Use of bispecific Anti-CD3 / CD20 polypeptide complex

Abstract

The present application discloses a pharmaceutical combination comprising a bispecific anti-CD3 / CD20 polypeptide complex and a second therapeutic agent, and use thereof in the preparation of a drug for treating non-Hodgkin lymphoma.

Description

Use of bispecific anti-CD3 / CD20 polypeptide complex TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and in particular relates to the use of bispecific anti-CD3 / CD20 polypeptide complex for treating tumors. BACKGROUND

[0002] CD20 is an activated glycosylated phosphoprotein expressed on the surface of B lymphocytes, with no expression of CD20 antigen in hematopoietic stem cells, progenitor cells and other normal tissues. The T cell CD3 receptor is a protein complex composed of four different chains (CD3 gamma chain, CD3 delta chain and two CD3 epsilon chains), which are associated with a molecule called T cell receptor (TCR) and intracellular zeta chain to generate activation signals in T lymphocytes. TCR, zeta chain and CD3 molecules constitute the TCR complex, in which TCR serves as a subunit for recognizing and binding to antigens, and CD3 serves as a subunit responsible for transmitting antigen stimulation to the signal transduction pathway and ultimately regulating T cell activity. CD3-TCR complex regulates T cell function in innate and adaptive immune responses, as well as cellular and humoral immune functions, including elimination of pathogenic organisms and control of tumor growth through cytotoxic effects. Anti-CD3 / CD20 bispecific antibodies can simultaneously target CD3 expressed on T cells and CD20 expressed on B cells, leading to T cell activation and T cell-mediated B cell killing.

[0003] Lymphoma is a group of malignant tumors originating from the lymphoid hematopoietic system, and is one of the malignant tumors with high incidence worldwide in recent years. It has many subtypes and is highly heterogeneous, which has caused serious threat to human life safety. Although anti-CD20 antibodies (e.g., rituximab) have outstanding clinical benefits in first-line and second-line treatment, relapse has always been a thorny problem in clinical practice, and these patients have poor prognosis. In addition, there are some patients who do not respond to rituximab treatment, and these patients lack standard treatment options.

[0004] SUMMARY

[0005] In one aspect, the present application provides a pharmaceutical combination comprising a bispecific anti-CD3 / CD20 polypeptide complex and a second therapeutic agent. In some embodiments, the pharmaceutical combination is used for treating a tumor.

[0006] In another aspect, the present application also provides a method for treating a tumor in a subject, comprising administering to the subject the pharmaceutical combination of the present application.

[0007] In another aspect, the present application also provides the use of the pharmaceutical combination of the present application in the preparation of a medicament for treating a tumor in a subject. In addition, the present application also provides the use of the pharmaceutical combination of the present application for treating a tumor in a subject.

[0008] In another aspect, the present application also provides a method of treating a tumor in a subject, comprising administering to the subject a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent.

[0009] In another aspect, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent in the manufacture of a medicament for treating a tumor in a subject. In addition, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent in the treatment of a tumor in a subject.

[0010] In another aspect, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in conjunction with a second therapeutic agent of the present application. In addition, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating a tumor in a subject in conjunction with a second therapeutic agent of the present application. In addition, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for a combination therapy for treating a tumor in a subject, wherein the medicament is administered in conjunction with a second therapeutic agent of the present application.

[0011] In some embodiments, in the methods and uses, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent can be administered sequentially and / or alternately.

[0012] In another aspect, the present application provides a kit for treating a tumor, comprising a pharmaceutical combination of the present application. In addition, the present application provides a kit for treating a tumor, comprising a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent, and instructions for using the bispecific anti-CD3 / CD20 polypeptide complex of the present application and the second therapeutic agent in conjunction to treat a tumor.

[0013] In some embodiments, the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug. In some embodiments, the immunomodulatory agent comprises an anti-CD20 antibody (e.g., Rituximab, Ofatumumab, Obinutuzumab), Lenalidomide, Thalidomide, and / or Pomalidomide. In some embodiments, the chemotherapeutic drug comprises a platinum-based antitumor drug (e.g., Oxaliplatin, Cisplatin, Carboplatin), an antimetabolite antitumor drug (e.g., Gemcitabine, Azacitidine), a nitrogen mustard antitumor drug (e.g., Cyclophosphamide, Ifosfamide), an anthracycline antitumor drug (e.g., Doxorubicin, Epirubicin), a vinca alkaloid antitumor drug (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), and / or a hormonal antitumor drug (e.g., Prednisone, Prednisolone). In some embodiments, the second therapeutic agent is Gemcitabine and Oxaliplatin. In some embodiments, the second therapeutic agent is Oxaliplatin, Gemcitabine, and Rituximab. In some embodiments, the second therapeutic agent is Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, and Prednisone. In some embodiments, the second therapeutic agent is Rituximab, Cyclophosphamide, Vincristine, Epirubicin, and Prednisone. In some embodiments, the second therapeutic agent is Lenalidomide. In some embodiments, the second therapeutic agent is Lenalidomide and Rituximab.

[0014] In some embodiments, each of the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is a liquid formulation or a solid formulation. In some specific embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is an injection solution. In some specific embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is a lyophilized formulation.

[0015] In some embodiments, the tumor is a lymphoma. In some embodiments, the tumor is a Hodgkin lymphoma. In some embodiments, the tumor is a non-Hodgkin lymphoma. In some specific embodiments, the tumor is a diffuse large B-cell lymphoma, a follicular lymphoma, a marginal zone lymphoma, and a mantle cell lymphoma. In some specific embodiments, the tumor is a relapsed and / or refractory diffuse large B-cell lymphoma. In some specific embodiments, the tumor is a newly diagnosed or treatment-naive diffuse large B-cell lymphoma. In some specific embodiments, the tumor is a relapsed and / or refractory follicular lymphoma and marginal zone lymphoma. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 shows a schematic representation of a bispecific anti-CD3 / CD20 polypeptide complex.

[0017] DETAILED DESCRIPTION

[0018] Pharmaceutical combination

[0019] In one aspect, the present application provides a pharmaceutical combination comprising a bispecific anti-CD3 / CD20 polypeptide complex and a second therapeutic agent.

[0020] In some embodiments, the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug. In some embodiments, the immunomodulatory agent comprises an anti-CD20 antibody (e.g., Rituximab, Ofatumumab, Obinutuzumab), Lenalidomide, Thalidomide, and / or Pomalidomide. In some embodiments, the chemotherapeutic drug comprises a platinum-based antitumor drug (e.g., Oxaliplatin, Cisplatin, Carboplatin), an antimetabolite antitumor drug (e.g., Gemcitabine, Azacitidine), a nitrogen mustard antitumor drug (e.g., Cyclophosphamide, Ifosfamide), an anthracycline antitumor drug (e.g., Doxorubicin, Epirubicin), a vinca alkaloid antitumor drug (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), and / or a hormonal antitumor drug (e.g., Prednisone, Prednisolone).

[0021] In some embodiments, the second therapeutic agent comprises one or more of an anti-CD20 antibody, a nitrogen mustard antitumor drug, an anthracycline antitumor drug, a vinca alkaloid antitumor drug, a hormonal antitumor drug, Lenalidomide, a platinum-based antitumor drug, an antimetabolite antitumor drug.

[0022] In some embodiments, the nitrogen mustard antitumor drug comprises Cyclophosphamide, Ifosfamide, Chlorambucil, Carmustine, Melphalan, and Bendamustine, preferably Cyclophosphamide or Ifosfamide.

[0023] In some embodiments, the anthracycline antitumor drug comprises Doxorubicin, Epirubicin, Pirarubicin, Aminoglutethimide, Aranotubicin, Idarubicin, Daunorubicin, Mitoxantrone, Idarubicin, Valrubicin, Zorubicin, Pixantrone, and Liposomal Doxorubicin, preferably Doxorubicin or Epirubicin.

[0024] In some embodiments, the vinca alkaloid antitumor drug comprises Vinblastine, Vincristine, Vindesine, Vinorelbine, and Vinflunine, preferably Vincristine or Vindesine.

[0025] In some embodiments, the hormonal antineoplastic drug comprises prednisone, prednisolone, dexamethasone, and methylprednisolone, preferably prednisone or prednisolone.

[0026] In some embodiments, the platinum antineoplastic drug comprises oxaliplatin, cisplatin, carboplatin, nedaplatin, satraplatin, miriplatin, lobaplatin, picoplatin, triplatin tetranitrate, phenanthriplatin, and satraplatin, preferably oxaliplatin.

[0027] In some embodiments, the antimetabolite antineoplastic drug comprises cytarabine, gemcitabine, azacitidine, and ancitabine, preferably gemcitabine.

[0028] In some embodiments, the second therapeutic agent comprises a platinum antineoplastic drug, an antimetabolite antineoplastic drug, and optionally an anti-CD20 antibody. In some embodiments, the second therapeutic agent comprises gemcitabine and oxaliplatin. In some embodiments, the second therapeutic agent comprises oxaliplatin, gemcitabine, and rituximab.

[0029] In some embodiments, the second therapeutic agent comprises an anti-CD20 antibody, a nitrogen mustard antineoplastic drug, an anthracycline antineoplastic drug, a vinca alkaloid antineoplastic drug, and a hormonal antineoplastic drug. In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone.

[0030] In some embodiments, the second therapeutic agent comprises lenalidomide and optionally an anti-CD20 antibody. In some embodiments, the second therapeutic agent comprises lenalidomide. In some embodiments, the second therapeutic agent comprises lenalidomide and rituximab.

[0031] In some embodiments, the pharmaceutical combination is packaged in the same kit, which further comprises instructions for using the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent in combination to treat a neoplasm. In other embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent of the pharmaceutical combination are packaged separately in respective kits, which further comprise instructions for using the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent in combination to treat a neoplasm.

[0032] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are each in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is a liquid formulation or a solid formulation. In some specific embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is an injection solution. In some specific embodiments, the pharmaceutical composition of the bispecific anti-CD3 / CD20 polypeptide complex is a lyophilized formulation.

[0033] In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 1-10 mg or 2-10 mg. In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, or a range formed by any of the aforementioned values. In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 1 mg, 2 mg, and / or 10 mg. In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 50-150 mg. In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, or a range formed by any of the aforementioned values. In some embodiments, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 80 mg.

[0034] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.01-200 mg, 0.1-100 mg, 0.3-50 mg, or 0.3-30 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.3-1 mg or 30-50 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.3 mg, 1 mg, 30 mg, or 50 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.3-3 mg, 0.3-1 mg, 10-30 mg, 30-80 mg, 30-50 mg, or 50-80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is formulated to be suitable for administration to a patient in a single dose or multiple doses of 0.3 mg, 3 mg, 30 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex.

[0035] In some embodiments, the pharmaceutical combination comprises 0.01-200 mg, 0.1-100 mg, 0.3-50 mg, or 0.3-30 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, or a range formed by any of the above values. In some embodiments, the pharmaceutical combination comprises 0.3-1 mg or 30-50 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.3 mg, 1 mg, 30 mg, or 50 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.3-3 mg, 0.3-1 mg, 10-30 mg, 30-80 mg, 30-50 mg, or 50-80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.3 mg, 3 mg, 30 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex.

[0036] In some embodiments, the pharmaceutical combination comprises 0.1-500 mg, 0.5-300 mg, 1-200 mg, or 1.3-200 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 61 mg, 61.3 mg, 61.5 mg, 70 mg, 80 mg, 90 mg, 100 mg, 101 mg, 101.3 mg, 101.5 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 300 mg, 400 mg, 500 mg, or a range formed by any of the aforementioned values. In some embodiments, the pharmaceutical combination comprises 0.1-1.5 mg, 0.3-1.3 mg, 20-60 mg, 30-50 mg, 60-180 mg, 90-150 mg, 1.3-90 mg, or 1.3-150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 1.3 mg, 30 mg, 50 mg, 90 mg, or 150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, 80-240 mg, 120-200 mg, or 30-200 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, 101.3 mg, 120 mg, or 200 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, or 30-120 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, or 101.3 mg of the anti-CD3 / CD20 polypeptide complex.In some embodiments, the pharmaceutical combination comprises 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 30 mg, 33.3 mg, or 90 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 33.3 mg, 50 mg, or 150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 33.3 mg, 80 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 30 mg, or 90 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 50 mg, or 130 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 80 mg, or 190 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 30 mg, or 60 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 3.3 mg, 80 mg, or 110 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination comprises 63.3 mg, 60 mg, 83.3 mg, 100 mg, 113.3 mg, or 160 mg of the anti-CD3 / CD20 polypeptide complex.

[0037] In some embodiments, the anti-CD3 / CD20 polypeptide complex is administered in a daily dose. In some embodiments, the anti-CD3 / CD20 polypeptide complex is administered in a once-daily dose.

[0038] In some embodiments, the anti-CD3 / CD20 polypeptide complex is administered in a unit dose.

[0039] In some embodiments, the anti-CD3 / CD20 polypeptide complex is administered in a dose for a treatment cycle, and each treatment cycle is 3 weeks (i.e., 21 days).

[0040] In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 0.1-500 mg, 0.5-300 mg, 1-200 mg, or 1.3-200 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 61 mg, 61.3 mg, 61.5 mg, 70 mg, 80 mg, 90 mg, 100 mg, 101 mg, 101.3 mg, 101.5 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 300 mg, 400 mg, 500 mg, or a range formed by any of the aforementioned values. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 0.1-1.5 mg, 0.3-1.3 mg, 20-60 mg, 30-50 mg, 60-180 mg, 90-150 mg, 1.3-90 mg, or 1.3-150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 1.3 mg, 30 mg, 50 mg, 90 mg, or 150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, 80-240 mg, 120-200 mg, or 30-200 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, 101.3 mg, 120 mg, or 200 mg of the anti-CD3 / CD20 polypeptide complex.In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, or 30-120 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, or 101.3 of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 30 mg, 33.3 mg, or 90 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 33.3 mg, 50 mg, or 150 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 33.3 mg, 80 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 30 mg, or 90 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 50 mg, or 130 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 80 mg, or 190 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 30 mg, or 60 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex. In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 3.3 mg, 80 mg, or 110 mg of the anti-CD3 / CD20 polypeptide complex.In some embodiments, the pharmaceutical combination is suitable for administration in a single treatment cycle comprising 63.3 mg, 60 mg, 83.3 mg, 100 mg, 113.3 mg, or 160 mg of the anti-CD3 / CD20 polypeptide complex.

[0041] Use

[0042] The present application also provides a method of treating a tumor in a subject comprising administering to the subject a pharmaceutical combination of the present application. In addition, the present application also provides use of a pharmaceutical combination of the present application in the manufacture of a medicament for treating a tumor in a subject. In addition, the present application also provides use of a pharmaceutical combination of the present application for treating a tumor in a subject.

[0043] The present application also provides a method of treating a tumor in a subject comprising administering to the subject a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent. In addition, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent in the manufacture of a medicament for treating a tumor in a subject. In addition, the present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and a second therapeutic agent for treating a tumor in a subject. The present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating a tumor in a subject, wherein the medicament is for use in conjunction with a second therapeutic agent of the present application. The present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating a tumor in a subject in conjunction with a second therapeutic agent of the present application. The present application also provides use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for a combination therapy for treating a tumor in a subject, wherein the medicament is administered in conjunction with a second therapeutic agent of the present application.

[0044] In some embodiments, the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug. In some embodiments, the immunomodulatory agent comprises an anti-CD20 antibody (e.g., Rituximab, Ofatumumab), Lenalidomide, Thalidomide, and / or Pomalidomide. In some embodiments, the chemotherapeutic drug comprises a platinum-based antitumor drug (e.g., Oxaliplatin, Cisplatin, Carboplatin), an antimetabolite antitumor drug (e.g., Gemcitabine, Azacitidine), a nitrogen mustard antitumor drug (e.g., Cyclophosphamide, Ifosfamide), an anthracycline antitumor drug (e.g., Doxorubicin, Epirubicin), a vinca alkaloid antitumor drug (e.g., Vinblastine, Vincristine, Vindesine, Vinorelbine), and / or a hormonal antitumor drug (e.g., Prednisone, Prednisolone).

[0045] In some embodiments, the second therapeutic agent comprises one or more of an anti-CD20 antibody, a nitrogen mustard antineoplastic drug, an anthracycline antineoplastic drug, a vinca alkaloid antineoplastic drug, a hormonal antineoplastic drug, lenalidomide, a platinum antineoplastic drug, an antimetabolite antineoplastic drug.

[0046] In some embodiments, the nitrogen mustard antineoplastic drug comprises cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, and bendamustine, preferably cyclophosphamide or ifosfamide.

[0047] In some embodiments, the anthracycline antineoplastic drug comprises doxorubicin, epirubicin, pirarubicin, amrubicin, aclarubicin, idarubicin, daunorubicin, mitoxantrone, valrubicin, pitarubicin, zorubicin, pixantrone, and liposomal doxorubicin, preferably doxorubicin or epirubicin.

[0048] In some embodiments, the vinca alkaloid antineoplastic drug comprises vinblastine, vincristine, vindesine, vinflunine, and vinorelbine, preferably vincristine or vindesine.

[0049] In some embodiments, the hormonal antineoplastic drug comprises prednisone, prednisolone, dexamethasone, and methylprednisolone, preferably prednisone or prednisolone.

[0050] In some embodiments, the platinum antineoplastic drug comprises oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miriplatin, lobaplatin, picoplatin, triplatin tetranitrate, phenanthriplatin, and satraplatin, preferably oxaliplatin.

[0051] In some embodiments, the antimetabolite antineoplastic drug comprises cytarabine, gemcitabine, azacitidine, and ancitabine, preferably gemcitabine.

[0052] In some embodiments, the second therapeutic agent comprises a platinum antineoplastic drug, an antimetabolite antineoplastic drug, and optionally an anti-CD20 antibody. In some embodiments, the second therapeutic agent comprises gemcitabine and oxaliplatin. In some embodiments, the second therapeutic agent comprises oxaliplatin, gemcitabine, and rituximab.

[0053] In some embodiments, the second therapeutic agent comprises an anti-CD20 antibody, a nitrogen mustard antineoplastic drug, an anthracycline antineoplastic drug, a vinca alkaloid antineoplastic drug, and a hormonal antineoplastic drug. In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone.

[0054] In some embodiments, the second therapeutic agent comprises lenalidomide and optionally an anti-CD20 antibody. In some embodiments, the second therapeutic agent comprises lenalidomide. In some embodiments, the second therapeutic agent comprises lenalidomide and rituximab.

[0055] In some embodiments, the tumor is a lymphoma. In some embodiments, the tumor is Hodgkin's lymphoma. In some embodiments, the tumor is non-Hodgkin's lymphoma. In some specific embodiments, the tumor is diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma. In some specific embodiments, the tumor is relapsed and / or refractory diffuse large B-cell lymphoma. In some specific embodiments, the tumor is newly diagnosed or treatment naive diffuse large B-cell lymphoma. In some specific embodiments, the tumor is relapsed and / or refractory follicular lymphoma and marginal zone lymphoma.

[0056] The present application also provides a method of treating non-Hodgkin's lymphoma in a subject comprising administering to the subject a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone for treating non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is for use in conjunction with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in conjunction with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone for treating non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in a combination therapy for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is administered in conjunction with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone.

[0057] The present application also provides a method of treating non-Hodgkin's lymphoma in a subject comprising administering to the subject a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, and cyclophosphamide. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, and cyclophosphamide in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application, rituximab, and cyclophosphamide in the treatment of non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is for use in combination with rituximab and cyclophosphamide. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in combination with rituximab and cyclophosphamide in the treatment of non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in a combination therapy for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is administered in combination with rituximab and cyclophosphamide.

[0058] The present application also provides a method of treating non-Hodgkin's lymphoma in a subject comprising administering to the subject a bispecific anti-CD3 / CD20 polypeptide complex of the present application and lenalidomide. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and lenalidomide in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject. In addition, the present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application and lenalidomide in the treatment of non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is for use in combination with lenalidomide. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in combination with lenalidomide in the treatment of non-Hodgkin's lymphoma in a subject. The present application also provides the use of a bispecific anti-CD3 / CD20 polypeptide complex of the present application in the manufacture of a medicament for use in a combination therapy for treating non-Hodgkin's lymphoma in a subject, wherein the medicament is administered in combination with lenalidomide.

[0059] In some embodiments, in the method or use, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are administered sequentially and / or alternately. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are each in the form of a pharmaceutical composition. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are each in the form of a pharmaceutical composition, and are administered sequentially and / or alternately.

[0060] In some embodiments, in the method or use, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are administered according to the same or different dosing regimen. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are administered according to different dosing regimens.

[0061] In some embodiments, in the method or use, the bispecific anti-CD3 / CD20 polypeptide complex is administered once every 3 weeks, twice every 3 weeks, three times every 3 weeks, once every 4 weeks, twice every 4 weeks, three times every 4 weeks, or four times every 4 weeks.

[0062] In some embodiments, in the methods or uses, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.01-200 mg, 0.1-100 mg, 0.3-50 mg, or 0.3-30 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, or a range formed by any of the above values, per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.3-1 mg or 30-50 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.3 mg, 1 mg, 30 mg, or 50 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.1-100 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.3-3 mg, 0.3-1 mg, 10-30 mg, 30-80 mg, 30-50 mg, or 50-80 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.3 mg, 1 mg, 3 mg, 10 mg, 30 mg, 50 mg, or 80 mg of anti-CD3 / CD20 polypeptide complex per administration. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.3 mg, 3 mg, 30 mg, 50 mg, or 80 mg of anti-CD3 / CD20 polypeptide complex per administration.

[0063] In some embodiments, in the method or use, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.01-50 mg / kg, 0.01-40 mg / kg, 0.01-30 mg / kg, 0.01-20 mg / kg, 0.01-10 mg / kg, 0.1-50 mg / kg, 0.1-40 mg / kg, 0.1-30 mg / kg, 0.1-20 mg / kg, 0.1-10 mg / kg, 0.3-50 mg / kg, 0.3-40 mg / kg, 0.3-30 mg / kg, 0.3-20 mg / kg, 0.3-10 mg / kg, or 0.5-5 mg / kg each time. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex is administered at a dose of 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, or a range formed by any of the above values each time.

[0064] In some embodiments, in the method or use, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent have the same or different treatment cycles. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent have the same treatment cycle, e.g., a treatment cycle is every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent have the same treatment cycle, e.g., a treatment cycle is every 3 weeks or 4 weeks. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent have the same treatment cycle, e.g., a treatment cycle is every 3 weeks. In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent have the same treatment cycle, e.g., a treatment cycle is every 4 weeks.

[0065] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered three times in the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered three times in each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered three times in the first treatment cycle, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the second and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered two times in the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered three times in each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered two times in the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered two times in the second treatment cycle, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the third and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered two times in the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered three times in each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the fourth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 9, 11, and 16 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 2, 9, and 16 of each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 9, 11, and 16 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 2 of each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles.In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 16 and 18 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 2, 9, and 16 of each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 16 and 18 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 2 and 9 of the second treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 2 of the third treatment cycle, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 9 and 16 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 2, 9, and 16 of each of the second through third treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 2 of each of the fourth through sixth treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the sixth and subsequent treatment cycles. In some embodiments, the second therapeutic agent is the R-CHOP regimen, i.e., rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, every 3 weeks is a treatment cycle, rituximab is administered once per treatment cycle, cyclophosphamide is administered once per treatment cycle, vincristine is administered once per treatment cycle, doxorubicin is administered once per treatment cycle, and prednisone is administered five times per treatment cycle.

[0066] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, three times of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the first treatment cycle, three times of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the second to third treatment cycles, and once of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, three times of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the first treatment cycle, and once of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the second and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, twice of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the first treatment cycle, three times of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the second to third treatment cycles, and once of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, twice of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the first treatment cycle, twice of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the second treatment cycle, and once of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the third and subsequent treatment cycles. In some embodiments, in the method or use, every 4 weeks is a treatment cycle, four times of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the first to second treatment cycles, twice of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the third to fourth treatment cycles, and once of the bispecific anti-CD3 / CD20 polypeptide complex is administered in each of the fifth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 8, day 10 and day 15 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1, day 8 and day 15 of each of the second to third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, every 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 8, day 10 and day 15 of the first treatment cycle, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the second and subsequent treatment cycles.In some embodiments, each 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 15 and 17 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1, day 8, and day 15 of each of the second through third treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, each 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 15 and 17 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 and day 8 of the second treatment cycle, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the third and subsequent treatment cycles. In some embodiments, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 2, day 9, day 16, and day 23 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1, day 8, day 15, and day 22 of the second treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 and day 15 of each of the third and fourth treatment cycles, and the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the fifth and subsequent treatment cycles. In some embodiments, the second therapeutic agent is a GemOx regimen, i.e., gemcitabine and oxaliplatin. In some embodiments, the second therapeutic agent comprises gemcitabine and oxaliplatin. Optionally, the second therapeutic agent further comprises rituximab. In some embodiments, each 3 weeks is a treatment cycle, gemcitabine is administered once per treatment cycle, and oxaliplatin is administered once per treatment cycle; optionally, rituximab is administered once in the first treatment cycle.

[0067] In some embodiments, in the method or use, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered four times in the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered twice in each of the second and subsequent treatment cycles. In some embodiments, in the method or use, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered four times in each of the first and second treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered twice in each of the third through sixth treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once in each of the seventh and subsequent treatment cycles. In some embodiments, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1, 3, 8, and 15 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1 and 15 of each of the second and subsequent treatment cycles. In some embodiments, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1, 8, 15, and 22 of each of the first and second treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1 and 15 of each of the third through sixth treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the seventh and subsequent treatment cycles. In some embodiments, the second therapeutic agent is lenalidomide. In some embodiments, each 4 weeks is a treatment cycle, lenalidomide is administered once per day on days 1-21 of each treatment cycle.

[0068] In some embodiments, in the method or use, each 3 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1, 8, and 15 of the first treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the second and subsequent treatment cycles. In some embodiments, each 4 weeks is a treatment cycle, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1, 8, 15, and 22 of each of the first through third treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on days 1 and 15 of each of the fourth through ninth treatment cycles, the bispecific anti-CD3 / CD20 polypeptide complex is administered once on day 1 of each of the tenth and subsequent treatment cycles. In some embodiments, the second therapeutic agent is R-CHOP regimen, GemOx regimen, or lenalidomide.

[0069] By using an escalation dosing for the first treatment cycle, on the one hand, the incidence of CRS can be significantly reduced, increasing safety, and on the other hand, the onset dose and target dose (i.e. the fixed dose described below) can be reached as soon as possible, increasing clinical benefit.

[0070] In some embodiments, in the method or use, a first, a second and a third escalating dose is administered prior to the first fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex to the subject.

[0071] In some embodiments, the third dose is not higher than the fixed dose.

[0072] In some embodiments, the fixed dose is 30-160 mg, 30-120 mg, 30-100 mg or 30-80 mg, preferably 30-80 mg or 50-80 mg, for example 30 mg, 40 mg, 50 mg, 60 mg, 70 mg or 80 mg. In some embodiments, the first dose is 0.1-0.3 mg (e.g. 0.1 mg, 0.2 mg, 0.3 mg), preferably 0.3 mg. In some embodiments, the second dose is 1-3 mg (e.g. 1 mg, 2 mg, 3 mg), preferably 3 mg. In some embodiments, the third dose is 10-30 mg (e.g. 10 mg, 20 mg, 30 mg), preferably 30 mg.

[0073] In some embodiments, in the method or use, a first, a second and a third escalating dose is administered prior to the first fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex to the subject; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0074] In some embodiments, the first, the second and the third dose are administered in the first treatment cycle, or the first, the second and the third dose are administered in the first to the second treatment cycle. In some embodiments, every 3 weeks or every 4 weeks is one treatment cycle.

[0075] In some embodiments, in the method or use, each 3 or 4 weeks is a treatment cycle, the first, second, and third doses of the bispecific anti-CD3 / CD20 polypeptide complex are administered in the first treatment cycle, and the fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the second and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0076] In some embodiments, in the method or use, each 3 or 4 weeks is a treatment cycle, the first and second doses of the bispecific anti-CD3 / CD20 polypeptide complex are administered in the first treatment cycle, the third dose and the fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered in the second treatment cycle, and the fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the third and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0077] In some embodiments, in the method or use, each 3 or 4 weeks is a treatment cycle, the first, second, third, and fixed doses of the bispecific anti-CD3 / CD20 polypeptide complex are administered in the first treatment cycle, and the fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered in the second and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0078] In some embodiments, the second dose is administered 1-3 days after the first dose, preferably 2 days after the first dose.

[0079] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose, a second dose and a third dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 9, day 11 and day 16 of the first treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2, day 9 and day 16 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2, day 9 and day 16 of the third treatment cycle, and a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0080] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose, a second dose and a third dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 9, day 11 and day 16 of the first treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of each of the second and third treatment cycles, and a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0081] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose and a second dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 16 and day 18 of the first treatment cycle, a third dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 and day 16 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2, day 9 and day 16 of the third treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 30 mg.

[0082] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose and a second dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 16 and day 18 of the first treatment cycle, a third dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the third treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 30 mg.

[0083] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose, a second dose and a third dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 8, day 10 and day 15 of the first treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1, day 8 and day 15 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1, day 8 and day 15 of the third treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 30 mg.

[0084] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose, a second dose and a third dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 8, day 10 and day 15 of the first treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the second and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, the fixed dose is 30 mg.

[0085] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose and a second dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on days 15 and 17, respectively, of the first treatment cycle, a third dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 8 and 15 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 1, 8, and 15 of the third treatment cycle, and a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0086] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, a first dose and a second dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on days 15 and 17, respectively, of the first treatment cycle, a third dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the second treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the second treatment cycle, and a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the third and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0087] In some embodiments, in the method or use, each 4 weeks is a treatment cycle, a first dose, a second dose and a third dose of the bispecific anti-CD3 / CD20 polypeptide complex are administered on day 1, day 3 and day 8, respectively, of the first treatment cycle, a fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, and the fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 and day 15 of each treatment cycle in the second and subsequent treatment cycles; wherein the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 80 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 50 mg, or the first dose is 0.3 mg, the second dose is 3 mg, the third dose is 30 mg, and the fixed dose is 30 mg.

[0088] In some embodiments, in the method or use, 0.1-500 mg, 0.5-300 mg, 1-200 mg, or 1.3-200 mg of the anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are administered per treatment cycle, every 3 or 4 weeks. In some embodiments, in the method or use, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 22 mg, 24 mg, 26 mg, 28 mg, 30 mg, 32 mg, 34 mg, 36 mg, 38 mg, 40 mg, 42 mg, 44 mg, 46 mg, 48 mg, 50 mg, 60 mg, 61 mg, 61.3 mg, 61.5 mg, 70 mg, 80 mg, 90 mg, 100 mg, 101 mg, 101.3 mg, 101.5 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 300 mg, 400 mg, 500 mg, or a range formed by any of the above values of the anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are administered per treatment cycle, every 3 weeks. In some embodiments, in the method or use, 0.1-1.5 mg, 0.3-1.3 mg, 20-60 mg, 30-50 mg, 60-180 mg, 90-150 mg, 1.3-90 mg, or 1.3-150 mg of the anti-CD3 / CD20 polypeptide complex, 200-500 mg / m2 or 300-500 mg / m2 of rituximab, 0.5-3 mg / m2 or 1-2 mg / m2 of vincristine, 500-1000 mg / m2 or 600-900 mg / m2 of cyclophosphamide, 30-100 mg / m2 or 30-60 mg / m2 of doxorubicin, and 200-800 mg or 400-600 mg of prednisone are administered per treatment cycle, every 3 weeks. In some embodiments, in the method or use, 1.3 mg, 30 mg, 50 mg, 90 mg, or 150 mg of the anti-CD3 / CD20 polypeptide complex, 375 mg / m2 of rituximab, 1.4 mg / m2 of vincristine, 750 mg / m2 of cyclophosphamide, 50 mg / m2 of doxorubicin, and 500 mg of prednisone are administered per treatment cycle, every 3 weeks.In some embodiments, in the method or use, 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, 80-240 mg, 120-200 mg, or 30-200 mg of the anti-CD3 / CD20 polypeptide complex, 800-1500 mg / m2, or 800-1250 mg / m2 of gemcitabine, and 65-150 mg / m2, or 80-120 mg / m2 of oxaliplatin are administered every 4 weeks for a treatment cycle. In some embodiments, 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, 101.3 mg, 120 mg, or 200 mg of the anti-CD3 / CD20 polypeptide complex, 1000 mg / m2 of gemcitabine, and 100 mg / m2 of oxaliplatin are administered every 4 weeks for a treatment cycle. In some embodiments, in the method or use, 20-60 mg, 30-50 mg, 40-120 mg, 60-100 mg, or 30-120 mg of the anti-CD3 / CD20 polypeptide complex, and 200-800 mg, or 200-600 mg of lenalidomide are administered every 4 weeks for a treatment cycle. In some embodiments, 30 mg, 50 mg, 60 mg, 61.3 mg, 100 mg, or 101.3 mg of the anti-CD3 / CD20 polypeptide complex, and 420 mg of lenalidomide are administered every 4 weeks for a treatment cycle.

[0089] In some embodiments, in the method or use, 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex, 200-500 mg / m2or 300-500 mg / m2rituximab, 0.5-3 mg / m2or 1-2 mg / m2vincristine, 500-1000 mg / m2or 600-900 mg / m2cyclophosphamide, 30-100 mg / m2or 30-60 mg / m2doxorubicin, and 200-800 mg or 400-600 prednisone are administered every 3 weeks for a treatment cycle. In some embodiments, 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex, 375 mg / m2rituximab, 1.4 mg / m2vincristine, 750 mg / m2cyclophosphamide, 50 mg / m2doxorubicin, and 500 mg prednisone are administered every 3 weeks for a treatment cycle. In some embodiments, 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex, 200-500 mg / m2or 300-500 mg / m2rituximab, 0.5-3 mg / m2or 1-2 mg / m2vincristine, 500-1000 mg / m2or 600-900 mg / m2cyclophosphamide, 30-100 mg / m2or 30-60 mg / m2doxorubicin, and 200-800 mg or 400-600 prednisone are administered every 3 weeks for a treatment cycle. In some embodiments, 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex, 375 mg / m2rituximab, 1.4 mg / m2vincristine, 750 mg / m2cyclophosphamide, 50 mg / m2doxorubicin, and 500 mg prednisone are administered every 3 weeks for a treatment cycle.

[0090] In some embodiments, in the method or use, 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex, 800-1500 mg / m2or 800-1250 mg / m2gemcitabine, and 65-150 mg / m2or 80-120 mg / m2oxaliplatin are administered every 3 weeks for a treatment cycle; optionally, 375 mg / m2rituximab is administered on the first treatment cycle. In some embodiments, 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex, 1000 mg / m2gemcitabine, and 100 mg / m2oxaliplatin are administered every 3 weeks for a treatment cycle; optionally, 375 mg / m2rituximab is administered on the first treatment cycle. In some embodiments, 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex, 800-1500 mg / m2or 800-1250 mg / m2gemcitabine, and 65-150 mg / m2or 80-120 mg / m2oxaliplatin are administered every 3 weeks for a treatment cycle; optionally, 375 mg / m2rituximab is administered on the first treatment cycle. In some embodiments, 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex, 1000 mg / m2gemcitabine, and 100 mg / m2oxaliplatin are administered every 3 weeks for a treatment cycle; optionally, 375 mg / m2rituximab is administered on the first treatment cycle.

[0091] In the methods or uses, each 4 weeks is a treatment cycle, and 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex and 200-800 mg or 200-600 mg of lenalidomide are administered per treatment cycle. In some embodiments, each 4 weeks is a treatment cycle, and 0.5-300 mg of the anti-CD3 / CD20 polypeptide complex and 420 mg of lenalidomide are administered per treatment cycle. In some embodiments, in the methods or uses, each 4 weeks is a treatment cycle, and 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex and 200-800 mg or 200-600 mg of lenalidomide are administered per treatment cycle. In some embodiments, each 4 weeks is a treatment cycle, and 3.3 mg, 30 mg, 33.3 mg, 50 mg, 60 mg, 80 mg, 90 mg, 110 mg, 130 mg, 150 mg, 190 mg, or 240 mg of the anti-CD3 / CD20 polypeptide complex and 420 mg of lenalidomide are administered per treatment cycle.

[0092] In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the first treatment cycle, 1 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 16 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 2, 9, and 16 of each of the second through third treatment cycles, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of each of the fourth through sixth treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the sixth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 11 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 16 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 2, 9, and 16 of each of the second through third treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 11 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 16 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of each of the second through third treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles.In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 16 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 18 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 9 and 16 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 2, 9, and 16 of the third treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 16 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 18 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the third treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles. In the method or use, rituximab 375 mg / ㎡ is administered on day 1 of each treatment cycle, vincristine 1.4 mg / ㎡ is administered on day 2 of the first treatment cycle, vincristine 1.4 mg / ㎡ is administered on day 1 of each of the second and subsequent treatment cycles, cyclophosphamide 750 mg / ㎡ is administered on day 2 of the first treatment cycle, cyclophosphamide 750 mg / ㎡ is administered on day 1 of each of the second and subsequent treatment cycles, doxorubicin 50 mg / ㎡ is administered on day 2 of the first treatment cycle, doxorubicin 50 mg / ㎡ is administered on day 1 of each of the second and subsequent treatment cycles, and prednisone 100 mg is administered daily on days 2-6 of the first treatment cycle, and prednisone 100 mg is administered daily on days 1-5 of each of the second and subsequent treatment cycles.

[0093] In some embodiments, in the method or use, every 4 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 2 of the first treatment cycle, 1 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 9 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on each of days 16 and 23 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on each of days 1, 8, 15, and 22 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on each of days 1 and 15 of each of the third and fourth treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fifth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 10 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on each of days 1, 8, and 15 of each of the second and third treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 10 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the second and subsequent treatment cycles.In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 17 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 8 and 15 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 1, 8, and 15 of the third treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the fourth and subsequent treatment cycles. In some embodiments, in the method or use, every 3 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 17 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the second treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the third and subsequent treatment cycles. In the method or use, gemcitabine 1000 mg / m2is administered daily on days 1 and 15 of each treatment cycle, and oxaliplatin 100 mg / m2is administered daily on days 1 and 15 of each treatment cycle; optionally, an anti-CD20 antibody (e.g., rituximab) can also be administered prior to the first treatment cycle, e.g., rituximab 375 mg / m2is administered 2 days prior to the first treatment cycle. In the method or use, gemcitabine 1000 mg / m2is administered on day 2 of the first treatment cycle, and gemcitabine 1000 mg / m2is administered on day 1 of each of the second and subsequent treatment cycles, oxaliplatin 100 mg / m2is administered on day 2 of the first treatment cycle, and oxaliplatin 100 mg / m2is administered on day 1 of each of the second and subsequent treatment cycles; optionally, an anti-CD20 antibody (e.g., rituximab) can also be administered in the first treatment cycle, e.g., rituximab 375 mg / m2is administered on day 1 of the first treatment cycle.

[0094] In some embodiments, in the method or use, each 4 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the first treatment cycle, 1 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 15 and 22 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 1, 8, 15, and 22 of the second treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 1 and 15 of each of the third through sixth treatment cycles, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of each of the seventh and subsequent treatment cycles. In some embodiments, in the method or use, each 4 weeks is a treatment cycle, 0.3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 1 of the first treatment cycle, 3 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 3 of the first treatment cycle, 30 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 8 of the first treatment cycle, 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on day 15 of the first treatment cycle, and 30 mg, 50 mg, or 80 mg of the bispecific anti-CD3 / CD20 polypeptide complex is administered on days 1 and 15 of each of the second and subsequent treatment cycles. In the method or use, 20 mg of lenalidomide is administered daily on days 1-21 of each treatment cycle; optionally, an anti-CD20 antibody (e.g., rituximab) can also be administered prior to the first treatment cycle, e.g., 375 mg / m2of rituximab is administered 3 days prior to the first treatment cycle.

[0095] In some embodiments, in the method or use, the dosing regimen (e.g., dosing cycle, dosing amount, and dose adjustment) of the bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent can be adjusted according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health status of the patient. For example, one treatment cycle of the bispecific anti-CD3 / CD20 polypeptide complex can be adjusted to 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, or 15 weeks.

[0096] bispecific anti-CD3 / CD20 polypeptide complex

[0097] The term "bispecific" means that there are two antigen binding moieties, each of which is capable of specific binding to a different antigen or to a different epitope on the same antigen. The bispecific anti-CD3 / CD20 polypeptide complex provided herein comprises a first antigen binding moiety associated with a second antigen binding moiety, and wherein one specifically binds to CD3 and the other specifically binds to CD20. That is, the first antigen binding moiety can specifically bind to CD3 and the second antigen binding moiety can specifically bind to CD20. Alternatively, the first antigen binding moiety can specifically bind to CD20 and the second antigen binding moiety can specifically bind to CD3. In this application, the terms "bispecific anti-CD3xCD20 polypeptide complex" and "polypeptide complex targeting CD3 and CD20" or "anti-CD3 and CD20 polypeptide complex" or "bispecific anti-CD3 / CD20 polypeptide complex" are used interchangeably.

[0098] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises a first antigen binding moiety associated with a second antigen binding moiety, wherein:

[0099] The first antigen binding moiety comprises:

[0100] a first polypeptide comprising, from N-terminus to C-terminus, a first heavy chain variable domain (VH) of a first antibody operably linked to a first T cell receptor (TCR) constant region (C1), and

[0101] a second polypeptide comprising, from N-terminus to C-terminus, a first light chain variable domain (VL) of the first antibody operably linked to a second TCR constant region (C2),

[0102] wherein C1 and C2 are capable of forming a dimer comprising at least one non-native interchain bond between C1 and C2, and the non-native interchain bond is capable of stabilizing the dimer, and

[0103] The second antigen binding moiety comprises:

[0104] a second heavy chain variable domain (VH2) of a second antibody operably linked to an antibody heavy chain CH1 domain, and

[0105] a second light chain variable domain (VL2) of the second antibody operably linked to an antibody light chain constant (CL) domain,

[0106] wherein one of the first antigen binding moiety and the second antigen binding moiety is an anti-CD3 binding moiety and the other is an anti-CD20 binding moiety,

[0107] The anti-CD3 binding moiety is derived from an anti-CD3 antibody comprising:

[0108] a) a heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 1,

[0109] b) a heavy chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 2,

[0110] c) a heavy chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 3,

[0111] d) a light chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 4,

[0112] e) a light chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 5, and

[0113] f) a light chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 6,

[0114] The anti-CD20 binding moiety is derived from an anti-CD20 antibody comprising:

[0115] a) a heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 7,

[0116] b) a heavy chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 8,

[0117] c) a heavy chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 9,

[0118] d) a light chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 10,

[0119] e) a light chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 11, and

[0120] f) a light chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 12.

[0121] In some embodiments, the anti-CD3 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex is derived from an anti-CD3 antibody comprising a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-CD3 binding portion is derived from an anti-CD3 antibody comprising a heavy chain variable domain sequence comprising a variant of the amino acid sequence of SEQ ID NO: 13, e.g., a heavy chain variable domain sequence with one or two additional serines at the C-terminus of SEQ ID NO: 13, and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 14.

[0122] In some embodiments, the anti-CD20 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex is derived from an anti-CD20 antibody comprising a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 15 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 16.

[0123] The CDR sequences of the anti-CD3 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex are shown below:

[0124] Table 1. CDRs of the anti-CD3 binding portion

[0125] The heavy chain and kappa light chain variable region sequences of the anti-CD3 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex are shown below:

[0126] VH-amino acid sequence (SEQ ID NO: 13):

[0127] Vκ-amino acid sequence (SEQ ID NO: 14):

[0128] The CDR sequences of the anti-CD20 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex are shown below:

[0129] Table 2. CDRs of the anti-CD20 binding portion

[0130] The heavy chain and kappa light chain variable region sequences of the anti-CD20 binding portion of the bispecific anti-CD3 / CD20 polypeptide complex are shown below:

[0131] VH-amino acid sequence (SEQ ID NO: 15):

[0132] Vk-amino acid sequence (SEQ ID NO: 16):

[0133] In some embodiments, the first antigen binding moiety comprises an alpha or beta constant region derived from a TCR.

[0134] In some embodiments, the first antigen binding moiety comprises a heavy chain variable domain and a light chain variable domain, each operably linked to a pair of TCR constant regions. In some embodiments, the pairing of TCR constant regions in the first antigen binding moiety is an alpha / beta TCR constant region.

[0135] The human TCR alpha chain constant region is referred to as TRAC, with NCBI Accession No. P01848.

[0136] There are two different variants of the human TCR beta chain constant region, referred to as TRBC1 and TRBC2 (IMGT nomenclature) (see also Toyonaga B et al., PNAS, Vol. 82, pp. 8624-8628, Immunology (1985)).

[0137] In some embodiments, the first and / or the second TCR constant region has been engineered to comprise one or more mutated amino acid residues responsible for forming a non-native interchain disulfide bond. In some embodiments, the first and / or the second TCR constant region has been engineered to comprise one or more mutated cysteine residues such that a non-native interchain disulfide bond can form between the two TCR constant regions. The non-native interchain disulfide bond is capable of stabilizing the first antigen binding moiety.

[0138] A TCR constant region comprising a mutated residue is also referred to herein as an "engineered" TCR constant region. In some embodiments, the first TCR constant region (C1) of the bispecific anti-CD3 / CD20 polypeptide complex comprises an engineered TCR alpha chain (Ca), and the second TCR constant region (C2) comprises an engineered TCR beta chain (Cp). In some embodiments, the C1 of the bispecific anti-CD3 / CD20 polypeptide complex comprises an engineered Cp, and the C2 comprises an engineered Ca.

[0139] In the bispecific anti-CD3 / CD20 polypeptide complex, the engineered TCR constant region comprises one or more mutated cysteine residues, the one or more mutated residues being comprised within the contact interface of the first and / or the second engineered constant region.

[0140] The term "dimer" refers to an associated structure formed by two molecules (e.g., polypeptides or proteins) via covalent or non-covalent interactions. A homodimer or homodimerization is formed by two identical molecules, while a heterodimer or heterodimerization is formed by two different molecules. The dimer formed by the first and the second TCR constant region is a heterodimer.

[0141] A "mutated" amino acid residue refers to an amino acid residue that is substituted, inserted, or added and is different from the corresponding native residue in its corresponding native TCR constant region. For example, if an amino acid residue at a particular position in a wild-type TCR constant region is referred to as a "native" residue, then its corresponding mutated residue is any residue that is different from the native residue but is at the same position on the TCR constant region. A mutated residue can be a different residue that substitutes the native residue at the same position, or a different residue that is inserted before the native residue and thus occupies its original position.

[0142] The term "contact interface" refers to a particular region on the polypeptides where the polypeptides interact / associate with each other. A contact interface contains one or more amino acid residues that are capable of interacting with the corresponding amino acid residues of the contact or association when the interaction occurs. The amino acid residues in the contact interface can or can not be in a contiguous sequence. For example, when the interface is three-dimensional, the amino acid residues within the interface can be separated from each other at different positions on the linear sequence.

[0143] In some embodiments, one or more disulfide bonds can be formed between the engineered Ca and the engineered Cβ. In some embodiments, the pairing of the cysteine residues is capable of forming a non-native interchain disulfide bond.

[0144] "XnY" is used throughout to mean that the nth amino acid residue X is substituted with amino acid residue Y, where X and Y are one-letter abbreviations for particular amino acid residues, respectively.

[0145] In the bispecific anti-CD3 / CD20 polypeptide complex, the engineered Cβ comprises or is SEQ ID NO: 17, and the engineered Ca comprises or is SEQ ID NO: 18.

[0146] The sequences of SEQ ID NO: 17 and SEQ ID NO: 18 are provided below:

[0147] In some embodiments, the first antigen binding moiety is linked to a first dimerization domain and the second antigen binding moiety is linked to a second dimerization domain, wherein the first dimerization domain and the second dimerization domain are associated. In some embodiments, the association is achieved via any suitable interaction or linkage or bond (e.g., via a linker, a disulfide bond, a hydrogen bond, an electrostatic interaction, a salt bridge, or a hydrophobic-hydrophilic interaction, or a combination thereof). Exemplary dimerization domains include, but are not limited to, an antibody hinge region, an antibody CH2 domain, an antibody CH3 domain, and other suitable protein monomers capable of dimerization and association with one another. The hinge region, CH2 and / or CH3 domains can be derived from any antibody isotype, such as IgGl, IgG2, and IgG4.

[0148] The term "dimerization domain" refers to a peptide domain that is capable of associating with one another to form a dimer, or in some examples, a peptide domain that enables two peptides to spontaneously dimerize.

[0149] In some embodiments, the first dimerization domain and / or the second dimerization domain comprises at least a portion of an antibody hinge region, which is optionally derived from IgGl, IgG2, or IgG4. In some embodiments, the first dimerization domain and / or the second dimerization domain optionally further comprises an antibody CH2 domain, and / or an antibody CH3 domain. In some embodiments, the first dimerization domain and / or the second dimerization domain comprises at least a portion of a hinge-Fc region, i.e., a hinge-CH2-CH3 domain.

[0150] In some embodiments, the first dimerization domain is operably linked to the first TCR constant region (Cl). In some embodiments, the first dimerization domain is operably linked to the C-terminus of the first TCR constant region.

[0151] In some embodiments, the second dimerization domain is operably linked to the antibody CH1 constant region of the second antigen binding moiety. In some embodiments, the second dimerization domain is operably linked to the C-terminus of the antibody CH1 constant region of the second antigen binding moiety.

[0152] In some embodiments, the first dimerization domain is operably linked to the C-terminus of the engineered TCR constant region, and together form a chimeric constant region. In some embodiments, the chimeric constant region comprises an engineered Cβ attached to a first hinge-Fc region derived from IgGl, IgG2, or IgG4. In some embodiments, the chimeric constant region comprises an engineered Cβ attached to a first hinge-first antibody CH2 domain and a first antibody CH3 domain derived from IgGl, IgG2, or IgG4.

[0153] These chimeric constant regions and second TCR constant region pairs are useful because they can be manipulated to fuse to desirable antibody variable regions to provide the bispecific anti-CD3 / CD20 polypeptide complexes described herein. For example, an antibody heavy chain variable region can be fused to the chimeric constant region (including C1) to thereby provide the first polypeptide chain of the bispecific anti-CD3 / CD20 polypeptide complexes described herein; and similarly, an antibody light chain variable region can be fused to the second TCR constant region (including C2) to thereby provide the second polypeptide chain of the bispecific anti-CD3 / CD20 polypeptide complexes described herein.

[0154] In some embodiments, the first and second dimerization domains are different and associate in a manner that favors heterodimerization and / or disfavors homodimerization. For example, the first and second dimerization domains can be selected so that they are not identical and preferentially form a heterodimer with each other rather than a homodimer with themselves.

[0155] In some embodiments, the first and second dimerization domains are capable of associating into a heterodimer via a knobs-into-holes, hydrophobic interaction, electrostatic interaction, hydrophilic interaction, or increased flexibility.

[0156] In certain embodiments, the first and second dimerization domains comprise CH2 and / or CH3 domains that are mutated to be capable of forming knobs-into-holes. The knob can be obtained by substituting a small amino acid residue with a large amino acid residue in the first CH2 / CH3 polypeptide, and the hole can be obtained by substituting a large amino acid residue with a small amino acid residue in the second CH2 / CH3 polypeptide. Details regarding the mutation sites for knobs-into-holes, etc. are described in Ridgway et al., Protein Engineering, 9(7), pp. 617-21 (1996); Merchant et al., Nature Biotechnology, 16(7), pp. 677-681 (1998); Spiess et al., Molecular Immunology, 67(2), pp. 95-106 (2015); Brinkman et al., mAbs, 9(2), pp. 182-212 (2017).

[0157] In the described bispecific anti-CD3 / CD20 polypeptide complex, the first antigen binding moiety and the second binding moiety can associate into an Ig-like structure. Ig-like structures resemble natural antibodies, having a Y-shaped configuration with two arms for antigen binding and a stem for association and stabilization. The resemblance to natural antibodies can provide a variety of advantages, such as good pharmacokinetics in vivo, desirable immune responses, and stability, among others.

[0158] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises four polypeptide chains: i) VH1-C1-hinge-CH2-CH3; ii) VL1-C2; iii) VH2-CH1-hinge-CH2-CH3, and iv) VL2-CL, wherein C1 and C2 are capable of forming a dimer comprising at least one non-native interchain bond, and two hinge regions and / or two CH3 domains are capable of forming one or more interchain bonds that can assist dimerization.

[0159] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises four polypeptide chains: i) VH1 operably linked to a first chimeric constant region; ii) VL1 operably linked to a second chimeric constant region; iii) VH2 operably linked to a conventional antibody heavy chain constant region, and iv) VL2 operably linked to a conventional antibody light chain constant region. In some embodiments, the first chimeric constant region can comprise C1-hinge-CH2-CH3, the parts of which are as defined above. In some embodiments, the second chimeric constant region can comprise C2, which is as defined above. In some embodiments, the conventional antibody heavy chain constant region can comprise CH1-hinge-CH2-CH3, the parts of which are as defined above. In some embodiments, the conventional antibody light chain constant region can comprise CL, which is as defined above.

[0160] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises the sequences set forth in SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22.

[0161] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises the sequences set forth in SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 21, and SEQ ID NO: 22.

[0162] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises a combination of the following four polypeptide sequences: SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO: 22.

[0163] In some embodiments, the bispecific anti-CD3 / CD20 polypeptide complex comprises the following five polypeptide chains: a) a first polypeptide chain having a sequence as set forth in SEQ ID NO: 19; b) a second polypeptide chain having a sequence as set forth in SEQ ID NO: 20; c) a third polypeptide chain having a sequence as set forth in SEQ ID NO: 21; d) a fourth polypeptide chain having a sequence as set forth in SEQ ID NO: 21; and e) a fifth polypeptide chain having a sequence as set forth in SEQ ID NO: 22.

[0164] In some embodiments, one or more amino acids at positions 193, 182, 203, 206, or 207 of the polypeptide as set forth in SEQ ID NO: 22 are modified to any amino acid other than serine and / or threonine, thereby eliminating a glycosylation site, preferably the amino acid at position 193 is modified. In some embodiments, the modification comprises one or more of S193X, S182X, S203X, S206X, S207X, wherein X is any amino acid other than serine (Ser) and / or threonine (Thr). In some embodiments, the amino acid at position 193 of the polypeptide as set forth in SEQ ID NO: 22 is modified to alanine (Ala), glycine (Gly), proline (Pro), or valine (Val). The mutation eliminates an O-glycosylation site, which is of the Corel configuration O-glycan type, with the structure NeuAc-Gal-GalNAc or NeuAc-Gal-(NeuAc)GalNAc.

[0165] The structure of the bispecific anti-CD3 / CD20 polypeptide complex W3278-U2T3.F18R-1.uIgG4.SP is schematically illustrated in FIG. 1, and the heavy and light chain amino acid sequences are set forth below (see, e.g., Chinese Patent Publication CN111484555A, the entire contents of which are incorporated by reference). W3278-U2T3.F18R-1.uIgG4.SP comprises the following five polypeptide chains: a) a first polypeptide chain having a sequence as set forth in SEQ ID NO: 19; b) a second polypeptide chain having a sequence as set forth in SEQ ID NO: 20; c) a third polypeptide chain having a sequence as set forth in SEQ ID NO: 21; d) a fourth polypeptide chain having a sequence as set forth in SEQ ID NO: 21; and e) a fifth polypeptide chain having a sequence as set forth in SEQ ID NO: 22.

[0166] Table 3. Heavy and light chain amino acid sequences of bispecific anti-CD3 / CD20 polypeptide complexes

[0167] Note: TCR sequences are in italics.

[0168] Second Therapeutic Agent

[0169] In some embodiments, the second therapeutic agent comprises a therapeutic drug for lymphoma. In some embodiments, the second therapeutic agent comprises a therapeutic drug for non-Hodgkin lymphoma. In some embodiments, the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug.

[0170] In some embodiments, the immunomodulatory agent comprises an anti-CD20 antibody (e.g., Rituximab, Ofatumumab, Obinutuzumab), Lenalidomide, Thalidomide, and / or Pomalidomide.

[0171] In some embodiments, the chemotherapeutic drug comprises one or more of platinum-based antitumor drugs (including but not limited to oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin, miriplatin, lobaplatin, triplatin tetranitrate, phenanthriplatin, satraplatin), camptothecin-based antitumor drugs (including but not limited to camptothecin, hydroxycamptothecin, aminocamptothecin, irinotecan, topotecan, exatecan, rubitecan, lurtotecan, gimatecan, karenitecin, 7-ethylcamptothecin), taxane-based antitumor drugs (including but not limited to paclitaxel and docetaxel), nitrogen mustard-based antitumor drugs (including but not limited to cyclophosphamide, ifosfamide, chlorambucil, carmustine, melphalan, bendamustine), antimetabolite-based antitumor drugs (including but not limited to fluorouracil-based antitumor drugs (including but not limited to carmofur, 5-fluorouracil, tegafur, capecitabine, tegafur, doxifluridine, trifluridine), cytosine-based antitumor drugs (including but not limited to cytarabine, gemcitabine, azacitidine, decitabine), purine-based antitumor drugs (including but not limited to mercaptopurine, fludarabine), antifolate-based antitumor drugs (including but not limited to methotrexate, pemetrexed)), anthracycline-based antitumor drugs (including but not limited to doxorubicin, epirubicin, pirarubicin, aminoglutethimide, valrubicin, idarubicin, daunorubicin, mitoxantrone, idarubicin, valrubicin, zorubicin, pixantrone, liposomal doxorubicin), vinca alkaloid-based antitumor drugs (including but not limited to vinblastine, vincristine, vindesine, vinflunine, and vinorelbine), podophyllotoxin-based antitumor drugs (including but not limited to etoposide, teniposide), hormone-based antitumor drugs (including but not limited to prednisone, prednisolone, dexamethasone, methylprednisolone sodium succinate), methyldopa, hexamethylmelamine, dacarbazine, mitomycin, actinomycin D (dactinomycin), bleomycin, pingyangmycin, temozolomide, procarbazine, peplomycin, eribulin, plinabulin, Sapacitabine, treosulfan, 153Sm-EDTMP, and encequidar.In some embodiments, the chemotherapeutic drug comprises one or more of platinum-based antitumor drugs (e.g., oxaliplatin, cisplatin, carboplatin), antimetabolite antitumor drugs (e.g., gemcitabine, azacitidine, cytarabine, methotrexate, fludarabine), nitrogen mustard antitumor drugs (e.g., cyclophosphamide, ifosfamide, bendamustine, chlorambucil), anthracycline antitumor drugs (e.g., doxorubicin, epirubicin, mitoxantrone), vinca alkaloid antitumor drugs (e.g., vinblastine, vincristine, vindesine, vinorelbine), podophyllotoxin alkaloid antitumor drugs (e.g., etoposide), and hormone antitumor drugs (e.g., prednisone, prednisolone, dexamethasone, methylprednisolone).

[0172] In some embodiments, the second therapeutic agent comprises rituximab, cyclophosphamide, ifosfamide, vincristine, doxorubicin, epirubicin, prednisone, gemcitabine, lenalidomide, etoposide, dexamethasone, oxaliplatin, cisplatin, carboplatin, cytarabine, methylprednisolone, mesna, mitoxantrone, bendamustine, methotrexate, bortezomib, chlorambucil, and / or fludarabine. In some embodiments, the second therapeutic agent is gemcitabine and oxaliplatin. In some embodiments, the second therapeutic agent is rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent is rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone. In some embodiments, the second therapeutic agent is lenalidomide. In some embodiments, the second therapeutic agent is rituximab, cyclophosphamide, vincristine, doxorubicin, etoposide, and prednisone. In some embodiments, the second therapeutic agent is rituximab, cyclophosphamide, vincristine, epirubicin, etoposide, and prednisone. In some embodiments, the second therapeutic agent is rituximab, dexamethasone, cisplatin, and cytarabine. In some embodiments, the second therapeutic agent is rituximab, ifosfamide, carboplatin, and etoposide. In some embodiments, the second therapeutic agent is rituximab, gemcitabine, cisplatin, and dexamethasone. In some embodiments, the second therapeutic agent is rituximab, etoposide, methylprednisolone, cisplatin, and cytarabine. In some embodiments, the second therapeutic agent is rituximab, gemcitabine, and oxaliplatin. In some embodiments, the second therapeutic agent is rituximab and lenalidomide. In some embodiments, the second therapeutic agent is rituximab, mesna, ifosfamide, mitoxantrone, and etoposide. In some embodiments, the second therapeutic agent is rituximab and bendamustine. In some embodiments, the second therapeutic agent is rituximab, mesna, cyclophosphamide, vincristine, doxorubicin, and dexamethasone. In some embodiments, the second therapeutic agent is rituximab, methotrexate, and cytarabine. In some embodiments, the second therapeutic agent is rituximab, cyclophosphamide, bortezomib, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent is rituximab and chlorambucil. In some embodiments, the second therapeutic agent is rituximab and fludarabine. In some embodiments, the second therapeutic agent is cyclophosphamide, vincristine, doxorubicin, and prednisone. In some embodiments, the second therapeutic agent is cyclophosphamide, vincristine, doxorubicin, etoposide, and prednisone. In some embodiments, the second therapeutic agent is etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone. In some embodiments, the second therapeutic agent is cyclophosphamide, mesna, doxorubicin, dexamethasone, and vincristine.In some embodiments, the second therapeutic agent is ifosfamide, carboplatin, and etoposide. In some embodiments, the second therapeutic agent is gemcitabine, cisplatin, and dexamethasone. In some embodiments, the second therapeutic agent is dexamethasone, cisplatin, and cytarabine. In some embodiments, the second therapeutic agent is etoposide, methylprednisolone, cisplatin, and cytarabine.

[0173] Mode of administration

[0174] The following are not intended to limit the mode of administration of the pharmaceutical combinations of the present application.

[0175] The components of the pharmaceutical combinations of the present application can each be administered, independently, by a variety of routes in suitable formulations. In some embodiments, the components of the pharmaceutical combinations of the present application can each be administered, independently, by intravenous injection, orally, and the like.

[0176] The pharmaceutical combinations of the present application can also include an additional therapeutic agent. In some embodiments, the additional therapeutic agent can be a tumor therapeutic agent known in the art.

[0177] Tumor

[0178] The tumors described herein are malignant tumors (i.e., cancers); the malignant tumors refer to any malignant and / or invasive growth resulting from abnormal cell growth.

[0179] In some embodiments, the tumor is a lymphoma. In some embodiments, the tumor is a newly diagnosed, unresectable, refractory, advanced, relapsed, and / or metastatic lymphoma. In some embodiments, the tumor is a newly diagnosed lymphoma. In some embodiments, the tumor is an unresectable lymphoma. In some embodiments, the tumor is a refractory lymphoma. In some embodiments, the tumor is an advanced lymphoma. In some embodiments, the tumor is a locally advanced lymphoma. In some embodiments, the tumor is a relapsed lymphoma. In some embodiments, the tumor is a metastatic lymphoma. In some embodiments, the tumor is a refractory, metastatic, and / or relapsed lymphoma. In some embodiments, the tumor is a refractory and / or relapsed lymphoma. In some embodiments, the tumor is a metastatic and / or relapsed lymphoma.

[0180] In some embodiments, the tumor is a non-Hodgkin lymphoma. In some embodiments, the tumor is a newly diagnosed, unresectable, refractory, advanced, relapsed, and / or metastatic non-Hodgkin lymphoma. In some embodiments, the tumor is a newly diagnosed non-Hodgkin lymphoma. In some embodiments, the tumor is an unresectable non-Hodgkin lymphoma. In some embodiments, the tumor is a refractory non-Hodgkin lymphoma. In some embodiments, the tumor is an advanced non-Hodgkin lymphoma. In some embodiments, the tumor is a locally advanced non-Hodgkin lymphoma. In some embodiments, the tumor is a relapsed non-Hodgkin lymphoma. In some embodiments, the tumor is a metastatic non-Hodgkin lymphoma. In some embodiments, the tumor is a refractory, metastatic, and / or relapsed non-Hodgkin lymphoma. In some embodiments, the tumor is a refractory and / or relapsed non-Hodgkin lymphoma. In some embodiments, the tumor is a metastatic and / or relapsed non-Hodgkin lymphoma.

[0181] In some embodiments, the non-Hodgkin lymphoma is a T-cell non-Hodgkin lymphoma (T-NHL) or a B-cell non-Hodgkin lymphoma (B-NHL). In some embodiments, the non-Hodgkin lymphoma is an aggressive non-Hodgkin lymphoma or an indolent non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma is primary mediastinal large B-cell lymphoma (PMBCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), lymphoblastic lymphoma (LBL), cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, marginal zone lymphoma, NK / T-cell lymphoma, and / or AIDS-related B-cell lymphoma.

[0182] In some embodiments, the diffuse large B-cell lymphoma includes, but is not limited to, non-specified diffuse large B-cell lymphoma or diffuse large B-cell lymphoma transformed from indolent lymphoma.

[0183] In some embodiments, the tumor is a newly diagnosed or treatment naive diffuse large B-cell lymphoma. In some embodiments, the tumor is a newly diagnosed or treatment naive follicular lymphoma. In some embodiments, the tumor is a newly diagnosed or treatment naive marginal zone lymphoma. In some embodiments, the tumor is a newly diagnosed or treatment naive mantle cell lymphoma.

[0184] In some embodiments, the tumor is a refractory, metastatic, and / or relapsed diffuse large B-cell lymphoma. In some embodiments, the tumor is a refractory, metastatic, and / or relapsed follicular lymphoma. In some embodiments, the tumor is a refractory, metastatic, and / or relapsed marginal zone lymphoma. In some embodiments, the tumor is a refractory, metastatic, and / or relapsed mantle cell lymphoma.

[0185] In some embodiments, the newly diagnosed non-Hodgkin's lymphoma patient has not previously received anti-neoplastic therapy. In some embodiments, the newly diagnosed non-Hodgkin's lymphoma patient has not previously received systemic therapy. In some embodiments, the refractory or metastatic non-Hodgkin's lymphoma patient has not previously received anti-neoplastic therapy. In some embodiments, the refractory or metastatic non-Hodgkin's lymphoma patient has not previously received systemic therapy. In some embodiments, the newly diagnosed non-Hodgkin's lymphoma is newly diagnosed diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and / or mantle cell lymphoma.

[0186] In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received one or more different anti-neoplastic therapies (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received systemic therapy (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received first line systemic therapy (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received second or third line systemic therapy (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received anti-CD20 antibody therapy (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received R-CHOP regimen therapy (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient has previously received hematopoietic stem cell transplantation (e.g., failed or ineligible for treatment). In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma patient is ineligible for hematopoietic stem cell transplantation. In some embodiments, the refractory, metastatic, and / or relapsed non-Hodgkin's lymphoma is refractory, metastatic, and / or relapsed diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and / or mantle cell lymphoma.

[0187] In some embodiments, the non-Hodgkin lymphoma is treatment-naïve or untreated diffuse large B-cell lymphoma. In some embodiments, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma that has not previously received antitumor therapy. In some embodiments, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma that has not previously received systemic therapy. In some embodiments, the patient with the treatment-naïve or untreated diffuse large B-cell lymphoma has not previously received antitumor therapy. In some embodiments, the patient with the treatment-naïve or untreated diffuse large B-cell lymphoma has not previously received systemic therapy.

[0188] In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior systemic treatment. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior at least first line systemic treatment. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior at least second line systemic treatment. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior at least third line systemic treatment. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior anti-CD20 antibody treatment. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior hematopoietic stem cell transplantation. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior at least first line systemic treatment and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior at least second line systemic treatment and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the non-Hodgkin's lymphoma is refractory and / or relapsed diffuse large B-cell lymphoma that has received prior anti-CD20 antibody treatment and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the refractory and / or relapsed diffuse large B-cell lymphoma patient has received one or more different anti-neoplastic treatments (e.g., failed or not applicable) previously. In some embodiments, the refractory and / or relapsed diffuse large B-cell lymphoma patient has received systemic treatment (e.g., failed or not applicable) previously. In some embodiments, the refractory and / or relapsed diffuse large B-cell lymphoma patient has received at least first line systemic treatment (e.g., failed or not applicable) previously. In some embodiments, the refractory and / or relapsed diffuse large B-cell lymphoma patient has received at least second line systemic treatment (e.g., failed or not applicable) previously. In some embodiments, the refractory and / or relapsed diffuse large B-cell lymphoma patient has received at least third line systemic treatment (e.g., failed or not applicable) previously.In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma has previously received anti-CD20 antibody therapy (e.g., failed or is not suitable for treatment). In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma has previously received hematopoietic stem cell transplantation (e.g., failed or is not suitable for treatment). In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma has previously received at least first line systemic therapy (e.g., failed or is not suitable for treatment) and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma has previously received at least second line systemic therapy (e.g., failed or is not suitable for treatment) and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation. In some embodiments, the patient with refractory and / or relapsed diffuse large B-cell lymphoma has previously received anti-CD20 antibody therapy (e.g., failed or is not suitable for treatment) and is ineligible for hematopoietic stem cell transplantation or has failed treatment with hematopoietic stem cell transplantation.

[0189] In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma. In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma that has received prior systemic treatment. In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma that has received prior at least first line systemic treatment. In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma that has received prior at least second line systemic treatment. In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma that has received prior at least third line systemic treatment. In some embodiments, the non-Hodgkin lymphoma is refractory and / or relapsed follicular lymphoma and marginal zone lymphoma that has received prior anti-CD20 antibody treatment. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received one or more different anti-tumor treatments (e.g., failed or is not eligible for treatment) prior. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received systemic treatment (e.g., failed or is not eligible for treatment) prior. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received at least first line systemic treatment (e.g., failed or is not eligible for treatment) prior. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received at least second line systemic treatment (e.g., failed or is not eligible for treatment) prior. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received at least third line systemic treatment (e.g., failed or is not eligible for treatment) prior. In some embodiments, the refractory and / or relapsed follicular lymphoma and marginal zone lymphoma patient has received anti-CD20 antibody treatment (e.g., failed or is not eligible for treatment) prior.

[0190] In some embodiments, the anti-CD20 antibody treatment refers to treatment with any antibody or antigen-binding fragment thereof that specifically binds to CD20, including polyclonal antibodies, monoclonal antibodies, single-chain Fv (scFv) antibodies, heavy-chain antibodies (HCAbs), light-chain antibodies (LC Abs), multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, etc., e.g., rituximab, ofatumumab, and obinutuzumab.

[0191] Technical effects

[0192] In general, the use of the pharmaceutical combinations of the present application will result in: a better therapeutic effect in reducing tumor growth or even eliminating the tumor compared to the administration of any of the drugs in the combination alone; a lower amount of administration compared to the administration of any of the drugs in the combination alone; a treatment that is well tolerated in patients with fewer adverse effects and / or complications compared to the administration of any of the drugs alone; a better disease control rate among the treated patients; a longer survival (e.g. median survival, progression free survival or overall survival) in the treated patients; a longer survival (e.g. median survival, progression free survival or overall survival) in the treated patients compared to standard chemotherapy; a longer duration of disease remission (DOR); and / or a better anti-tumor activity with superior anti-tumor synergistic effects compared to the administration of any of the drugs in the combination alone.

[0193] The pharmaceutical combinations and treatment regimens of the present application have a better therapeutic effect in the treatment of lymphomas, especially non-Hodgkin's lymphoma (e.g. diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma), with beneficial effects in at least one of CRR, ORR, DCR, DOR, PFS, OS, TTR, tolerability and side effects. For example, the pharmaceutical combinations and treatment regimens of the present application have a better therapeutic effect in the treatment of newly diagnosed or treatment naive diffuse large B-cell lymphoma, with beneficial effects in at least one of CRR, ORR, DCR, DOR, PFS, OS, TTR, tolerability and side effects. For another example, the pharmaceutical combinations and treatment regimens of the present application have a better therapeutic effect in the treatment of relapsed and / or refractory diffuse large B-cell lymphoma, with beneficial effects in at least one of CRR, ORR, DCR, DOR, PFS, OS, TTR, tolerability and side effects. For another example, the pharmaceutical combinations and treatment regimens of the present application have a better therapeutic effect in the treatment of relapsed and / or refractory follicular lymphoma and marginal zone lymphoma, with beneficial effects in at least one of CRR, ORR, DCR, DOR, PFS, OS, TTR, tolerability and side effects.

[0194] Definitions

[0195] The following terms as used herein shall have the following meanings unless otherwise indicated. A particular term should not be construed as indefinite or unclear if not specifically defined, but should be understood in accordance with the ordinary meaning in the art. When a trade name appears in the present application, it is intended to designate the corresponding commercial product or its active ingredient.

[0196] The articles “a,” “an,” and “the” are used here to refer to one or more of the grammatical objects of the article (i.e., at least one). For example, “a polypeptide complex” refers to one or more polypeptide complexes.

[0197] Unless the context otherwise requires, the words “comprising,” “including,” and “containing” will be understood to mean including the stated steps or elements or a group of steps or elements, but not excluding any other steps or elements or a group of steps or elements. “Comprising of” means including and limited to what follows the phrase “comprising of.” Therefore, the phrase “comprising of” indicates that the listed elements are necessary or required, and no other elements may be present. “Substantially comprising” means including any elements listed following this phrase, and is limited to other elements that do not impede or contribute to the activity or function of the listed elements as detailed herein. Therefore, the phrase “substantially comprising” indicates that the listed elements are necessary or required, but other elements are optional and may be present or absent depending on whether they affect the activity or function of the listed elements.

[0198] The terms "polypeptide," "peptide," and "protein" are used interchangeably herein to refer to a polymer of amino acid residues, or a collection of polymer of amino acid residues. These terms apply to amino acid polymers in which one or more amino acid residues are artificial chemical mimics of corresponding naturally occurring amino acids, as well as to naturally occurring and non-naturally occurring amino acid polymers. The term "amino acid" refers to both naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, such as serine, glycine, proline and the like, as well as those modified after translation, such as hydroxyproline, gamma-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure (i.e., an alpha carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group) as a naturally occurring amino acid, but having modified R group, such as homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but otherwise function in a manner similar to the naturally occurring amino acids. The alpha-carbon refers to the first carbon atom attached to a functional group, such as a carbonyl group. The beta carbon refers to the second carbon atom bound to the alpha carbon, and this nomenclature continues in the Greek-letter order for carbon atoms. Amino acid mimetics refers to chemical compounds that have structures that differ from the general structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid. The term "protein" generally refers to large polypeptides. The term "peptide" generally refers to short polypeptides. Polypeptide sequences are generally depicted with the amino-terminal (N-terminal) end of the polypeptide sequence on the left; the carboxy-terminal (C-terminal) end of the polypeptide sequence on the right. "Polypeptide complex" as used herein refers to a complex comprising one or more polypeptides associated with performing a certain function. In certain embodiments, the polypeptides are immunologically related.

[0199] The term "antibody" encompasses any immunoglobulin, monoclonal antibody, polyclonal antibody, multispecific antibody, or bispecific (bivalent) antibody that can bind a particular antigen. A natural, intact antibody comprises two heavy chains and two light chains. Each heavy chain is comprised of one variable region ("HCVR") and first, second, and third constant regions (CH1, CH2, CH3, respectively), while each light chain is comprised of one variable region ("LCVR") and one constant region (CL). The heavy chains of mammals can be classified as alpha, delta, epsilon, gamma, and mu, and the light chains of mammals can be classified as lambda or kappa. Antibodies are "Y"-shaped, with the stem of the "Y" shape being comprised of the second and third constant regions of the two heavy chains, which are joined by disulfide bonds. Each arm of the "Y" shape comprises the variable region and first constant region of one of the heavy chains, which is joined to the variable region and constant region of one of the light chains. The variable regions of the light and heavy chains are responsible for antigen binding. Each chain's variable region contains three hypervariable loops known as complementarity determining regions (CDRs) (the CDRs of the light (L) chain comprise LCDR1, LCDR2, LCDR3, and the CDRs of the heavy (H) chain comprise HCDR1, HCDR2, HCDR3). The boundaries of the CDRs of an antibody can be determined by the Kabat, Chothia, or Al-Lazikani numbering schemes (Al-Lazikani, B., Chothia, C, Lesk, A. M., J. Mol. Biol., 273(4), 927 (1997); Chothia, C. et al., J Mol Biol. Dec 5; 186(3):651-63 (1985); Chothia, C. and Lesk, A. M., J. Mol. Biol., 196, 901 (1987); Chothia, C. et al., Nature. Dec 21-28; 342(6252):877-83 (1989); Kabat E. A. et al., National Institutes of Health, Bethesda, Md. (1991)). Of these, the three CDRs are separated by continuous portions of the framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The HCVR and LCVR each comprise four FRs, and the CDRs and FRs are arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions. Antibodies can be assigned to classes on the basis of the amino acid sequences of the constant regions of their heavy chains. Depending on whether they contain the alpha, delta, epsilon, gamma, and mu heavy chains, antibodies can be assigned to five major classes or isotypes: IgA, IgD, IgE, IgG, and IgM.Several major antibody classes can also be divided into subclasses, such as IgGl (gamma 1 heavy chain), IgG2 (gamma 2 heavy chain), IgG3 (gamma 3 heavy chain), IgG4 (gamma 4 heavy chain), IgAl (alpha 1 heavy chain), or IgA2 (alpha 2 heavy chain), etc.

[0200] The term "variable domain" when used in reference to an antibody refers to the variable region of an antibody or fragment thereof that comprises one or more CDRs. Although a variable domain can comprise an entire variable region (e.g., HCVR or LCVR), it can also comprise less than an entire variable region but still retain the ability to bind to an antigen or form an antigen binding site.

[0201] The term "antigen binding portion" refers to an antibody fragment formed from a portion of an antibody that contains one or more CDRs or any other antibody fragment that binds to an antigen but does not have the structure of an intact antibody. Examples of antigen binding portions include, but are not limited to, variable domains, variable regions, diabodies, Fab, Fab', F(ab')2, Fv fragments, disulfide stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide stabilized diabodies (ds diabody), multispecific antibodies, camelized single domain antibodies, nanobodies, domain antibodies, and bivalent domain antibodies. An antigen binding portion can bind to the same antigen as the parent antibody. In certain embodiments, an antigen binding portion can comprise one or more CDRs from a particular human antibody grafted to framework regions from one or more different human antibodies. More detailed forms of antigen binding portions are described in Spiess et al., 2015 (supra) and Brinkman et al., mAbs, 9(2), pp. 182-212 (2017), the entire contents of which are incorporated herein by reference.

[0202] "Fab" of an antibody refers to that portion of an antibody that is bounded by a disulfide bond between the light chain (comprising a variable region and a constant region) and the variable region and first constant region of a heavy chain. In certain embodiments, the constant region of both the light chain and the heavy chain are replaced by a TCR constant region.

[0203] "Fab'" refers to a Fab fragment that includes a portion of the hinge region.

[0204] "F(ab')2" refers to a dimer of Fab.

[0205] "Fragment difficult (Fd)" of an antibody refers to the half of the amino terminal end of a heavy chain fragment that can combine with a light chain to form a Fab.

[0206] The "Fc" of an antibody refers to the portion of the antibody that is composed of the second (CH2) and third (CH3) constant regions of a first heavy chain linked by disulfide bonds to the second and third constant regions of a second heavy chain. The Fc portion of an antibody is responsible for various effector functions, such as ADCC and CDC, but does not participate in antigen binding.

[0207] A "hinge region" with respect to an antibody comprises the portion of the heavy chain molecule connecting the CH1 domain to the CH2 domain. This hinge region comprises about 25 amino acid residues and is flexible, allowing the two N-terminal antigen binding regions to move independently.

[0208] The "Fv" of an antibody refers to the minimum antibody fragment that contains a complete antigen binding site. The Fv fragment consists of the variable domain of one light chain bound to the variable domain of one heavy chain. Several Fv designs are provided, including dsFv, in which the linkage between the two domains is enhanced by the introduction of a disulfide bond; and scFv, in which the two domains can be joined together by a peptide linker into a single polypeptide. Fv constructs have been generated that contain the variable domain of a heavy immunoglobulin chain or a light immunoglobulin chain linked to the variable and constant domains of the corresponding immunoglobulin heavy or light chain. Fv has also been multimerized to form diabodies and triabodies (Maynard et al., Annu Rev Biomed Eng 2 339-376 (2000)).

[0209] When "percent sequence identity" is used in reference to an amino acid sequence (or nucleic acid sequence), it refers to the percentage of amino acid residues (or nucleic acid residues) in a candidate sequence that are identical with a reference sequence after aligning the sequences and introducing gaps, if necessary, to maximize the percent sequence identity. The conservative substitutions of amino acid residues are considered or not considered as identical residues. Alignment can be achieved by tools disclosed in the art, such as BLASTN, BLASTp (National Center for Biotechnology Information website (NCBI), see also Altschul S.F. et al., J. Mol. Biol., 215:403-410 (1990); Stephen F. et al., Nucleic Acids Res., 25:3389-3402 (1997)), ClustalW2 (European Bioinformatics Institute website, see also Higgins D.G. et al., Methods in Enzymology, 266:383-402 (1996); Larkin M.A. et al., Bioinformatics (Oxford, England), 23(21):2947-8 (2007)), and ALIGN or Megalign (DNASTAR) software, to determine percent sequence identity of the amino acid (or nucleic acid) sequences. The default parameters of the tools can be used by a person skilled in the art or can be adjusted as appropriate for the alignment, for example by choosing the appropriate algorithm.

[0210] The term "operably linked" or "operably linked" refers to the arrangement of two or more biological sequences in such a way that they are in a relationship that allows them to function in a desired manner, whether or not there is a spacer or linker. When used in reference to a polypeptide, the term is intended to mean that the polypeptide sequences are linked in such a way as to allow the product of the linkage to have a desired biological function. For example, an antibody variable region can be operably linked to a constant region to form a stable product having antigen binding activity. The term can also be used in reference to polynucleotides. For example, when a polynucleotide encoding a polypeptide is operably linked to a regulatory sequence (e.g., a promoter, enhancer, silencer sequence, etc.), the term is intended to mean that the polynucleotide sequence is linked in such a way as to allow the polypeptide to be expressed from the polynucleotide under the control of the regulatory sequence.

[0211] The term "fusion" or "fused" when used in reference to an amino acid sequence (e.g., a peptide, polypeptide, or protein) refers to the combination of two or more amino acid sequences into a single amino acid sequence that does not occur in nature, for example, by chemical linkage or recombinant means. The fused amino acid sequence can be produced by recombination of two genes encoding polynucleotide sequences, and can be expressed by methods of introducing a construct containing the recombined polynucleotide into a host cell.

[0212] The term "spacer" refers to an artificial amino acid sequence of 1, 2, 3, 4, or 5 amino acid residues, or 5 to 15, 20, 30, 50, or more amino acid residues in length, linked by peptide bonds and used to join one or more polypeptides. A spacer can or can not have a secondary structure. Spacer sequences are well known in the art, see, e.g., Holliger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993); Poljak et al., Structure 2:1121-1123 (1994). Any suitable spacer known in the art can be used.

[0213] The term "mutation" or "mutated" when used in reference to an amino acid residue means a substitution, insertion, or addition of an amino acid residue.

[0214] A native "T cell receptor" or native "TCR" is a heterodimeric T cell surface protein that associates with invariant CD3 chains to form a complex capable of mediating signal transduction. The TCR belongs to the immunoglobulin superfamily and is similar to a half-antibody with a single heavy chain and a single light chain. The native TCR has an extracellular portion, a transmembrane portion, and an intracellular portion. The extracellular domain of the TCR has a proximal membrane constant region and a distal membrane variable region.

[0215] The term "treatment" generally refers to any manipulation for achieving a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. As used herein, "treatment" covers any treatment of a patient, including, but not limited to, preventing or preventing the recurrence of a disease, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, ameliorating or eliminating symptoms of the disease, increasing the frequency and duration of symptom-free periods, and improving or eliminating the prognostic outlook for the disease.

[0216] A "therapeutically effective amount" or "therapeutically effective dose" is any amount of a drug, when used alone or in conjunction with another therapeutic agent, that protects a subject from the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by determining the activity of the agent in in vitro assays.

[0217] The term "pharmaceutical combination" means a combination of two or more active ingredients administered in any order in any sequence (including administration as individual active ingredients in a single formulation, or administration as separate formulations each containing one of the active ingredients, or administration as a single formulation containing two or more of the active ingredients, or administration as a single formulation containing one of the active ingredients and one or more additional ingredients). The active ingredients can be administered simultaneously, or sequentially, in any order, in separate formulations or in a single formulation.

[0218] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0219] The term "pharmaceutical composition" means a mixture of an active ingredient, with a pharmaceutically-acceptable carrier. The goal of a pharmaceutical composition is to facilitate administration of the active ingredient to a subject. In this document, the terms "pharmaceutical composition" and "formulation" are used synonymously and are interchangeable.

[0220] The terms "administer," "administering," "administration," or "give" mean the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0221] The terms "subject," "patient," or "host" are used interchangeably. A "subject," "patient," or "host" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and hamsters. In some embodiments, the term "subject," "patient," or "host" is a mammal. In some embodiments, the subject, patient, or host is a mouse. In some embodiments, the subject, patient, or host is a human.

[0222] The term "single dose" refers to the smallest unit of packaging containing a certain amount of a drug, for example, a single tablet in a box of seven tablets, or a single injection in a bottle. The term "multiple dose" is composed of multiple single doses.

[0223] The term "unit dose" refers to the dose of active ingredient contained in the smallest unit of packaging, for example, the dose of antibody contained in a single injection of an antibody injection.

[0224] The use of the term "flat dose" means that the dose administered to a patient is independent of the patient's weight or body surface area (BSA). A flat dose is thus specified as an absolute amount of a pharmaceutical agent (e.g., a bispecific anti-CD3 / CD20 polypeptide complex), rather than as a mg / kg dose. For example, a 60 kg human and a 100 kg human would receive the same dose of a bispecific anti-CD3 / CD20 polypeptide complex.

[0225] As used herein, "treatment failure" is defined as disease progression or relapse during treatment or after the last treatment.

[0226] The following examples are provided to better illustrate the present application and should not be construed as limiting the scope of the application. All such specific compositions, materials, and methods exemplified are within the scope of the application. These specific compositions, materials, and methods are not intended to limit the present application but are presented for purposes of exemplification only. Those skilled in the art will recognize numerous equivalents to the specific compositions, materials, and methods described herein. Such equivalents are within the scope of the present application and are encompassed by the claims herein. It is understood that various modifications can be made in the method of the present application and additional or other changes can be made therein without departing from the scope of the present application. It is intended that such modifications and changes be included within the scope of the application as set forth in the following claims. Examples

[0227] Example 1 Clinical Trial of Non-Hodgkin's Lymphoma

[0228] 1. Inclusion Criteria

[0229] Subjects who meet all of the following inclusion criteria are eligible for enrollment in this trial:

[0230] (1) The subject voluntarily enrolls in the study, signs the informed consent form (ICF), and is in good compliance;

[0231] (2) Age: 18-80 years old (at the time of signing the ICF); both male and female are allowed; ECOG PS score: 0-2 points; life expectancy of more than 3 months;

[0232] (3) Patients with B-cell non-Hodgkin's lymphoma (including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma, etc.) diagnosed by histology or cytology in accordance with the 2022 WHO diagnostic criteria, wherein the diffuse large B-cell lymphoma includes non-specific type diffuse large B-cell lymphoma and indolent lymphoma transformed diffuse large B-cell lymphoma;

[0233] (4) Immunophenotypic analysis shows that the tumor is CD20 positive;

[0234] (5) According to the 2014 Lugano standard, there is at least one measurable lesion, i.e. the long diameter of lymph node lesion is > 15 mm or the long diameter of extranodal lesion is > 10 mm according to CT cross-sectional imaging; PET-CT scan shows PET positive;

[0235] (6) Major organ function is normal, i.e. meets the following criteria:

[0236] 1) Blood routine examination (within 14 days before screening without blood transfusion or correction with hematopoietic stimulating factor drugs): absolute neutrophil count (ANC) ≥ 1.0 x 10 9 / L; platelet ≥ 75 x 10 9 / L (if accompanied by bone marrow invasion, platelet ≥ 50 x 10 9 / L); hemoglobin (HGB) ≥ 80 g / L;

[0237] 2) Blood biochemistry examination: total bilirubin (TBIL) ≤ 1.5 x upper limit of normal (ULN), and ≤ 3 x ULN for patients with Gilbert syndrome; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN, and ALT and AST ≤ 5 x ULN if accompanied by liver metastasis; serum creatinine (Cr) ≤ 1.5 x ULN or creatinine clearance rate estimated by Cockcroft-Gault glomerular filtration formula ≥ 50 mL / min;

[0238] 3) Urine routine examination: urine routine examination shows that urine protein < ++; if urine protein ≥ ++, 24-hour urine protein quantification ≤ 1.0 g needs to be confirmed;

[0239] 4) Coagulation function examination: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤ 1.5 x ULN (without anti-coagulation therapy);

[0240] 5) Cardiac ultrasound evaluation: left ventricular ejection fraction (LVEF) ≥ 50%;

[0241] 6) 12-lead electrocardiogram evaluation: QTc < 450 ms (male), QTc < 470 ms (female);

[0242] (7) Negative serum or urine pregnancy test within 7 days before the first administration, and must be a non-lactating subject; female subjects of childbearing potential agree to use contraceptive measures (such as intrauterine device, contraceptive drugs or condom) during the study period and within 12 months after the end of the study; male subjects agree to use contraceptive measures during the study period and within 12 months after the end of the study.

[0243] 2. Test drug

[0244] (1) W3278-U2T3.F18R-1.uIgG4.SP injection (specification: 10 mg / 2 mL / bottle, 1 mg / 1 mL / bottle or 80 mg / bottle)

[0245] (2) R-CHOP regimen: rituximab, vincristine, cyclophosphamide, doxorubicin and prednisone

[0246] (3) GemOx regimen: gemcitabine and oxaliplatin

[0247] (4) Lenalidomide capsules: specification 5 mg / capsule, 10 mg / capsule.

[0248] 3. Treatment regimen

[0249] (1) W3278-U2T3.F18R-1.uIgG4.SP injection combined with R-CHOP regimen, each treatment cycle is 21 days

[0250] 1) The regimen is suitable for treating: patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (for example, patients with relapsed or refractory B-cell non-Hodgkin's lymphoma who have received at least one line of systemic treatment previously and have not received R-CHOP regimen treatment or have received R-CHOP regimen treatment for more than 2 years after complete remission), or patients with newly diagnosed diffuse large B-cell lymphoma, follicular lymphoma and marginal zone lymphoma who have not received systemic anti-tumor treatment previously.

[0251] 2) The specific administration regimen is as follows:

[0252] W3278-U2T3.F18R-1.uIgG4.SP injection:

[0253] Method one: each administration is once on the 9th day, the 11th day and the 16th day of the 1st treatment cycle, once on the 2nd day, the 9th day and the 16th day of each of the 2nd-3rd treatment cycles, once on the 1st day of each of the 4th-8th treatment cycles, the dose on the 9th day of the 1st treatment cycle is 0.3 mg, the dose on the 11th day of the 1st treatment cycle is 3 mg, the dose on the 16th day of the 1st treatment cycle is 30 mg, and the dose of each administration at other times is 30 mg, 50 mg or 80 mg, intravenous infusion;

[0254] Method Two: once on days 9, 11, and 16 of cycle 1, once on day 2 of each of cycles 2-3, and once on day 1 of each of cycles 4-8, with a dose of 0.3 mg on day 9 of cycle 1, a dose of 3 mg on day 11 of cycle 1, a dose of 30 mg on day 16 of cycle 1, and a dose of 30 mg, 50 mg, or 80 mg at all other times, as an intravenous infusion;

[0255] Method Three: once on days 16 and 18 of cycle 1, once on days 2, 9, and 16 of each of cycles 2-3, and once on day 1 of each of cycles 4-8, with a dose of 0.3 mg on day 16 of cycle 1, a dose of 3 mg on day 18 of cycle 1, a dose of 30 mg on day 2 of cycle 2, and a dose of 30 mg, 50 mg, or 80 mg at all other times, as an intravenous infusion;

[0256] Method Four: once on days 16 and 18 of cycle 1, once on days 2 and 9 of cycle 2, once on day 2 of cycle 3, and once on day 1 of each of cycles 4-8, with a dose of 0.3 mg on day 16 of cycle 1, a dose of 3 mg on day 18 of cycle 1, a dose of 30 mg on day 2 of cycle 2, and a dose of 30 mg, 50 mg, or 80 mg at all other times, as an intravenous infusion;

[0257] Rituximab: once on day 1 of each cycle through cycle 6, at a dose of 375 mg / m2 each time;

[0258] Vincristine: once on day 2 of cycle 1, and once on day 1 of each subsequent cycle through cycle 6, at a dose of 1.4 mg / m2 (not to exceed 2 mg) each time;

[0259] Cyclophosphamide: once on day 2 of cycle 1, and once on day 1 of each subsequent cycle through cycle 6, at a dose of 750 mg / m2 each time;

[0260] Doxorubicin: once on day 2 of cycle 1, and once on day 1 of each subsequent cycle through cycle 6, at a dose of 50 mg / m2 each time;

[0261] Prednisone: once a day on days 2-6 of cycle 1, and once a day on days 1-5 of each subsequent cycle, orally, until cycle 6; 100 mg per dose.

[0262] (2) W3278-U2T3.F18R-1.uIgG4.SP injection combined with GemOx regimen, 21 days per cycle

[0263] 1) The regimen is applicable to the treatment of: patients with relapsed or refractory diffuse large B-cell lymphoma (e.g., patients with diffuse large B-cell lymphoma who are ineligible for hematopoietic stem cell transplantation or who have failed treatment after transplantation or relapsed after transplantation, and whose disease has progressed during the most recent treatment or relapsed after treatment completion or confirmed no objective remission after adequate treatment).

[0264] 2) The specific administration regimen is as follows:

[0265] W3278-U2T3.F18R-1.uIgG4.SP injection:

[0266] Method one: once a day on days 8, 10 and 15 of cycle 1, once a day on days 1, 8 and 15 of each of cycles 2-3, once a day on day 1 of each of cycles 4-18, 0.3 mg on day 8 of cycle 1, 3 mg on day 10 of cycle 1, 30 mg on day 15 of cycle 1, and 30 mg, 50 mg or 80 mg at other times, intravenous infusion;

[0267] Method two: once a day on days 8, 10 and 15 of cycle 1, once a day on day 1 of each of cycles 2-18, 0.3 mg on day 8 of cycle 1, 3 mg on day 10 of cycle 1, 30 mg on day 15 of cycle 1, and 30 mg, 50 mg or 80 mg at other times, intravenous infusion;

[0268] Method three: administration once on day 15 and day 17 of the first treatment cycle, administration once on day 1, day 8 and day 15 of each of the second to third treatment cycles, administration once on day 1 of each of the fourth to eighteenth treatment cycles, the dose administered on day 15 of the first treatment cycle is 0.3 mg, the dose administered on day 17 of the first treatment cycle is 3 mg, the dose administered on day 1 of the second treatment cycle is 30 mg, and the dose administered each time thereafter is 30 mg, 50 mg or 80 mg, intravenous infusion;

[0269] Method four: administration once on day 15 and day 17 of the first treatment cycle, administration once on day 1 and day 8 of the second treatment cycle, administration once on day 1 of each of the third to eighteenth treatment cycles, the dose administered on day 15 of the first treatment cycle is 0.3 mg, the dose administered on day 17 of the first treatment cycle is 3 mg, the dose administered on day 1 of the second treatment cycle is 30 mg, and the dose administered each time thereafter is 30 mg, 50 mg or 80 mg, intravenous infusion;

[0270] Gemcitabine: administration once on day 2 of the first treatment cycle, and administration on day 1 of each cycle thereafter until the sixth treatment cycle, the dose administered each time is 1000 mg / ㎡;

[0271] Oxaliplatin: administration once on day 2 of the first treatment cycle, and administration on day 1 of each cycle thereafter until the sixth treatment cycle, the dose administered each time is 100 mg / ㎡;

[0272] Rituximab: administration once on day 1 of the first treatment cycle, the dose administered each time is 375 mg / ㎡.

[0273] (3) W3278-U2T3.F18R-1.uIgG4.SP injection solution combined with lenalidomide, each treatment cycle is 28 days

[0274] 1) The regimen is suitable for treating: patients with follicular lymphoma and marginal zone lymphoma who have not received systemic anti-tumor treatment and are in initial treatment, patients with follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma who have relapsed or are refractory (for example, patients with follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma who have relapsed or are refractory after receiving at least one line of systemic treatment (including CD20 monoclonal antibody)).

[0275] 2) The specific administration regimen is shown below:

[0276] W3278-U2T3.F18R-1.uIgG4.SP injection: once on day 1, day 3, day 8 and day 15 of the first treatment cycle, and once on day 1 and day 15 of each treatment cycle in the second to twelfth treatment cycles; the dose on day 1 of the first treatment cycle is 0.3 mg, the dose on day 3 of the first treatment cycle is 3 mg, the dose on day 8 of the first treatment cycle is 30 mg, and the dose of each subsequent administration is 30 mg, 50 mg or 80 mg, intravenous infusion;

[0277] Lenalidomide: once a day from day 1 to day 21 of each treatment cycle, oral administration, until the twelfth treatment cycle, the dose of each administration is 20 mg;

[0278] Rituximab can be administered once 375 mg / ㎡ three days before the first administration.

[0279] 4. Evaluation criteria

[0280] The efficacy is evaluated according to the evaluation criteria revised in the 2014 Lugano Conference.

[0281] The severity of adverse events is judged according to the NCI-CTC AE 5.0 standard of the United States National Cancer Institute-General Adverse Event Terminology.

[0282] 5. Endpoint indicators

[0283] Complete remission rate (CRR), objective remission rate (ORR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), remission duration (DOR), time to remission (TTR), etc.

[0284] Adverse event incidence: the occurrence of all adverse events (AE), serious adverse events (SAE) and treatment-related adverse events (TRAEs), and abnormal laboratory test indicators;

[0285] Pharmacokinetic / pharmacodynamic related indicators: pharmacokinetic (PK) parameters, immunogenicity (ADA) incidence, etc.

[0286] 6. Results

[0287] (1) W3278-U2T3.F18R-1.uIgG4.SP injection combined with R-CHOP regimen

[0288] The bispecific anti-CD3 / CD20 polypeptide complex W3278-U2T3.F18R-1.uIgG4.SP of the present application combined with R-CHOP regimen shows good efficacy in patients with diffuse large B-cell lymphoma, especially in patients with newly diagnosed diffuse large B-cell lymphoma who have not received systemic anti-tumor therapy, which relieves and controls the patient's condition, has a high complete remission rate and objective remission rate, a long remission duration, a long progression-free survival and overall survival, and a low incidence and severity of adverse events. The specific results of the exemplary patients are shown below.

[0289] (1) Patient 1

[0290] Diagnosis: Newly diagnosed diffuse large B-cell lymphoma

[0291] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with R-CHOP regimen (W3278-U2T3.F18R-1.uIgG4.SP is administered in mode one, and the dose is 50 mg each time at other times)

[0292] According to the efficacy evaluation criteria, the best treatment effect of the patient is CR (complete remission) so far.

[0293] (2) Patient 2

[0294] Diagnosis: Newly diagnosed diffuse large B-cell lymphoma

[0295] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with R-CHOP regimen (W3278-U2T3.F18R-1.uIgG4.SP is administered in mode one, and the dose is 50 mg each time at other times)

[0296] According to the efficacy evaluation criteria, the best treatment effect of the patient is PR (partial remission) so far.

[0297] (3) Patient 3

[0298] Diagnosis: Newly diagnosed diffuse large B-cell lymphoma

[0299] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with R-CHOP regimen (W3278-U2T3.F18R-1.uIgG4.SP is administered in mode one, and the dose is 50 mg each time at other times)

[0300] According to the efficacy evaluation criteria, the best treatment effect of the patient is PR (partial remission) so far.

[0301] (2) W3278-U2T3.F18R-1.uIgG4.SP injection combined with GemOx regimen

[0302] The bispecific anti-CD3 / CD20 polypeptide complex W3278-U2T3.F18R-1.uIgG4.SP of the present application combined with GemOx regimen shows good efficacy in patients with diffuse large B-cell lymphoma, especially in patients with relapsed and / or refractory diffuse large B-cell lymphoma (e.g., patients with diffuse large B-cell lymphoma who are not suitable for hematopoietic stem cell transplantation or who have failed treatment after transplantation or relapsed after treatment, and who have progressed during the last treatment or relapsed after treatment or confirmed no objective remission after adequate treatment), which can relieve and control the disease of patients, and has high complete remission rate and objective remission rate, long remission duration, long progression-free survival and overall survival, low incidence and severity of adverse events, and the specific results of exemplary patients are shown below.

[0303] (1) Patient 1

[0304] Diagnosis: relapsed and / or refractory diffuse large B-cell lymphoma, Lugano stage IV;

[0305] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with GemOx regimen (W3278-U2T3.F18R-1.uIgG4.SP is administered in mode one, and the dose of each administration at other times is 80 mg);

[0306] According to the efficacy evaluation criteria, the best treatment effect of the patient is CR (complete remission) so far.

[0307] (2) Patient 2

[0308] Diagnosis: relapsed and / or refractory diffuse large B-cell lymphoma, Lugano stage IV;

[0309] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with GemOx regimen (W3278-U2T3.F18R-1.uIgG4.SP is administered in mode one, and the dose of each administration at other times is 80 mg);

[0310] According to the efficacy evaluation criteria, the best treatment effect of the patient is PR (partial remission) so far.

[0311] (3) Patient 3

[0312] Diagnosis: relapsed and / or refractory diffuse large B-cell lymphoma, Lugano stage IV;

[0313] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with GemOx regimen (W3278-U2T3.F18R-1.uIgG4.SP was administered in Mode 1, and the dose of each administration at other times was 80 mg);

[0314] According to the efficacy evaluation criteria, the best treatment effect of the patient was PR (partial remission) until now.

[0315] (3) W3278-U2T3.F18R-1.uIgG4.SP injection combined with lenalidomide

[0316] The bispecific anti-CD3 / CD20 polypeptide complex W3278-U2T3.F18R-1.uIgG4.SP of the present application combined with lenalidomide showed good efficacy in patients with follicular lymphoma, especially in patients with relapsed or refractory follicular lymphoma (for example, patients with relapsed or refractory follicular lymphoma who had received at least one line of systemic treatment (including CD20 monoclonal antibody) previously), which relieved and controlled the patient's condition, and the complete remission rate and objective remission rate were high (up to the data statistics day, a total of 15 patients could be evaluated, the ORR was 100%, and the CRR was 67%), the remission duration was long, the progression-free survival and overall survival were long, the incidence and severity of adverse events were low, and the specific results of the exemplary patients are shown below.

[0317] (1) Patient 1

[0318] Diagnosis: relapsed or refractory follicular lymphoma, Lugano stage IV;

[0319] Number of previous treatment lines: one line

[0320] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with lenalidomide (the dose of each administration at other times was 50 mg);

[0321] According to the efficacy evaluation criteria, the best treatment effect of the patient was CR (complete remission) until now.

[0322] (2) Patient 2

[0323] Diagnosis: relapsed or refractory follicular lymphoma, Lugano stage IV;

[0324] Number of previous treatment lines: two lines

[0325] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with lenalidomide (the rest of the time, the dose of each administration was 50 mg);

[0326] According to the efficacy evaluation criteria, the best treatment effect of the patient was CR (complete remission) by the present.

[0327] (3) Patient 3

[0328] Diagnosis: relapsed or refractory follicular lymphoma, Lugano stage IV;

[0329] Number of previous treatment lines: two lines

[0330] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with lenalidomide (the rest of the time, the dose of each administration was 50 mg);

[0331] According to the efficacy evaluation criteria, the best treatment effect of the patient was CR (complete remission) by the present.

[0332] The bispecific anti-CD3 / CD20 polypeptide complex W3278-U2T3.F18R-1.uIgG4.SP of the present application combined with lenalidomide shows good efficacy in patients with marginal zone lymphoma, especially in patients with relapsed or refractory marginal zone lymphoma (for example, patients with relapsed or refractory marginal zone lymphoma who have received at least one line of systemic treatment (including CD20 monoclonal antibody)), which relieves and controls the patient's condition, and has a high complete remission rate and objective remission rate, a long remission duration, a long progression-free survival and overall survival, a low incidence and severity of adverse events, and the specific results of the exemplary patients are shown below.

[0333] (1) Patient 1

[0334] Diagnosis: relapsed or refractory marginal zone lymphoma;

[0335] Number of previous treatment lines: four lines

[0336] Dosing regimen: W3278-U2T3.F18R-1.uIgG4.SP injection combined with lenalidomide (the rest of the time, the dose of each administration was 50 mg);

[0337] According to the efficacy evaluation criteria, the best treatment effect of the patient was CR (complete remission) by the present.

[0338] Those skilled in the art should further appreciate that the application can be embodied in other specific forms without departing from the spirit or central attributes of the application. The above described embodiments are to be considered in all respects only as illustrative and not restrictive, and the scope of the application should be, therefore, determined not with reference to such above description, but instead should be determined with reference to the appended claims, along with their full scope of equivalents to which such claims are entitled.

Claims

1. A pharmaceutical combination comprising a bispecific anti-CD3 / CD20 polypeptide complex and a second therapeutic agent, wherein, the bispecific anti-CD3 / CD20 polypeptide complex comprises a first antigen binding moiety associated with a second antigen binding moiety, wherein: the first antigen binding moiety comprises: a first polypeptide comprising, from N-terminus to C-terminus, a first heavy chain variable domain (VH) of a first antibody operably linked to a first T cell receptor (TCR) constant region (C1), and a second polypeptide comprising, from N-terminus to C-terminus, a first light chain variable domain (VL) of the first antibody operably linked to a second TCR constant region (C2), wherein C1 and C2 are capable of forming a dimer comprising at least one non-native inter-chain bond between C1 and C2, and the non-native inter-chain bond is capable of stabilizing the dimer, wherein C1 comprises an engineered TCR beta chain (Cβ) as set forth in SEQ ID NO: 17, and C2 comprises an engineered TCR alpha chain (Cα) as set forth in SEQ ID NO: 18, and the second antigen binding moiety comprises: a second heavy chain variable domain (VH2) of a second antibody operably linked to an antibody heavy chain CH1 domain, and a second light chain variable domain (VL2) of the second antibody operably linked to an antibody light chain constant (CL) domain, wherein one of the first antigen binding moiety and the second antigen binding moiety is an anti-CD3 binding moiety and the other is an anti-CD20 binding moiety, the anti-CD3 binding moiety is derived from an anti-CD3 antibody comprising: a) a heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 1, b) a heavy chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 2, c) a heavy chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 3, d) a light chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 4, e) a light chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 5, and f) a light chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 6, the anti-CD20 binding moiety is derived from an anti-CD20 antibody comprising: a) a heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 7, b) a heavy chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 8, c) a heavy chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 9, d) a light chain CDR1 comprising an amino acid sequence selected from SEQ ID NO: 10, e) a light chain CDR2 comprising an amino acid sequence selected from SEQ ID NO: 11, and f) a light chain CDR3 comprising an amino acid sequence selected from SEQ ID NO: 12; the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug.

2. The pharmaceutical combination of claim 1, wherein, The anti-CD3 binding moiety comprises a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence variant of SEQ ID NO: 13 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:

14.

3. The pharmaceutical combination of claim 1 or 2, wherein, The anti-CD20 binding moiety comprises a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 15 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:

16.

4. The pharmaceutical combination according to any one of claims 1-3, wherein, The bispecific anti-CD3 / CD20 polypeptide complex comprises sequences set forth in SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO:

22.

5. The pharmaceutical combination according to any one of claims 1-4, wherein, The bispecific anti-CD3 / CD20 polypeptide complex comprises: a first polypeptide chain having a sequence set forth in SEQ ID NO: 19, a second polypeptide chain having a sequence set forth in SEQ ID NO: 20, a third polypeptide chain having a sequence set forth in SEQ ID NO: 21, a fourth polypeptide chain having a sequence set forth in SEQ ID NO: 21, and a fifth polypeptide chain having a sequence set forth in SEQ ID NO:

22.

6. The pharmaceutical combination according to any one of claims 1-5, wherein, The second therapeutic agent comprises: a) one or more of an anti-CD20 antibody, a nitrogen mustard antineoplastic drug, an anthracycline antineoplastic drug, a vinca alkaloid antineoplastic drug, a hormonal antineoplastic drug, lenalidomide, a platinum antineoplastic drug, an antimetabolite antineoplastic drug; b) gemcitabine and oxaliplatin; c) gemcitabine, oxaliplatin, and rituximab; d) rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone; e) rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone; f) lenalidomide; or g) lenalidomide and rituximab.

7. The pharmaceutical combination according to any one of claims 1-6, wherein, The bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are each in the form of a pharmaceutical composition.

8. The pharmaceutical combination according to any one of claims 1-7, wherein, The unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 1-10 mg, 2-10 mg, or 50-150 mg; preferably, the unit dose of the bispecific anti-CD3 / CD20 polypeptide complex is 1 mg, 2 mg, 10 mg, or 80 mg.

9. The pharmaceutical combination according to any one of claims 1-8, wherein, The bispecific anti-CD3 / CD20 polypeptide complex is prepared to be suitable for administration to a patient in a single dose or multiple doses of 0.1-100 mg of the anti-CD3 / CD20 polypeptide complex; preferably, the bispecific anti-CD3 / CD20 polypeptide complex is prepared to be suitable for administration to a patient in a single dose or multiple doses of 0.3 mg, 3 mg, 30 mg, 50 mg, or 80 mg of the anti-CD3 / CD20 polypeptide complex.

10. Use of the pharmaceutical combination of any one of claims 1-9 in the manufacture of a medicament for treating non-Hodgkin lymphoma.

11. Use of a bispecific anti-CD3 / CD20 polypeptide complex and a second therapeutic agent in the manufacture of a medicament for treating non-Hodgkin lymphoma, wherein, The bispecific anti-CD3 / CD20 polypeptide complex comprises a first antigen binding moiety associated with a second antigen binding moiety, wherein: the first antigen binding moiety comprises: a first polypeptide comprising, from N-terminus to C-terminus, a first heavy chain variable domain (VH) of a first antibody operably linked to a first T cell receptor (TCR) constant region (C1), and a second polypeptide comprising, from N-terminus to C-terminus, a first light chain variable domain (VL) of the first antibody operably linked to a second TCR constant region (C2), wherein C1 and C2 are capable of forming a dimer comprising at least one non-native interchain bond between C1 and C2, and the non-native interchain bond is capable of stabilizing the dimer, wherein C1 comprises an engineered TCR beta chain (Cβ) as set forth in SEQ ID NO: 17, and C2 comprises an engineered TCR alpha chain (Cα) as set forth in SEQ ID NO: 18, and the second antigen binding moiety comprises: a second heavy chain variable domain (VH2) of a second antibody operably linked to an antibody heavy chain CH1 domain, and a second light chain variable domain (VL2) of the second antibody operably linked to an antibody light chain constant (CL) domain, wherein one of the first antigen binding moiety and the second antigen binding moiety is an anti-CD3 binding moiety and the other is an anti-CD20 binding moiety, the anti-CD3 binding moiety is derived from an anti-CD3 antibody comprising: a) a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1, b) a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, c) a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, d) a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, e) a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, and f) a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, the anti-CD20 binding moiety is derived from an anti-CD20 antibody comprising: a) a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 7, b) a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 8, c) a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9, d) a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 10, e) a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 11, and f) a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12; the second therapeutic agent is an immunomodulatory agent and / or a chemotherapeutic drug.

12. The use according to claim 11, wherein, The anti-CD3 binding moiety comprises a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence variant of SEQ ID NO: 13 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:

14.

13. Use according to claim 11 or 12, wherein, The anti-CD20 binding moiety comprises a heavy chain variable domain sequence comprising the amino acid sequence of SEQ ID NO: 15 and a light chain variable domain sequence comprising the amino acid sequence of SEQ ID NO:

16.

14. The use according to any one of claims 11 to 13, wherein, The bispecific anti-CD3 / CD20 polypeptide complex comprises sequences as set forth in SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, and SEQ ID NO:

22.

15. The use according to any one of claims 11-14, wherein, The bispecific anti-CD3 / CD20 polypeptide complex comprises: a first polypeptide chain having a sequence as set forth in SEQ ID NO: 19, a second polypeptide chain having a sequence as set forth in SEQ ID NO: 20, a third polypeptide chain having a sequence as set forth in SEQ ID NO: 21, a fourth polypeptide chain having a sequence as set forth in SEQ ID NO: 21, and a fifth polypeptide chain having a sequence as set forth in SEQ ID NO:

22.

16. The use according to any one of claims 11-15, wherein, The second therapeutic agent comprises: a) one or more of an anti-CD20 antibody, a nitrogen mustard antineoplastic drug, an anthracycline antineoplastic drug, a vinca alkaloid antineoplastic drug, a hormonal antineoplastic drug, lenalidomide, a platinum antineoplastic drug, an antimetabolite antineoplastic drug; b) gemcitabine and oxaliplatin; c) gemcitabine, oxaliplatin, and rituximab; d) rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone; e) rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone; f) lenalidomide; or g) lenalidomide and rituximab.

17. The use according to any one of claims 11-16, wherein, The bispecific anti-CD3 / CD20 polypeptide complex and the second therapeutic agent are each in the form of a pharmaceutical composition, and can be administered sequentially and / or alternately.

18. The use according to any one of claims 11-17, wherein, The bispecific anti-CD3 / CD20 polypeptide complex is administered once every 3 weeks, twice every 3 weeks, three times every 3 weeks, once every 4 weeks, twice every 4 weeks, three times every 4 weeks, or four times every 4 weeks.

19. The use according to any one of claims 11-18, wherein, Before administering a first fixed dose of the bispecific anti-CD3 / CD20 polypeptide complex to the subject, a first dose, a second dose, and a third dose are administered in an escalation manner, wherein the fixed dose is 30-80 mg, the first dose is 0.1-0.3 mg, the second dose is 1-3 mg, and the third dose is 10-30 mg. Alternatively, the fixed dose is 50-80 mg, 30 mg, 50 mg, or 80 mg, the first dose is 0.3 mg, the second dose is 3 mg, and the third dose is 30 mg. Alternatively, the second dose is administered 1-3 days after the first dose; preferably, the second dose is administered 2 days after the first dose. Optionally, the first dose, the second dose and the third dose are administered in the first treatment cycle, or the first dose, the second dose and the third dose are administered in the first to second treatment cycles. Optionally, each 3 weeks or each 4 weeks is a treatment cycle.

20. The use according to any one of claims 10-19, wherein, The non-Hodgkin lymphoma is diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma and mantle cell lymphoma. Optionally, the diffuse large B-cell lymphoma is relapsed and / or refractory diffuse large B-cell lymphoma; the diffuse large B-cell lymphoma is relapsed and / or refractory diffuse large B-cell lymphoma that has received at least one line of systemic treatment previously; or the diffuse large B-cell lymphoma is relapsed and / or refractory diffuse large B-cell lymphoma that has received anti-CD20 antibody treatment previously; the diffuse large B-cell lymphoma is relapsed and / or refractory diffuse large B-cell lymphoma that has received at least one line of systemic treatment previously and is not suitable for hematopoietic stem cell transplantation or has failed hematopoietic stem cell transplantation treatment; or the diffuse large B-cell lymphoma is relapsed and / or refractory diffuse large B-cell lymphoma that has received anti-CD20 antibody treatment previously and is not suitable for hematopoietic stem cell transplantation or has failed hematopoietic stem cell transplantation treatment. Optionally, the diffuse large B-cell lymphoma is newly diagnosed or treatment naive diffuse large B-cell lymphoma; the diffuse large B-cell lymphoma is diffuse large B-cell lymphoma that has not received systemic treatment; or the diffuse large B-cell lymphoma is newly diagnosed or treatment naive diffuse large B-cell lymphoma that has not received systemic treatment. Optionally, the follicular lymphoma is relapsed and / or refractory follicular lymphoma; the follicular lymphoma is relapsed and / or refractory follicular lymphoma that has received at least one line of systemic treatment previously; or the follicular lymphoma is relapsed and / or refractory follicular lymphoma that has received anti-CD20 antibody treatment previously. Optionally, the marginal zone lymphoma is relapsed and / or refractory marginal zone lymphoma; the marginal zone lymphoma is relapsed and / or refractory marginal zone lymphoma that has received at least one line of systemic treatment previously; or the marginal zone lymphoma is relapsed and / or refractory marginal zone lymphoma that has received anti-CD20 antibody treatment previously.

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