration by injection, such as intravenous infusion; and the second active ingredient is for oral administration.

[0300] The drug combination in the ninth aspect is used to treat non-small cell lung cancer, particularly advanced non-small cell lung cancer, more particularly advanced non-small cell lung cancer that has failed or is intolerant to standard treatment.

[0301] In one embodiment, the first active ingredient (e.g., molecule 2149) is administered by intravenous infusion at a dose of 0.2 μg / kg to 1 mg / kg of body weight, administered once a week, with one treatment cycle every three weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once a week, with one treatment cycle every three weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once every two weeks, with one treatment cycle every four weeks; or at a dose of 1 mg / kg to 3 mg / kg of body weight, administered once every three weeks, with one treatment cycle every three weeks. Treatment cycle; Alternatively, the first active ingredient is administered by intravenous infusion, with an initial dose of 0.2 μg / kg to 1 mg / kg body weight (e.g., 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg on day 8±1, and a maintenance dose every two weeks; or 0.2 μg / kg to 1 mg / kg (e.g., an initial dose of 100 μg / kg or 1 mg / kg) on ​​day 1, a maintenance dose of 2 mg / kg or 3 mg / kg on day 8±1, and a maintenance dose every three weeks;

[0302] The second active ingredient is for oral administration, with a dosage of 8 mg to 12 mg, once a day, for 2 consecutive weeks, followed by 1 week of rest, with one treatment cycle consisting of three weeks.

[0303] In a preferred embodiment, the second active ingredient (e.g., anlotinib dihydrochloride) is used for oral administration, with a dosage of 12 mg (when the second active ingredient is a pharmaceutically acceptable salt of anlotinib, such as dihydrochloride, calculated as anlotinib), once a day, for 2 consecutive weeks, and 1 week of rest, with each three weeks as a treatment cycle.

[0304] The ninth aspect also includes a method for treating non-small cell lung cancer, particularly advanced non-small cell lung cancer, and more particularly advanced non-small cell lung cancer that has failed or is intolerant to standard treatment, using the drug combination described above, the method comprising administering the first active ingredient and the second active ingredient in the same or different pharmaceutical compositions simultaneously or separately at the dosage and dosage regimen described above.

[0305] The ninth aspect also includes use of the above-mentioned drug combination for treating non-small cell lung cancer, particularly advanced non-small cell lung cancer, more particularly advanced non-small cell lung cancer that has failed or is intolerant to standard treatment.

[0306] The ninth aspect also includes the use of the above-mentioned drug combination for preparing a pharmaceutical product for treating non-small cell lung cancer, especially advanced non-small cell lung cancer, more especially advanced non-small cell lung cancer that has failed or is intolerant to standard treatment.

[0307] The pharmaceutical combination described in aspects 7 to 9 above may further comprise other suitable active ingredients in addition to the first active ingredient and the second active ingredient, provided that the other suitable active ingredients do not impair the beneficial effects of the first active ingredient and the second active ingredient. Preferably, the pharmaceutical combination described in aspects 7 to 9 above comprises the first active ingredient and the second active ingredient as the only active ingredients.

[0308] In some embodiments, the first active ingredient can be in the form of a single-dose administration unit as defined herein. In some embodiments, the first active ingredient can provide a patient with any dosage level as described herein, for example, any dosage level defined in any one of Embodiments 43-59.

[0309] In some embodiments, the first active ingredient may be in the form of a kit comprising one or more single-dose administration units, wherein the one or more single-dose administration units are administered according to a dosing regimen as defined herein, e.g., as defined in any one of Embodiments 43-59.

[0310] In another aspect, the present invention relates to a kit or package comprising the pharmaceutical combination described in aspects 7 to 9 above. In one embodiment, the kit or package comprises: a pharmaceutical composition comprising a first active ingredient; a pharmaceutical composition comprising a second active ingredient; and instructions for use, wherein the instructions for use describe a method for administering the pharmaceutical composition. In a preferred embodiment, the kit or package comprises: a pharmaceutical composition comprising the first active ingredient as the sole active ingredient; a pharmaceutical composition comprising the second active ingredient as the sole active ingredient; and instructions for use, wherein the instructions for use describe a method for administering the two pharmaceutical compositions. The pharmaceutical composition optionally contains a pharmaceutically acceptable excipient.

[0311] The drug combination of the present invention has an effective therapeutic effect on the cancer it treats, and even shows additive, enhanced or synergistic therapeutic effects, and has acceptable safety.

[0312] The above aspects and embodiments and each feature thereof as well as the following definitions may be arbitrarily combined to form embodiments that are not directly described in the specification but are consistent with the spirit of the present invention, and these embodiments are also included in the scope of the present invention.

[0313] definition

[0314] Herein, wild-type "interleukin-2" or "IL-2" refers to the parent IL-2 protein used as a template for introducing a mutation or combination of mutations of the present invention, preferably a naturally occurring IL-2 protein, such as a natural IL-2 protein derived from humans, mice, rats, or non-human primates, including unprocessed (e.g., signal peptide not removed) and processed (e.g., signal peptide removed) forms. A full-length natural human IL-2 sequence including a signal peptide is shown in SEQ ID NO: 1, and the sequence of its mature protein is shown in SEQ ID NO: 2. In addition, this expression also includes naturally occurring IL-2 allelic variants and splice variants, isoforms, homologs, and species homologs. This expression also includes variants of natural IL-2, for example, the variant may have at least 95%-99% or higher identity with natural IL-2 or have no more than 1-10 or 1-5 amino acid mutations (e.g., conservative substitutions), and preferably has substantially the same IL-2Rα binding affinity and / or IL2Rβγ binding affinity as the natural IL-2 protein. Therefore, in some embodiments, wild-type IL-2 may comprise amino acid mutations that do not affect its binding to the IL-2 receptor compared to the natural IL-2 protein, for example, a natural human IL-2 protein (uniprot: P60568) with the mutation C125S introduced at position 125 belongs to the wild-type IL-2 of the present invention. An example of a wild-type human IL-2 protein comprising a C125S mutation is shown in SEQ ID NO: 3. In some embodiments, the wild-type IL-2 sequence may have at least 85%, 95%, or even at least 96%, 97%, 98%, or 99% or more amino acid sequence identity with the amino acid sequence of SEQ ID NO: 1 or 2 or 3.

[0315] In this article, amino acid mutations can be amino acid substitutions, deletions, insertions and additions. Any combination of substitutions, deletions, insertions and additions can be performed to obtain a final mutant protein construct with desired properties (e.g., reduced IL-2Rα binding affinity and / or improved drugability and / or weakened IL-2Rβγ). Amino acid deletions and insertions include deletions and insertions at the amino and / or carboxyl termini of the polypeptide sequence, as well as deletions and insertions within the polypeptide sequence. For example, an alanine residue can be deleted at position 1 of the full-length human IL-2, or one or more amino acids can be deleted in the B'C' loop region to shorten the length of the loop region. In some embodiments, the preferred amino acid mutation is an amino acid substitution, such as a combination of single amino acid substitutions or replacement of an amino acid sequence segment. For example, the B'C' loop region sequence of wild-type IL-2 can be replaced in whole or in part with a different sequence (e.g., the B'C' loop of IL-15), preferably to obtain a B'C' loop region sequence with a shortened length.

[0316] When referring to amino acid positions in IL-2 protein or IL-2 sequence segments herein, reference is made to the wild-type human IL-2 protein (also referred to as IL-2 WT ) is identified by the amino acid sequence of SEQ ID NO:3. The corresponding amino acid positions in other IL-2 proteins or polypeptides (including full-length sequences or truncated fragments) can be identified by amino acid sequence alignment with SEQ ID NO:3. Therefore, in the present invention, unless otherwise indicated, amino acid positions of IL-2 proteins or polypeptides are those numbered according to SEQ ID NO:3. For example, reference to "F42" refers to the phenylalanine residue F at position 42 of SEQ ID NO:3, or to the amino acid residue at the corresponding position in another IL-2 polypeptide sequence. At the same time, for ease of understanding and comparison, when the mutations of the present invention involve truncation or deletion of sites in certain specific segments (for example, the sequence of the B'C' loop region, i.e., positions 73-83 of SEQ ID NO: 3, a total of 11 amino acid residues), given the specific mutation region and its mutation pattern, the numbering of amino acid residues outside of that region remains unchanged. For example, after the sequence of the B'C' loop region, i.e., positions 73-83 of SEQ ID NO: 3, a total of 11 amino acid residues, is truncated to 7 amino acid residues, the numbers 80-83 are no longer assigned, and the position number of the next amino acid residue immediately following the B'C' loop region remains 84. Sequence alignment for amino acid position determination can be performed using the Basic Local Alignment Search Tool available at https: / / blast.ncbi.nlm.nih.gov / Blast.cgi using default parameters.

[0317] When referring to IL-2 muteins herein, single amino acid substitutions are described as follows: [original amino acid residue / position / substituted amino acid residue]. For example, a substitution of lysine at position 35 with glutamic acid can be represented as K35E. When multiple alternative amino acid substitutions (e.g., D, E) are possible at a given position (e.g., K35), the amino acid substitution can be represented as: K35D / E. Accordingly, single amino acid substitutions can be linked by a plus sign (+) or a minus sign (-) to represent combined mutations at multiple given positions. For example, a combined mutation at positions F42A, N88R, and S127E can be represented as: F42A+N88R+S127E, or F42A-N88R-S127E.

[0318] In this article, "percentage of sequence identity" can be determined by comparing two optimally aligned sequences within a comparison window. Preferably, sequence identity is determined over the full length of a reference sequence (e.g., SEQ ID NO: 3). Methods for comparing sequences are well known in the art. Suitable algorithms for determining percentages of sequence identity include, for example, BLAST and BLAST 2.0 algorithms (see Altschul et al., Nuc. Acids Res. 25: 3389-402, 1977 and Altschul et al. J. Mol. Biol. 215: 403-10, 1990). Software for performing BLAST analysis can be obtained from the National Center for Biotechnology Information. For the purposes of this application, percentage identity is determined using the Basic Local Alignment Search Tool available from https: / / blast.ncbi.nlm.nih.gov / Blast.cgi using default parameters.

[0319] In this article, antibody Fc fragment refers to the C-terminal region of the immunoglobulin heavy chain containing the constant region of at least a portion, and can include native sequence Fc fragments and variant Fc fragments. Native sequence Fc fragments encompass naturally occurring various immunoglobulin Fc sequences, such as various Ig subtypes and the Fc regions of their allotypes (Gestur Vidarsson et al., IgG subclasses and allotypes:from structure to effector functions, 20 October 2014, doi:10.3389 / fimmu.2014.00520.). In some embodiments, human IgG heavy chain Fc fragment extends from Cys226 of the heavy chain or from Pro230 to the carboxyl terminus. In another embodiment, the C-terminal lysine (Lys447) of the Fc- fragment may or may not exist. In other embodiments, the Fc fragment is a variant Fc fragment comprising a mutation, such as comprising L234A-L235A mutations. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc fragment is based on the EU numbering system, also known as the EU index, as described in Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242. In some embodiments, the antibody Fc fragment can have an IgG1 hinge sequence or a portion of an IgG1 hinge sequence at the N-terminus, such as the sequence from E216 to T225 or the sequence from D221 to T225 according to EU numbering. The hinge sequence can contain mutations.

[0320] IL-2 protein belongs to a short-chain type I cytokine family member with a four-alpha helical bundle (A, B, C, D) structure. In this article, the term "B'C'Loop" or "B'C' loop region" or "B'C' loop sequence" is used interchangeably and refers to the connecting sequence between the B helix and the C helix of the IL-2 protein. The B'C' loop sequence of an IL-2 protein can be determined by crystal structure analysis of IL-2 (e.g., PDB: 2ERJ). For the purposes of the present invention, according to the numbering of SEQ ID NO: 3, the B'C' loop sequence refers to the sequence of the residue at position 72 and the residue at position 84 in the IL-2 polypeptide. In the wild-type IL-2 proteins of SEQ ID NO: 1, 2 and 3, the connecting sequence includes A73-R83, a total of 11 amino acids.

[0321] An "antigen-binding fragment" refers to a molecule, other than an intact antibody, that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; dAb (domain antibody); linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies such as VHH; diabodies or fragments thereof; or camelid antibodies.

[0322] The term "linker" as used herein refers to any molecule that enables the direct connection of the different parts of the fusion protein. Examples of covalently linked linkers between different parts of the fusion protein include peptide linkers and non-protein polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes or copolymers of polyethylene glycol and polypropylene glycol. According to the present invention, the term "peptide linker" refers to an amino acid sequence, wherein the sequence connects the amino acid sequence of the first part of the fusion protein to the second part of the fusion protein. For example, a peptide linker can connect the IL-2 part of the fusion protein to an Fc domain or a fragment thereof. For example, a peptide linker can also connect an antibody to IL-2, such as connecting the C-terminal end of an antibody heavy chain to IL-2. Preferably, the peptide linker has a length that is sufficient to connect the two entities in a manner that allows them to maintain their conformations relative to each other so as not to interfere with desired activity. The peptide linker may mainly include or may not mainly include the following amino acid residues: Gly, Ser, Ala or Thr. Useful linkers include glycine-serine polymers, including, for example, (GS)n, (GSGGS)n, (GGGGS)n, (GGGS)n, and (GGGGS)nG, where n is an integer of at least 1 (and preferably 2, 3, 4, 5, 6, 7, 8, 9, 10). Useful linkers also include glycine-alanine polymers, alanine-serine polymers, and other flexible linkers. Preferably, the linker of the present invention is (GGGGS)n, where n=1, 2, 3, 4, or 5, preferably 2. Preferably, the linker of the present invention is SEQ ID NO: 5.

[0323] The term "fusion" as used herein refers to a fusion formed by connecting two or more initially separate proteins / genes / compounds. If the entity constituting the fusion is a protein (including an antibody or a fragment thereof), it is referred to as a fusion protein. For example, IL-2 can be connected to an Fc dimer to form an IL-2 fusion protein. The fusion of IL-2 and an antibody or a fragment thereof can also be referred to as a fusion protein. The connection between the two entity molecules constituting the fusion can be achieved through or without a linker.

[0324] As used herein, the term "PD-1 / IL-2R bispecific fusion protein" refers to a polypeptide molecule comprising at least one IL-2 molecule and at least one PD-1 antibody or antibody fragment. As described herein, the IL-2 molecule can be linked to the antibody through a variety of interactions and in a variety of configurations. For example, a fusion protein of IL-2 and Fc can dimerize with a fragment of an antibody molecule comprising heavy and light chains to form a fusion protein. Preferably, the fusion protein of the present invention has the structure shown in Figure 1, or the structure shown in Figure 1 in which the IL-2 portion is interchanged with the PD-1 antibody portion.

[0325] As used herein, the terms "first" and "second" are used with respect to Fc domains or monomers, etc., to facilitate differentiation when there is more than one of each type of module. Unless explicitly stated otherwise, the use of these terms is not intended to confer a particular order or orientation upon the fusion proteins.

[0326] The term "initial dose" as used herein refers to a dosage that is administered to an individual before a normal dose of an anti-tumor drug (such as a fusion protein of the present invention) is administered, thereby improving the individual's tolerance to the normal dose subsequently administered, and / or causing the normal dose subsequently administered to produce fewer or less severe adverse events in the individual. Typically, the initial dose is a lower dose, for example, 2-50% of a normal dose, for example, about 2%, 3.33%, 5%, 6.67%, 10%, 15%, 16.67%, 20%, 25%, 30%, 33.3%, 35%, 40%, 45% or 50% or a range consisting of any two of them. In some embodiments, when the single dose of a normal dose is >= 0.6 mg / kg, particularly >= 1 mg / kg body weight, a lower dose (such as 100 μg / kg) is administered first as an initial dose.

[0327] As used herein, the terms "normal dose" and "therapeutic dose" are used interchangeably to refer to an amount sufficient to alleviate, improve, or prevent one or more symptoms of a solid tumor or hematological tumor, or to delay or prevent the progression of the solid tumor or hematological tumor (e.g., disease-free progression, prolonged survival, etc.). The normal dose can be administered once or multiple times.

[0328] As used herein, the term "treatment cycle" refers to a specific time period expressed in days or weeks that is repeated on a regular schedule. A treatment cycle can be repeated one or more times (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 times or more). During a treatment cycle, administration can be performed once or multiple times. For cases where the treatment cycle is repeated multiple times, each treatment cycle can be continuous or separated by a period of time (e.g., due to various reasons, including non-disease reasons, the administration cannot be scheduled).

[0329] The expression "8±1" day as used herein means day 7, 8 or 9, preferably day 8.

[0330] Herein, the dosage unit "μg / kg" represents micrograms of the fusion protein of the present invention per kilogram of individual body weight, and the dosage unit "mg / kg" represents milligrams of the fusion protein of the present invention per kilogram of individual body weight.

[0331] As used herein, "QD" means dosing once daily, "QW" means dosing once weekly, "Q2W" means dosing once every two weeks, and "Q3W" means dosing once every three weeks.

[0332] The term "treat" as used herein refers to alleviating or reducing the severity of at least one symptom or indication, temporarily or permanently eliminating the cause of the symptoms, delaying or inhibiting tumor growth, reducing tumor cell load or tumor burden, promoting tumor regression, causing tumor shrinkage, necrosis and / or disappearance, preventing tumor recurrence, preventing or inhibiting metastasis, inhibiting the growth of metastatic tumors, eliminating the need for surgery, increasing individual survival, and / or improving the patient's quality of life, etc.

[0333] The term "objective response rate" or "ORR" used in this article is one of the important indicators to measure the efficacy of anti-tumor drugs. It refers to the proportion of patients whose tumor volume is reduced by 30% and can be maintained for more than 4 weeks. This proportion is the sum of the number of patients with complete remission (CR) and partial remission (PR).

[0334] The term "disease control rate" or "DCR" as used herein refers to the percentage of tumor patients with complete remission (CR), partial remission (PR) and stable disease (SD) after receiving a certain treatment.

[0335] The terms "complete remission (CR)", "partial remission (PR)", "stable disease (SD)" and "progressive disease (PD)" are terms commonly used in the art to evaluate the effectiveness of tumor treatment and have the meanings commonly understood in the art. Generally, complete remission (CR) means that the tumor has completely disappeared, and this disappearance lasts for at least one month. Partial remission (PR) means that the tumor volume has decreased, but it has not completely disappeared. Generally, when the tumor volume decreases by 50% or more, it is considered a partial remission. Stable disease (SD) means that there is no obvious change in the size of the tumor, which means that the disease has not worsened, but there is no obvious improvement. Progressive disease (PD) means that the size of the tumor has increased or new tumors have appeared, which usually means that the patient's tumor is not well controlled.

[0336] As used herein, the term "overall survival" or "OS" refers to the time from the first dose of an investigational drug to the death of a patient from any cause.

[0337] The term "progression-free survival" or "PFS" as used herein refers to the time from the first use of an investigational drug to the occurrence of disease progression or death from any cause.

[0338] The terms "cancer", "tumor" and "tumor" used in this article are used interchangeably and refer to tissue masses formed by abnormal and uncontrolled cell proliferation. They can occur in any part of the human body and are characterized by expansion and infiltration into surrounding tissues.

[0339] As used herein, the term "solid tumor" refers to an abnormal mass of tissue that generally does not contain cysts or fluid areas. Solid tumors can be benign (non-cancerous) or malignant (cancer), particularly malignant solid tumors.

[0340] The term "other solid tumors" used in this article refers to solid tumors other than colorectal cancer, melanoma, non-squamous non-small cell lung cancer, hepatocellular carcinoma, and lymphoma, including but not limited to renal cancer, esophageal cancer (such as esophageal squamous cell carcinoma), gastric cancer (such as gastric and gastroesophageal junction adenocarcinoma), pancreatic cancer, breast cancer (such as triple-negative breast cancer), bile duct cancer, ovarian cancer, cervical cancer, endometrial cancer, head and neck cancer (such as head and neck squamous cell carcinoma), etc.

[0341] The term "standard treatment failure" as used herein means that the cancer associated with the term has not brought significant therapeutic benefits to the patient after treatment with at least one first-line treatment drug, or even all available treatment drugs. For example, the term "advanced melanoma that has failed previous immunotherapy" as used herein means that patients with advanced melanoma have no significant therapeutic benefits after treatment with immunotherapy. Interleukin-2 (IL-2) is a cytokine secreted mainly by antigen-activated CD4+ T cells with a molecular weight of approximately 15.5kDa. IL-2 is one of the earliest immunotherapies approved for anti-tumor treatment. The FDA approved high-dose IL-2 for the treatment of metastatic renal epithelial cell carcinoma and metastatic melanoma in 1992 and 1998, respectively. If a patient with advanced melanoma has been treated with IL-2 but no significant therapeutic benefit is observed, it is considered "advanced melanoma that has failed previous immunotherapy."

[0342] The term "intolerant to standard treatment" as used herein means that the cancer to which the term relates is treated with at least one first-line treatment drug, or even all available treatment drugs, causing excessive side effects to the patient, resulting in an inappropriate benefit / risk ratio.

[0343] The term "pharmaceutically acceptable" as used herein means that the substances, compositions, dosage forms, etc. described thereafter do not have excessive toxicity, irritation, allergic reactions or other undesirable properties to mammals, especially humans, and have a reasonable benefit / risk ratio when applied to animals or humans.

[0344] The term "pharmaceutically acceptable salt" as used herein includes, but is not limited to, acid addition salts or base addition salts, for example, acid addition salts formed with inorganic acids, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; and acid addition salts formed with organic acids, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, and salts with the formula HOOC-(CH2) n -COOH (wherein n is 0-4) and alkanedicarboxylic acid salts, etc. "Pharmaceutically acceptable salts" also include base addition salts formed by compounds with acidic groups and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium and ammonium.

[0345] The term "pharmaceutical composition" as used herein refers to a single pharmaceutical preparation comprising an active ingredient and optionally one or more pharmaceutically acceptable excipients. The pharmaceutical preparation can be used for various routes of administration, such as oral administration, parenteral administration, topical administration, etc. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intraarterial, intramuscular, intraarticular, intrasynovial, intrasternal, intraspinal, intracranial bolus or infusion, etc. The pharmaceutical preparation can be in any suitable dosage form, such as tablets, hard capsules, soft capsules, powders, suppositories, solutions, emulsions, suspensions, gels, creams, ointments, sprays, etc. Pharmaceutically acceptable excipients suitable for preparing various preparations are known in the art (see, for example, Luo Mingsheng and Gao Tianhui, eds., "Compendium of Pharmaceutical Excipients", 2nd edition, January 2006, Sichuan Science and Technology Press). For example, excipients used to prepare tablets or hard capsules include diluents (such as corn starch, lactose, dextrose, sucrose, mannitol, sorbitol, and cellulose), lubricants (such as magnesium stearate), disintegrants (such as cross-linked sodium carboxymethylcellulose and sodium starch glycolate), binders (such as starch paste and povidone), colorants (such as titanium dioxide, β-carotene, and sunset yellow), etc. Excipients used to prepare injections include solvents (such as water for injection, glucose solution, physiological saline, and 1,3-butanediol), surfactants (such as Tween 80), etc. Pharmaceutical compositions can contain 1-99% w / w, preferably 1-50% w / w, and more preferably 1-20% w / w of the active ingredient.

[0346] As used herein, the term "pharmaceutical combination" may be a fixed combination, i.e., a single pharmaceutical composition comprising a first active ingredient and a second active ingredient, or a non-fixed combination (e.g., a kit or pack) comprising: a pharmaceutical composition comprising the first active ingredient, a pharmaceutical composition comprising the second active ingredient, and instructions describing a method for administering the pharmaceutical composition. The active ingredients in the pharmaceutical combination of the present invention may be administered in a single pharmaceutical composition or in separate pharmaceutical compositions, administered simultaneously, without specific time restrictions, or administered separately at equal or different time intervals, to provide a beneficial therapeutic effect in the patient, preferably such that the two active ingredients exhibit additive, enhanced, or synergistic therapeutic effects in the patient, and / or fewer side effects.

[0347] The pharmaceutical combination of the present invention may further comprise, in addition to the first active ingredient and the second active ingredient, another active ingredient, provided that the aforementioned beneficial effects of the first active ingredient and the second active ingredient are not affected. Similarly, the other active ingredient may be in the same pharmaceutical composition as the first active ingredient and / or the second active ingredient or in separate pharmaceutical compositions. The active ingredients in the pharmaceutical combination of the present invention may have the same or different dosage forms and may be administered by the same or different routes of administration.

[0348] The dosing regimen and dosage of the active ingredients in the pharmaceutical combination of the present invention are selected based on a variety of factors, including the type, species, age, weight, sex and overall health of the patient; the disease to be treated and its severity; the route of administration, etc. A physician, clinician or veterinarian with ordinary skills can easily determine the effective amount required.

[0349] As used herein, the term "about" when used in reference to a particular stated value means that the value may vary by no more than 5%, preferably no more than 1%, of the stated value. For example, the expression "about 100" as used herein includes 95 and 105 and all values ​​therebetween (e.g., 95.1, 95.2, 96, etc.).

[0350] All numerical ranges herein should be understood to disclose each numerical value (including end values) and numerical value subset within the range, regardless of whether the numerical value or numerical value subset is specifically disclosed in addition. For example, when any numerical range is mentioned, it should be deemed to mention each numerical value within the numerical range. The present invention relates to all values ​​falling within these ranges, all smaller ranges, and the upper or lower limit of the range of numerical values.

[0351] It will be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present invention. The scope of the present invention is limited only by the appended claims.

[0352] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the invention belongs. In this document, technical and scientific terms not specifically defined herein have the meaning commonly understood by one of ordinary skill in the art to which the invention belongs. BRIEF DESCRIPTION OF THE DRAWINGS

[0353] FIG1 is a schematic diagram of the structure of the PD-1 / IL-2R bispecific antibody fusion protein 2149.

[0354] FIG2 is a dosing regimen for the Phase Ia clinical study of molecule 2149.

[0355] FIG3 shows the dosing schedule for the Phase Ia clinical study of molecule 2149 and / or bevacizumab. Example

[0356] The following examples are provided to illustrate the present invention. These examples are illustrative only and do not limit the scope of the present invention and the appended claims in any way. Likewise, the present invention is not limited to any specific preferred embodiments described herein. Those skilled in the art may modify the present invention without departing from the spirit and scope of the present invention.

[0357] Example 1. Phase Ia / Ib Clinical Study of PD-1 / IL-2R Bispecific Antibody Fusion Protein 2149 in Subjects with Advanced Solid Tumors or Lymphomas

[0358] The PD-1 / IL-2R bispecific fusion protein 2149 has been studied in multiple different cancer models, including metastatic cancer models and PD-1 resistance models. The results of these preclinical studies showed that the PD-1 / IL-2R bispecific fusion protein 2149 showed anti-tumor activity and prolonged survival in different cancer models. In the crab-eating monkey experiment, molecule 2149 also showed good efficacy at a tolerable dose level. These results indicate that molecule 2149 treatment has potential therapeutic benefits for patients with recurrent or refractory tumors who have limited treatment options and no known radical cure.

[0359] During this trial, risks will be continuously assessed and safety data will be regularly evaluated. If any evidence is found indicating that there are risks that make continued trial unjustified, this clinical trial will be terminated.

[0360] The Phase Ia clinical trial aims to determine the maximum tolerated dose (MTD) of the drug through dose-limiting toxicity (DLT) observation according to the dose escalation scheme of the trial plan.

[0361] To avoid the discomfort or additional risks associated with venipuncture and multiple blood sample collections, this trial permitted the use of indwelling intravenous catheters. Furthermore, the blood sample collection design minimized the number of sample collections and the total blood volume, while still meeting the requirements for the pharmacokinetic study of the study drug, to reduce associated risks and improve subject compliance.

[0362] 1. Study objectives and endpoints

[0363] 2. Study Design

[0364] Study plan

[0365] This is an open-label, multicenter Phase Ia / Ib study designed to evaluate the safety, tolerability, and preliminary efficacy of molecule 2149 in subjects with advanced, recurrent, or metastatic solid tumors or lymphomas, determine the maximum tolerated dose (MTD) or maximum administered dose (MAD), and ultimately determine the recommended Phase II dose (RP2D).

[0366] Phase Ia, Part A:

[0367] The dose-escalation study of Part A of Phase Ia will adopt accelerated titration and Bayesian optimal interval (BOIN) design in stages, with a total of 8 dose groups and a planned maximum sample size of 48 cases.

[0368] Molecule 2149 is administered by intravenous infusion once a week (QW), with a DLT observation period of 21 days after the first dose. After the DLT observation period, subjects will continue to receive the same dose of study drug until disease progression, intolerable toxicity, the subject's unwillingness to continue participating in the study, other reasons for discontinuing study treatment, or 24 months of treatment (whichever occurs first).

[0369] Accelerated titration phase:

[0370] The accelerated titration dose escalation phase was divided into four dose groups (0.2 μg / kg, 2 μg / kg, 10 μg / kg, and 30 μg / kg). The starting dose and dosing frequency of molecule 2149 were 0.2 μg / kg, QW. In the accelerated titration phase, one subject was enrolled in each dose group. If no CTCAE ≥ grade 2 toxicity related to molecule 2149 was observed during the DLT observation period, the subsequent dose groups continued to adopt the accelerated titration design and enrolled one subject for DLT observation; if CTCAE ≥ grade 2 toxicity related to molecule 2149 was observed during the DLT observation period (fever, nausea / vomiting, anemia, fatigue, and any grade 2 symptoms or abnormal laboratory test values ​​present at baseline), two more subjects were enrolled at the current dose, and the dose escalation was carried out using the BOIN design starting from this dose group. (For example, during the accelerated titration phase, one subject is enrolled in the 30 μg / kg dose group. If CTCAE grade ≥ 2 toxicity related to molecule 2149 is observed during the DLT observation period, the dose will be increased starting from the 30 μg / kg dose group and the study will be switched to a BOIN design to continue enrolling subjects.)

[0371] BOIN dose escalation phase:

[0372] The BOIN dose escalation phase has four dose groups (100μg / kg, 300μg / kg, 600μg / kg and 1mg / kg). The target toxicity rate of the maximum tolerated dose in the dose escalation part of this study is 0.3. Each dose group is allowed to enroll 3-6 subjects for the first time. After the DLT observation is completed, if subsequent enrollment is still required according to the dose increase / exclusion rules, the dose group will continue to enroll subjects for treatment. The MTD is defined as the dose level at which the DLT incidence rate is closest to the target toxicity rate (i.e., 0.3) within 21 days (28 days for Q2W dosing) of the subject's first receipt of the study drug. The dose increase / exclusion decision depends on the posterior probability of the toxicity rate. If the probability that the posterior DLT incidence rate of the current dose is greater than the target toxicity rate is greater than 95%, the current and above doses will be eliminated. Please refer to the table below for specific dose increase / exclusion rules.

[0373] Footnote: If more than 12 people are dosed at a single dose in extreme cases, refer to the BOIN-designed dosage rule table at https: / / trialdesign.org / .

[0374] The conditions for early termination of the dose escalation study are: 1) the lowest dose is eliminated due to toxicity; or 2) the number of subjects at a certain dose reaches 6 and the next group of subjects is allocated to maintain the original dose; or 3) the total number of subjects in the trial reaches the maximum sample size of 48.

[0375] During the dose escalation phase, if a subject experiences DLT, the dosing interval for subsequent dosing for that subject may be extended based on human pharmacokinetics, safety data, preclinical data, etc., after discussion with the investigator. During the dose escalation phase, if the following situations occur, including but not limited to considering that subsequent QW escalation of subjects cannot be performed, the dosing frequency may be adjusted based on human pharmacokinetics, safety data, preclinical data, etc., after discussion with the investigator, to dose escalation once every two weeks (Q2W) or once every three weeks (Q3W). The DLT observation period is 28 days (Q2W) and 21 days (Q3W) after the first dose, respectively.

[0376] During the dose escalation phase, if the MTD is not observed, higher doses may be explored based on human pharmacokinetics, safety data, preclinical data, etc., after discussion with researchers.

[0377] Phase Ia, Part B:

[0378] The sponsor may further expand the enrollment, observe safety, and conduct dose optimization studies (including but not limited to extending the dosing interval, etc.) based on the PK, safety, and preliminary efficacy data of Phase Ia Part A. Specifically:

[0379] (1) Select the safety-certified dose groups in Part A of Phase Ia, and enroll 3-20 subjects in each dose group for QW / Q2W / Q3W dosing studies.

[0380] (2) After the safety assessment of Part A of Phase Ia is completed at 600 μg / kg QW, Part B will proceed to 1 mg / kg Q3W and 1 mg / kg Q2W. Initially, 3-6 subjects will be enrolled for safety assessment. If no intolerable safety signals are observed, the dose group will continue to be enrolled. If intolerable safety signals are observed, the safety assessment committee will decide to explore other doses or other dosing intervals based on human pharmacokinetics, safety data, preclinical data, etc. Each dose group can enroll 10-30 subjects. Enrollment of each dose group can be carried out simultaneously or sequentially.

[0381] (3) After the safety assessment of Part B is completed for the 1 mg / kg Q3W and 1 mg / kg Q2W doses, Part B will be conducted with the 1.5 mg / kg Q3W dose. Initially, 3-6 subjects will be enrolled for safety assessment. If no intolerable safety signals are observed, the dose group will continue to be enrolled. If intolerable safety signals are observed, the safety assessment committee will decide to explore other doses or other dosing intervals based on human pharmacokinetics, safety data, preclinical data, etc. Each dose group can enroll 10-30 subjects.

[0382] (4) After the safety evaluation of Part B is completed at 1.5 mg / kg Q3W, the drug will be administered at 2 mg / kg Q3W. Initially, 3-6 subjects will be enrolled for safety evaluation. If no intolerable safety signals are observed, the dose group will continue to be enrolled. If intolerable safety signals are observed, the Safety Assessment Committee will decide to explore other doses or other dosing intervals based on human pharmacokinetics, safety data, preclinical data, etc. Each dose group can enroll 10-30 subjects.

[0383] (5) After the safety assessment of Part B is completed at 2 mg / kg Q3W, the drug will be administered at 2 mg / kg Q2W and 3 mg / kg Q3W. First, 3-6 subjects will be enrolled for safety assessment. If no intolerable safety signals are seen, the dose group will continue to be enrolled. If intolerable safety signals are seen, the Safety Assessment Committee will decide to explore other doses or other dosing intervals based on human pharmacokinetics, safety data, preclinical data, etc. Each dose group can enroll 10-30 subjects. Enrollment of each dose group can be carried out simultaneously or sequentially.

[0384] (6) Part B combined therapy dose exploration: After the safety evaluation of Part B 1.5mg / kg Q3W single drug is completed, the dose exploration of Part B combined with bevacizumab (trade name: Dayouton) will be carried out. The dosing regimen of molecule 2149 includes three dose groups: 1.5mg / kg Q3W, 2mg / kg Q3W, and 3mg / kg Q3W (it may also be possible to increase the dose of molecule 2149 combination that has been verified to be safe, or explore other doses based on the accumulated safety data, efficacy data, PK / PD data and other molecule 2149 clinical research data, etc.), and the dose of bevacizumab is 7.5mg / kg Q3W. First, 3-6 subjects will be enrolled for safety evaluation. If no intolerable safety signals are found, the dose group can continue to expand the enrollment. If intolerable safety signals are found, the safety assessment committee will decide to explore other doses or other dosing intervals based on human pharmacokinetics, safety data, preclinical data, etc. Each dose group can enroll 10-30 subjects. Based on the accumulated safety data from monotherapy, dose escalation of combination therapy may involve administering a low-dose 2149 (≤100 μg / kg) (C1D-7) as a priming dose, followed by a planned dose of 2149 seven days later (C1D1, ±1 day). For example, for the 2 mg / kg and 3 mg / kg dose groups, after discussion with the investigator, a single dose of 100 μg / kg of 2149 could be administered on C1D-7, followed by 2 mg / kg or 3 mg / kg of 2149, respectively, seven days later (C1D1, ±1 day). Sponsors will likely evaluate the benefits and risks of escalated dosing by comparing the safety and efficacy of the two dosing regimens.

[0385] For tumor types where efficacy signals are observed, the same tumor type and the same dosing regimen (including combined bevacizumab treatment) can be further expanded to 20 to 50 subjects based on the original preset sample size. Researchers can also terminate the exploration of a certain dosing method early based on the efficacy, safety, clinical pharmacology and other data obtained. During the implementation process, the sponsor may further adjust the number of enrolled cases based on PK, preliminary efficacy and safety data, and the actual number of enrolled cases may be different from the planned number of enrolled cases. At the same time, based on the preliminary analysis results of anti-tumor efficacy and biomarkers, some populations with specific biomarkers may be prospectively enrolled in specific tumor types in the future, such as expanding the enrollment of approximately 30 patients with advanced colorectal cancer with PD-L1 CPS ≥ 1.

[0386] Phase Ia, Part C

[0387] Phase Ia Part C is a randomized, controlled dose optimization phase. This phase can proceed after safety evaluation of the 3 mg / kg dose every 3 weeks (generally requiring at least six subjects to receive this dose for at least one cycle). This phase will enroll 60-90 patients with advanced non-small cell lung cancer (NSCLC) without known driver mutations who have failed prior immunotherapy. They will be randomly assigned in a 1:1:1 ratio to receive 2149 600 μg / kg every 3 weeks, 1.5 mg / kg every 3 weeks, or 3 mg / kg every 3 weeks. (Participants will receive a low-dose 2149 ≤ 100 μg / kg as a priming dose on C1D-7, followed by a planned full-dose 2149 dose seven days later (C1D1, ±1 day). Randomization will be stratified by tumor pathology (adenocarcinoma vs. squamous cell carcinoma) and number of prior systemic treatment lines (1 vs. ≥2 lines). The sponsor may decide to discontinue enrollment in a particular dose group based on a comprehensive review of previous data. The sponsor may decide whether to further expand enrollment based on PK, preliminary efficacy and safety data.

[0388] Phase Ib

[0389] The researchers and sponsor determined the recommended dose and frequency of molecule 2149 in Phase Ib based on the PK, safety, and efficacy data obtained in Phase Ia. Phase Ib is a preliminary study to evaluate the safety and efficacy of molecule 2149 in subjects with advanced or metastatic solid tumors or lymphomas, and includes the following cohorts:

[0390] Cohort A: subjects with advanced colorectal cancer who failed standard treatment:

[0391] Cohort A2: Approximately 30-60 subjects with advanced colorectal cancer who have failed standard treatment will be enrolled and treated with molecule 2149 combined with bevacizumab.

[0392] Note:

[0393] 1) The doses of molecule 2149 and bevacizumab will be determined by the sponsor and investigators after reviewing the Phase Ia clinical data and other molecule 2149 clinical study data. During the trial, the dose or frequency of molecule 2149 and / or bevacizumab may be adjusted based on a comprehensive analysis of safety, efficacy, PK, and PD data from enrolled subjects.

[0394] 2) During the enrollment process, based on the preliminary analysis results of anti-tumor efficacy and biomarkers, some populations with specific biomarkers, such as those with PD-L1 CPS ≥ 1, may be prospectively enrolled.

[0395] 3) During the trial, as data accumulates, after discussion between the sponsor and the investigator, subjects with specific disease characteristics (e.g., subjects without liver metastasis) may be further enriched.

[0396] Cohort B: Subjects with advanced melanoma:

[0397] Cohort B1: 20-30 patients with advanced melanoma who had not undergone immunotherapy were enrolled and treated with molecule 2149 combined with bevacizumab.

[0398] Cohort B2: 20-40 patients with advanced melanoma who had previously failed immunotherapy were enrolled and received molecule 2149 combined with bevacizumab.

[0399] Cohort B3: 20-30 subjects with advanced melanoma who have not received systemic treatment were enrolled and received molecule 2149 combined with dacarbazine.

[0400] Cohort C: Subjects with advanced non-small cell lung cancer who have failed or are intolerant to standard treatment:

[0401] Cohort C1: 20-60 subjects with advanced non-small cell lung cancer who have failed or are intolerant to standard treatment will be enrolled and receive molecule 2149 monotherapy.

[0402] Cohort C2: 20-80 subjects with non-squamous advanced non-small cell lung cancer who failed or were intolerant to standard treatment were enrolled and received treatment with molecule 2149 combined with bevacizumab.

[0403] Cohort C3: 20-80 subjects with advanced non-small cell lung cancer who failed or were intolerant to standard treatment were enrolled and received treatment with molecule 2149 combined with anlotinib.

[0404] Cohort D: 20-60 subjects with advanced hepatocellular carcinoma who have not received systemic treatment were enrolled and treated with molecule 2149 combined with bevacizumab.

[0405] Cohort E: 20-60 patients with advanced renal cell carcinoma who failed or were intolerant to standard treatment were enrolled and received molecule 2149 combined with bevacizumab.

[0406] Cohort F: 20-40 subjects with other advanced solid tumors or lymphomas who have failed or are intolerant to standard treatment will be enrolled and treated with molecule 2149 combined with bevacizumab.

[0407] During the enrollment process of the above cohorts, based on the preliminary analysis results of anti-tumor efficacy and biomarkers, some specific biomarker populations may be prospectively enrolled in the future, such as tumor-related CD8 + T cells ≥ 1% of the population, or based on the tumor tissue CD8 with the best clinical benefit +T cell cut-off value is used to enrich the population; or the population with PD-L1 CPS ≥ 1.

[0408] If, during the course of the trial, an adverse change in the risk / benefit ratio of a cohort of subjects is found, further enrollment of this cohort may be stopped to protect the safety of the subjects after discussion between the investigator and the sponsor.

[0409] Supplementary Notes

[0410] This study allows subjects to undergo self-dose escalation. After comprehensively evaluating the possible clinical benefits and potential safety risks of the subjects, the researchers and sponsors will decide whether they can enter treatment at a higher dose level that has been confirmed to be safe. After self-dose escalation, all subject safety monitoring, PK sampling, tumor imaging examinations and other visits should continue to follow the previous arrangements. For subjects receiving molecule 2149 monotherapy, after the researchers and sponsors comprehensively evaluate the possible clinical benefits and potential safety risks of the subjects, the subsequent treatment cycle can be adjusted to molecule 2149 combined with bevacizumab treatment.

[0411] For patients receiving a single dose of ≥600 μg / kg, a single low-dose 2149 (≤100 μg / kg) (C1D-7) is recommended as a priming dose, followed by scheduled administration of the normal dose of 2149 7 days later (C1D1, ±1 day). For example, for patients receiving 2 mg / kg Q3W, 2 mg / kg Q2W, and 3 mg / kg Q3W, after discussion with the investigator, a single dose of 100 μg / kg of 2149 is recommended on C1D-7, followed by administration of 2 mg / kg Q3W, 2 mg / kg Q2W, and 3 mg / kg Q3W, respectively, 7 days later (C1D1, ±1 day). The sponsor will evaluate the benefits and risks of a graded dosing regimen by comparing the safety and efficacy of the two dosing regimens (with and without a priming dose). It will also be possible to compare the differences in safety, efficacy, PK and biomarkers of different initial doses (e.g., 30 μg / kg and 100 μg / kg) to select the optimal initial dose.

[0412] Subjects will receive study drug treatment until disease progression, intolerable toxicity, the subject's unwillingness to continue participating in the study, other reasons for stopping study treatment, or the treatment duration reaches 24 months (whichever occurs first).

[0413] As the research progresses and data accumulates, after discussion between the sponsor and the investigator, for subjects in whom clinical benefits are observed (e.g., achieving SD or above efficacy and lasting for more than 2 months), the dosing interval of molecule 2149 may be extended (e.g., 3 to 8 weeks) for maintenance treatment, or sintilimab may be used for maintenance treatment instead; it is also possible to adopt a fixed treatment cycle of molecule 2149 followed by sintilimab maintenance treatment, for example: 4 to 6 cycles of molecule 2149 induction treatment, followed by sintilimab maintenance treatment.

[0414] This study evaluated the efficacy of the subjects according to RECIST v1.1 or Lugano 2014 criteria. Tumor imaging was performed every 6 weeks (±7 days) after C1D1 until disease progression, initiation of new anti-tumor therapy, unwillingness to continue the study, loss to follow-up, death, or study termination (whichever occurred first).

[0415] Subjects will undergo an end-of-treatment visit within 10 days of confirmed discontinuation of treatment. Safety follow-up should be conducted 30 (+7) days after the last dose, followed by survival follow-up (every 12 weeks ±7 days).

[0416] 2.2. Dose-limiting toxicity (DLT)

[0417] In this study, DLT refers to any of the following adverse events related to 2149 and meeting the following severity levels, occurring between Days 1 and 21 (28 days for Q2W dosing) in the Phase Ia accelerated titration and BOIN dose escalation phases. The severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (CRS will be evaluated according to the CRS criteria). During the accelerated titration phase, if a subject receives less than 75% of the intended dose in the first cycle due to reasons other than toxicity (e.g., disease progression, missed appointments, non-compliance, subject withdrawal), the sponsor may replace the subject with a new one.

[0418] (1) Hematological toxicity:

[0419] Grade 4 neutropenia lasting more than 5 days;

[0420] Febrile neutropenia, defined as an absolute neutrophil count (ANC) <1.0 x 10 9 / L and a single temperature > 38.3°C or a continuous temperature (> 1 hour) ≥ 38°C;

[0421] Grade 3 thrombocytopenia with bleeding or transfusion required;

[0422] Grade 4 thrombocytopenia;

[0423] Grade 4 anemia that cannot be explained by underlying disease;

[0424] (2) Non-hematological toxicity:

[0425] Grade ≥3 irAEs (excluding well-controlled grade 3 endocrine disorders and grade 3 tumor-site inflammatory reactions) that do not improve to grade ≤2 within 7 days or to grade ≤1 within 21 days after intervention.

[0426] Any other grade ≥3 non-hematologic toxicity, except for the following:

[0427] √Grade 3 fatigue, fever or constipation;

[0428] √ Grade 3 nausea, vomiting, or diarrhea lasting ≤ 3 days after best supportive care;

[0429] √First-time transient grade 3 CRS, for example, recovery to baseline or ≤ grade 1 within 72 hours;

[0430] Grade 3 skin toxicity that improves within 24 hours with treatment (e.g., chlorpheniramine maleate);

[0431] √Grade 3 hypotension or hypertension;

[0432] √Grade 3 capillary leak syndrome lasting ≤7 days;

[0433] Grade 3 allergic reactions, such as immediate allergic reactions that can be quickly controlled by symptomatic treatment;

[0434] √ In the event of Grade 3 QTc prolongation (QTcF ≥ 501ms) in asymptomatic subjects, it is recommended to immediately repeat the test, be re-evaluated by professionals, and correct potential reversible causes, such as electrolyte abnormalities or hypoxia. If Grade 3 QTc prolongation persists after any reversible cause is corrected, the event is considered a DLT;

[0435] Grade 3 asymptomatic electrolyte abnormalities lasting ≤ 3 days, without clinical complications, and recovering on their own or responding to appropriate medical intervention;

[0436] √ Asymptomatic Grade 3 amylase or lipase elevation; Grade 3 glutamyltransferase elevation, Grade 3 ALT or AST elevation that persists for <7 days despite intervention;

[0437] Grade 3 bone / joint pain lasting ≤ 3 days, without clinical complications, and recovering on its own or responding to appropriate medical intervention;

[0438] √ Other laboratory test abnormalities that are considered by the investigator to be grade 3 asymptomatic, not clinically significant, and capable of spontaneous recovery or resolution with appropriate medical intervention.

[0439] (3) Liver function test results that meet Hy's rule criteria:

[0440] Elevation of AST and / or ALT >3× ULN (or >3× baseline if elevated due to liver involvement at study entry), and

[0441] Total bilirubin ≥2 × ULN in the absence of cholestasis (ie, serum alkaline phosphatase [ALP] <2 × ULN), and

[0442] ●Unexplained findings such as viral liver injury, previous or acute liver disease, or other medications or conditions that can cause liver injury.

[0443] (4) Any death related to the study drug cannot be ruled out.

[0444] (5) Any other toxicity of any grade that the investigator and the sponsor consider necessary to terminate the disease early after discussion.

[0445] Remark:

[0446] Grade 3 or 4 infusion-related reactions (IRRs) are not considered DLTs. However, if a Grade 4 IRR or Grade 3 IRR occurs after premedication, the subject will need to stop study treatment and be replaced with a new subject.

[0447] ●All grade ≥3 irAEs require review by the safety assessment committee to determine whether they are DLTs.

[0448] DLT can evaluate subjects who meet any of the following conditions:

[0449] (a) During the dose-escalation phase, a DLT occurred within the DLT observation window.

[0450] (b) Receive at least 75% of the planned dose in Cycle 1 and complete the DLT observation window. If dosing is delayed due to treatment-related toxicity during the DLT observation period, the DLT observation period will be extended, which will be determined by the Safety Assessment Committee.

[0451] During the accelerated titration phase, subjects who do not meet the above conditions will need to be recruited as new subjects.

[0452] 2.3. Maximum tolerated dose (MTD) and maximum administered dose (MAD)

[0453] The MTD was defined as the dose level at which the DLT rate was closest to the target toxicity rate (i.e., 0.3) within 21 days (28 days for Q2W dosing) of the subject's first dose of study drug.

[0454] During the dose-escalation phase, once the MTD is reached, that dose becomes the maximum administered dose (MAD). If the MTD is not reached, the highest dose in each part of the study design becomes the MAD. In this study, if the MTD is not reached, the maximum dose in the Phase Ia dose-escalation phase is 1 mg / kg.

[0455] 3. Study Population

[0456] 3.1 Inclusion criteria

[0457] Included subjects (subjects must meet all of the following criteria):

[0458] (1) Sign the written informed consent and be able to comply with the visit arrangements and related procedures specified in the protocol.

[0459] (2) Age ≥ 18 years old, regardless of gender.

[0460] (3) Unresectable locally advanced or metastatic solid tumors or lymphomas confirmed by histology or cytology;

[0461] Phase Ia study:

[0462] Priority is given to patients with advanced colorectal cancer, melanoma, non-small cell lung cancer, triple-negative breast cancer, pancreatic cancer, bile duct cancer, ovarian cancer, cervical cancer, and head and neck squamous cell carcinoma. The Phase Ia Part B specific biomarker enrichment cohort includes patients with advanced colorectal cancer confirmed by histopathology with a PD-L1 CPS ≥ 1 and confirmed as proficient mismatch repair (pMMR) or microsatellite stable (MSS) according to local standards. Phase Ia Part C dose optimization includes patients with histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer that is inoperable and ineligible for radical concurrent chemoradiotherapy, according to the 8th edition TNM staging system for lung cancer by the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification. For non-squamous non-small cell lung cancer, the absence of known driver gene mutations (including at least EGFR, ALK, ROS1, and cMET, and written evidence must be provided) must be confirmed by histological or cytological specimens. For squamous non-small cell lung cancer, if driver gene mutation testing has been performed in the past, the absence of known driver gene mutations (including at least EGFR, ALK, ROS1, and cMET, and written evidence must be provided) must be confirmed by histological or cytological specimens.

[0463] Phase Ib study, including 6 cohorts, including:

[0464] Cohort A: subjects with histopathologically confirmed advanced colorectal cancer, confirmed as proficient mismatch repair (pMMR) or microsatellite stable (MSS) by local criteria;

[0465] Cohort B: subjects with advanced melanoma confirmed by histopathological examination;

[0466] Cohort C: subjects with advanced non-small cell lung cancer confirmed by histopathological examination;

[0467] Cohort D: unresectable or metastatic hepatocellular carcinoma confirmed by histopathological examination;

[0468] Cohort E: subjects with advanced renal cell carcinoma confirmed by histopathological examination;

[0469] Cohort F: other advanced solid tumors or lymphomas confirmed by histology or cytology.

[0470] (4) Phase Ia and Phase Ib cohorts A, C, E, and F: subjects who have progressed after at least one line of standard treatment, or are not suitable for standard treatment due to intolerable toxicity, or have no standard treatment (Note: patients who have failed PD-1 / PD-L1 treatment are allowed to be included).

[0471] Phase Ia Part C Dose Optimization: Patients who have failed at least one line of systemic anti-cancer therapy, including immunotherapy.

[0472] Phase Ib cohorts B3 and D: Patients who had not previously received any systemic anti-tumor treatment for advanced melanoma or hepatocellular carcinoma.

[0473] Phase Ib Cohort B1: Patients who have not received prior systemic immunotherapy for advanced melanoma.

[0474] Phase Ib Cohort B2: Patients who have failed at least one line of systemic anti-tumor treatment, including immunotherapy.

[0475] (5) At least one measurable lesion according to RECIST v1.1 (solid tumors) or Lugano 2014 (lymphoma) criteria.

[0476] (6) Eastern Cooperative Oncology Group performance status score (ECOGPS) is 0 or 1.

[0477] (7) Expected survival time ≥ 3 months.

[0478] (8) Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age agree to strictly take effective contraceptive measures throughout the treatment period and for 6 months after the treatment period.

[0479] 3.2 Exclusion criteria

[0480] Subjects should not be included in this study if they meet any of the following criteria:

[0481] (1) Pregnant or lactating women, or women who plan to become pregnant before, during, or within 6 months after the last dose of the study drug.

[0482] (2) Active or untreated central nervous system metastases (such as brain or leptomeningeal metastases) confirmed by imaging assessment during the screening period or previous imaging assessment. Patients with asymptomatic brain metastases can participate in this study. Patients whose symptoms have been stable for ≥2 weeks after treatment of brain metastases and whose brain metastases have not increased or further enlarged after the end of treatment can also participate in this study as long as they meet all of the following criteria:

[0483] ◆Measurable lesions outside the central nervous system;

[0484] ◆No metastases to the meninges, midbrain, pons, medulla oblongata, or spinal cord, and no multiple cerebellar metastases;

[0485] ◆No compression of the cerebral aqueduct, third or fourth ventricle, or spinal cord;

[0486] ◆Stop hormone therapy 14 days before the first dose of study drug.

[0487] (3) For lymphoma: patients with blood malignancies other than lymphoma.

[0488] (4) Baseline * Any of the following hematological abnormalities (within 7 days before the first dose of study drug) (if lymphoma involves the bone marrow, the investigator may adjust the inclusion criteria at his / her discretion):

[0489] Hemoglobin <90 g / L

[0490] Absolute neutrophil count (ANC) <1.5 × 109 / L

[0491] Platelet count <100 × 109 / L

[0492] Eosinophil count >1.5 × ULN (Upper limit of normal)

[0493] *Throughout the protocol, "baseline" is defined as the last available observation before the first dose of study drug. Subjects must not have received blood product transfusions (including red blood cell suspensions, apheresis platelets, cryoprecipitate, etc.), erythropoietin, or colony-stimulating factors, or other supportive therapies within 7 days prior to blood sample collection.

[0494] (5) Any of the following serum biochemical abnormalities at baseline (within 7 days before the first dose):

[0495] Total bilirubin >1.5× the upper limit of normal (ULN) (if conjugated bilirubin is ≤ULN, inclusion in the study is allowed);

[0496] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × ULN;

[0497] Serum creatinine >1.5×ULN or creatinine clearance (CCr) <45 mL / min (CCr calculated using the Cockcroft-Gault formula (actual body weight)).

[0498] ◆Albumin <32g / L.

[0499] (6) Any of the following coagulation parameter abnormalities at baseline (within 7 days before the first dose):

[0500] International normalized ratio (INR) >1.5 × ULN (>3 × ULN if receiving stable anticoagulation);

[0501] Partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT]) >1.5 × ULN (>3 × ULN if receiving stable anticoagulation).

[0502] (7) History of active thrombosis, deep vein thrombosis, or pulmonary embolism within 4 weeks before the first dose of study drug, unless the patient has been adequately treated and the investigator believes the condition is stable.

[0503] (8) Active uncontrolled bleeding or known bleeding tendency.

[0504] (9) Cardiovascular and cerebrovascular diseases with significant clinical significance, including:

[0505] ◆Need for antiarrhythmic drug treatment due to ventricular arrhythmia or other uncontrolled arrhythmias;

[0506] Severe conduction disturbances (such as third-degree atrioventricular block);

[0507] HR-corrected QT interval (QTc interval, calculated using the Fridericia method) ≥ 480 ms;

[0508] ◆Uncontrolled arterial hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) despite standard treatment;

[0509] ◆History of myocarditis;

[0510] Left ventricular ejection fraction (LVEF) < 50%;

[0511] ◆Current congestive heart failure requiring treatment;

[0512] ◆Class III or IV cardiovascular disease according to the New York Heart Association (NYHA) cardiac function classification;

[0513] ◆History of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty or stent implantation within 6 months before the first dose of study drug.

[0514] ◆ Cerebrovascular accident or transient ischemic attack occurred within 6 months before the first administration of study drug;

[0515] ◆Known to have active epileptic seizures.

[0516] (10) History of interstitial pneumonia, pulmonary fibrosis, pneumoconiosis, drug-related pneumonia, radiation pneumonia, etc. that require steroid hormones or other treatments, as well as severe abnormalities in lung function or other forms of restrictive lung disease.

[0517] (11) History of allergic constitution, asthma, or atopic dermatitis.

[0518] (12) Accompanied by pleural effusion or pericardial effusion requiring repeated drainage or with obvious symptoms.

[0519] (13) Subjects currently or recently (within 6 months) suffer from major gastrointestinal diseases or conditions, including:

[0520] ◆History of inflammatory bowel disease;

[0521] ◆Grade 2 or higher diarrhea occurred within 2 weeks before the first dose of study drug.

[0522] (14) Active autoimmune disease requiring systemic treatment (such as the use of disease-modifying drugs, corticosteroids, or immunosuppressants) occurred within 2 years before the first dose. Replacement therapy (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment;

[0523] (15) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

[0524] (16) Subjects with known or suspected allergies to the study drugs and any excipients.

[0525] (17) The subject has a history of significant toxicity related to the administration of immune checkpoint inhibitors that required permanent discontinuation of treatment.

[0526] (18) Subjects with any previous anti-tumor treatment-related unresolved grade 1 toxicity, except for persistent grade 2 alopecia, peripheral neuropathy, hypomagnesemia, and toxicity that is expected to be irreversible but is stably controlled by medication (such as hypothyroidism stably controlled by replacement therapy, hypertension with blood pressure stably controlled below 160 / 100 mmHg by antihypertensive drug treatment).

[0527] (19) Patients have not fully recovered from previous surgery or have undergone any major surgery within 4 weeks before the first dose of study drug.

[0528] (20) Subjects with uncontrolled tumor-related pain or symptomatic hypercalcemia.

[0529] (21) Known HIV positive, active hepatitis B, hepatitis C (HCV), or tuberculosis.

[0530] Patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) should undergo hepatitis B virus (HBV) DNA testing. If the HBV DNA copy number is ≤2.5×10 3 If the number of copies / ml is ≤500IU / ml or below the detection limit, the subjects can be enrolled. HBsAg(+) subjects should receive anti-HBV treatment during the entire study drug treatment period to avoid viral reactivation. For subjects with anti-HBc(+), HBsAg(-), anti-HBs(-) and HBV viral load(-), they do not need to receive preventive anti-HBV treatment, but need to be closely monitored for viral reactivation;

[0531] ◆Subjects with positive hepatitis C virus serology but negative HCV RNA test or below the detection limit are allowed to be included in the study;

[0532] ◆ Subjects receiving HCV treatment and with undetectable viral load results were allowed to participate in the study.

[0533] (22) Severe / active / uncontrolled infection, infection requiring systemic intravenous antibiotics, or fever of unknown cause (>38°C) within 2 weeks before the first dose of study drug.

[0534] (23) There is any history or current evidence of any disease, treatment, or laboratory abnormality that, in the judgment of the investigator, may compromise the safety of the subject, interfere with obtaining informed consent, affect subject compliance, or affect the safety evaluation of the study drug.

[0535] (24) Suffering from mental illness, altered mental status, or substance abuse that impedes understanding the informed consent process and / or completing necessary research-related evaluations.

[0536] (25) Due to known or foreseeable reasons, the investigator believes that the subject is unable to meet the requirements of the protocol.

[0537] (26) Other malignant tumors diagnosed within 5 years before the first dose, with the exception of radically resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin and / or radically resected carcinoma in situ, as well as localized prostate cancer and papillary thyroid carcinoma after radical resection.

[0538] (27) Excluded drugs and other treatments (subjects must not receive any of the following treatments):

[0539] (a) IL-2 / IL-15 cytokines. The use of IL-2 / IL-15 as an adjunctive component of adoptive cell therapy or as an immunomodulatory therapy for immunocompromised patients is permitted;

[0540] (b) Patients have received any chemotherapy or small molecule targeted therapy within 2 weeks or 5 half-lives (whichever is shorter) before the first dose of study drug and have not experienced delayed toxicity, except for the following:

[0541] ◆Use of nitrosourea antitumor drugs and mitomycin C within 6 weeks before the first dose of study drug.

[0542] (c) Use of any antibody treatment within 4 weeks before the first dose of study drug;

[0543] (d) Participation in any clinical trial of medical devices or other therapeutic interventions within 2 weeks before the first dose of study drug;

[0544] (e) palliative radiotherapy within 2 weeks before the first dose of study drug;

[0545] (f) Use of live vaccines for the prevention of infectious diseases within 28 days before the first dose of study drug;

[0546] (g) Received immunosuppression or systemic steroid therapy (>10 mg / day prednisone equivalent) within 2 weeks before the first dose of study drug.

[0547] Exclusion criteria applicable to specific Phase 1b cohorts:

[0548] Queue A2, Queue B1, Queue B2, Queue C2, Queue D, Queue E, and Queue F:

[0549] (1) The subject has a history of significant toxicity related to bevacizumab administration that requires permanent discontinuation of treatment.

[0550] Queue C3:

[0551] (1) Gastrointestinal diseases or surgical history that the investigator believes may affect the absorption of the oral study drug anlotinib.

[0552] (2) The subject has a history of significant toxicity related to anlotinib and requires permanent discontinuation of treatment.

[0553] 4. Study Treatment and Concomitant Therapy

[0554] 4.1 Treatment options

[0555] *: For details on the specific dosing regimen, please refer to “Study Design”

[0556] 4.2 Preparation and Administration of Study Drug

[0557] Drug 2149 is a sterile injection packaged in vials for intravenous infusion. Available in 3 mg (3 ml) and 12 mg (12 ml) vials, it is a clear to slightly opalescent, colorless to slightly yellowish liquid free of foreign matter.

[0558] Administer 2149 according to the above treatment plan, diluting with 0.9% sodium chloride solution if necessary. The final concentration of 2149 should be maintained between 0.02 and 0.80 mg / ml. Unless otherwise indicated clinically, the infusion time should be controlled within 30 to 60 minutes (± 10 minutes). It is recommended that the prepared solution be used immediately. If not, it can be stored at 2 to 8°C in the dark for 8 hours, or at room temperature for 4 hours (including the infusion time).

[0559] 4.3 Concomitant Therapy

[0560] 4.2.1 Permitted Concomitant Therapy

[0561] Other therapies permitted during the trial included:

[0562] (1) Medication that is judged by the investigator to be in compliance with the protocol (e.g., for the treatment of disease-related symptoms and concomitant treatment of various treatment-related AEs).

[0563] (2) Subjects who need long-term medication due to underlying diseases such as hypertension and diabetes can continue to take medication.

[0564] (3) Preventive treatment or treatment of infusion-related and / or allergic reactions

[0565] (4) Prophylactic use of cell growth factors (except for the first cycle) is permitted based on clinical indications and guidelines. Therapeutic use of cell growth factors is permitted during the study.

[0566] (5) Palliative local radiotherapy is used for isolated lesions (excluding target lesions) during the study treatment.

[0567] (6) Supportive treatment to relieve tumor-related symptoms is allowed, such as bisphosphonate treatment for bone metastases.

[0568] (7) Hormone therapy used for pretreatment before administration of study drugs; immunosuppression or systemic hormone therapy not exceeding 10 mg prednisone equivalent per day for non-pretreatment reasons; and hormone therapy to stimulate appetite:

[0569] Hormone therapy for pretreatment before study drug administration

[0570] Glucocorticoid preparations for nasal, ophthalmic, inhaled, and topical use

[0571] Stable hormone therapy for prostate cancer

[0572] Stable ovarian suppression hormone therapy, hormonal contraceptive therapy, or postmenopausal hormone replacement therapy

[0573] Intra-articular steroid injections

[0574] Low-dose steroid maintenance therapy for other conditions (e.g., acute asthma exacerbations, cerebral edema, etc.)

[0575] In subjects with stable disease or sustained remission, high-dose corticosteroids are allowed to treat acute intercurrent illnesses (e.g., immune-related AEs, etc.). Study drug treatment should be interrupted at this time.

[0576] Subjects with neuroendocrine tumors receiving stable hormone therapy with somatostatin analogs

[0577] 4.2.2 Prohibited concomitant treatments

[0578] Subjects are prohibited from receiving the following treatments during the study treatment period:

[0579] Other systemic chemotherapy or biological treatments with anti-tumor effects.

[0580] Immunotherapy not specified in this protocol.

[0581] ・Investigational drugs other than investigational drugs.

[0582] Immunosuppressive or immunostimulatory drugs, unless otherwise stated under "Permitted Concomitant Therapy".

[0583] Any vaccine treatment used to prevent an infectious disease (such as human papillomavirus vaccine), except inactivated vaccines (such as influenza vaccine).

[0584] Radiotherapy for tumor control (palliative radiotherapy is permitted as long as it is not directed at the target lesion, such as radiotherapy to relieve pain from bone metastases or symptoms from brain metastases).

[0585] Medications and other treatments that are specifically excluded in the exclusion criteria.

[0586] It is important that the investigator review each medication (prescription and over-the-counter) that the subject receives before the start of the study and at each study visit.

[0587] At each visit, the subject must be asked about any new medications they are receiving;

[0588] To reduce the risk of adverse drug interactions, every effort should be made to limit the number of concomitant medications that are truly necessary;

[0589] During the administration of this drug, patients should avoid taking any hepatotoxic medications (i.e., medications with a hepatotoxicity warning in the product labeling). Investigators are encouraged to review each potential hepatotoxic medication by searching www.livertox.nih.gov.

[0590] The use of prohibited drugs listed in the exclusion criteria is not allowed.

[0591] 5. Efficacy Evaluation

[0592] 5.1 Evaluation of Efficacy in Subjects with Solid Tumors

[0593] Tumor assessments were performed using RECIST v1.1. Tumor imaging typically included contrast-enhanced CT or MRI of the chest, abdomen, and pelvis. If the subject is allergic to the contrast agent used for enhanced CT or MRI, unenhanced CT or MRI may be considered; additional CT or MRI of other sites may be performed if necessary. Bone scans may be performed for patients suspected of bone metastases. Imaging techniques should be consistent across all subjects during the study. Baseline assessments will be performed within 28 days prior to C1D1, and investigators may collect imaging results from the first 28 days of C1D1 for evaluation. Tumor imaging assessments will be performed every 6 weeks (±7 days) after C1D1 study drug administration, and every 12 weeks (±14 days) after 48 weeks, until disease progression, initiation of new anticancer therapy, subject's refusal to continue study participation, loss to follow-up, death, or study termination, whichever occurs first. Subjects who withdraw from treatment early for reasons other than disease progression should undergo imaging as scheduled in the protocol. Planned tumor imaging examinations cannot be postponed due to treatment delays, holidays, or any other reasons. If disease progression is suspected based on clinical or laboratory findings before the next scheduled assessment, an unplanned assessment should be performed. For subjects who first document a response [complete response (CR) or partial response (PR)], an imaging assessment should be performed 4-6 weeks (+7 days) later to confirm the response. Thereafter, imaging assessments should be performed according to the original established assessment cycle until radiographic disease progression is documented.

[0594] For subjects who discontinue treatment due to disease progression, a tumor imaging examination should be performed at the time of discontinuation of treatment. If the time of the previous scan is no more than 4 weeks from the time of discontinuation of treatment, it is not mandatory to perform a scan at the time of discontinuation of treatment. For subjects who discontinue treatment due to confirmed disease progression, this scan is the last tumor imaging examination required by the study. For subjects who discontinue treatment without evidence of disease progression, efforts should be made to continue to monitor their disease status through tumor imaging examinations according to their tumor assessment schedule during treatment until disease progression, intolerable toxicity, the subject's unwillingness to continue to participate in the study, death, or other circumstances specified in the protocol that require discontinuation of treatment, whichever occurs first.

[0595] 5.2 Evaluation of Efficacy in Lymphoma Subjects

[0596] 5.2.1 Bone marrow examination

[0597] Subjects will undergo bone marrow examinations, including bone marrow smear cytology and bone marrow biopsy, at baseline and subsequently on a scheduled basis, except in the following circumstances:

[0598] The subject underwent bone marrow examination according to clinical practice standards within 60 days before the first dose of study drug.

[0599] The subject had a bone marrow examination after the last treatment, and the results showed lymphoma invading the bone marrow.

[0600] For subjects whose lymphoma did not invade the bone marrow at baseline, a repeat bone marrow examination is not necessary to confirm the radiographic CR indication. For subjects with a positive baseline bone marrow examination, if a radiographic complete response occurs during treatment, a repeat bone marrow examination is required (completed within 2 weeks of the radiographic assessment). If feasible, all bone marrow examinations should include a unilateral aspirate and biopsy; if sufficient material is available, bone marrow flow cytometry can also be performed to evaluate the lymphoma bone marrow invasion.

[0601] 5.2.2 Radiographic evaluation

[0602] Imaging evaluation of patients with lymphoma was performed according to the Lugano 2014 criteria. Baseline imaging should be performed within 28 days before the first dose of study drug. The investigator should confirm the presence of at least one measurable lesion (defined as a lymph node lesion with a long diameter >15 mm and an extranodal lesion with a long diameter >10 mm as assessed by CT / MRI) based on a PET-CT scan and enhanced CT scan (whole-body imaging, including the cervical, thorax, abdomen, and pelvis; for patients allergic to CT contrast agents, enhanced MRI may be used). PET scans were performed at baseline, every 12 weeks (±7 days) after C1D1 administration, upon confirmation of CR or PD, as otherwise deemed necessary by the investigator, and at treatment discontinuation (±7 days). Enhanced CT scans were performed at baseline, every 6 weeks (±7 days) after C1D1 administration, every 12 weeks (±14 days) after 48 weeks, and as deemed necessary by the investigator until disease progression, initiation of new anticancer therapy, patient refusal to continue study participation, loss to follow-up, death, or study discontinuation, whichever occurred first.

[0603] 6. Pharmacokinetics

[0604] Collect 3.5 ml of whole blood, separate the serum, and aliquot and freeze for PK analysis. If necessary, PK samples will be used for immunogenicity testing. During the clinical study, the sponsor may adjust, reduce, or discontinue PK sampling and / or testing based on clinical development needs, overall development strategy, and patient protection.

[0605] 7. Immunogenicity Analysis

[0606] 5 ml of whole blood will be collected using a vacutainer, serum will be separated, and aliquots will be frozen for 2149 ADA and / or NAb analysis. If necessary, immunogenicity samples will be used to measure 2149 concentration. During the clinical study, the sponsor may reduce or discontinue sampling and / or testing based on clinical development needs, overall development strategy, and patient protection.

[0607] 8. Pharmacodynamic Analysis

[0608] Collect approximately 4 mL of whole blood for receptor occupancy and immune cell subtype analysis. During the clinical research process, the sponsor may reduce or stop sampling and / or testing according to the clinical development needs, overall development strategy, and the perspective of protecting subjects, etc.

[0609] 9. Safety assessment

[0610] 9.1 Laboratory tests

[0611] 9.1.1 Routine laboratory safety assessment

[0612] HBcAb: Hepatitis B core antibody; HBeAb: Hepatitis B e antibody; HBeAg: Hepatitis B e antigen; HBsAb: Hepatitis B surface antibody; HBsAg: Hepatitis B surface antigen; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HGB: Hemoglobin content; HIV: Human immunodeficiency virus. TBIL: Total serum bilirubin; DBIL: Direct bilirubin; IBIL: Indirect bilirubin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BNP: B-type natriuretic peptide; TSH: Thyroid-stimulating hormone; FT3: Free triiodothyronine; FT4: Free tetraiodothyronine; IFN-γ: Interferon γ; TNF-α: Tumor necrosis factor α; IL-8: Interleukin 8; IL-6: Interleukin 6; IL-10: Interleukin 10.

[0613] 9.1.2 Liver function tests

[0614] The researcher needs to regularly check the patient's liver enzyme levels. If

[0615] (1) For patients with normal baseline levels, AST or ALT increases to > 3 × ULN;

[0616] (2) For patients with abnormal baseline levels, if the baseline AST or ALT ≤ 2.5 × ULN, it increases to ≥ 3 times the baseline level after medication; or if the baseline 2.5 × ULN < AST or ALT < 5 × ULN, it increases to ≥ 2 times the baseline level after medication;

[0617] (3) Total bilirubin increases to ≥ 2 × ULN without cholestasis

[0618] Recheck the 4 commonly used serum measurements (ALT, AST, ALP, and TBL) within 48 to 72 hours to confirm the abnormality and determine whether they are elevated or decreased. If the recheck results are consistent with the previous ones and meet (1) + (3) or (2) + (3), then it is defined as a potential Hy's Law case and the Hepatotoxicity Questionnaire in the appendix of the CRF should be completed to collect further information to determine whether it is a potential Hy's Law case or a true Hy's Law case.

[0619] Hy's Law (HL): In addition to the investigational drug, there is no other reasonable explanation for AST or ALT ≥ 3×ULN combined with total bilirubin ≥ 2×ULN. These reasons include elevated ALP caused by cholestasis, viral hepatitis, other drugs, etc.

[0620] 9.2 Clinical examination

[0621] 9.2.1 Physical Examination

[0622] A complete physical examination includes: general status, respiratory, cardiovascular, abdominal, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities), genitals / anus (if applicable), and neurologic assessment.

[0623] 9.2.2 Vital Signs Examination

[0624] Vital signs will be checked as described in the visit schedule. Vital signs include temperature, pulse, respiratory rate, and blood pressure.

[0625] 9.2.3-lead electrocardiogram examination

[0626] Resting 12-lead ECGs will be analyzed at a local laboratory according to the visit schedule.

[0627] Subjects should be resting for the examination. All 12-lead ECGs should be recorded while the subject is resting in the supine position. Further ECGs will be performed if clinically indicated, such as in the event of a cardiac adverse event. The investigator will complete the ECG assessment on the day of the examination and record the results on the electrocardiogram. The same assessment method should be used throughout the study.

[0628] The investigator should evaluate all ECGs according to the clinically significant abnormal / not clinically significant abnormal categories. If the abnormal result is clinically significant, the investigator should record it as an AE in the eCRF.

[0629] 9.2.4 Assessment and Examination During and After Infusion

[0630] Pulse, blood pressure, respiratory rate, and body temperature were collected during the study drug infusion, at least 2 hours after the first dose of study drug, and at least 1 hour after subsequent infusions. Patients were carefully observed for any evidence of treatment-related AEs. Fingerprint oxygen saturation (SaO2) was collected at least 2 hours after the first dose of study drug, and at least 1 hour after subsequent infusions.

[0631] 9.3 Safety Assessment Committee

[0632] The Safety Assessment Committee is composed of the sponsor and investigators. After the completion of DLT observation for the previous dose cohort during the Phase 1a dose-escalation phase, the Safety Assessment Committee will conduct an evaluation and determine whether to proceed to the next dose cohort. Unexpected safety events or intolerable safety signals during Phase 1a Part B may also trigger a Safety Assessment Committee discussion. If specific safety concerns are identified, external experts may be invited to work with the sponsor to form an independent Safety Assessment Committee to assess, determine, and provide guidance on safety issues.

[0633] 10. Tissue Biomarker Analysis

[0634] With the permission of the ethics committee, tumor tissue (including archived or freshly collected) sections of the subjects will be collected according to the visit form for biomarker analysis. 10 tumor tissue sections will be collected for PD-L1 expression level and tumor microenvironment detection. With the approval of the ethics committee, the consent of the subjects, and the investigator's opinion that conditions permit, the subjects will provide 10 tumor tissue sections prepared from fresh tumor biopsy or puncture specimens (or tumor tissue specimens obtained by surgery after neoadjuvant therapy) for PD-L1 expression level and tumor microenvironment detection when objective response or disease progression occurs. If the test fails, if there are remaining sections at the clinical center, additional sections may be required.

[0635] 11. Results

[0636] solid tumors

[0637] Eligible patients who failed or were intolerant to standard therapy were enrolled. 2149 was administered intravenously using an accelerated titration (0.2, 2, 10, 30 μg / kg QW) and a Bayesian optimal interval (BOIN) design (0.1, 0.3, 0.6, 1 mg / kg QW). Further dose optimization was evaluated at 0.3, 0.6, and 1 mg / kg Q2W and 0.6, 1, 1.5, 2, and 3 mg / kg Q3W. Endpoints were safety and efficacy according to RECIST v1.1.

[0638] Of the 326 patients enrolled (60.7% male, 63.3% ECOGP1), 168 were dosed at 1 mg / kg, 99 at less than 1 mg / kg, and 59 at greater than 1 mg / kg. A total of 272 patients (≥0.1 mg / kg, 77 with non-small cell lung cancer [NSCLC], 67 with melanoma, 79 with colorectal cancer, and 49 with other tumors) underwent at least one post-baseline tumor assessment. The overall ORR was 17.6% (95% CI: 13.3-22.7), and the DCR was 57.0% (95% CI: 50.9-62.9). The ORR for patients treated with IO (n=185) was 17.8% (95% CI: 12.6-24.1), and the DCR was 62.2% (95% CI: 54.8-69.2). In NSCLC (n=77, prior tx ≥ 2L: 79.2%, including 8 with EGFR mutations), the ORR was 22.1% (95% CI: 13.4-33.0) and the DCR was 67.5% (95% CI: 55.9-77.8). Among them, the ORR in patients treated with IO (n=72) was 22.2% (95% CI: 13.3-33.6) and the DCR was 68.1% (95% CI: 56.0-78.6). In squamous NSCLC (n = 36, previous tx ≥ 2L: 69.4%, 35 IO treatment, 1 IHC test was EGFR positive), the ORR was 30.6% (95% CI: 16.3-48.1), the DCR was 75.0% (95% CI: 57.8-87.9), and the median PFS was 5.5 months (95% CI: 4.0-NC), of which 14 patients (38.9%) had events. All squamous NSCLC patients (3 mg / kg Q3W) had a partial response (n = 4). In mucosal melanoma (n = 25), the ORR was 32.0% (95% CI: 14.9-53.5) and the DCR was 68.0% (95% CI: 46.5-85.1).

[0639] 145 and 7 subjects were enrolled in the 1mg / kg Q2W dose group and the 3mg / kg Q3W dose group, respectively, and all subjects received an initial dose of 100μg. Overall, 1mg / kg Q2W and 3mg / kg Q3W had controllable safety. The TEAE incidence rate in the 1mg / kg Q2W dose group was 90.3%, of which the incidence rate of TEAEs above grade 3 was 21.4%, and the incidence rate of treatment-emergent adverse events (TRAEs) above grade 3 related to 2149 was 17.9%. The TEAE incidence rate in the 3mg / kg Q3W dose group was 71.4%, of which the incidence rate of TEAEs above grade 3 was 28.6%, and the incidence rate of treatment-emergent adverse events (TRAEs) above grade 3 related to 2149 was 14.3%.

[0640] Molecule 2149 has shown good efficacy in patients with advanced malignancies. 2149 has demonstrated good clinical benefit in patients with advanced melanoma who have failed or are intolerant to standard treatment. As of January 11, 2024, a total of 57 subjects underwent at least one tumor assessment, 16 of whom achieved a best overall response of partial remission (PR), for an overall ORR of 28.1%.

[0641] In the ongoing study, a total of 347 patients with advanced solid tumors who had failed or were intolerant to standard treatment were enrolled, including 100 patients with non-small cell lung cancer (NSCLC), 89 patients with melanoma, 102 patients with colorectal cancer (CRC), and 56 patients with other tumors. Baseline characteristics of the patients were as follows: median age 58.0; ECOGPS1: 64.5%; ≥2 lines of previous systemic therapy: 81.8%; previous immunotherapy: 67.7%; liver metastases: 33.1%; lung metastases: 57.3%; bone metastases: 19.6%; brain metastases: 3.2%. Molecule 2149 was administered intravenously according to an accelerated titration (0.2, 2, 10, 30 μg / kg QW) and a BOIN design (100, 300, 600, 1000 μg / kg QW), with further dose optimization evaluated at 300, 600, 1000 μg / kg Q2W and 600, 1000, 1500, 2000, 3000 μg / kg Q3W (see Figure 2). In the ≥600 μg / kg dose group, patients received a single initial dose of 100 μg / kg 7 days before receiving the first expected full dose. The endpoints were safety and efficacy according to RECIST v1.1. The overall efficacy is shown in Table 1 below.

[0642] Table 1. Overall efficacy in patients treated at dose levels ≥ 0.1 mg / kg

[0643] *Patients underwent at least 1 tumor evaluation.

[0644] #Includes 81 patients with NSCLC, 77 patients with melanoma, 98 patients with CRC, and 44 patients with other tumors.

[0645] Durable DoR (duration of response) was observed. Of the 52 responders (CR and PR), 38 remained disease-free, and 9 patients even maintained tumor response after end-of-treatment (EOT). The median DoR (95% CI) was 8.1 months (4.2, NC).

[0646] Table 2. Safety evaluation

[0647] 1The events were graded according to the Common Terminology Assessment of Adverse Events (CTCAE) version 5.0.

[0648] 2 TRSAE: treatment-related serious adverse event.

[0649] Conclusions: 2149 was well tolerated in all patients and showed encouraging efficacy in solid tumors, particularly advanced NSCLC and melanoma. Furthermore, 2149 had a favorable safety profile in patients.

[0650] Bowel cancer

[0651] The prognosis for advanced colorectal cancer (CRC) is poor, and available treatment options are limited. This study enrolled eligible patients with locally advanced or metastatic colorectal cancer (CRC) who had failed or were intolerant to standard therapy and received intravenous 2149 at dose levels of 0.1-3 mg / kg QW / Q2W / Q3W (see Figure 3). In the ≥600 μg / kg dose group, patients were given a single initial dose of 100 μg / kg 7 days before receiving the first expected full dose.

[0652] Of the 68 patients enrolled (male: 55.9%, median age: 55.5 years, ECOGP1: 50.0%, liver metastases: 61.8%; prior treatment ≥3 lines: 76.5%; prior immunotherapy: 27.9%), 24 patients received 0.6 mg / kg Q2W and 20 patients received 1 mg / kg Q2W. 57 (83.8%) patients had microsatellite stable (MSS) / mismatch repair gene normal (pMMR), and the microsatellite status of the remaining 11 (16.2%) patients was unknown. The median follow-up time was 5.3 months (95% CI: 4.4-6.9). 65 patients (95.6%) reported treatment-emergent adverse events (TEAEs), of which 22 patients (32.4%) reported TEAEs of grade ≥3. Common TEAEs (≥20%) were arthralgia (35.3%), anemia (32.4%), pyrexia (22.1%), and decreased serum albumin (20.6%). Treatment-related adverse events (TRAEs) were reported in 62 (91.2%) patients, of which 16 (23.5%) reported TRAEs of grade ≥3. Immune-related adverse events (irAEs) were reported in 22 patients (32.4%), of which 4 patients (5.9%) reported irAEs of grade ≥3. Severe TRAEs were reported in 12 patients (17.6%). TRAEs leading to treatment interruption were reported in 25 (36.8%) patients, and TRAEs leading to treatment discontinuation were reported in 2 patients (2.9%). No TRAEs leading to death were reported. Patients who had at least one post-baseline tumor assessment were included in the efficacy evaluation group. In all evaluable patients (n=63), the overall ORR was 12.7% (95% CI: 5.6-23.5). In patients with liver metastases (n=38), the ORR was 13.2% (95% CI: 4.4-28.1). In patients with PD-L1 CPS ≥ 1 (n=13), the ORR was 30.8% (95% CI: 9.1-61.4) and the DCR was 76.9% (95% CI: 46.2-95.0). A prospective cohort of CRC patients with PD-L1 CPS ≥ 1 has been initiated.

[0653] Conclusions: 2149 showed good efficacy and manageable safety in patients with advanced colorectal cancer. Preliminary efficacy of 2149 was observed, particularly in patients with PD-L1 CPS ≥ 1.

[0654] In the study of molecule 2149 plus bevacizumab, eligible patients with locally advanced or metastatic colorectal cancer (CRC) who had failed or were intolerant to standard therapy were enrolled. The baseline characteristics of the patients are shown in Table 3 below. Patients were dosed intravenously according to the following regimens: 1.5 mg / kg 2149 every 3 weeks plus 7.5 mg / kg bevacizumab (Beva) every 3 weeks, 2 mg / kg 2149 every 3 weeks plus 7.5 mg / kg bevacizumab (Beva) every 3 weeks, or 3 mg / kg 2149 every 3 weeks plus 7.5 mg / kg bevacizumab (Beva) every 3 weeks (see Figure 3, Phase Ia Part B combination). In the ≥600 μg / kg dose group, patients received a single initial dose of 100 μg / kg 7 days prior to receiving the first intended full dose. Endpoints were safety and efficacy according to RECIST v1.1. The median follow-up was 3.8 months (range: 0-125). Preliminary treatment effects are shown in Table 4 below.

[0655] Table 3. Baseline characteristics of CRC patients enrolled in the molecule 2149 + bevacizumab study

[0656] Table 4. Preliminary therapeutic effects of the combination of molecule 2149 + bevacizumab in CRC patients

[0657] *Five of the patients with SD had tumor shrinkage >20%.

[0658] **Denotes patients who experienced at least one treatment-emergent adverse event.

[0659] As can be seen, molecule 2149 combined with bevacizumab showed encouraging efficacy and manageable safety in patients with advanced CRC, especially in patients without liver metastasis. In particular, when molecule 2149 was administered at a dose of 3 mg / kg, it showed a superior therapeutic effect compared to 2149 alone.

[0660] Melanoma

[0661] Eligible patients with advanced melanoma who had failed or were intolerant to standard therapy were enrolled and received 2149 intravenously at dose levels of 0.1-3 mg / kg QW / Q2W / Q3W (see Figure 2). In the ≥600 μg / kg dose group, patients were given a single initial dose of 100 μg / kg 7 days before receiving the first expected full dose.

[0662] Among the 67 patients enrolled (55.2% female, median age: 59.0 years, ECOG P1: 74.6%, ≥2 prior lines of therapy: 59.7%, prior IO: 89.6%), 17 had cutaneous melanoma, 22 had acral melanoma, 25 had mucosal melanoma, and 3 had melanoma of unknown primary. The median treatment duration was 12.0 weeks (range: 2.0-43.6), of whom 38 (56.7%) remained on treatment. All patients were included in the safety analysis. Treatment-emergent adverse events (TEAEs) occurred in 63 (94.0%) patients. TEAEs of grade 3 or higher occurred in 16 (23.9%) patients, and TRAEs of grade 3 or higher occurred in 12 (17.9%) patients. Common TEAEs (≥20%) were arthralgia (34.3%), hyperthyroidism (29.9%), and anemia (25.4%). One patient (1.5%) experienced a TEAE leading to treatment discontinuation. No patient experienced a TEAE leading to death. Patients with at least one post-baseline tumor assessment were included in the efficacy evaluation group.

[0663] In all evaluable patients (n=57), the best overall response was partial remission (PR) in 16 patients, stable disease (SD) in 25 patients, and progressive disease (PD) in 16 patients. The overall ORR was 28.1% (95% CI: 17.0-41.5%), and the DCR was 71.9% (95% CI: 58.5-83.0). In patients with prior IO (n=52), the ORR was 21.2% (95% CI: 11.1-34.7), and the DCR was 67.3% (95% CI: 52.9-79.7). In patients with prior IO at 1 mg / kg Q2W (n=25), the ORR was 32.0% (95% CI: 14.9-53.5), and the DCR was 80.0% (95% CI: 59.3-93.2). Biomarker analysis of baseline tumor areas revealed significantly higher CD8 T cell infiltration (measured by cell positivity and density) in PR / SD patients compared with PD patients (p < 0.05).

[0664] This study is ongoing. As of April 16, 2024, this study further provides efficacy data for molecule 2149 in melanoma patients, see Tables 5-7.

[0665] Table 5. Efficacy of molecule 2149 (1 mg / kg Q2W) in immunotherapy of melanoma patients

[0666] *Patients had at least one post-baseline tumor assessment.

[0667] Durable responses were observed. Of the 11 responders (CR and PR), 9 had confirmed PR, 1 is awaiting confirmation, and 1 was lost to follow-up. The median DoR (duration of response, months) (95% CI) could not be calculated (NC) because some patients were still in progression-free survival at the time of statistical cutoff, thus the longest progression-free survival was not clearly defined.

[0668] The median PFS of molecule 2149 in various melanomas is shown in Table 4 below, with a median follow-up of 4.2 months.

[0669] Table 6.

[0670] Table 7. Efficacy of molecule 2149 (≥0.3 mg / kg) in patients with mucosal melanoma who had not received immunotherapy (IO)

[0671] *Patients underwent at least 1 post-baseline tumor assessment.

[0672] Among the 6 responders (CR and PR), 5 had confirmed PR and 1 is awaiting confirmation.

[0673] Conclusions: In patients with advanced melanoma, 2149 showed encouraging efficacy across different tumor subtypes and in patients with prior IO, with an acceptable and manageable safety profile.

[0674] lung cancer

[0675] This study enrolled eligible patients with advanced non-small cell lung cancer (NSCLC) who had failed standard therapy. Molecule 2149 was administered intravenously at the following regimens: 2-600 μg / kg QW, 0.3 / 0.6 / 1 mg / kg Q2W, or 1.5 / 2 / 3 mg / kg Q3W. In the ≥600 μg / kg dose group, patients were given an initial dose of 100 μg / kg 7 days before receiving the first expected full dose. The endpoints were safety, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) according to RECIST v1.1. The median duration of exposure to molecule 2149 was 10 weeks (range: 2.0-56.7). The results are shown below.

[0676] Table 8. Effects of molecule 2149 on NSCLC

[0677] **Patients had at least 1 tumor assessment and were followed for at least 12 weeks or until the end of the study.

[0678] The median PFS (progression-free survival) of molecule 2149 (1 mg / kg and 1.5 mg / kg) in sqNSCLC (n=28) was 5.5 months (95% CI: 1.5, 8.3) with a median follow-up of 7.5 months (95% CI: 7.0-11.0).

[0679] The results of the best overall response of molecule 2149 (1 mg / kg, 1.5 mg / kg and 3 mg / kg) in sqNSCLC by PD-L1 expression (n=56) are shown below in Table 9. As can be seen, the responses were similar in PD-L1 TPS < 1% and TPS ≥ 1%.

[0680] Table 9.

[0681] Table 10. Safety evaluation

[0682] Note: One patient at the 1 / 1.5 mg / kg dose and all 57 patients at the 3 mg / kg dose received an initial dose of 0.1 mg / kg 7 days prior to the first expected full dose of treatment.

[0683] result:

[0684] Molecule 2149 was well tolerated in sqNSCLC with a manageable safety profile. No new safety signals were observed. Across all dose levels, TRAEs ≥ Grade 3 were reported in 20.1% of patients, and TRAEs leading to treatment discontinuation were reported in 6.0%. At the 3 mg / kg dose every 3 weeks, TRAEs ≥ Grade 3 were reported in 17.5% of patients, and TRAEs leading to treatment discontinuation were reported in 5.3%.

[0685] Molecule 2149 demonstrated encouraging efficacy in patients with advanced NSCLC. Among all NSCLC patients, the ORR was 20.8% and the DCR was 74.4%. Among sqNSCLC patients treated at 1 or 1.5 mg / kg, the ORR was 22.2%, the DCR was 70.4%, and the median PFS was 5.5 months. Among sqNSCLC patients treated at 3 mg / kg, the ORR was 34.5%, and the DCR was 89.7%.

[0686] Example 2. Phase II study of the safety, tolerability, and efficacy of PD-1 / IL-2R bispecific antibody fusion protein 2149 in subjects with advanced melanoma

[0687] In previous clinical studies, 2149 demonstrated encouraging efficacy in melanoma subjects. Among eight efficacy-evaluable subjects, two with mucosal melanoma and one with cutaneous melanoma achieved partial responses at the first tumor assessment. The cutaneous melanoma subject had previously received and failed pembrolizumab, with overall safety and tolerability being favorable. This study enrolled subjects who had previously failed at least one line of systemic standard therapy to maximize treatment benefit.

[0688] Based on the existing safety and efficacy data, the controllable safety characteristics and positive efficacy signals demonstrated by 2149 in clinical studies suggest that the risks of 2149 treatment for subjects with advanced melanoma are controllable and benefits are expected.

[0689] 1. Study objectives and endpoints

[0690] 2. Study Design

[0691] This is an open-label, multicenter Phase II study designed to evaluate the safety, tolerability, and preliminary efficacy of 2149 in subjects with advanced melanoma. The study includes the following two cohorts, with no more than 60 subjects enrolled in each cohort:

[0692] Cohort A: Unresectable locally advanced or metastatic melanoma (excluding uveal melanoma) that has progressed or recurred after prior treatment with an immune checkpoint inhibitor.

[0693] In this study, patients who have failed immune checkpoint inhibitor therapy must meet the following criteria: 1) have received at least two cycles of immune checkpoint inhibitor therapy. Patients who have experienced disease progression after only one cycle of immune checkpoint inhibitor therapy, excluding pseudoprogression, are allowed to enroll. 2) Disease progression occurs during immune checkpoint inhibitor therapy or within six months of the last immune checkpoint inhibitor treatment. Patients who have received subsequent chemotherapy, targeted therapy, or other therapies after progression on immune checkpoint inhibitor therapy and have experienced disease progression are allowed to enroll.

[0694] Cohort B: Unresectable locally advanced or metastatic melanoma (excluding uveal melanoma) not treated with systemic immune checkpoint inhibitors. Patients with prior adjuvant immune checkpoint inhibitor therapy and other systemic therapies (such as chemotherapy, anti-angiogenic therapy, and patients with driver gene mutations are allowed to receive targeted therapy) are allowed.

[0695] To determine the optimal dosing strategy for 2149 in melanoma patients, this study plans to explore two doses of 2149: 1 mg / kg Q2W or 3 mg / kg Q3W. A gradient dosing strategy will be employed, with a single dose of ≤100 μg / kg 2149 administered on C1D1, followed by 1 mg / kg Q2W or 3 mg / kg Q3W 7 days later. The decision to administer 1 mg / kg Q2W or 3 mg / kg Q3W can be made by the investigator based on the individual patient's specific needs and must be agreed upon with the sponsor.

[0696] This study allows subjects to self-escalate their dose. If a subject does not experience a Grade 2 or higher adverse event related to the study drug that leads to suspension or discontinuation of treatment while receiving a low-dose of 2149 (e.g., 1 mg / kg), the investigator and sponsor will review all data and determine whether the subject can subsequently receive a higher dose of 2149 (3 mg / kg). Following dose escalation, safety monitoring, PK sampling, tumor imaging, and other visits should continue according to the previous schedule.

[0697] Subjects will receive study drug treatment until disease progression, intolerable toxicity, the subject's unwillingness to continue participating in the study, other reasons for stopping study treatment, or the treatment duration reaches 24 months (whichever occurs first).

[0698] This study allows investigators to lower the study drug dose (e.g., 600 μg / kg) or extend the dosing interval (e.g., every 3 weeks) based on the subject's clinical condition (including but not limited to safety, tolerability, and efficacy). In principle, the study drug can be lowered by up to two dose levels. If the investigator assesses that further dose reductions can still benefit the subject, they should discuss this with the sponsor. The maximum duration of study drug administration is 24 months.

[0699] In this study, when the drug is administered Q2W, the first cycle is 35 days after the first dose (i.e., the starting dose of the gradient administration), and visits are conducted every 28 days from the second cycle. When the drug is administered Q3W, the first cycle is 28 days after the first dose, and visits are conducted every 21 days from the second cycle.

[0700] This study evaluated the efficacy of the subjects according to the RECIST v1.1 evaluation criteria. During the study, the subjects underwent tumor imaging assessment every 6 weeks (±7 days) within 54 weeks of the first dose and every 12 weeks (±7 days) thereafter until disease progression, initiation of new anti-cancer treatment, unwillingness to continue the study, loss to follow-up, death, or study termination (whichever occurred first).

[0701] Subjects will have an end-of-treatment visit within 10 days after confirmation of discontinuation of treatment. Safety follow-up should be conducted 30 (+7) days after the last dose.

[0702] 3. Dose selection

[0703] This study used gradient dosing (a single dose of ≤100 μg / kg 2149 on C1D1, followed by 1 mg / kg Q2W or 3 mg / kg Q3W 2149 7 days later) to explore the safety, tolerability, and preliminary efficacy of 2149 in subjects with advanced melanoma.

[0704] 4. Study Population

[0705] 4.1 Inclusion criteria

[0706] Included subjects (subjects must meet all of the following criteria):

[0707] (1) Sign the written informed consent and be able to comply with the visit arrangements and related procedures specified in the protocol.

[0708] (2) Age ≥ 18 years old, regardless of gender.

[0709] (3) Unresectable locally advanced or metastatic melanoma confirmed by histology or cytology (according to the American Joint Committee on Cancer (AJCC) 8th edition stage III-IV. If the investigator assesses that the patient's stage II disease is unresectable, the patient will be allowed to enroll after discussion and agreement with the sponsor.

[0710] (4) Cohort A: Unresectable locally advanced or metastatic melanoma (excluding uveal melanoma) that has progressed or recurred after prior immune checkpoint inhibitor therapy. If an immune checkpoint inhibitor has been previously received as an adjuvant or neoadjuvant therapy and the disease progresses to unresectable or metastatic melanoma during treatment or within 6 months after cessation of treatment, this treatment can be counted as first-line systemic therapy.

[0711] Cohort B: Unresectable locally advanced or metastatic melanoma (excluding uveal melanoma) not treated with systemic immune checkpoint inhibitors. Previous adjuvant treatment with immune checkpoint inhibitors is permitted. Previous treatment with other systemic therapies (e.g., chemotherapy, anti-angiogenic therapy, and targeted therapy for patients with driver gene mutations) is permitted.

[0712] (5) According to the RECIST v1.1 criteria, there is at least one measurable lesion (target lesion).

[0713] ◆For lesions that have previously received radiotherapy or intratumoral injection, lesions that progress after treatment can be considered measurable lesions.

[0714] ◆Target lesions in this study must be measurable by imaging (enhanced CT or MRI). Lesions on the skin or other superficial sites that cannot be repeatedly measured by imaging can only be considered non-target lesions.

[0715] (6) Eastern Cooperative Oncology Group performance status score (ECOGPS) is 0 or 1.

[0716] (7) Expected survival time ≥ 3 months.

[0717] (8) Female subjects of childbearing age or male subjects whose partners are female subjects of childbearing age agree to strictly take effective contraceptive measures throughout the treatment period and for 6 months after the treatment period.

[0718] 4.2 Exclusion criteria

[0719] Subjects should not be included in this study if they meet any of the following criteria:

[0720] (1) Pregnant or lactating women, or women who plan to become pregnant before, during, or within 6 months after the last dose of the study drug.

[0721] (2) Active or symptomatic central nervous system metastases (including brain parenchyma, leptomeninges, and spinal cord metastases) confirmed by imaging assessment during the screening period or previous imaging assessments. Subjects with central nervous system metastases unexpectedly detected during the screening period or clinically stable after treatment may participate in this study as long as they meet all of the following criteria:

[0722] ◆Measurable lesions outside the central nervous system;

[0723] ◆No metastases to the meninges, midbrain, pons, medulla oblongata, or spinal cord, and no multiple cerebellar metastases;

[0724] ◆No compression of the cerebral aqueduct, third or fourth ventricle, or spinal cord;

[0725] ◆For subjects with untreated CNS metastases: The investigator assesses that no immediate treatment for CNS metastases is required; the number of CNS metastases is ≤3, and the longest diameter of each lesion is ≤5mm.

[0726] ◆For subjects with previously treated central nervous system metastases, the following criteria must be met simultaneously: 1) Complete treatment for central nervous system metastases (such as whole-brain radiotherapy, stereotactic radiotherapy, or other equivalent treatments) ≥14 days before the first dose of study drug; 2) After completing treatment for central nervous system metastases, repeat imaging examinations confirm no new brain metastases or evidence of enlargement of existing brain metastases (the interval between the head imaging examination and the use of the same imaging technology must be ≥4 weeks from the pre-treatment interval); 3) No need for hormone treatment and stable symptoms for ≥14 days before the first dose of study drug.

[0727] (3) Baseline * Any of the following hematologic abnormalities (within 7 days before the first dose of study drug):

[0728] Hemoglobin <90 g / L

[0729] Absolute neutrophil count (ANC) <1.5 × 10 9 / L

[0730] Platelet count <100 × 10 9 / L

[0731] * Throughout the protocol, "baseline" is defined as the last available observation before the first dose of study drug. Subjects must not have received blood product transfusions (including red blood cell suspensions, apheresis platelets, cryoprecipitate, etc.), erythropoietin, or colony-stimulating factor support within 7 days prior to blood sample collection.

[0732] (4) Any of the following serum biochemical abnormalities at baseline (within 7 days before the first dose):

[0733] Total bilirubin >1.5× the upper limit of normal (ULN);

[0734] Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × ULN; if the patient has liver metastasis, AST or ALT > 5.0 × ULN;

[0735] Serum creatinine >1.5×ULN or creatinine clearance (CCr) <45 mL / min (CCr calculated using the Cockcroft-Gault formula (actual body weight)).

[0736] ◆Albumin <30g / L.

[0737] (5) Any of the following coagulation parameter abnormalities at baseline (within 7 days before the first dose):

[0738] International normalized ratio (INR) >1.5 × ULN (>3 × ULN if receiving stable anticoagulation);

[0739] Partial thromboplastin time (PTT) (or activated partial thromboplastin time [aPTT]) >1.5 × ULN (>3 × ULN if receiving stable anticoagulation).

[0740] (6) History of active thrombosis, deep vein thrombosis, or pulmonary embolism within 4 weeks before the first dose of study drug, unless the patient has been adequately treated and the investigator believes the condition is stable.

[0741] (7) Active uncontrolled bleeding or known bleeding tendency.

[0742] (8) Cardiovascular and cerebrovascular diseases with significant clinical significance, including:

[0743] ◆Arrhythmias that are symptomatic, clinically unstable, or require clinical intervention;

[0744] HR-corrected QT interval (QTc interval, calculated using the Fridericia method) ≥ 480 ms;

[0745] ◆Uncontrolled arterial hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) despite standard treatment;

[0746] ◆History of myocarditis;

[0747] Left ventricular ejection fraction (LVEF) < 50%;

[0748] ◆Current congestive heart failure requiring treatment;

[0749] ◆According to the New York Heart Association (NYHA) cardiac function classification, II-IV heart failure;

[0750] ◆History of acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty or stent implantation within 6 months before the first dose of study drug.

[0751] ◆ Cerebrovascular accident or transient ischemic attack occurred within 6 months before the first administration of study drug;

[0752] ◆Known history of epileptic seizures.

[0753] (9) History of interstitial pneumonia, pulmonary fibrosis, pneumoconiosis, drug-related pneumonia, radiation pneumonia, etc. that require steroid hormones or other treatments, as well as severe abnormalities in lung function or other forms of restrictive lung disease.

[0754] (10) History of allergic constitution, asthma, or atopic dermatitis.

[0755] (11) Patients with moderate to large amounts of ascites or symptomatic ascites requiring clinical intervention as shown by imaging. Only patients with small amounts of ascites as shown by imaging but no symptoms can be selected.

[0756] (12) Patients with moderate bilateral pleural effusion, or large pleural effusion in one side, or patients with respiratory dysfunction requiring drainage.

[0757] (13) Subjects currently or recently (within 6 months) suffer from major gastrointestinal diseases or conditions, including:

[0758] ◆History of inflammatory bowel disease;

[0759] ◆Grade 2 or higher diarrhea occurred within 2 weeks before the first dose of study drug.

[0760] (14) Active autoimmune disease requiring systemic treatment (such as the use of disease-modifying drugs, corticosteroids, or immunosuppressants) occurred within 2 years before the first dose. Replacement therapy (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) is not considered systemic treatment;

[0761] (15) Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

[0762] (16) Subjects with known or suspected allergies to the study drugs and any excipients.

[0763] (17) The subject has a history of significant toxicity related to the administration of immune checkpoint inhibitors that required permanent discontinuation of treatment.

[0764] (18) The subject has unresolved grade 1 toxicity related to any previous anti-tumor treatment (excluding alopecia, fatigue, hypothyroidism requiring only thyroid hormone replacement therapy, hyperglycemia requiring only insulin replacement therapy, electrolyte abnormalities requiring only symptomatic treatment, and other conditions assessed by the investigator as not affecting study drug treatment).

[0765] (19) Patients have not fully recovered from previous surgery or have undergone any major surgery within 4 weeks before the first dose of study drug.

[0766] (20) Subjects with uncontrolled tumor-related pain or symptomatic hypercalcemia.

[0767] (21) Known to be HIV positive, have active hepatitis B, hepatitis C (HCV), or tuberculosis.

[0768] Patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) should undergo hepatitis B virus (HBV) DNA testing. If the HBV DNA copy number is ≤2.5×10 3 If the number of copies / ml is ≤500IU / ml or below the detection limit, the subjects can be enrolled. HBsAg(+) subjects should receive anti-HBV treatment during the entire study drug treatment period to avoid viral reactivation. For subjects with anti-HBc(+), HBsAg(-), anti-HBs(-) and HBV viral load(-), they do not need to receive preventive anti-HBV treatment, but need to be closely monitored for viral reactivation;

[0769] ◆Subjects with positive hepatitis C virus serology but negative HCV RNA test or below the detection limit are allowed to be included in the study;

[0770] ◆ Subjects receiving HCV treatment and with undetectable viral load results were allowed to participate in the study.

[0771] ◆Subjects with previously cured or clinically stable old tuberculosis as assessed by the investigator are allowed to be included in the study.

[0772] (22) Severe / active / uncontrolled infection, infection requiring systemic intravenous antibiotics, or fever of unknown cause (>38.3°C, lasting more than 3 weeks) within 2 weeks before the first dose of study drug.

[0773] (23) There is any history or current evidence of any disease, treatment, or laboratory abnormality that, in the judgment of the investigator, may compromise the safety of the subject, interfere with obtaining informed consent, affect subject compliance, or affect the safety evaluation of the study drug.

[0774] (24) Suffering from mental illness, altered mental status, or substance abuse that impedes understanding the informed consent process and / or completing necessary research-related evaluations.

[0775] (25) Due to known or foreseeable reasons, the investigator believes that the subject is unable to meet the requirements of the protocol.

[0776] (26) Diagnosed with primary uveal or ocular melanoma within 5 years before the first dose, and other pathologically confirmed malignant tumors, exceptions include radically resected basal cell carcinoma of the skin, squamous cell carcinoma of the skin and / or radically resected carcinoma in situ, localized prostate cancer after radical resection, papillary thyroid carcinoma, and other malignant tumors that have been radically resected and have no known active disease for at least 2 years before study entry and have a very low risk of recurrence.

[0777] (27) Excluded drugs and other treatments (subjects must not receive any of the following treatments):

[0778] (a) IL-2 / IL-15 cytokines. The use of IL-2 / IL-15 as neoadjuvant or adjuvant therapy, or as a component of cell therapy, is permitted;

[0779] (b) Patients have received any chemotherapy or small molecule targeted therapy within 2 weeks or 5 half-lives (whichever is shorter) before the first dose of study drug and have not experienced delayed toxicity, except for the following:

[0780] ◆Use of nitrosourea antitumor drugs and mitomycin C within 6 weeks before the first dose of study drug.

[0781] (c) Use of any antibody treatment within 4 weeks before the first dose of study drug;

[0782] (d) Participation in any clinical trial of medical devices or other therapeutic interventions within 2 weeks before the first dose of study drug;

[0783] (e) palliative radiotherapy within 2 weeks before the first dose of study drug;

[0784] (f) Use of live vaccines for the prevention of infectious diseases within 28 days before the first dose of study drug;

[0785] (g) Received immunosuppression or systemic steroid therapy (>10 mg / day prednisone equivalent) within 2 weeks before the first dose of study drug.

[0786] 5. Research treatment

[0787] 5.1 Treatment options

[0788] The treatment regimen for this study is as follows:

[0789] Remark:

[0790] 1: If the subject does not experience an adverse event of severity ≥ Grade 2 related to the study drug that leads to drug suspension or discontinuation during treatment with low-dose 2149, the investigator and sponsor will review all the information and decide whether the subject can subsequently receive high-dose 2149 treatment.

[0791] 2: This study used a gradient administration method, with a single dose of ≤100 μg / kg 2149 given on C1D1, and 1 mg / kg Q2W or 3 mg / kg Q3W given 7 days later.

[0792] 5.2 Preparation and Administration of Study Drug

[0793] The formulation and administration of the study drug were the same as in Example 1.

[0794] 6. Safety Assessment

[0795] Laboratory tests

[0796] Laboratory tests include complete blood count, blood biochemistry, myocardial enzyme spectrum and troponin, urine routine, viral serology, coagulation function indicators, thyroid function, stool routine, cytokines (IFN-γ, TNF-α, IL-8, IL-6, IL-10), pregnancy test, liver function test, etc.

[0797] Clinical examination

[0798] Clinical examinations included a physical examination (general appearance, respiratory, cardiovascular, abdominal, skin, head and neck (including ears, eyes, nose, and throat), lymph node, thyroid, musculoskeletal (including spine and extremities), genital / anal (if applicable), and neurologic assessment); vital sign checks (temperature, pulse, respiratory rate, and blood pressure); a 12-lead electrocardiogram (ECG); and in- and post-infusion assessments and examinations (for any treatment-related AEs).

[0799] 6.3. Echocardiography

[0800] Echocardiograms will be analyzed at a local laboratory according to the visit schedule, including during the screening period and as clinically indicated. Further examinations will be performed as clinically indicated, such as in the event of a cardiac adverse event. The investigator will complete the echocardiographic assessment on the day of the examination and document the results. The same assessment method should be used throughout the study.

[0801] Investigators should assess all echocardiographic findings according to the clinically significant abnormal / not clinically significant abnormal categories. If a clinically significant abnormal finding is present, the investigator should document the finding as an AE in the eCRF.

[0802] 6.4. Pulmonary function

[0803] If baseline imaging studies document potential evidence of interstitial pneumonia, pulmonary fibrosis, or other drug-related pulmonary toxicity, or if there are indications for pulmonary symptoms, pulmonary function testing is recommended. Pulmonary function testing includes pulmonary ventilation and diffusion capacity. Pulmonary ventilation function test assessment includes at least: FVC, FEV1, RV and TLC, and pulmonary diffusion capacity test assessment includes at least DLCO. Pulmonary function testing is assessed by the investigator and performed when clinically necessary. The investigator completes the pulmonary function assessment on the day of the examination and records the assessment results. The same assessment method should be used throughout the study. The investigator should evaluate all pulmonary function results according to the clinically significant abnormality / non-clinically significant abnormality category. If the result is clinically significant, the investigator should record the result as an AE in the eCRF.

[0804] See Example 1 for details.

[0805] 7. Efficacy Evaluation

[0806] Baseline evaluations will be performed within 28 days prior to C1D1. Investigators may collect imaging data within 28 days prior to C1D1 (bone scans performed within 3 months prior to C1D1 are acceptable). Baseline tumor imaging studies include contrast-enhanced CT scans (covering the chest, abdomen, and pelvis; for subjects allergic to CT contrast agents, contrast-enhanced MRI is acceptable) and contrast-enhanced MRI of the head. Contrast-enhanced CT, contrast-enhanced MRI, or bone scans of other sites may be performed if necessary. If brain metastases are detected on baseline contrast-enhanced head MRI, a contrast-enhanced head MRI will be performed at each subsequent tumor imaging assessment. If no brain metastases are detected on baseline contrast-enhanced head MRI, a repeat contrast-enhanced head MRI will be performed if the investigator suspects brain metastases during treatment. Regular bone scans (e.g., every 12 weeks) are recommended for subjects with bone metastases at baseline. For subjects without bone metastases at baseline, a repeat bone scan will be performed if the investigator suspects bone metastases during treatment. Contrast-enhanced CT and contrast-enhanced MRI examinations will be performed at baseline, every 6 weeks (±7 days) for 54 weeks after the first dose, every 12 weeks (±7 days) after the first dose, and as deemed necessary by the investigator. The timing of bone scans was determined by the investigator (subjects with bone metastases were recommended to be evaluated every 12 weeks). All subjects underwent regular tumor imaging assessments until disease progression, initiation of new anti-tumor treatment, unwillingness to continue the study, loss to follow-up, death, or study termination, whichever occurred first.

[0807] 8. Pharmacokinetic Analysis

[0808] Collect 3.5 ml of whole blood, separate the serum, and store in aliquots for PK analysis. If necessary, the PK sample will be used for immunogenicity testing.

[0809] 9. Immunogenicity Analysis

[0810] 5 ml of whole blood will be collected in a vacutainer tube, serum will be separated, and aliquots will be frozen for 2149 ADA and / or NAb analysis. If necessary, immunogenicity samples will be used for 2149 concentration testing.

[0811] 10. Tissue Biomarker Analysis

[0812] With the permission of the ethics committee, tumor tissue (including archived or freshly collected) sections of the subjects will be collected according to the visit form for biomarker analysis. Subjects who are successfully enrolled will provide 10 tumor tissue sections (optional) for PD-L1 expression level and tumor microenvironment detection. With the approval of the ethics committee, the consent of the subjects, and the investigator's opinion that conditions permit, the subjects will provide 10 tumor tissue sections (optional) prepared from fresh tumor biopsy or puncture specimens (or tumor tissue specimens obtained by surgery after neoadjuvant therapy) for PD-L1 expression level and tumor microenvironment detection when objective response or disease progression occurs or when clinical judgment requires. If the test fails, if there are remaining sections at the clinical center, additional sections may be required.

[0813] 11. Peripheral Blood Biomarker Analysis

[0814] With the approval of the ethics committee, approximately 3.5 mL of peripheral blood will be sampled according to the visit form for analysis of sCD25 levels in peripheral blood.

[0815] 12. Results

[0816] As of July 5, 2024, the results of this study are as follows:

[0817] Table 11. Baseline characteristics of enrolled patients

[0818] *: In the initial version of the clinical protocol, a dose of 1.5 mg / kg was allowed. This was the first patient enrolled in this study and was not excluded to ensure data integrity.

[0819] Table 12. Overall efficacy

[0820] Table 13. Safety evaluation

[0821] Overall, the above doses (1 mg / kg Q2W and 3 mg / kg Q3W) have controllable safety and good efficacy. 2149 has good efficacy in patients with advanced malignant tumors. In particular, 2149 has shown good clinical benefit in patients with advanced melanoma who have failed or are intolerant to standard treatment. In summary, 2149 has excellent anti-tumor effects and a controllable safety profile in melanoma subjects who have failed standard treatment, reducing the exposure of patients with advanced tumors to ineffective dosing regimens and improving the subjects' tolerance to the study drug.

[0822] Sequence Listing:

Claims

1. Use of a PD-1 / IL-2R bispecific antibody fusion protein for the treatment of solid tumors or hematological tumors, wherein the PD-1 / IL-2R bispecific antibody fusion protein comprises: (a) a first monomer comprising an IL-2 mutant protein fused to an Fc fragment, optionally via a linker or not, wherein the IL-2 mutant protein has T3A+N88R+S130R mutations and the IL15B’C’ loop region AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO:3); and (b) a second monomer comprising one heavy chain and one light chain of an antibody that specifically binds to PD-1.

2. The use according to claim 1, wherein the IL-2 mutant protein comprises the following amino acid sequence or consists of the following amino acid sequence: The amino acid sequence of SEQ ID NO:4; or An amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO:4 and having T3A+N88R+S130R mutations and the IL15B’C’ loop region AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO:3).

3. The use according to claim 1, wherein the linker comprises (GGGGS)n, where n is equal to 1, 2, 3 or 4, such as SEQ ID NO:

5.

4. The use according to any one of claims 1-3, wherein the heavy chain of the antibody that specifically binds to PD-1 comprises an Fc fragment, and the Fc fragment and the Fc fragment fused to the IL-2 mutant protein are Fc fragments of IgG1, IgG2, IgG3 or IgG4, such as human IgG1 Fc.

5. The use according to claim 4, wherein the Fc fragment has a mutation that reduces binding to Fcγ receptors, such as the L234A / L235A mutation or L234A / L235E / G237A.

6. The use according to claim 4 or 5, wherein the Fc fragment of the first monomer comprises a Knob mutation, the Fc fragment of the heavy chain of the second monomer comprises a Hole mutation, or the Fc fragment of the first monomer comprises a Hole mutation and the Fc fragment of the heavy chain of the second monomer comprises a Knob mutation. For example, the Hole mutation is the Y349C, T366S, L368A, Y407V mutation, and / or the Knob mutation is the T366W and S354C mutation.

7. The use according to claim 6, wherein, The Fc fragment of the first monomer comprises the following amino acid sequence or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:6, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in SEQ ID NO:6; Or The heavy chain Fc fragment of the antibody of the second monomer comprises the following amino acid sequence or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO: 12, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in SEQ ID NO:

12.

8. The use according to any one of claims 1-6, wherein the first monomer comprises: the amino acid sequence shown in SEQ ID NO: 7; or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence of SEQ ID NO: 7 and comprising the T3A+N88R+S130R mutation and the IL15B’C’ loop region AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO: 3) in the IL-2 mutant protein, and / or comprising the S354C / T366W mutation in the Fc fragment, and optionally the L234A / L235A mutation.

9. The use according to any one of claims 1-7, wherein the heavy chain of the antibody specifically binding to PD-1 comprises HCDR1, HCDR2 and HCDR3, and the light chain of the antibody specifically binding to PD-1 comprises LCDR1, LCDR2 and LCDR3, wherein the amino acid sequences of HCDR1, HCDR2 and HCDR3 are shown as SEQ ID NO: 9, 10 and 11 respectively, and the amino acid sequences of LCDR1, LCDR2 and LCDR3 are shown as SEQ ID NO: 16, 17 and 18 respectively.

10. The use according to claim 9, wherein the heavy chain of the antibody specifically binding to PD-1 comprises the heavy chain variable region VH, and the light chain of the antibody specifically binding to PD-1 comprises the light chain variable region VL, wherein VH comprises the amino acid sequence shown in SEQ ID NO: 8 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to or consisting of the amino acid sequence, and VL comprises the amino acid sequence shown in SEQ ID NO: 15 or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to or consisting of the amino acid sequence.

11. Use according to claim 9 or 10, wherein the heavy chain comprises the following amino acid sequence or consists of the following amino acid sequence: The amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence containing a Hole mutation having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in SEQ ID NO:14; the light chain comprises the following amino acid sequence or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:20, or an amino acid sequence having 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequence shown in SEQ ID NO:

20.

12. The use according to claim 1, wherein the first monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:7; the heavy chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:14; the light chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:

20.

13. The use according to any one of the preceding claims, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: the dose level is 0.2 μg / kg to 3 mg / kg body weight, such as 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight or a range composed of any two of them.

14. Use according to any one of the preceding claims, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: a dose of 0.2 μg / kg to 3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), for example 0.2 μg / kg, 2 μg / kg, 10 μg / kg, 30 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 2.5 mg / kg, 3 mg / kg body weight or a range composed of any two of them, for example a dose of 30 μg / kg - 3 mg / kg, 0.1 - 3 mg / kg, 0.1 - 2 mg / kg, 0.6 - 3 mg / kg, 0.6 - 2 mg / kg, 1 - 3 mg / kg or 1 - 2 mg / kg body weight; wherein, The fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks for once-weekly or once-three-weekly administration and four weeks for once-two-weekly administration.

15. The use according to any one of the preceding claims, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: administered at 1 - 3 mg / kg body weight or 1 - 2 mg / kg body weight once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks for once-weekly or once-three-weekly administration and four weeks for once-two-weekly administration; preferably, administered at 0.3, 0.6, 1 or 2 mg / kg body weight once every two weeks (Q2W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is four weeks; or administered at 0.6, 1, 1.5, 2 or 3 mg / kg body weight once every three weeks (Q3W), wherein the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks.

16. The use according to any one of the preceding claims, wherein when the single-dose administration dose ≥ 0.6 mg / kg body weight, a dose of the fusion protein ≤ 200 μg / kg body weight is administered by injection, preferably intravenous injection, once as an initial dose 7 ± 1 days before the first single-dose administration dose.

17. Use according to claim 16, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: an initial dose of 0.2 - 200 μg / kg body weight is administered on day 1, and a normal dose of 0.6 - 3 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8 ± 1.

18. Use according to any one of claims 16 - 17, wherein the initial dose is 2 - 200 μg / kg body weight, preferably 30 - 200 μg / kg body weight, more preferably 30 - 150 μg / kg body weight, and most preferably 30 - 100 μg / kg body weight.

19. Use according to claim 17 or 18, wherein the normal dose is a dose of 0.6 - 3 mg / kg, or 0.6 - 2.5 mg / kg, or 0.6 - 2 mg / kg, or 1 - 3 mg / kg, or 1 - 2.5 mg / kg, or 1 - 2 mg / kg body weight administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W), and wherein the normal dose of the fusion protein is administered for one or more treatment cycles, the treatment cycle being three weeks for once a week or once every three weeks administration and four weeks for once every two weeks administration.

20. Use according to any one of claims 17 - 19, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: an initial dose of 30 - 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6 - 3 mg / kg, such as 0.6 - 2 mg / kg, such as 1 - 3 mg / kg, such as 1 - 2 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W), or once every three weeks (Q3W) starting from day 8 ± 1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, the treatment cycle being three weeks for once a week or once every three weeks administration and four weeks for once every two weeks administration.

21. Use according to any one of claims 17 - 20, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing schedule: an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, 2 mg / kg body weight is administered once every two weeks (Q2W) starting from day 8 ± 1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, the treatment cycle being four weeks; or an initial dose of 100 μg / kg body weight is administered on day 1, and a normal dose of 0.6, 1, 1.5, 2 or 3 mg / kg body weight is administered once every three weeks (Q3W) starting from day 8 ± 1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, the treatment cycle being three weeks.

22. Use according to any one of claims 14-21, wherein, When there are more than one treatment cycle, the treatment cycles can be consecutive or spaced apart.

23. Use according to any one of the preceding claims, wherein the solid tumor or hematological tumor is selected from colorectal cancer (including rectal cancer, colon cancer, colorectal cancer), melanoma, lung cancer (such as non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer), breast cancer (such as triple-negative breast cancer), pancreatic cancer, cholangiocarcinoma, ovarian cancer, cervical cancer, uterine cancer, head and neck cancer (such as head and neck squamous cell carcinoma), liver cancer (such as hepatocellular carcinoma), kidney cancer (such as renal cell carcinoma), gastric cancer, lymphoma, leukemia or multiple myeloma; Preferably, the solid tumor or hematological tumor is selected from colorectal cancer, melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), breast cancer, pancreatic cancer, cholangiocarcinoma, ovarian cancer, cervical cancer, head and neck cancer (such as head and neck squamous cell carcinoma), hepatocellular carcinoma, renal cell carcinoma and lymphoma; More preferably, the solid tumor or hematological tumor is selected from colorectal cancer, melanoma and non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer).

24. Use according to any one of the preceding claims, wherein the solid tumor or hematological tumor is refractory to standard therapy or intolerant to standard therapy, advanced, recurrent, metastatic or unresectable.

25. Use according to any one of the preceding claims, wherein the solid tumor or hematological tumor is selected from: Melanoma, such as cutaneous melanoma, acral melanoma, mucosal melanoma or melanoma of unknown primary origin, especially those that are refractory or intolerant to standard therapy, advanced, recurrent, metastatic or unresectable; such as unresectable locally advanced or metastatic melanoma that has progressed or recurred after prior treatment with immune checkpoint inhibitors, or unresectable locally advanced or metastatic melanoma that has not been treated with systemic immune checkpoint inhibitors; Colorectal cancer, preferably colorectal cancer that is refractory or intolerant to standard therapy, advanced, recurrent, metastatic or unresectable, especially colorectal cancer with normal mismatch repair genes (pMMR) and / or microsatellite stability (MSS); and Non-small cell lung cancer, including squamous and non-squamous non-small cell lung cancer, especially non-small cell lung cancer without known driver gene mutations that is refractory or intolerant to standard therapy, advanced, recurrent, metastatic or unresectable.

26. A method for treating a solid tumor or hematological tumor in an individual, the method comprising administering to an individual in need thereof an effective amount of a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of claims 1-12.

27. The method according to claim 26, wherein the PD-1 / IL-2R bispecific antibody fusion protein is administered by injection, preferably intravenous injection, according to a dosing regimen as defined in any one of claims 13-22.

28. The method according to claim 26, wherein the fusion protein is administered by injection, preferably intravenous injection, according to the following dosing regimen: An initial dose of 100 μg / kg body weight is administered on Day 1, and a normal dose of 0.6, 1, 2 mg / kg body weight is administered once every two weeks (Q2W) starting from Day 8 ± 1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, and the treatment cycle is four weeks; or An initial dose of 100 μg / kg body weight is administered on Day 1, and a normal dose of 0.6, 1, 1.5, 2 or 3 mg / kg body weight is administered once every three weeks (Q3W) starting from Day 8 ± 1, wherein the normal dose of the fusion protein is administered for one or more treatment cycles, and the treatment cycle is three weeks.

29. The method according to any one of claims 26 - 28, wherein the solid tumor and hematological tumor are as defined in any one of claims 23 - 25.

30. A pharmaceutical composition for treating a solid tumor or a hematological tumor, which comprises a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of claims 1 - 12, and the pharmaceutical composition is administered by injection, preferably intravenous injection, according to a dosing regimen as defined in any one of claims 13 - 22.

31. A drug combination for treating a solid tumor or a hematological tumor, the drug combination comprising: (i) A first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein, and the PD-1 / IL-2R bispecific antibody fusion protein comprises: (a) a first monomer, which comprises an IL-2 mutant protein fused to an Fc fragment, optionally via or without a linker, wherein the IL-2 mutant protein has T3A+N88R+S130R mutations and an IL15B’C’ loop region of AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO:3); and (b) a second monomer, which comprises a heavy chain and a light chain of an antibody that specifically binds to PD-1; and (ii) A second active ingredient, which is bevacizumab.

32. The drug combination according to claim 31, wherein the IL-2 mutant protein comprises the following amino acid sequence or consists of the following amino acid sequence: The amino acid sequence of SEQ ID NO:4; or An amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence of SEQ ID NO:4 and having T3A+N88R+S130R mutations and an IL15B’C’ loop region of AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO:3).

33. The drug combination according to claim 31, wherein the linker comprises (GGGGS)n, where n is an integer of at least 1, such as 1, 2, 3 or 4, such as SEQ ID NO:

5.

34. The pharmaceutical combination according to any one of claims 31 - 33, wherein the heavy chain of the specific binding PD-1 antibody comprises an Fc fragment, and the Fc fragment and the Fc fragment fused with the IL-2 mutant protein are Fc fragments of IgG1, IgG2, IgG3 or IgG4, for example, human IgG1 Fc.

35. The pharmaceutical combination according to claim 34, wherein the Fc fragment has a mutation for binding to the Fcγ receptor, such as the L234A / L235A mutation or L234A / L235E / G237A.

36. The pharmaceutical combination according to claim 34 or 35, wherein the Fc fragment of the first monomer comprises a Knob mutation, and the Fc fragment of the heavy chain of the second monomer comprises a Hole mutation, or the Fc fragment of the first monomer comprises a Hole mutation and the Fc fragment of the heavy chain of the second monomer comprises a Knob mutation. For example, the Hole mutation is the Y349C, T366S, L368A, Y407V mutation, and / or the Knob mutation is the T366W and S354C mutation.

37. The pharmaceutical combination according to claim 36, wherein the Fc fragment of the first monomer comprises the following amino acid sequence or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:6, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:6; or the Fc fragment of the heavy chain of the second monomer comprises the following amino acid sequence or consists of the following amino acid sequence: the amino acid sequence shown in SEQ ID NO:12, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:

12.

38. The pharmaceutical combination according to any one of claims 31 - 36, wherein the first monomer comprises: the amino acid sequence shown in SEQ ID NO:7; or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence of SEQ ID NO:7 and comprising the T3A+N88R+S130R mutation and the IL15B’C’ loop region AGDASIH relative to wild-type IL-2 (such as the amino acid sequence shown in SEQ ID NO:3) in the IL-2 mutant protein, and / or comprising S354C / T366W in the Fc fragment, and optionally the L234A / L235A mutation.

39. The pharmaceutical combination according to any one of claims 31-37, wherein the heavy chain of the antibody specifically binding to PD-1 comprises HCDR1, HCDR2 and HCDR3, and the light chain of the antibody specifically binding to PD-1 comprises LCDR1, LCDR2 and LCDR3, wherein the amino acid sequences of HCDR1, HCDR2 and HCDR3 are shown as SEQ ID NO:9, 10 and 11 respectively, and the amino acid sequences of LCDR1, LCDR2 and LCDR3 are shown as SEQ ID NO:16, 17 and 18 respectively.

40. The pharmaceutical combination according to claim 39, wherein the heavy chain of the antibody specifically binding to PD-1 comprises the heavy chain variable region VH, and the light chain of the antibody specifically binding to PD-1 comprises the light chain variable region VL. Among them, The VH comprises the amino acid sequence shown in SEQ ID NO:8 or consists of the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:8, and the VL comprises the amino acid sequence shown in SEQ ID NO:15 or consists of the amino acid sequence shown in SEQ ID NO:15, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:

15.

41. The pharmaceutical combination according to claim 39 or 40, wherein the heavy chain comprises the following amino acid sequence or consists of the following amino acid sequence: The amino acid sequence shown in SEQ ID NO:14, or an amino acid sequence containing a Hole mutation having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:14; the light chain comprises the amino acid sequence shown in SEQ ID NO:20 or consists of the amino acid sequence shown in SEQ ID NO:20, or an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequence shown in SEQ ID NO:

20.

42. The pharmaceutical combination according to claim 31, wherein the first monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:7; the heavy chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:14; and the light chain of the second monomer comprises or consists of the amino acid sequence shown in SEQ ID NO:

20.

43. The pharmaceutical combination according to any one of claims 31-42, wherein the first active ingredient is for administration by injection, such as intravenous infusion; the second active ingredient is for administration by injection, such as intravenous infusion.

44. The pharmaceutical combination according to any one of claims 31-42, wherein the first active ingredient is administered by injection, preferably intravenous injection, according to the dosing regimen defined in any one of claims 13-22; and the second active ingredient is for intravenous infusion, at a dose of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, with a treatment cycle of four weeks, or administered once every three weeks, with a treatment cycle of three weeks, and administered for one or more treatment cycles.

45. The pharmaceutical combination according to claim 44, wherein the first active ingredient is used for injection, preferably intravenous injection, as follows: administered at a dose of 0.6-3 mg / kg, such as 0.6-2 mg / kg, such as 1-3 mg / kg, such as 1-2 mg / kg body weight, once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W), and administered for one or more treatment cycles, with a treatment cycle of three weeks; or, an initial dose of 30-100 μg / kg body weight is administered on day 1, and starting from day 8±1, a normal dose of 0.6-3 mg / kg, such as 0.6-2 mg / kg, such as 1-3 mg / kg, such as 1-2 mg / kg body weight is administered once a week (QW), once every two weeks (Q2W) or once every three weeks (Q3W), wherein the normal dose is administered for one or more treatment cycles, with a treatment cycle of three weeks; and the second active ingredient is for intravenous infusion, at a dose of 5-15 mg / kg body weight (such as 5, 7.5, 10, 12.5, 15 mg / kg body weight or a range composed of any two of them), administered once every two weeks, with a treatment cycle of four weeks, or administered once every three weeks, with a treatment cycle of three weeks, and administered for one or more treatment cycles.

46. The pharmaceutical combination according to any one of claims 31-42, wherein The first active ingredient (such as molecule 2149) is used for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is used for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8th ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8th ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is used for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle.

47. The pharmaceutical combination according to any one of claims 31-46, wherein the solid tumor or hematological tumor is selected from intestinal cancer (including rectal cancer, colon cancer, colorectal cancer), melanoma, non-small cell lung cancer (including squamous and non-squamous non-small cell lung cancer), hepatocellular carcinoma, renal cell carcinoma, lymphoma or other advanced solid tumors.

48. The pharmaceutical combination according to claim 47, wherein the solid tumor is colorectal cancer, preferably advanced colorectal cancer, more preferably advanced colorectal cancer with failure of standard treatment; The first active ingredient (such as molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8th ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8th ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle; preferably, the second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 10 mg / kg body weight (such as 5 mg / kg body weight or 7.5 mg / kg body weight), administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle; especially 7.5 mg / kg, administered once every three weeks (Q3W).

49. The pharmaceutical combination according to claim 47, wherein the solid tumor is melanoma, preferably advanced melanoma, more preferably advanced melanoma that has not been immunotherapied or advanced melanoma with prior immunotherapy failure; The first active ingredient (e.g., molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (e.g., 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8 ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (e.g., an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8 ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle; preferably, the second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg body weight or 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle.

50. The pharmaceutical combination according to claim 47, wherein the solid tumor is non-small cell lung cancer, such as squamous or non-squamous non-small cell lung cancer (preferably advanced non-squamous non-small cell lung cancer, more preferably advanced non-squamous non-small cell lung cancer with standard treatment failure or intolerance), hepatocellular carcinoma (preferably advanced hepatocellular carcinoma, more preferably advanced hepatocellular carcinoma without systemic treatment), or renal cell carcinoma (preferably advanced renal cell carcinoma, more preferably advanced renal cell carcinoma with standard treatment failure or intolerance); The first active ingredient (e.g., molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (e.g., 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8th ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (e.g., an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8th ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle; preferably, the second active ingredient is for intravenous infusion administration, with a dosage of 10 mg / kg body weight to 15 mg / kg body weight (e.g., 10 mg / kg body weight, 12.5 mg / kg body weight or 15 mg / kg body weight), administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle.

51. The pharmaceutical combination according to claim 47, wherein the solid tumor is lymphoma and other solid tumors, preferably lymphoma or other advanced solid tumors with standard treatment failure or intolerance; The first active ingredient (such as molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8 ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8 ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight to 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle; preferably, the second active ingredient is for intravenous infusion administration, with a dosage of 5 mg / kg body weight, 7.5 mg / kg, 10 mg / kg, 12.5 mg / kg body weight or 15 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle, or administered once every three weeks, and every three weeks is a treatment cycle.

52. A pharmaceutical combination for treating melanoma, the pharmaceutical combination comprising: (i) A first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of claims 1-12 or claims 31-42; and (ii) A second active ingredient, which is dacarbazine.

53. The pharmaceutical combination according to claim 52, wherein the first active ingredient is for injection administration, such as intravenous infusion, for example, administered by injection, preferably intravenous injection, according to the administration regimen defined in any one of claims 13-22; the second active ingredient is administered by injection, such as intravenous infusion, intravenous bolus injection, arterial infusion or arterial bolus injection.

54. The pharmaceutical combination according to claim 53, wherein, The first active ingredient (such as molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8th ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8th ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient, dacarbazine, is administered by intravenous or arterial infusion. When administered by intravenous or arterial infusion, the dosage of dacarbazine is 2.5 - 6 mg / kg body weight or 200 - 400 mg / m 2 body surface area, administered once daily for 5 - 10 consecutive days, then discontinued, with each treatment cycle being 3 - 6 weeks, or the dosage is 650 - 1450 mg / m 2 body surface area, administered once every 4 - 6 weeks, and correspondingly each treatment cycle is 4 - 6 weeks; when administered by intravenous or arterial bolus injection, the dosage of dacarbazine is 200 - 400 mg / m 2 , administered once daily for 5 consecutive days, then discontinued, with each treatment cycle being 3 - 4 weeks.

55. The pharmaceutical combination according to any one of claims 52 - 54, wherein the melanoma is advanced melanoma that has not been systemically treated; the second active ingredient, dacarbazine, is administered by intravenous infusion at a dose of 850 mg / m 2 body surface area, once every four weeks, with each four - week period being a treatment cycle; or is administered by intravenous infusion at a dose of 650 - 1050 mg / m 2 body surface area (e.g., 850 mg / m 2 body surface area), once every three weeks, with each three - week period being a treatment cycle; or is administered by intravenous bolus at a dose of 200 - 300 mg / m 2 body surface area (e.g., 250 mg / m 2 body surface area), once daily for 5 consecutive days, then discontinued, with each four - week period being a treatment cycle; or is administered by intravenous bolus at a dose of 200 - 300 mg / m 2 body surface area (e.g., 250 mg / m 2 body surface area), once daily for 5 consecutive days, then discontinued, with each three - week period being a treatment cycle.

56. A pharmaceutical combination for treating non-small cell lung cancer, the pharmaceutical combination comprising: (i) A first active ingredient, which is a PD-1 / IL-2R bispecific antibody fusion protein as defined in any one of claims 1-12 or claims 31-42; and (ii) A second active ingredient, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein W is O; Z is O; G is CR; a is 0; c is 1; b is 1; R is H or C 1-6 alkyl; Yes R1, R2, and R3 are each independently selected from H, halogen, and C 1-6 alkoxy groups; R4 and R5 are each independently selected from H or C 1-6 alkyl; R6 is H.

57. The pharmaceutical combination according to claim 56, wherein the second active ingredient is anlotinib or a pharmaceutically acceptable salt thereof, such as anlotinib dihydrochloride.

58. The pharmaceutical combination according to claim 55 or 57, wherein the first active ingredient is for injection administration, such as intravenous infusion, and is administered by injection, preferably intravenous injection, according to the dosing regimen defined in any one of claims 13-22; the second active ingredient is for oral administration.

59. According to claim 58, wherein The first active ingredient (such as molecule 2149) is for intravenous infusion administration, with a dosage of 0.2 μg / kg body weight to 1 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once a week, and every three weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every two weeks, and every four weeks is a treatment cycle; or a dosage of 1 mg / kg body weight to 3 mg / kg body weight, administered once every three weeks, and every three weeks is a treatment cycle; or, the first active ingredient is for intravenous infusion administration, an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight is given on the 8th ± 1 day, and the maintenance dose is given once every two weeks; or an initial dose of 0.2 μg / kg body weight to 1 mg / kg body weight (such as an initial dose of 100 μg / kg body weight or 1 mg / kg body weight) is given on the first day, a maintenance dose of 2 mg / kg body weight or 3 mg / kg is given on the 8th ± 1 day, and the maintenance dose is given once every three weeks; The second active ingredient is for oral administration, with a dosage of 8 mg to 12 mg, administered once a day, continuously administered for 2 weeks, stopped for 1 week, and every three weeks is a treatment cycle.

60. The pharmaceutical combination according to any one of claims 56 - 59, wherein the non-small cell lung cancer is advanced non-small cell lung cancer, preferably advanced non-small cell lung cancer with standard treatment failure or intolerance; the second active ingredient (such as anlotinib dihydrochloride) is for oral administration, with a dosage of 12 mg (when the second active ingredient is a pharmaceutically acceptable salt of anlotinib such as dihydrochloride, calculated as anlotinib), administered once a day, continuously administered for 2 weeks, stopped for 1 week, and every three weeks is a treatment cycle.

61. The pharmaceutical combination according to any one of claims 31 - 60, wherein the pharmaceutical combination comprises the first active ingredient and the second active ingredient as the only active ingredients.

62. The pharmaceutical combination according to any one of claims 31 - 61, wherein the pharmaceutical combination is in the form of a kit or a package, and the kit or the package has: a pharmaceutical composition comprising the first active ingredient; a pharmaceutical composition comprising the second active ingredient; an instruction manual, and the instruction manual records the administration methods of the two pharmaceutical compositions.

63. Use of the pharmaceutical combination according to any one of claims 31 - 61 in the preparation of a drug.

64. A method for treating cancer, the method comprising administering the pharmaceutical combination according to any one of claims 31 - 61, wherein the first active ingredient and the second active ingredient are administered simultaneously in a single pharmaceutical composition or simultaneously or separately in separate pharmaceutical compositions.

65. A single-dose administration unit comprising a therapeutically effective amount, for a single treatment, of a fusion protein as defined in any one of claims 1-12, for example from 10 μg to 300 mg of a fusion protein as defined in any one of claims 1-12; preferably, the single-dose administration unit is for administration by injection.

66. A kit comprising one or more single-dose administration units according to claim 65, and instructions for use indicating that the one or more single-dose administration units are to be administered according to a dosing regimen as defined in any one of embodiments 13-22.

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