Anti-CD79b antibody-drug conjugate combined with immunotherapeutic agent and chemotherapeutic agent for treating tumor

Abstract

The present invention relates to an anti-CD79b antibody-drug conjugate combined with an immunotherapeutic agent and a chemotherapeutic agent for treating a tumor, and in particular to a use of the anti-CD79b antibody-drug conjugate combined with the immunotherapeutic agent and / or the chemotherapeutic agent in the preparation of a drug for treating a tumor.

Description

Anti-CD79b antibody-drug conjugate combined with immunotherapy and chemotherapy for tumor treatment

[0001] This disclosure claims priority from patent application numbers CN 2024101502193 and CN2024114725503, which are incorporated herein by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to a method for treating tumors by combining an anti-CD79b antibody-drug conjugate with an immunotherapeutic agent and / or a chemotherapeutic agent and its medical use. Background Art

[0003] The B cell antigen receptor (BCR) complex is the most prominent molecule on the surface of B cells. The BCR complex consists of membrane immunoglobulins (mIgs), which recognize and bind antigens, and heterodimers of Igα (CD79a) and Igβ (CD79b), which transmit antigenic stimulation signals. Igα and Igβ are 47 kDa and 37 kDa glycoproteins, respectively, and belong to the immunoglobulin superfamily. The genes encoding Igα and Igβ are called mb-1 and B29, respectively. Both Igα and Igβ contain an Ig-like domain at the amino terminus of their extracellular membrane regions. Both Igα and Igβ serve as substrates for protein tyrosine kinases and participate in BCR signaling. The BCR is widely expressed on B cell lymphomas and normal B cells. CD79b is highly specific to the B-cell lineage and is highly expressed in a variety of B-cell NHLs. It has a broad mechanism of action for killing B-cell tumors. Preclinical studies have also verified that using CD79b as a binding site is more efficient than targeting CD79a. Therefore, drug development targeting CD79b is expected to become an effective means of treating B-cell lymphoma, especially DLBCL.

[0004] Polatuzumab vedotin (Polivy) is an ADC developed by Roche that targets CD79b. It is currently approved by the National Medical Products Administration (NMPA) and the FDA for use in combination with rituximab and bendamustine (BR) for R / R DLBCL, and in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for previously untreated DLBCL. However, clinical results have shown that vepotuzumab has a high degree of neurotoxicity, which limits its clinical dosing window. Therefore, the development of safe and effective new treatment options targeting the CD79b target remains a major challenge in this field. Summary of the Invention

[0005] The present disclosure provides methods and medical uses of anti-CD79b antibody-drug conjugates combined with immunotherapeutic agents and / or chemotherapeutic agents for treating tumors.

[0006] In a first aspect, the present disclosure provides use of an anti-CD79b antibody-drug conjugate combined with an immunotherapeutic agent in the preparation of a drug for treating tumors.

[0007] In a second aspect, the present disclosure provides use of an anti-CD79b antibody-drug conjugate in combination with a chemotherapeutic agent in the preparation of a drug for treating tumors.

[0008] In a third aspect, the present disclosure provides use of an anti-CD79b antibody-drug conjugate in combination with an immunotherapeutic agent and a chemotherapeutic agent in the preparation of a drug for treating tumors.

[0009] In a fourth aspect, the present disclosure provides use of a combination of an anti-CD79b antibody drug conjugate and an immunotherapeutic agent in the preparation of a medicament for treating tumors.

[0010] In a fifth aspect, the present disclosure provides use of a combination of an anti-CD79b antibody drug conjugate and a chemotherapeutic agent in the preparation of a medicament for treating tumors.

[0011] In a sixth aspect, the present disclosure provides use of a combination of an anti-CD79b antibody-drug conjugate, an immunotherapeutic agent, and a chemotherapeutic agent in the preparation of a medicament for treating tumors.

[0012] In a seventh aspect, the present disclosure provides use of a pharmaceutical composition in the preparation of a drug for treating tumors; wherein the pharmaceutical composition comprises: 1) an anti-CD79b antibody-drug conjugate and an immunotherapeutic agent; 2) an anti-CD79b antibody-drug conjugate and a chemotherapeutic agent; 3) an anti-CD79b antibody-drug conjugate, an immunotherapeutic agent, and a chemotherapeutic agent.

[0013] In an eighth aspect, the present disclosure provides use of an anti-CD79b antibody drug conjugate for treating a subject having a tumor, wherein the subject is also administered: (1) an immunotherapeutic agent; (2) a chemotherapeutic agent; or (3) an immunotherapeutic agent and a chemotherapeutic agent.

[0014] In a ninth aspect, the present disclosure provides use of an immunotherapeutic agent and / or a chemotherapeutic agent for treating a subject suffering from a tumor, wherein the subject is also administered an anti-CD79b antibody drug conjugate.

[0015] In a tenth aspect, the present disclosure provides a pharmaceutical composition comprising any one of the following:

[0016] 1) an anti-CD79b antibody-drug conjugate and an immunotherapeutic agent; 2) an anti-CD79b antibody-drug conjugate and a chemotherapeutic agent; 3) an anti-CD79b antibody-drug conjugate, an immunotherapeutic agent, and a chemotherapeutic agent.

[0017] In an eleventh aspect, the present disclosure provides a method for treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of: 1) an anti-CD79b antibody drug conjugate and an immunotherapeutic agent; 2) an anti-CD79b antibody drug conjugate and a chemotherapeutic agent; 3) an anti-CD79b antibody drug conjugate, an immunotherapeutic agent, and a chemotherapeutic agent; 4) an anti-CD79b antibody drug conjugate.

[0018] In a twelfth aspect, the present disclosure provides a method for reducing adverse reactions caused by an anti-CD79b antibody-drug conjugate in a subject, comprising administering to a subject in need: 1) an anti-CD79b antibody-drug conjugate and an immunotherapeutic agent; 2) an anti-CD79b antibody-drug conjugate and a chemotherapeutic agent; 3) an anti-CD79b antibody-drug conjugate, an immunotherapeutic agent, and a chemotherapeutic agent; 4) an anti-CD79b antibody-drug conjugate.

[0019] In some embodiments, the adverse effect is neurotoxicity. In some embodiments, the adverse effect is peripheral neurotoxicity.

[0020] In some embodiments, the tumor is a B-cell lymphoma.

[0021] In some embodiments, the tumor is follicular lymphoma.

[0022] In some embodiments, the tumor is marginal zone lymphoma.

[0023] In some embodiments, the tumor is diffuse large B-cell lymphoma. In some embodiments, the diffuse large B-cell lymphoma comprises primary DLBCL and indolent lymphoma-transformed DLBCL.

[0024] In some embodiments, the subject having the tumor has previously received at least one line of anti-tumor therapy.

[0025] In some embodiments, the subject with the tumor has previously received at least one line of anti-tumor therapy and has not achieved remission after the last line of treatment or has had disease progression after treatment.

[0026] Exemplarily, the subject has previously received at least one line of anti-tumor treatment, achieved remission during treatment, and relapsed more than 6 months after the end of treatment; or, the subject has previously received at least one line of anti-tumor treatment, had no obvious therapeutic effect during treatment, or relapsed within 6 months after the end of treatment.

[0027] In some embodiments, the subject having the tumor is a treatment-naive patient who has not previously received anti-tumor therapy.

[0028] In some embodiments, the subject has the diffuse large B-cell lymphoma, and the diffuse large B-cell lymphoma is relapsed or refractory diffuse large B-cell lymphoma is relapsed.

[0029] For example, a subject with relapsed or refractory diffuse large B-cell lymphoma must have received ≥1 line of systemic anti-tumor therapy in the past and has not achieved remission after the last line of treatment or has experienced disease progression after treatment:

[0030] Relapse: Remission during treatment, but relapse more than 6 months after treatment completion;

[0031] Refractory: No significant therapeutic effect during treatment, or relapse within 6 months after treatment.

[0032] In some embodiments, the subject has Lugano stage I-II, or stage III-IV. In some embodiments, the subject has diffuse large B-cell lymphoma, and the diffuse large B-cell lymphoma has Lugano stage I-II, or stage III-IV.

[0033] In some embodiments, the subject has an IPI score of 0-1, 2, 3, or 4-5. In some embodiments, the subject has diffuse large B-cell lymphoma, and the diffuse large B-cell lymphoma has an IPI score of 0-1, 2, 3, or 4-5.

[0034] In some embodiments, the subject with diffuse large B-cell lymphoma has not previously received lymphoma-related systemic anti-tumor therapy.

[0035] In the present disclosure, systemic anti-tumor treatment regimens are well known to those skilled in the art, such as those disclosed in treatment guidelines approved by regulatory authorities, including but not limited to detailed and up-to-date information on standard treatment regimens for various cancers provided in the NCCN Guidelines and the CSCO Guidelines.

[0036] Immunotherapy agents, chemotherapy agents

[0037] In some embodiments, the immunotherapeutic agent is an anti-CD20 antibody. In some specific embodiments, the anti-CD20 antibody is rituximab. In other embodiments, the anti-CD20 antibody can also be obinutuzumab, ofatumumab, ublituximab, etc.

[0038] In some embodiments, the chemotherapeutic agent is selected from any one or any combination (any 2, 3, 4, 5, 6, 7, 8, etc.) of the following: gemcitabine, platinum drugs, cyclophosphamide, anthracycline drugs (e.g., doxorubicin), vinca alkaloid drugs (e.g., vincristine), prednisone, ifosfamide, etoposide phosphate.

[0039] In some embodiments, the platinum drugs are selected from oxaliplatin or carboplatin. In some embodiments, the platinum drugs can also be other types of drugs, e.g., cisplatin, nedaplatin, lobaplatin, etc.

[0040] In some embodiments, the chemotherapeutic agent is selected from any of the following combinations:

[0041] (a) Gemcitabine and oxaliplatin;

[0042] (b) Cyclophosphamide, anthracycline drugs (e.g., doxorubicin), vinca alkaloid drugs (e.g., vincristine), and prednisone;

[0043] (c) Ifosfamide, carboplatin, and etoposide;

[0044] (d) Ifosfamide and carboplatin.

[0045] In some embodiments, the chemotherapeutic agent is selected from any of the following combinations:

[0046] (a) Gemcitabine and oxaliplatin;

[0047] (b) Cyclophosphamide, doxorubicin, vincristine, and prednisone;

[0048] (c) Ifosfamide, carboplatin, and etoposide;

[0049] (d) Ifosfamide and carboplatin.

[0050] In some embodiments, the anthracycline drugs can also be replaced by other chemotherapeutic drugs of the same type with comparable efficacy, e.g., epirubicin replaces doxorubicin. In some embodiments, the vinca alkaloid drugs can be replaced by other chemotherapeutic drugs of the same type with comparable efficacy. For example, vindesine replaces vincristine.

[0051] In some embodiments, the administration cycle of any of the chemotherapeutic agents is preferably once every 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0052] <R-Gemox Regimen>

[0053] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, gemcitabine, and oxaliplatin.

[0054] <R-CHOP regimen>

[0055] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, cyclophosphamide, anthracyclines (e.g., doxorubicin), vinca alkaloids (e.g., vincristine), and prednisone.

[0056] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

[0057] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, and prednisone.

[0058] <R-ICE regimen>

[0059] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, ifosfamide, carboplatin, and etoposide.

[0060] <R-IC regimen>

[0061] In some embodiments, the combination of the immunotherapeutic agent and the chemotherapeutic agent is: rituximab, ifosfamide, and carboplatin.

[0062] Anti-CD79b antibody-drug conjugate combined with an immunotherapeutic agent and a chemotherapeutic agent

[0063] In some embodiments, the combination of the anti-CD79b antibody-drug conjugate with the immunotherapeutic agent and the chemotherapeutic agent is selected from any of the following combinations:

[0064] (a) Anti-CD79b antibody-drug conjugate, rituximab, gemcitabine, and oxaliplatin;

[0065] (b) Anti-CD79b antibody-drug conjugate, rituximab, cyclophosphamide, anthracyclines (e.g., doxorubicin), vinca alkaloids (e.g., vincristine), and prednisone;

[0066] (c) Anti-CD79b antibody-drug conjugate, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone;

[0067] (d) Anti-CD79b antibody-drug conjugate, rituximab, ifosfamide, carboplatin, and etoposide;

[0068] (e) Anti-CD79b antibody drug conjugate, rituximab, and ifosfamide.

[0069] In some embodiments, the doxorubicin is liposomal doxorubicin. In some embodiments, anthracyclines can be replaced by other similar chemotherapy drugs with comparable efficacy, for example, epirubicin can be substituted for doxorubicin. In some embodiments, vinca alkaloids can be substituted by other similar chemotherapy drugs with comparable efficacy, for example, vindesine can be substituted for vincristine.

[0070] In some embodiments, the subject is a subject who has not previously received lymphoma-related systemic anti-tumor treatment, and the subject is administered the following drug combination:

[0071] Anti-CD79b antibody-drug conjugate, rituximab, cyclophosphamide, anthracyclines (e.g., doxorubicin), vinca alkaloids (e.g., vincristine), and prednisone.

[0072] In some embodiments, the subject has previously received ≥1 line of systemic anti-tumor therapy, and the subject is administered the following drug combination:

[0073] anti-CD79b antibody-drug conjugate, rituximab, gemcitabine, and oxaliplatin;

[0074] anti-CD79b antibody-drug conjugate, rituximab, ifosfamide, carboplatin, and etoposide; or

[0075] Anti-CD79b antibody-drug conjugate, rituximab, and ifosfamide.

[0076] In some embodiments, the subject has not previously received gemcitabine treatment, and the subject is administered the following drug combination: an anti-CD79b antibody drug conjugate, rituximab, gemcitabine, and oxaliplatin.

[0077] In some embodiments, the subject is a relapsed or refractory DLBCL subject who has not previously received gemcitabine treatment, and the subject is administered the following drug combination: an anti-CD79b antibody drug conjugate, rituximab, gemcitabine, and oxaliplatin.

[0078] In some embodiments, the subject has not previously received ifosfamide treatment, and the subject is administered the following drug combination: an anti-CD79b antibody drug conjugate, rituximab, ifosfamide, carboplatin, and etoposide; or an anti-CD79b antibody drug conjugate, rituximab, and ifosfamide.

[0079] In some embodiments, the subject is a subject with relapsed or refractory DLBCL who has not previously received ifosfamide treatment, and the subject is administered the following drug combination: an anti-CD79b antibody drug conjugate, rituximab, ifosfamide, carboplatin, and etoposide; or an anti-CD79b antibody drug conjugate, rituximab, and ifosfamide.

[0080] Dosage regimen

[0081] In some embodiments, any of the foregoing uses or methods employs any of the following dosing regimens:

[0082] (1) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 5 mg / m 2 to about 2000 mg / m 2 of gemcitabine, and approximately 1-500 mg / m 2 Oxaliplatin;

[0083] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0084] (2) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 1 mg / m 2 to about 1000 mg / m 2 Cyclophosphamide, about 1 mg / m 2 to about 500 mg / m 2 Anthracycline drugs, about 0.1mg / m 2 to about 100 mg / m 2 of vinca alkaloids, and about 1 mg / dose to about 1000 mg / dose of prednisone;

[0085] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0086] (3) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 0.1 mg / m 2 to about 100 mg / m 2 Ifosfamide, about 1 mg to about 2000 mg of carboplatin, and about 1 mg / m 2 / time to about 500mg / m 2 / times etoposide;

[0087] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0088] (4) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 0.1 mg / m 2 to about 100 mg / m 2 of ifosfamide, and about 1 mg to about 2000 mg of carboplatin;

[0089] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0090] (5) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 1000 mg / m 2 of gemcitabine, and approximately 100 mg / m 2 Oxaliplatin;

[0091] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0092] (6) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 750 mg / m 2 Cyclophosphamide, about 30-40 mg / m 2 Anthracyclines (eg, doxorubicin), approximately 1.4 mg / m 2 of a vinca alkaloid (e.g., vincristine) and about 100 mg of prednisone;

[0093] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0094] (7) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 5 mg / m 2 Ifosfamide, ≤800 mg of carboplatin, and approximately 100 mg / m 2 of etoposide;

[0095] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0096] (8) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 5 mg / m 2 of ifosfamide and ≤800 mg of carboplatin;

[0097] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0098] In some embodiments, the dosing regimen is as shown in any of the following:

[0099] (9) about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of an anti-CD79b antibody drug conjugate, about 375 mg / m 2 Rituximab, approximately 1000 mg / m 2 of gemcitabine, and approximately 100 mg / m 2 Oxaliplatin;

[0100] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0101] (10) about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of an anti-CD79b antibody drug conjugate, about 375 mg / m 2 Rituximab, approximately 750 mg / m 2 Cyclophosphamide, about 30-40 mg / m2 Anthracyclines (eg, doxorubicin), approximately 1.4 mg / m 2 of a vinca alkaloid (e.g., vincristine) and about 100 mg of prednisone;

[0102] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0103] (11) about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of an anti-CD79b antibody drug conjugate, about 375 mg / m 2 Rituximab, approximately 5 mg / m 2 Ifosfamide, ≤800 mg of carboplatin, and approximately 100 mg / m 2 of etoposide;

[0104] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0105] (12) about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of an anti-CD79b antibody drug conjugate, about 375 mg / m 2 Rituximab, approximately 5 mg / m 2 of ifosfamide and ≤800 mg of carboplatin;

[0106] And, the administration cycle is every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks, preferably every 3 weeks.

[0107] In some embodiments, the rituximab is administered prior to the anti-CD79b antibody drug conjugate.

[0108] In some embodiments, the dosing regimen is as shown in any of the following:

[0109] (13) The administration cycle is 3 weeks, and about 1 mg / m2 is administered on the first day of each cycle. 2 to about 1000 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 5 mg / m 2 to about 2000 mg / m 2 of gemcitabine, and about 1-500 mg / m 2 of oxaliplatin.

[0110] (14) The administration cycle is 3 weeks, and about 1 mg / m2 is administered on the first day of each cycle. 2 to about 1000 mg / m 2Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Cyclophosphamide, about 1 mg / m 2 to about 500 mg / m 2 anthracyclines, and about 0.1 mg / m 2 to about 100 mg / m 2 A vinca alkaloid drug is used, and about 1 mg / time to about 1000 mg / time of prednisone is administered on the 2nd, 3rd, 4th, 5th, and 6th days of each cycle.

[0111] (15) The dosage cycle is 3 weeks, and about 1 mg / m2 is administered on the first day of each cycle. 2 to about 1000 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 0.1 mg / m on day 3 of each cycle 2 to about 100 mg / m 2 Ifosfamide and about 1 mg to about 2000 mg of carboplatin, administered at about 1 mg / m2 on days 2, 3, and 4 of each cycle 2 / time to about 500mg / m 2 / time of etoposide.

[0112] (16) The administration cycle is 3 weeks, and about 1 mg / m2 is administered on the first day of each cycle. 2 to about 1000 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 0.1 mg / m on day 3 of each cycle 2 to about 100 mg / m 2 of ifosfamide, and about 1 mg to about 2000 mg of carboplatin.

[0113] In some embodiments, the dosing regimen is as shown in any of the following:

[0114] (17) The administration cycle is 3 weeks, and about 50 mg / m2 is administered on the first day of each cycle. 2 to about 500 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 500 mg / m 2 About 1500 mg / m 2of gemcitabine, and approximately 50-150 mg / m 2 of oxaliplatin.

[0115] (18) The dosage cycle is 3 weeks, and about 50 mg / m2 is administered on the first day of each cycle. 2 to about 500 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 500 mg / m 2 to about 1000 mg / m 2 Cyclophosphamide, about 10 mg / m 2 to about 100 mg / m 2 anthracyclines, and about 0.1 mg / m 2 to about 100 mg / m 2 A vinca alkaloid drug is used, and about 50 mg / time to about 200 mg / time of prednisone is administered on the 2nd, 3rd, 4th, 5th, and 6th days of each cycle.

[0116] (19) The dosage cycle is 3 weeks, and about 50 mg / m2 is administered on the first day of each cycle. 2 to about 500 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 1 mg / m on day 3 of each cycle 2 to about 10 mg / m 2 Ifosfamide and about 10 mg to about 800 mg of carboplatin, administered at about 50 mg / m2 on days 2, 3, and 4 of each cycle 2 / time to about 150mg / m 2 / time of etoposide.

[0117] (20) The dosage cycle is 3 weeks, and about 50 mg / m2 is administered on the first day of each cycle. 2 to about 500 mg / m 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 1 mg / m on day 3 of each cycle 2 to about 10 mg / m 2 of ifosfamide, and about 10 mg to about 800 mg of carboplatin.

[0118] In some embodiments, the dosing regimen is as shown in any of the following:

[0119] (21) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 1000 mg / m 2 of gemcitabine, and approximately 100 mg / m 2 of oxaliplatin.

[0120] (22) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate, about 750 mg / m 2 Cyclophosphamide, about 30-40 mg / m 2 anthracyclines, and about 1.4 mg / m 2 Vinca alkaloids (e.g., approximately 1.4 mg / m 2 vincristine, the maximum dose of which is 2 mg), and prednisone, approximately 100 mg / time, is administered on the 2nd, 3rd, 4th, 5th, and 6th days of each cycle.

[0121] (23) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 5 mg / kg on day 3 of each cycle 2 Ifosfamide and ≤800 mg of carboplatin, approximately 100 mg / m2 on days 2, 3, and 4 of each cycle 2 / time of etoposide.

[0122] (24) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab, about 1.0 mg / kg to about 10 mg / kg of anti-CD79b antibody drug conjugate on day 2 of each cycle, and about 5 mg / m on day 3 of each cycle 2 Ifosfamide, and ≤800mg of carboplatin.

[0123] In some embodiments, the dosing regimen is as shown in any of the following:

[0124] (25) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab, about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of anti-CD79b antibody drug conjugate, about 1000 mg / m 2 of gemcitabine, and approximately 100 mg / m2 of oxaliplatin.

[0125] (26) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab, about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg of anti-CD79b antibody drug conjugate, about 750 mg / m 2 Cyclophosphamide, about 30-40 mg / m 2 anthracyclines, and about 1.4 mg / m 2 Vinca alkaloids (e.g., approximately 1.4 mg / m 2 vincristine, the maximum dose of which is 2 mg), and prednisone, approximately 100 mg / time, is administered on the 2nd, 3rd, 4th, 5th, and 6th days of each cycle.

[0126] (27) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab at about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg on day 2 of each cycle and an anti-CD79b antibody drug conjugate at about 5 mg / kg on day 3 of each cycle 2 Ifosfamide and ≤800 mg of carboplatin, approximately 100 mg / m2 on days 2, 3, and 4 of each cycle 2 / time of etoposide.

[0127] (28) The dosage cycle is 3 weeks, and about 375 mg / m2 is administered on the first day of each cycle. 2 Rituximab at about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg on day 2 of each cycle and an anti-CD79b antibody drug conjugate at about 5 mg / kg on day 3 of each cycle 2 Ifosfamide, and ≤800mg of carboplatin.

[0128] In some embodiments, in any of the aforementioned dosing regimens, the anti-CD79b antibody drug conjugate, rituximab, gemcitabine, oxaliplatin, cyclophosphamide, anthracycline, vinca alkaloids, prednisone, ifosfamide, carboplatin, and etoposide are each independently as follows:

[0129] <Anti-CD79b Antibody Drug Conjugate>

[0130] In some embodiments, the anti-CD79b antibody drug conjugate is administered at a dose of about 0.1 mg / kg to about 20 mg / kg, for example, about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 12 mg / kg, about 1.0 mg / kg to about 10.5 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 9 mg / kg, about 1.5 mg / kg to about 10.5 mg, about 1.5 mg / kg to about 9.0 mg / kg. g / kg; about 3.0 mg / kg to about 9.0 mg / kg; about 4.5 mg / kg to about 9.0 mg / kg; about 6.0 mg / kg to about 9.0 mg / kg; about 7.5 mg / kg to about 9.0 mg / kg; about 1.5 mg / kg to about 7.5 mg / kg; about 1.5 mg / kg to about 6.5 mg / kg; about 1.0 mg / kg to about 4.8 mg / kg; about 3.0 mg / kg to about 7.5 mg / kg; or any range therebetween.In some embodiments, the anti-CD79b antibody drug conjugate is administered at a dose selected from about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg. kg, about 2.6mg / kg, about 2.7mg / kg, about 2.8mg / kg, about 2.9mg / kg, about 3.0mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.8mg / kg, about 4.0mg / kg, about 4.2mg / kg, about 4.3mg / kg, about 4.5mg / kg, about 4.6mg / kg, about 4.8mg / kg, about 5.0mg / kg, about 5.1mg / kg g / kg, about 5.3mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.8mg / kg, about 6.0mg / kg, about 6.1mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7.0mg / kg, about 7.2mg / kg, about 7.4mg / kg, about 7.5mg / kg, about 7.6mg / kg, about 7.8mg / kg, about 8. 0 mg / kg, about 8.1 mg / kg, about 8.3 mg / kg, about 8.5 mg / kg, about 8.8 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 12 mg / kg, about 12.5 mg / kg, about 13 mg / kg, about 13.5 mg / kg, about 14 mg / kg, about 16 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, or any range therebetween.

[0131] In some embodiments, the anti-CD79b antibody drug conjugate is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks. In some specific embodiments, the anti-CD79b antibody drug conjugate is administered once every three weeks.

[0132] In some embodiments, the administration regimen of the anti-CD79b antibody drug conjugate is selected from any one of the following:

[0133] (a1) a dose of about 0.1 mg / kg to about 20 mg / kg, with a dosing frequency of once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks;

[0134] (a2) the dosage is about 1.0 mg / kg to about 10.5 mg / kg, and the administration frequency is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks;

[0135] (a3) the dosage is about 1.0 mg / kg to about 9.0 mg / kg, and the administration frequency is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks;

[0136] (a4) the dosage is about 1.0 mg / kg to about 8.0 mg / kg, and the administration frequency is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks;

[0137] (a5) The dosage is about 1.0 mg / kg to about 6.0 mg / kg, and the administration frequency is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks.

[0138] (a6) the dosage is about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 10 mg / kg; the administration frequency is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks;

[0139] (a7) the dosage is about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, or about 10 mg / kg; the administration frequency is selected from once every 2 weeks, once every 3 weeks, or once every 4 weeks;

[0140] (a8) The dosage of the anti-CD79b antibody-drug conjugate is about 2.7 mg / kg, and the administration frequency is once every three weeks.

[0141] (a9) The dosage of the anti-CD79b antibody-drug conjugate is about 3.6 mg / kg, and the administration frequency is once every three weeks.

[0142] (a 10) The dosage of the anti-CD79b antibody drug conjugate is about 4.8 mg / kg, and the administration frequency is once every three weeks.

[0143] (a 11 ) The dosage of the anti-CD79b antibody drug conjugate is about 6.4 mg / kg, and the administration frequency is once every three weeks.

[0144] (a 12 ) The dosage of the anti-CD79b antibody drug conjugate is about 8.0 mg / kg, and the administration frequency is once every three weeks.

[0145] (a 13 ) The dosage of the anti-CD79b antibody drug conjugate is about 1.2 mg / kg, and the administration frequency is once every three weeks.

[0146] (a 14 ) The dosage of the anti-CD79b antibody drug conjugate is about 10.0 mg / kg, and the administration frequency is once every three weeks.

[0147] In some specific embodiments, in the dosing regimen described in any one of (a1) to (a7) above, the anti-CD79b antibody drug conjugate is administered once every three weeks.

[0148] In some embodiments, the anti-CD79b antibody drug conjugate is derived from an antibody drug conjugate of any structure in WO2023143347A1 and WO2022022508A1. The present disclosure incorporates the structures, preparation methods, and other related contents of the immunoconjugates in the above patents into the present disclosure by reference.

[0149] In some embodiments, the anti-CD79b antibody drug conjugate has a structure as shown in the following formula:

[0150] Wherein: n is 1 to 10, n is a decimal or an integer; Pc is an anti-CD79b antibody.

[0151] In some embodiments, n is a decimal or integer from 1 to 6. In some embodiments, n is a decimal or integer from 1 to 4. In some embodiments, n is 4.0 ± 0.6. In some embodiments, n is 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, or 4.9.

[0152] In this disclosure, "antibody" is used in the broadest sense to cover various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies or antigen-binding fragments thereof (also referred to as "antigen-binding portions"), so long as they exhibit the desired antigen-binding activity.

[0153] In some embodiments, the anti-CD79b antibody is derived from any type of anti-CD79b antibody or antigen-binding fragment thereof in WO2022022508A1, and the present disclosure incorporates the antibody sequences, preparation methods and other related contents in the above patents into the present disclosure by reference.

[0154] In some embodiments, the anti-CD79b antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

[0155] (1) The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, SEQ ID NO:6 and SEQ ID NO:7, respectively; and / or the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, respectively.

[0156] (2) the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, respectively; and / or the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively.

[0157] (3) The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 in the sequence shown in SEQ ID NO: 3; and / or, the light chain variable region comprises LCDR1, LCDR2 and LCDR3 in the sequence shown in SEQ ID NO: 4.

[0158] In some specific embodiments, the anti-CD79b antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:11, SEQ ID NO:6 and SEQ ID NO:7, respectively; and, the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:8, SEQ ID NO:9 and SEQ ID NO:10, respectively.

[0159] The CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact numbering systems. In some specific embodiments, the CDRs are defined according to the Chothia numbering system.

[0160] The aforementioned CDR sequences are shown in the following table:

[0161] Table 1. CDR sequences obtained using the Chothia numbering system

[0162] In some embodiments, the anti-CD79b antibody comprises any one, any two, any three, any four, any five or six CDRs selected from HCDR1 set forth in SEQ ID NO: 11 or 5, and HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 set forth in SEQ ID NO: 6-10.

[0163] In some embodiments, the anti-CD79b antibody is a murine antibody, a chimeric antibody, a humanized antibody, a human antibody, or an antigen-binding fragment of any of the foregoing. In some specific embodiments, the anti-CD79b antibody is selected from a humanized antibody or an antigen-binding fragment thereof.

[0164] In some embodiments, the VH of the anti-CD79b antibody comprises the amino acid sequence shown in SEQ ID NO: 3, or an amino acid sequence having at least 80% or 90% sequence identity thereto; and the VL comprises the amino acid sequence shown in SEQ ID NO: 4, or an amino acid sequence having at least 80% or 90% sequence identity thereto.

[0165] In some embodiments, the VH of the anti-CD79b antibody comprises the amino acid sequence shown in SEQ ID NO: 1, or an amino acid sequence having at least 80% or 90% sequence identity thereto; and the VL comprises the amino acid sequence shown in SEQ ID NO: 2, or an amino acid sequence having at least 80% or 90% sequence identity thereto.

[0166] >mAb015 VH:

[0167] >mAb015 VL:

[0168] >hAb015-10 VH:

[0169] >hAb015-10 VL:

[0170] In some embodiments, the anti-CD79b antibody comprises any one or two of the above-mentioned VH and VL.

[0171] In some embodiments, the anti-CD79b antibody further comprises an antibody constant region; for example, the heavy chain constant region of the antibody constant region is selected from human IgG1, IgG2, IgG3 and IgG4 constant regions and variants thereof; the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and variants thereof.

[0172] The above light chain variable region and light chain constant region sequences are combined to form a light chain sequence, and each heavy chain variable region and heavy chain constant region are combined to form a heavy chain sequence. An exemplary humanized antibody sequence is shown below:

[0173] >hAb015-10 heavy chain:

[0174] >hAb015-10 light chain:

[0175] In some embodiments, the anti-CD79b antibody comprises a heavy chain and a light chain, wherein the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 12 or at least 80%, 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 13 or at least 80%, 90% identical thereto.

[0176] In some embodiments, the anti-CD79b antibody comprises any one or two of the aforementioned heavy and light chains.

[0177] In the context of the present disclosure, "at least 80%" and "at least 90%" encompass 80% and above, for example at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range therebetween.

[0178] In some embodiments, the anti-CD79b antibody drug conjugate is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-CD79b antibody drug conjugate is administered by intravenous injection.

[0179] In some embodiments, the anti-CD79b antibody drug conjugate is configured in an injectable form. Exemplarily, the injectable form of the anti-CD79b antibody drug conjugate is an injection solution or a lyophilized powder injection, which comprises the anti-CD79b ER3 antibody drug conjugate and one or more pharmaceutically acceptable excipients.

[0180] In some embodiments, the pharmaceutical composition comprising the anti-CD79b antibody drug conjugate further comprises one or more of a buffer, a stabilizer, an osmotic pressure regulator, a surfactant, and a solvent.

[0181] In some embodiments, the buffer is selected from any one of acetate buffer, histidine salt buffer, Tris-hydrochloride buffer, Tris-citrate buffer, phosphate buffer or succinate buffer. In some embodiments, the buffer is histidine salt buffer or succinate buffer. In some embodiments, the buffer is histidine-hydrochloride buffer or succinic acid-sodium succinate buffer.

[0182] In some embodiments, the surfactant is a nonionic surfactant. Exemplarily, the surfactant is selected from poloxamer (e.g., poloxamer 188), polysorbate (e.g., polysorbate 20 (i.e., PS20), polysorbate 80 (i.e., PS80)), polyhydroxyalkylene, Triton, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine. In some embodiments, the surfactant is a polysorbate or poloxamer. In some embodiments, the surfactant is a polysorbate 80, polysorbate 20 or poloxamer 188.

[0183] In some embodiments, the osmotic pressure regulator is a sugar (including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc.), an amino acid (including arginine, glycine, cysteine, histidine, etc.) or a salt (sodium chloride, potassium chloride, calcium chloride, etc.). In some embodiments, the osmotic pressure regulator is a sugar selected from the group consisting of glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, xylitol, sorbitol (also known as sorbitol), mannitol, milibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltitol, lactitol and iso-maltulose. In some embodiments, the osmotic pressure regulator is selected from one or more of the group consisting of sucrose, trehalose, sorbitol, arginine, proline, glycine and sodium chloride. In some embodiments, the osmotic pressure regulating agent is a non-reducing disaccharide; in some embodiments, the osmotic pressure regulating agent is trehalose and / or sucrose; in some embodiments, the osmotic pressure regulating agent is sucrose.

[0184] In some embodiments, the pharmaceutical composition comprising the anti-CD79b antibody drug conjugate further comprises a solvent. Exemplarily, the solvent is selected from, but not limited to, a non-toxic physiologically acceptable liquid carrier, such as normal saline, water for injection, glucose solution (e.g., 5% glucose injection, glucose and sodium chloride injection), and the like.

[0185] <Rituximab>

[0186] In some embodiments, the immunotherapeutic agent is administered at a dose of about 1 mg / m 2 to about 1000 mg / m 2 For example, about 1 mg / m 2 , about 2.5mg / m 2 , about 5mg / m 2 , about 10mg / m 2 , about 12.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2, about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 900mg / m 2 , about 1000mg / m 2 ; or any range between these point values.

[0187] In some specific embodiments, the immunotherapeutic agent is administered at a dose of about 375 mg / m 2 .

[0188] In some embodiments, the immunotherapeutic agent is preferably administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the immunotherapeutic agent is administered once every 3 weeks.

[0189] In some embodiments, the dosing regimen of rituximab is selected from any one of the following:

[0190] (b1) The dosage of rituximab is about 1 mg / m 2 to about 1000 mg / m 2 , the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0191] (b2) The dosage of rituximab is about 10 mg / m 2 to about 1000 mg / m 2, the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0192] (b3) The dosage of rituximab is about 50 mg / m 2 to about 1000 mg / m 2 , the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0193] (b4) The dosage of rituximab is about 50 mg / m 2 to about 500 mg / m 2 , the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0194] (b5) The dosage of rituximab is about 100 mg / m 2 to about 500 mg / m 2 , the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0195] (b6) The dosage of rituximab is about 325 mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , the dosing frequency is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks;

[0196] (b7) The dosage of rituximab is about 325 mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , the frequency of administration is once every 3 weeks;

[0197] (b8) The dosage of rituximab is about 375 mg / m 2 , the dosing frequency is once every 3 weeks;

[0198] In some embodiments, in the dosing regimen described in any one of (b1) to (b6) above, the administration frequency of rituximab is once every 3 weeks.

[0199] <Gemcitabine>

[0200] In some embodiments, the dosage of gemcitabine is about 5 mg / m 2 to about 2000 mg / m 2 , for example, about 5 mg / m 2 , about 10 mg / m 2 , about 12.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , about 900mg / m 2 , about 1000mg / m 2 , about 1100mg / m 2 , about 1125mg / m 2 , about 1150mg / m 2, about 1175mg / m 2 , about 1200mg / m 2 , about 1225mg / m 2 , about 1250mg / m 2 , about 1275mg / m 2 , about 1300mg / m 2 , about 1325mg / m 2 , about 1350mg / m 2 , about 1375mg / m 2 , about 1400mg / m 2 , about 1425mg / m 2 , about 1450mg / m 2 , about 1475mg / m 2 , about 1500mg / m 2 , about 1600mg / m 2 , about 1700mg / m 2 , about 1750mg / m 2 , about 1800mg / m 2 , about 1900mg / m 2 , about 2000mg / m 2 Or any range between these point values.

[0201] In some embodiments, the dosage of gemcitabine is about 1000 mg / m 2 .

[0202] In some embodiments, the administration frequency of gemcitabine is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the administration frequency of gemcitabine is once every 3 weeks.

[0203] In some embodiments, the dosage of gemcitabine is about 5 mg / m 2 to about 2000 mg / m 2 In some specific embodiments, the dosage of gemcitabine is about 1000 mg / m 2 , gemcitabine was administered once every 3 weeks.

[0204] <Oxaliplatin>

[0205] In some embodiments, the dosage of oxaliplatin is about 1 mg / m 2 to about 500 mg / m 2 , for example, about 5 mg / m 2 , about 10 mg / m 2 , about 12.5mg / m 2, about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , about 500mg / m 2 Or any range between these point values.

[0206] In some embodiments, the dosage of oxaliplatin is about 100 mg / m 2 .

[0207] In some embodiments, oxaliplatin is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, oxaliplatin is administered once every 3 weeks.

[0208] In some embodiments, the dosage of oxaliplatin is about 1 mg / m 2 to about 500 mg / m 2 In some specific embodiments, the dosage of oxaliplatin is about 100 mg / m2 , oxaliplatin was administered once every 3 weeks.

[0209] <Cyclophosphamide>

[0210] In some embodiments, the cyclophosphamide is administered at a dose of about 1 mg / m 2 to about 1000 mg / m 2 , for example, about 1 mg / m 2 , about 2.5mg / m 2 , about 5mg / m 2 , about 10mg / m 2 , about 12.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2 , about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , about 500mg / m 2 , about 600mg / m 2 , about 700mg / m 2 , about 750mg / m 2, about 800mg / m 2 , about 900mg / m 2 , about 1000mg / m 2 ; or any range between these point values.

[0211] In some embodiments, the cyclophosphamide is administered at a dose of about 750 mg / m 2 .

[0212] In some embodiments, the cyclophosphamide is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the cyclophosphamide is administered once every 3 weeks.

[0213] In some embodiments, the cyclophosphamide is administered at a dose of about 1 mg / m 2 to about 1000 mg / m 2 In some specific embodiments, the dosage of cyclophosphamide is about 750 mg / m 2 The frequency of cyclophosphamide administration is once every 3 weeks.

[0214] <Anthracyclines>

[0215] In some embodiments, the anthracycline is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 , for example, about 5 mg / m 2 , about 10 mg / m 2 , about 12.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , about 150mg / m 2 , about 175mg / m 2, about 200mg / m 2 , about 225mg / m 2 , about 250mg / m 2 , about 275mg / m 2 , about 300mg / m 2 , about 325mg / m 2 , about 350mg / m 2 , about 375mg / m 2 , about 400mg / m 2 , about 425mg / m 2 , about 450mg / m 2 , about 475mg / m 2 , about 500mg / m 2 Or any range between these point values.

[0216] In some embodiments, the anthracycline is administered at a dose of 30-40 mg / m 2 , 30-50 mg / m 2 , 30-60 mg / m 2 In some embodiments, the anthracycline is doxorubicin, and the dosage of doxorubicin is 30-40 mg / m 2 .

[0217] In some embodiments, the anthracycline is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the anthracycline is administered once every 3 weeks.

[0218] In some embodiments, the anthracycline is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 In some specific embodiments, the dosage of the anthracycline is about 30-40 mg / m 2 , anthracyclines are administered once every 3 weeks.

[0219] <Vinca alkaloids>

[0220] In some embodiments, the vinca alkaloid drug is administered at a dose of about 0.1 mg / m 2 to about 100 mg / m 2 , for example, about 0.1 mg / m 2 , about 0.2mg / m 2 , about 0.3mg / m 2 , about 0.4mg / m 2 , about 0.5mg / m 2 , about 0.6mg / m2 , about 0.7mg / m 2 , about 0.8mg / m 2 , about 0.9mg / m 2 , about 1.0mg / m 2 , about 1.1mg / m 2 , about 1.2mg / m 2 , about 1.3mg / m 2 , about 1.4 mg / m 2 , about 1.5mg / m 2 , about 1.6mg / m 2 , about 1.7mg / m 2 , about 1.8mg / m 2 , about 1.9mg / m 2 , about 2.0mg / m 2 , about 2.1mg / m 2 , about 2.2mg / m 2 , about 2.3mg / m 2 , about 2.4mg / m 2 , about 2.5mg / m 2 , about 2.6mg / m 2 , about 2.7mg / m 2 , about 2.8mg / m 2 , about 2.9mg / m 2 , about 3.0mg / m 2 , about 3.25 mg / m 2 , about 3.5 mg / m 2 , about 3.75 mg / m 2 , about 4.0 mg / m 2 , about 4.25 mg / m 2 , about 4.5 mg / m 2 , about 4.75 mg / m 2 , about 5.0 mg / m 2 , about 5.25 mg / m 2 , about 5.5 mg / m 2 , about 5.75 mg / m 2 , about 6.0 mg / m 2 , about 6.25mg / m 2 , about 6.5 mg / m 2 , about 6.75 mg / m 2 , about 7.0 mg / m 2 , about 7.25 mg / m 2 , about 7.5 mg / m 2 , about 7.75 mg / m 2 , about 8.0 mg / m 2 , about 9.0 mg / m2 , about 10 mg / m 2 , about 12.5 mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 .

[0221] In some embodiments, the vinca alkaloid is administered at a dose of about 1.4 mg / m 2 In some embodiments, the vinca alkaloid drug is administered at a dose of no more than 2 mg. In some embodiments, the vinca alkaloid drug is doxorubicin, and the dose of doxorubicin is about 1.4 mg / m 2 In some embodiments, the dose of doxorubicin administered is no more than 2 mg.

[0222] In some embodiments, the vinca alkaloids are administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the vinca alkaloids are administered once every 3 weeks.

[0223] In some embodiments, the anthracycline is administered at a dose of about 1 mg / m 2 to about 500 mg / m 2 In some specific embodiments, the dosage of the anthracycline is about 30-40 mg / m 2 , anthracyclines are administered once every 3 weeks.

[0224] <Prednisone>

[0225] In some embodiments, the dosage of prednisone is about 1 mg / time to about 1000 mg / time, for example, about 5 mg / time, about 10 mg / time, about 12.5 mg / time, about 15 mg / time, about 17.5 mg / time, about 20 mg / time, about 25 mg / time, about 30 mg / time, about 35 mg / time, about 40 mg / time, about 45 mg / time, about 50 mg / time, about 60 mg / time, about 70 mg / time, about 75 mg / time, about 80 mg / time, about 90 mg / time, about 100 mg / time, g / time, about 125mg / time, about 150mg / time, about 175mg / time, about 200mg / time, about 225mg / time, about 250mg / time, about 275mg / time, about 300mg / time, about 325mg / time, about 350mg / time, about 375mg / time, about 400mg / time, about 425mg / time, about 450mg / time, about 475mg / time, about 500mg / time, about 510mg / time, about 520mg / time, about 530mg / time, about 540mg / time, about 550mg / time, about 560mg / time, about 580mg / time, about 590mg / time, about 600mg / time, about 610mg / time, about 620mg / time, about 630mg / time, about 640mg / time, about 650mg / time, about 660mg / time, about 680mg / time, about 690mg / time, about 700mg / time, about 710mg / time, about 720mg / time, about 730mg / time, about 740mg / time, about 750mg / time, about 760mg / time, about 780mg / time g / time, about 790 mg / time, about 800 mg / time, about 810 mg / time, about 820 mg / time, about 830 mg / time, about 840 mg / time, about 850 mg / time, about 860 mg / time, about 880 mg / time, about 890 mg / time, about 900 mg / time, about 910 mg / time, about 920 mg / time, about 930 mg / time, about 940 mg / time, about 950 mg / time, about 960 mg / time, about 980 mg / time, about 990 mg / time, and about 1000 mg / time.

[0226] In some embodiments, the dosage of prednisone is about 100 mg per administration.

[0227] In some embodiments, prednisone is administered at least once every week, at least once every two weeks, at least once every three weeks, at least once every four weeks, at least once every six weeks, or at least once every eight weeks. In some embodiments, prednisone is administered at least once every three weeks. In some embodiments, prednisone is administered three, four, or five times every three weeks. In some embodiments, prednisone is administered five times every three weeks.

[0228] In some embodiments, the dosage of prednisone is about 1 mg / time to about 1000 mg / time, and the administration frequency is 3 times, 4 times, or 5 times every 3 weeks. In some specific embodiments, the dosage of prednisone is about 100 mg / time, and the administration frequency is 5 times every 3 weeks.

[0229] <Ifosfamide>

[0230] In some embodiments, the dosage of ifosfamide is about 0.1 mg / m 2 to about 100 mg / m 2 , for example, about 0.1 mg / m 2 , about 0.5 mg / m 2 , about 0.75 mg / m 2 , about 1.0 mg / m 2 , about 1.25 mg / m 2 , about 1.5 mg / m 2 , about 1.75 mg / m 2 , about 2.0 mg / m 2 , about 2.25 mg / m 2 , about 2.5 mg / m 2 , about 2.75 mg / m 2 , about 3.0 mg / m 2 , about 3.25 mg / m 2 , about 3.5 mg / m 2 , about 3.75 mg / m 2 , about 4.0 mg / m 2 , about 4.25 mg / m 2 , about 4.5 mg / m 2 , about 4.75 mg / m 2 , about 5.0 mg / m 2 , about 5.25 mg / m 2 , about 5.5 mg / m 2 , about 5.75 mg / m 2 , about 6.0 mg / m 2 , about 6.25mg / m 2 , about 6.5 mg / m 2 , about 6.75 mg / m 2 , about 7.0 mg / m 2 , about 7.25 mg / m 2 , about 7.5 mg / m 2 , about 7.75 mg / m 2 , about 8.0 mg / m 2 , about 9.0 mg / m 2 , about 10 mg / m 2 , about 12.5 mg / m2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 25mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 75mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , about 100mg / m 2 .

[0231] In some embodiments, the dosage of ifosfamide is about 5 mg / m 2 .

[0232] In some embodiments, the administration frequency of ifosfamide is once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the administration frequency of ifosfamide is once every 3 weeks.

[0233] In some embodiments, the dosage of ifosfamide is about 0.1 mg / m 2 to about 100 mg / m 2 In some specific embodiments, the dosage of ifosfamide is about 5 mg / m 2 , ifosfamide was administered once every 3 weeks.

[0234] <Carboplatin>

[0235] In some embodiments, the dosage of carboplatin is about 1 mg to about 2000 mg, for example, about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg. g, about 500 mg, about 600 mg, about 700 mg, about 750 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1900 mg, about 2000 mg, or any range therebetween.

[0236] In some embodiments, the dosage of carboplatin administered is ≤800 mg; for example, about 5 mg, about 10 mg, about 12.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 40 0mg, about 425mg, about 450mg, about 475mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 780mg, about 790mg, about 800mg.

[0237] In some embodiments, the carboplatin is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks. In some specific embodiments, the carboplatin is administered once every 3 weeks.

[0238] In some embodiments, the dosage of carboplatin is about 1 mg to about 2000 mg, and the administration frequency is once every 3 weeks. In some specific embodiments, the dosage of carboplatin is ≤800 mg, and the administration frequency is once every 3 weeks.

[0239] <Etoposide>

[0240] In some embodiments, the etoposide is administered at a dose of about 1 mg / m 2 / time to about 500mg / m 2 / time, for example, about 5 mg / m 2 / time, about 10mg / m 2 / time, about 12.5mg / m 2 / time, about 15mg / m 2 / time, about 17.5mg / m 2 / time, about 20mg / m 2 / time, about 25mg / m 2 / time, about 30mg / m 2 / time, about 35mg / m 2 / time, about 40mg / m 2 / time, about 45mg / m 2 / time, about 50mg / m 2 / time, about 60mg / m 2 / time, about 70mg / m 2 / time, about 75mg / m 2 / time, about 80mg / m 2 / time, about 90mg / m 2 / time, about 100mg / m 2 / time, about 125mg / m 2 / time, about 150mg / m 2 / time, about 175mg / m 2 / time, about 200mg / m 2 / time, about 225mg / m 2 / time, about 250mg / m 2 / time, about 275mg / m 2 / time, about 300mg / m 2 / time, about 325mg / m 2 / time, about 350mg / m 2 / time, about 375mg / m 2 / time, about 400mg / m 2 / time, about 425mg / m 2 / time, about 450mg / m 2 / time, about 475mg / m 2 / time, about 500mg / m 2 / times or any range between these point values.

[0241] In some embodiments, the dosage of etoposide is 30-40 mg / m 2 , 30-50 mg / m 2 , 30-60 mg / m 2 In some embodiments, the etoposide is doxorubicin, and the dosage of doxorubicin is 30-40 mg / m 2 .

[0242] In some embodiments, etoposide is administered at least once every week, at least once every two weeks, at least once every three weeks, at least once every four weeks, at least once every six weeks, or at least once every eight weeks. In some embodiments, etoposide is administered at least once every three weeks. In some embodiments, etoposide is administered three times, four times, or five times every three weeks. In some embodiments, etoposide is administered three times every three weeks.

[0243] In some embodiments, the etoposide is administered at a dose of about 1 mg / m 2 / time to about 500mg / m 2 / time, the administration frequency is 2 times, 3 times or 4 times every 3 weeks. In some specific embodiments, the dosage of etoposide is about 100 mg / m 2 / time, and the administration frequency of etoposide is 3 times every 3 weeks.

[0244] In some embodiments, as in any of the foregoing methods or uses, wherein the subject administered the anti-CD79b antibody drug conjugate has reduced clinical adverse reactions. In some embodiments, the clinical adverse reaction is peripheral nervous system toxicity. In some specific embodiments, the subject administered the anti-CD79b antibody drug conjugate of the present disclosure has reduced clinical adverse reactions compared to subjects administered vepotuzumab. In some specific embodiments, the subject administered the anti-CD79b antibody drug conjugate of the present disclosure has reduced peripheral nervous system toxicity compared to subjects administered vepotuzumab.

[0245] In some embodiments, the anti-CD79b antibody-drug conjugates disclosed herein, administered alone or in combination with immunotherapeutic agents or chemotherapeutic agents to patients with B-cell lymphoma, can achieve sustained remission in patients and exhibit potent anti-tumor activity. In addition, the single-agent or combined treatment regimens disclosed herein have low neurotoxicity and can improve the quality of life of patients, thereby providing a safe and effective clinical treatment regimen for patients with B-cell lymphoma.

[0246] the term

[0247] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0248] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[0249] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0250] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each instance of a number or numerical range preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0251] The term "and / or," such as "X and / or Y," should be understood to mean "X and Y" or "X or Y" and should be used to provide clear support for both meanings or either meaning.

[0252] In some embodiments, the present disclosure defines:

[0253] Antibody-drug conjugates (ADCs) link antibodies or antibody fragments to biologically active cytotoxins or small molecule drugs with cell-killing activity via a stable chemical linker. These ADCs leverage the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficacy of the cytotoxin, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, ADCs can precisely bind to tumor cells while minimizing their effects on normal cells.

[0254] An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate shows no significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often change the chemical structure of a protein include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (assessed by methods such as peptide mapping in combination with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (assessed by measuring isoaspartate content, peptide mapping, etc.).

[0255] An antibody drug conjugate "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical formulation is prepared.

[0256] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0257] As used herein, the term "antibody" is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. An antibody may refer to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant regions of immunoglobulins' heavy chains differ, resulting in different antigenicity. Accordingly, immunoglobulins can be divided into five classes, or so-called immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Igs of the same class can be further divided into different subclasses based on differences in the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five classes of Ig can have either kappa or lambda chains. The approximately 110 amino acids near the N-terminus of both the heavy and light chains of antibodies vary greatly in sequence and constitute the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and constitute the constant region (C region). The variable region consists of three hypervariable regions (CDRs) and four framework regions (FRs) whose sequences are relatively conserved. These three hypervariable regions determine the specificity of the antibody and are also known as complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.

[0258] For the determination or definition of CDRs, the definitive delineation of CDRs and the identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be accomplished by any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0259] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, for example: "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), "Chothia" numbering convention, "ABM" numbering convention, "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001) and ImMunoGenTics (IMGT) numbering convention (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9: 2278), etc.

[0260] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retains the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Exemplary binding fragments encompassed by the term "antigen-binding fragment" include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a dsFv, a stable antigen-binding fragment formed by an interchain disulfide bond between VH and VL; (vi) scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.

[0261] The terms "specific binding", "selective binding", "selectively binds" and "specifically binds" refer to the binding of an antibody to a predetermined epitope on an antigen. -8 M, for example, less than approximately 10 -9 M, 10 -10 M, 10 -11 Binds with an affinity (KD) of M or less.

[0262] The term "KD" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. Typically, the antibodies of the present disclosure exhibit dissociation equilibrium constants of less than about 10-7 M, for example, less than about 10-7 M. -8 M, 10 -9 M or 10 -10 The IL-5 binding protein binds to IL-5 with a dissociation equilibrium constant (KD) of M or less, e.g., as determined using surface plasmon resonance (SPR) technology in a BIACORE instrument.

[0263] "Homology" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if every position in two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100. For example, if 6 out of 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous; if 95 out of 100 positions in the two sequences match or are homologous, then the two sequences are 95% homologous. Typically, when aligning two sequences, the comparison is performed to give the maximum percentage homology. For example, the comparison can be performed using the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm commonly used for sequence analysis: BLAST ALGORITHMS: Altschul, SF et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al., (1993) Nature Genet. 3: 266-272; Madden, TL et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J. et al., (1997) Genome Res. 7: 649-656. Other conventional BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those skilled in the art.

[0264] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ or a biological fluid, refers to the contacting of an exogenous drug, therapeutic agent, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. "Administering" and "treating" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0265] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0266] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0267] The terms "subject" and "patient" refer to mammals, particularly primates, and especially humans.

[0268] The "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of an anti-CD79b antibody drug conjugate and at least one dose of an immunotherapeutic agent and / or a chemotherapeutic agent within a certain time limit, wherein both drugs show a pharmacological effect. The time limit can be within a dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, or within 12 hours. Anti-CD79b antibody drug conjugates and other types of drugs can be administered simultaneously or sequentially. This period includes such treatments, in which anti-CD79b antibody drug conjugates and other types of drugs are administered by the same route of administration or different routes of administration. The combined mode of administration described in the present disclosure is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0269] In the anti-CD79b antibody drug conjugates of the present disclosure, "n" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody, which is the average number of drugs per ADC molecule after the coupling reaction is identified by hydrophobic chromatography (HIC) mass spectrometry.

[0270] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity. DETAILED DESCRIPTION

[0271] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0272] Example 1. Preparation of anti-CD79b antibody drug conjugates

[0273] The anti-CD79b antibody drug conjugate is ADC-6 prepared in Example 3-3 of WO2023143347A1 (incorporated herein by reference in its entirety), and has the following structure:

[0274] RP-HPLC calculated average value: n=3.46.

[0275] The anti-CD79b antibody is derived from antibody hAb015-10 of WO2022022508A1 (incorporated herein by reference in its entirety), and its CDR sequences are shown in Table 1. The full length of the heavy chain of antibody hAb015-10 is shown in SEQ ID NO: 12, and the full length of the light chain is shown in SEQ ID NO: 13.

[0276] Example 2. Phase I clinical study of the safety, tolerability, pharmacokinetics and efficacy of ADC-6 for injection in patients with B-cell lymphoma

[0277] 1. Trial Drug

[0278] 1) ADC-6 prepared in Example 1. Sterile powder for injection, specification: 70 mg / bottle.

[0279] 2. Enrollment of subjects

[0280] 1) Age ≥ 18 years old, regardless of gender;

[0281] 2) ECOG performance status of 0 or 1;

[0282] 3) Expected survival ≥ 12 weeks;

[0283] 4) B-cell lymphoma confirmed by cytology or histology;

[0284] 5) Patients who have received ≥1 line of standard anti-tumor treatment and have not achieved remission after the most recent treatment or have experienced disease progression after treatment (for FL, there must be an indication for treatment); if the standard treatment includes CD20-targeted therapy, the patient must have previously received adequate treatment containing rituximab or other CD20-targeted drugs or have experienced disease progression or intolerance during treatment; in addition, patients with MCL, CLL / SLL, or WM must have received at least 2 lines of treatment in the past, including BTK inhibitors.

[0285] 6) DLBCL subjects in the efficacy expansion phase are required to have received ≥2 lines of systemic anti-tumor therapy in the past;

[0286] 7) Patients with measurable lesions (for lymphoma, the long diameter of the lymph node lesions must be >1.5 cm or the long diameter of the extranodal lesions must be >1.0 cm; this requirement is not mandatory for single-drug dose escalation studies).

[0287] 3. Clinical plan

[0288] The starting dose of ADC-6 is 0.1 mg / kg, and 11 dose groups are preset (0.1 mg / kg, 0.3 mg / kg, 0.6 mg / kg, 1.2 mg / kg, 1.8 mg / kg, 2.7 mg / kg, 3.6 mg / kg, 4.8 mg / kg, 6.4 mg / kg, 8.0 mg / kg, 10 mg / kg); it is administered by intravenous drip once every 3 weeks (Q3W), with 21 days as a treatment cycle, and the first cycle (21 days) is used as the DLT observation.

[0289] 4. Results

[0290] 4.1 The main adverse events (AEs) were hematological toxicity, abnormal laboratory test values, and gastrointestinal reactions, most of which were grade 1-2. Adverse events (TEAEs) occurring in ≥20% of patients during treatment were: decreased neutrophil count, decreased white blood cell count, nausea, vomiting, decreased platelet count, increased blood bilirubin, increased aspartate aminotransferase, COVID-19, and increased alanine aminotransferase. Grade ≥3 TEAEs occurring in ≥2 cases were: decreased neutrophil count (34.7%), decreased white blood cell count (20.4%), COVID-19 pneumonia (12.2%), progressive tumor (12.2%), infectious pneumonia (10.2%), anemia (10.2%), decreased lymphocyte count (8.2%), decreased platelet count (8.2%), and bacterial pneumonia (6.1%). Among 27 efficacy-evaluable DLBCL subjects (7 at 1.8 mg / kg, 7 at 2.7 mg / kg, and 9 at 3.6 mg / kg; all previously treated with ≥1 line of standard therapy), the overall ORR (objective response rate) was 59.3% (16 / 27) and the CRR (complete response rate) was 18.5% (5 / 27).

[0291] From the above results, it can be seen that ADC-6 showed preliminary efficacy in the treatment of DLBCL in the Phase I study, with good safety and no reported peripheral neurotoxicity, and has clinical potential for further development of combination treatment options.

[0292] Example 3. Phase I clinical study of the safety, tolerability, pharmacokinetics and efficacy of ADC-6 for injection in patients with B-cell lymphoma

[0293] 1. Research Methods

[0294] The study subjects were patients with histologically confirmed B-NHL who had received ≥1 prior anticancer therapy but had an inadequate response or disease progression. The dose-escalation (D-ESC) portion initially began with accelerated infusions of 0.1 and 0.3 mg / kg, followed by a switch to the i3+3 regimen, with the dose increasing from 0.6 mg / kg (q3w, intravenous).

[0295] In the dose expansion (D-EXP) portion, additional patients were enrolled at the selected dose (approximately 10-12 patients per dose level). The primary objectives were to evaluate the safety and tolerability of ADC-6 and to determine the RP2D.

[0296] 2. Test results

[0297] 2.1. As of November 7, 2023, a total of 49 patients were enrolled (1, 1, 7, 3, 13, 13 and 11 patients in the 0.1, 0.3, 0.6, 1.2, 1.8, 2.7 and 3.6 mg / kg dose groups, respectively), including 33 patients with diffuse large B-cell lymphoma (DLBCL), 12 patients with follicular lymphoma (FL) and 4 patients with marginal zone lymphoma (MZL). The median number of previous treatments received by patients was 2 (ranging from 1 to 9). Overall, 20 patients (40.8%) experienced grade ≥3 treatment-related adverse events, of which the most common adverse event (≥20%) was decreased neutrophil count.

[0298] Forty-one patients with baseline target lesions underwent at least one post-baseline assessment; the ORR was 56.1% (95% CI, 39.8-71.5), with a 6-month DoR of 62.7% (95% CI, 26.7-84.8). By subtype, the ORR was 51.9% in patients with DLBCL (57.1% and 77.8% in the 2.7 and 3.6 mg / kg groups, respectively), 63.6% in patients with FL, and 66.7% in patients with MZL (Table). The mean half-life of the conjugated antibody ranged from 4.7 to 5.3 days in the 1.8-3.6 mg / kg groups, with a volume of distribution close to that of human plasma. Exposure to free toxin in plasma was low, with a toxin / conjugated antibody molar ratio of less than 1%, and no accumulation was observed.

[0299] Table 2. Efficacy results of ADC-6 in treating cancer patients

[0300] Data are shown as n(%) or % (95% CI).

[0301] 2.2. As of November 19, 2024, 33 patients (67.3%) had experienced Grade ≥3 TEAEs, of which the most common adverse event (≥20%) was decreased neutrophil count. In 49 patients (FAS), ADC-6 monotherapy achieved an ORR of 51.0% (95% CI: 36.34, 65.58), a CRR of 10.2% (95% CI: 3.40, 22.23), an mPFS of 6.7 months [3.02, NR], and an mDOR of NR [5.19, NR]. In 33 patients with relapsed or refractory DLBCL (FAS), the ORR was 48.5% (95% CI: 30.80, 66.46), the CRR was 15.2% (95% CI: 5.11, 31.90), the mPFS was 4.3 months [1.41, NR], and the mDOR was 10.4 months [4.21, NR]. In the 1.8-3.6 mg / kg groups, the mean half-life of the conjugated antibody was 4.7-5.3 days, and the volume of distribution was close to that of human plasma. Exposure to free toxin in plasma was low, with a toxin / conjugated antibody molar ratio of less than 1%, and no accumulation was observed.

[0302] Table 3. Efficacy results of ADC-6 in treating cancer patients [1] Estimated using the Clopper-Pearson method. [2] Estimated using the Brookmeyer and Crowley method. Data are presented as n(%) or % (95% CI).

[0303] Example 4. Phase IB / II Study of ADC-6 Combination Therapy for Injection in B-Cell Lymphoma

[0304] 1. Trial Drug

[0305] ADC-6 prepared in Example 1.

[0306] Rituximab injection.

[0307] Gemcitabine hydrochloride for injection.

[0308] Oxaliplatin for injection.

[0309] Ifosfamide for injection

[0310] Carboplatin for injection

[0311] Etoposide soft capsules

[0312] Cyclophosphamide for injection

[0313] Doxorubicin liposome injection (or other anthracycline of the investigator's choice)

[0314] Vincristine sulfate for injection (or other vinca alkaloids of the investigator's choice)

[0315] Prednisone acetate tablets

[0316] 2. Enrollment of subjects

[0317] 2.1 Subjects must meet all of the following criteria to be included in this study:

[0318] 1. According to the 2016 WHO Classification of Lymphoid Tumors, patients are diagnosed with diffuse large B-cell lymphoma (DLBCL), including primary DLBCL and DLBCL transformed from indolent lymphoma;

[0319] 2. The subject's previous systemic anti-tumor treatment should meet the following requirements:

[0320] Phase Ib dose escalation, Phase Ib dose expansion, relapsed / refractory cohort, and Phase II subjects must have received ≥ 1 line of systemic anti-cancer therapy and have not achieved remission or experienced disease progression after the last line of therapy:

[0321] Relapse: Remission during treatment, but relapse more than 6 months after treatment completion;

[0322] Refractory: No significant therapeutic effect during treatment, or relapse within 6 months after treatment;

[0323] Participants in the Phase Ib treatment-naive cohort had not previously received systemic anti-tumor therapy for lymphoma;

[0324] 3. Measurable lesions (lymphoma requires the long diameter of lymph node lesions to be greater than 1.5 cm or the long diameter of extranodal lesions to be greater than 1.0 cm);

[0325] 4. The expected survival period is at least 3 months;

[0326] 5. Age ≥ 18 years old;

[0327] 6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;

[0328] 2.2 Subjects who meet any of the following criteria will not be allowed to participate in this study:

[0329] In the Phase Ib dose-escalation / dose-expansion phase, patients receiving the R-Gemox regimen and those in Phase II Cohort 1 had previously received gemcitabine. In the Phase Ib dose-escalation / dose-expansion phase, patients receiving the R-ICE / R-IC regimen and those in Phase II Cohorts 2a / 2b had previously received ifosfamide.

[0330] 3. Dosage regimen

[0331] 3.1 Dose escalation / expansion phase (Phase Ib):

[0332] 3.1.1 Dose-Escalation Phase: ADC-6 will be administered in a dose-escalating manner, while the immunochemotherapy regimen will be fixed-dose. Investigators will select either the R-Gemox regimen (for patients not previously treated with gemcitabine) or the R-ICE / R-IC regimen (for patients not previously treated with ifosfamide) based on the subject's prior treatment history. The starting dose of ADC-6 is 2.7 mg / kg, with at least two dose cohorts (2.7 mg / kg and 3.6 mg / kg) planned. Additional dose cohorts may be added based on the results of dose exploration with ADC-6 monotherapy or combination therapy.

[0333] 3.1.2 Dose expansion includes relapsed and refractory cohorts and first-line treatment cohorts.

[0334] Relapsed / Refractory Cohort: ADC-6 treatment will continue until disease progression, the subject requests to withdraw from the study, or intolerable toxicity occurs, whichever occurs first; immunochemotherapy will continue until disease progression, the subject requests to withdraw from the study, or intolerable toxicity occurs, or 6-8 treatment cycles (R-Gemox regimen) are completed, or 4-6 treatment cycles (R-ICE / RIC regimen) are completed, whichever occurs first.

[0335] Treatment-naive cohort: The dose for this cohort will be determined based on the actual dose-finding results of the relapsed / refractory cohort. This cohort will enroll subjects who have not previously received lymphoma-related systemic anti-tumor therapy. Subjects will receive ADC-6 combined with six cycles of R-CHOP and two additional cycles of R.

[0336] 3.2 Efficacy expansion stage (Phase II):

[0337] Cohort 1: Patients with relapsed or refractory DLBCL who have received ≥1 line of systemic anti-cancer therapy and have not received gemcitabine will be enrolled. Subjects will receive ADC-6 combined with 6-8 cycles of R-GemOx.

[0338] Cohort 2a / 2b: Enrolled patients with relapsed or refractory DLBCL who have received ≥1 line of systemic anti-cancer therapy and have not received ifosfamide. Subjects will receive ADC-6 combined with 4-6 cycles of R-ICE (Cohort 2a) or R-IC (Cohort 2b).

[0339] The total ADC-6 dosage is calculated based on the subject's pre-dose weight and administered via intravenous drip; administration is once every three weeks (Q3W), with each three-week treatment cycle comprising one treatment cycle. For other drug infusion requirements, refer to the relevant drug instructions and clinical practice. The specific dosing regimen is shown in Tables 3-6 below:

[0340] Table 4. Phase Ib dose escalation / expansion phase combined with R-Gemox regimen and Phase II cohort 1 medication schedule

[0341] Table 5. Medication schedule for the Phase Ib treatment-naive cohort

[0342] *The table lists the recommended anthracyclines and vinca alkaloids and their corresponding doses for the R-CHOP regimen. If necessary, the investigator may select alternative chemotherapy drugs of the same class with comparable efficacy based on the institution's medical practices and guidelines, in consultation with the sponsor. These include: epirubicin instead of liposomal doxorubicin, and vindesine instead of vincristine.

[0343] Table 6. Phase Ib dose escalation / expansion phase combined with R-ICE / R-IC regimen and Phase II cohort 2a / 2b medication schedule

[0344] 4. Results Evaluation

[0345] 4.1 Efficacy Evaluation: Efficacy was evaluated using the 2014 Lugano lymphoma CT-based efficacy evaluation criteria. Efficacy analysis included complete response rate (CRR), objective response rate (ORR), disease control rate (DCR), DoR, PFS, and OS.

[0346] 4.2 Safety evaluation: Safety evaluation was performed using the NCI-CTCAE 5.0 standard.

[0347] 5. Research Results

[0348] As of November 19, 2024, a total of 37 subjects were enrolled in the ADC-6 1.8 mg / kg combination with R-GemOx trial. The median number of lines of treatment was 1 (range: 1-3). 70.3% of the subjects had Lugano stage III-IV disease, 62.2% were refractory to the last line of treatment, and 56.8% were primary refractory. The baseline conditions are detailed in Table 1.

[0349] Table 7. Baseline characteristics of patients receiving ADC-6 (1.8 mg / kg) combined with R-GemOx *The best response at the end of the treatment period is SD / PD, or PR / CR / NE with progression during treatment or within 6 months after the end of treatment.

[0350] Treatment results showed that among 37 patients with DLBCL who received ADC-6 (1.8 mg / kg) combined with R-GemOx, 19 achieved complete remission (CR) and 8 achieved partial remission, with an ORR of 73.0% (27 / 37) and a CRR of 51.4% (19 / 37). Of the 27 subjects who achieved remission, 23 (85.2%) achieved remission at the time of the first efficacy assessment (end of C2, every 3 weeks as a cycle); and continued deepening of remission, CR, usually occurred at the second treatment assessment (end of C4), and all patients who achieved remission were in sustained remission. The above efficacy data are preliminary results, and the trial is still ongoing. No DLTs occurred among the 37 subjects. TEAEs occurring in ≥20% of patients were: decreased platelet count, anemia, increased aspartate aminotransferase, decreased white blood cell count, decreased neutrophil count, increased alanine aminotransferase, hypokalemia, nausea, hyperuricemia, vomiting, cough, increased blood alkaline phosphatase, and decreased lymphocyte count. Grade ≥3 TEAEs occurring in ≥2 patients were: decreased platelet count (29.7%), decreased neutrophil count (21.6%), decreased white blood cell count (24.3%), anemia (13.5%), decreased lymphocyte count (10.8%), and hypokalemia (5.4%).

[0351] These results demonstrate that the ADC-6 and R-GemOx combination therapy exhibits potent anti-tumor activity and rapid, durable clinical responses. Furthermore, no patients reported peripheral neurotoxicity during treatment, demonstrating a favorable safety profile and ensuring safe and effective clinical benefits for patients.

Claims

1. Use of an anti-CD79b antibody-drug conjugate in combination with (1) an immunotherapeutic agent and / or (2) a chemotherapeutic agent in the preparation of a medicament for treating tumors; in, The anti-CD79b antibody drug conjugate has a structure as shown in the following formula: wherein Pc is an anti-CD79b antibody, and n is an integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 6; Preferably, the tumor is a B-cell lymphoma.

2. The use according to claim 1, wherein The subject administered with the anti-CD79b antibody drug conjugate has reduced clinical adverse reactions, preferably peripheral nervous system toxicity.

3. The use according to claim 1 or 2, wherein the anti-CD79b antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (1) The VH comprises HCDR1, HCDR2 and HCDR3 of the sequence shown in SEQ ID NO: 3, and the VL comprises LCDR1, LCDR2 and LCDR3 of the sequence shown in SEQ ID NO: 4; (2) the VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 11, SEQ ID NO: 6 and SEQ ID NO: 7, respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively; or, (3) The VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 5, SEQ ID NO: 6 and SEQ ID NO: 7, respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 8, SEQ ID NO: 9 and SEQ ID NO: 10, respectively.

4. The use according to any one of claims 1 to 3, wherein The anti-CD79b antibody is a murine antibody, a chimeric antibody, a humanized antibody or a human antibody; Preferably, the VH of the anti-CD79b antibody comprises a sequence as shown in SEQ ID NO: 3, or a sequence having at least 80% or at least 90% homology thereto, and the VL of the anti-CD79b antibody comprises a sequence as shown in SEQ ID NO: 4, or a sequence having at least 80% or at least 90% homology thereto; More preferably, the heavy chain of the anti-CD79b antibody comprises a sequence shown in SEQ ID NO: 12, or a sequence having at least 80% or at least 90% homology thereto, and the light chain of the anti-CD79b antibody comprises a sequence shown in SEQ ID NO: 13, or a sequence having at least 80% or at least 90% homology thereto.

5. The use according to any one of claims 1 to 4, wherein The anti-CD79b antibody drug conjugate is administered at a dosage of about 0.1 mg / kg to about 20 mg / kg, preferably about 1.0 mg / kg to about 10 mg / kg, preferably about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg; more preferably about 1.8 mg / kg, about 2.7 mg / kg, or about 3.6 mg / kg; and / or, The anti-CD79b antibody drug conjugate is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks.

6. The use according to any one of claims 1 to 5, wherein The immunotherapeutic agent is an anti-CD20 antibody, preferably rituximab; The dosage of the immunotherapeutic agent is preferably about 1 mg / m 2 to about 1000 mg / m 2 , more preferably about 375 mg / m 2 The administration frequency of the immunotherapy agent is preferably once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks or once every eight weeks.

7. The use according to any one of claims 1 to 6, wherein The chemotherapeutic agent is selected from any one or any combination of the following: gemcitabine, platinum drugs (e.g., oxaliplatin, carboplatin), cyclophosphamide, anthracycline drugs (e.g., doxorubicin), vinca alkaloid drugs (e.g., vincristine), prednisone, ifosfamide, etoposide; Preferably, the chemotherapeutic agent comprises any one of the following combinations: (a) Gemcitabine and oxaliplatin; (b) cyclophosphamide, anthracyclines (e.g., doxorubicin), vinca alkaloids (e.g., vincristine), and prednisone; (c) ifosfamide, carboplatin, and etoposide; (d) ifosfamide and carboplatin; Preferably, the dosage of gemcitabine is about 5 mg / m 2 to about 2000 mg / m 2 , more preferably about 1000 mg / m 2 ; The dosage of oxaliplatin is about 1 mg / m 2 to about 500 mg / m 2 , more preferably about 100 mg / m 2 ; The dosage of cyclophosphamide is about 1 mg / m 2 to about 1000 mg / m 2 , more preferably about 750 mg / m 2 ; The anthracycline drug is about 1 mg / m 2 to about 500 mg / m 2 , more preferably 30-40 mg / m 2 ; The dosage of the vinca alkaloid drug is about 0.1 mg / m 2 to about 100 mg / m 2 , more preferably about 1.4 mg / m 2 , more preferably not more than 2 mg; The dosage of prednisone is about 1 mg / time to about 1000 mg / time, more preferably about 100 mg / time; The dosage of ifosfamide is about 0.1 mg / m 2 to about 100 mg / m 2 , more preferably about 5 mg / m 2 ; The dosage of carboplatin is about 1 mg to about 2000 mg, more preferably ≤ 800 mg; The dosage of etoposide is about 1 mg / m 2 to about 500 mg / m 2 / time, more preferably about 100 mg / m 2 / Second-rate; The chemotherapy agent is preferably administered every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks or every 8 weeks; More preferably, the administration frequency of gemcitabine, oxaliplatin, cyclophosphamide, anthracyclines, vinca alkaloids, ifosfamide, and carboplatin is once every 2 weeks, once every 3 weeks, or once every 4 weeks, the administration frequency of prednisone is 3 times, 4 times, or 5 times every 3 weeks, and the administration frequency of etoposide is 3 times or 4 times every 3 weeks.

8. The use according to any one of claims 1 to 7, wherein The (1) immunotherapeutic agent and / or (2) chemotherapeutic agent is selected from any combination of the following: (a) Rituximab, gemcitabine, and oxaliplatin; (b) rituximab, cyclophosphamide, anthracyclines (e.g., doxorubicin), vinca alkaloids (e.g., vincristine), and prednisone; (c) rituximab, ifosfamide, carboplatin, and etoposide; (d) Rituximab, ifosfamide, and carboplatin.

9. The use according to any one of claims 1 to 8, wherein A combination of any of the following drugs is given every 2 weeks, every 3 weeks, or every 4 weeks: (1) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 5 mg / m 2 to about 2000 mg / m 2 of gemcitabine, and approximately 1-500 mg / m 2 Oxaliplatin; (2) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 1 mg / m 2 to about 1000 mg / m 2 Cyclophosphamide, about 1 mg / m 2 to about 500 mg / m 2 Anthracycline drugs, about 0.1mg / m 2 to about 100 mg / m 2 of vinca alkaloids, and about 1 mg / dose to about 1000 mg / dose of prednisone; (3) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 0.1 mg / m 2 to about 100 mg / m 2 Ifosfamide, about 1 mg to about 2000 mg of carboplatin, and about 1 mg / m 2 / time to about 500mg / m 2 / times etoposide; (4) about 1.0 mg / kg to about 10 mg / kg of an anti-CD79b antibody drug conjugate, about 1 mg / m 2 to about 1000 mg / m 2 Rituximab, approximately 0.1 mg / m 2 to about 100 mg / m 2 of ifosfamide, and about 1 mg to about 2000 mg of carboplatin; (5) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 1000 mg / m 2 of gemcitabine, and approximately 100 mg / m 2 Oxaliplatin; (6) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 750 mg / m 2 Cyclophosphamide, about 30-40 mg / m 2 Anthracyclines (eg, doxorubicin), approximately 1.4 mg / m 2 of a vinca alkaloid (e.g., vincristine) and about 100 mg of prednisone; (7) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 5 mg / m 2 Ifosfamide, ≤800 mg of carboplatin, and approximately 100 mg / m 2 of etoposide; (8) about 0.1 mg / kg, about 0.3 mg / kg, about 0.6 mg / kg, about 1.2 mg / kg, about 1.8 mg / kg, about 2.7 mg / kg, about 3.6 mg / kg, about 4.8 mg / kg, about 6.4 mg / kg, about 8.0 mg / kg, about 10 mg / kg of anti-CD79b antibody drug conjugate, about 375 mg / kg 2 Rituximab, approximately 5 mg / m 2 Ifosfamide and ≤800 mg of carboplatin.

10. The use according to claim 9, wherein The rituximab is administered before the anti-CD79b antibody drug conjugate, preferably: Rituximab was administered on day 1 of each dosing cycle, and anti-CD79b antibody-drug conjugate, gemcitabine, and oxaliplatin were administered on day 2; Rituximab was administered on day 1 of each dosing cycle, anti-CD79b antibody-drug conjugate, cyclophosphamide, anthracycline, and vinca alkaloids were administered on day 2, and prednisone was administered on days 2, 3, 4, 5, and 6, respectively; Rituximab is administered on day 1 of each dosing cycle, anti-CD79b antibody-drug conjugate is administered on day 2, ifosfamide and carboplatin are administered on day 3, and etoposide is administered on days 2, 3, and 4, respectively; or Rituximab was administered on day 1 of each dosing cycle, anti-CD79b antibody-drug conjugate was administered on day 2, and ifosfamide and carboplatin were administered on day 3.

11. The use according to any one of claims 1 to 10, wherein The B cell lymphoma is diffuse large B cell lymphoma, follicular lymphoma and marginal zone lymphoma; preferably, the diffuse large B cell lymphoma is selected from relapsed, refractory or previously untreated diffuse large B cell lymphoma.

12. The use according to any one of claims 1 to 11, wherein The subject with the tumor has previously received at least one line of anti-tumor treatment, preferably has previously received at least one line of anti-tumor treatment and has not achieved remission after the last line of treatment or has experienced disease progression after treatment; Preferably, the subject is administered an anti-CD79b antibody drug conjugate, rituximab, gemcitabine and oxaliplatin, and has not previously received gemcitabine treatment; or, The subject is administered an anti-CD79b antibody drug conjugate, ifosfamide, and carboplatin and has not previously received ifosfamide treatment; or The subject was administered an anti-CD79b antibody drug conjugate, etoposide, ifosfamide, and carboplatin and had not previously received ifosfamide treatment.

13. The use according to any one of claims 1 to 12, wherein The subject having the tumor has a Lugano stage I-II, or III-IV; and / or an IPI score of 0-1, 2, 3, or 4-5.

14. A pharmaceutical composition comprising a) an anti-CD79b antibody-drug conjugate, and b) an immunotherapeutic agent and / or a chemotherapeutic agent; the anti-CD79b antibody-drug conjugate has a structure as shown in the following formula: in, Pc is an anti-CD79b antibody, n is an integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 6; Preferably, the anti-CD79b antibody drug conjugate, immunotherapeutic agent, and chemotherapeutic agent are defined as any one of claims 1 to 10, respectively; Preferably, the pharmaceutical composition is used to treat a subject suffering from a tumor, preferably a B-cell lymphoma, more preferably as defined in any one of claims 11-13.

15. A method for treating a tumor, comprising administering a therapeutically effective amount of an anti-CD79b antibody drug conjugate to a subject in need thereof, The anti-CD79b antibody drug conjugate is administered at a dosage of about 0.1 mg / kg to about 20 mg / kg, preferably about 1.0 mg / kg to about 10 mg / kg; The anti-CD79b antibody drug conjugate has a structure as shown in the following formula: in, Pc is an anti-CD79b antibody, n is an integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 6; the tumor is preferably a B-cell lymphoma, more preferably as defined in any one of claims 11 to 13; Preferably, the method further comprises administering an immunotherapeutic agent and / or a chemotherapeutic agent; Preferably, the anti-CD79b antibody drug conjugate, immunotherapeutic agent, and chemotherapeutic agent are defined as any one of claims 1 to 10, respectively.

16. A method for reducing adverse reactions caused by an anti-CD79b antibody-drug conjugate in a subject, comprising administering to a subject in need thereof an antibody-drug conjugate having the structure shown below: in, Pc is an anti-CD79b antibody, n is an integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 6; Preferably, the method further comprises administering an immunotherapeutic agent and / or a chemotherapeutic agent; Preferably, the adverse reaction is neurotoxicity, more preferably peripheral neurotoxicity (PN); Preferably, the subject is a tumor patient, and the tumor is preferably a B-cell lymphoma, more preferably as defined in any one of claims 11 to 13; Preferably, the anti-CD79b antibody drug conjugate, immunotherapeutic agent, and chemotherapeutic agent are defined as any one of claims 1 to 10, respectively.