Application of anti-CD20 antibody drug conjugate in preparation of drug for treating non-Hodgkin lymphoma

Abstract

The invention relates to an application of an anti-CD20 antibody drug conjugate in preparation of a drug for treating NHL. The drug has a good clinical curative effect and safety in treatment of recurrent or refractory NHL subjected to at least two standard treatments.

Description

Use of anti-CD20 antibody-drug conjugates in the preparation of drugs for treating non-Hodgkin's lymphoma

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the priority benefit of Chinese invention patent application No. CN202310223225.2 filed on March 9, 2023, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The present invention relates to the field of pharmaceutical technology, and in particular to use of an anti-CD20 antibody-drug conjugate in preparing a drug for treating non-Hodgkin's lymphoma. Background Art

[0004] Non-Hodgkin lymphoma (NHL) is the seventh most common cancer type worldwide, accounting for approximately 4% to 5% of new cancer cases and 3% to 4% of cancer-related deaths, affecting approximately 1.5 million people worldwide. NHL is a collective term for a group of malignant proliferative disorders of the lymphoid system, encompassing numerous types of lymphocytic neoplasms, primarily arising from B lymphocytes (>85%), with a smaller proportion arising from T cells and natural killer cells. B-cell-derived NHL subtypes include diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), and Burkitt lymphoma (BL).

[0005] Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and is clinically classified using the Han's classification, which includes germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) subtypes. Currently, the recommended first-line treatment regimen includes R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). For relapsed or refractory DLBCL, second-line options include chemotherapy with other agents that have no cross-resistance to CHOP plus rituximab or a personalized regimen. If patients are eligible for transplantation and achieve a complete remission (CR) or partial remission (PR), they are treated with hematopoietic stem cell transplantation (HSCT) plus local radiotherapy (RT, 30-40 Gy) after chemotherapy or enter a clinical trial. If patients are not eligible for transplantation or their disease remains stable or progresses after treatment, they are placed in a clinical trial or receive best supportive care.

[0006] However, among patients treated with the R-CHOP regimen, 10%-15% develop primary refractory disease (i.e., incomplete remission or relapse within 6 months of treatment), and another 20%-25% experience disease progression within 2 years of initial remission (POD24), resulting in poor treatment outcomes for these patients. Patients with late relapse (>2 years after treatment) have better outcomes but may experience relapse of indolent lymphoma. For patients with chemotherapy-sensitive relapsed or refractory disease, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) have the potential to result in a cure. However, due to advanced age and comorbidities, only half of relapsed and refractory patients are suitable for ASCT.

[0007] A study by Crump M et al. showed that approximately 73% of relapsed / refractory DLBCL patients could not achieve remission after second-line or later-line treatment. The SCHOLAR-1 study enrolled 603 patients to evaluate the prognosis of relapsed / refractory DLBCL patients. The results showed that the objective response rate (ORR) was 26% and the median OS was only 6.3 months, which was not satisfactory (Crump M, Neelapu SS, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017; 130(16): 1800-180).

[0008] A multicenter real-world (REAL-TREND) study conducted in China also showed similar results to the study of Crump M et al. The study included 2,778 patients with DLBCL over 5 years, and the cumulative incidence of refractory DLBCL patients in 5 years was estimated to be 20%. The remission rate and OS of these refractory DLBCL patients were very low, with an objective response rate (ORR) of only 30%, including a complete remission rate (CR) of 9%, a median OS of only 5.9 months, and a 2-year OS rate of only 16% (Wang et al. Outcomes in refractory diffuse large B-cell lymphoma: results from a multicenter real-world study in China. Cancer Communications. 2021; 41: 229-239.).

[0009] Therefore, there is still a need to find more effective drugs and treatments for relapsed or refractory DLBCL.

[0010] Summary of the Invention

[0011] The present invention aims to provide an anti-CD20 antibody-drug conjugate for use in the preparation of a medicament for treating non-Hodgkin's lymphoma. The anti-CD20 antibody-drug conjugate has good clinical efficacy and safety in treating relapsed or refractory non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma, after at least two standard treatments.

[0012] The first aspect of the present invention discloses use of an anti-CD20 antibody-drug conjugate in the preparation of a drug for treating patients with non-Hodgkin's lymphoma.

[0013] The anti-CD20 antibody-drug conjugate has the following structure:

[0014] The mAb is rituximab or a biosimilar thereof, and the drug-antibody ratio (DAR) is 1 to 8. The preferred DAR is 4.2±1, the more preferred DAR is 4.2±0.5, and the even more preferred DAR is 4.2±0.3.

[0015] According to a specific embodiment of the present invention, the anti-CD20 antibody-drug conjugate can be the anti-CD20 ADC "TRS005", and its preparation method can be referred to the patent application publication text CN108452319A, the full text of which is incorporated into the present invention.

[0016] The drug for treating non-Hodgkin's lymphoma of the present invention can also be prepared from a pharmaceutical preparation comprising the anti-CD20 antibody-drug conjugate and a carrier or excipient, wherein the pharmaceutical preparation is a liquid preparation or a lyophilized preparation.

[0017] The carrier or excipient is selected from the following group: pH buffer, osmotic pressure regulator, lyophilized powder excipient, protein protectant, solubilizer, and water for injection.

[0018] The pH buffer includes histidine hydrochloride buffer, acetate buffer, phosphate buffer, citrate buffer or Tris buffer, and preferably the pH buffer is histidine hydrochloride buffer.

[0019] The protein protective agent includes trehalose, sucrose, lactose or glucose, and preferably the protein protective agent is sucrose.

[0020] The osmotic pressure regulator includes mannitol or sodium chloride, and the preferred osmotic pressure regulator is mannitol.

[0021] The solubilizer includes polysorbate 80, polysorbate 20 or poloxamer 188, and the preferred solubilizer is polysorbate 80.

[0022] Furthermore, the liquid or lyophilized preparation comprises the above-mentioned anti-CD20 antibody-drug conjugate, histidine hydrochloride, trehalose, mannitol and polysorbate 80.

[0023] The non-Hodgkin's lymphoma patients described in the present invention are patients with relapsed or refractory non-Hodgkin's lymphoma after receiving at least two standard treatments, including but not limited to patients with follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma or chronic lymphocytic leukemia.

[0024] In some embodiments, the non-Hodgkin's lymphoma patient of the present invention is a patient with relapsed or refractory diffuse large B-cell lymphoma after receiving at least two standard treatments.

[0025] Furthermore, the diffuse large B-cell lymphoma patient is a germinal center B-cell-like diffuse large B-cell lymphoma (GCB) patient and / or a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

[0026] Furthermore, the diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

[0027] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH ≥ 250 and / or a baseline LDH < 250.

[0028] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH ≥ 250.

[0029] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of ≥60 years and / or <60 years.

[0030] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age ≥ 60 years old.

[0031] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage ≥III and / or ≤II.

[0032] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage ≥III.

[0033] A second aspect of the present invention discloses a method for treating a patient with non-Hodgkin's lymphoma.

[0034] The method comprises administering to the patient an effective dose of an anti-CD20 antibody drug conjugate having the following structure:

[0035] The mAb is rituximab or a biosimilar thereof, and the drug-antibody ratio (DAR) is 1 to 8. The preferred DAR is 4.2±1, the more preferred DAR is 4.2±0.5, and the even more preferred DAR is 4.2±0.3.

[0036] According to a specific embodiment of the present invention, the anti-CD20 antibody-drug conjugate can be the anti-CD20 ADC "TRS005", and its preparation method can be referred to the patent application publication text CN108452319A, the full text of which is incorporated into the present invention.

[0037] When administering the anti-CD20 antibody-drug conjugate to a non-Hodgkin's lymphoma patient, the anti-CD20 antibody-drug conjugate can be administered in the form of a pharmaceutical preparation comprising the anti-CD20 antibody-drug conjugate and a carrier or excipient, wherein the pharmaceutical preparation is a liquid preparation or a lyophilized preparation.

[0038] The carrier or excipient is selected from the following group: pH buffer, osmotic pressure regulator, lyophilized powder excipient, protein protectant, solubilizer, and water for injection.

[0039] The pH buffer includes histidine hydrochloride buffer, acetate buffer, phosphate buffer, citrate buffer or Tris buffer, and preferably the pH buffer is histidine hydrochloride buffer.

[0040] The protein protective agent includes trehalose, sucrose, lactose or glucose, and preferably the protein protective agent is sucrose.

[0041] The osmotic pressure regulator includes mannitol or sodium chloride, and the preferred osmotic pressure regulator is mannitol.

[0042] The solubilizer includes polysorbate 80, polysorbate 20 or poloxamer 188, and the preferred solubilizer is polysorbate 80.

[0043] Furthermore, the liquid or lyophilized preparation comprises the above-mentioned anti-CD20 antibody-drug conjugate, histidine hydrochloride, trehalose, mannitol and polysorbate 80.

[0044] In some embodiments, the anti-CD20 antibody drug conjugate is administered in an amount of 0.05 mg / kg to 2.7 mg / kg.

[0045] Preferably, the administration amount of the anti-CD20 antibody drug conjugate is 0.1 mg / kg-2.3 mg / kg.

[0046] Preferably, the administration amount of the anti-CD20 antibody drug conjugate is 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.3 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2.1 mg / kg, or 2.3 mg / kg.

[0047] More preferably, the administration amount of the anti-CD20 antibody drug conjugate is 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.8 mg / kg, or 2.1 mg / kg.

[0048] Most preferably, the anti-CD20 antibody drug conjugate is administered at an amount of 1.8 mg / kg.

[0049] The non-Hodgkin's lymphoma patients are patients whose disease has relapsed or is refractory after receiving at least two standard treatments, including patients with follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma or chronic lymphocytic leukemia.

[0050] In some embodiments, the non-Hodgkin's lymphoma patient of the present invention is a patient with relapsed or refractory diffuse large B-cell lymphoma after receiving at least two standard treatments.

[0051] Furthermore, the diffuse large B-cell lymphoma patient is a germinal center B-cell-like diffuse large B-cell lymphoma (GCB) patient and / or a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

[0052] Furthermore, the diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

[0053] Furthermore, the diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient, and the administration amount of the anti-CD20 antibody drug conjugate is 1.5 mg / kg or 1.8 mg / kg.

[0054] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH ≥ 250 and / or a baseline LDH < 250.

[0055] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH ≥ 250.

[0056] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH ≥ 250, and the administration amount of the anti-CD20 antibody drug conjugate is 1.8 mg / kg.

[0057] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of ≥60 years and / or <60 years.

[0058] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age ≥ 60 years old.

[0059] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of ≥60 years old, and the administration amount of the anti-CD20 antibody drug conjugate is 1.8 mg / kg.

[0060] In some embodiments, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage ≥III and / or ≤II.

[0061] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage ≥III.

[0062] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage ≥III, and the administration amount of the anti-CD20 antibody drug conjugate is 1.8 mg / kg.

[0063] In some embodiments, the anti-CD20 antibody drug conjugate can be administered in a single dose or multiple doses.

[0064] Preferably, the anti-CD20 antibody drug conjugate is administered multiple times, and the administration frequency can be once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W) or once every four weeks (Q4W).

[0065] Preferably, the dosing frequency is once every three weeks (Q3W). Studies have shown that the anti-CD20 antibody drug conjugate of the present invention has similar pharmacokinetic (PK) characteristics after a single dose and four cycles of administration, and is almost completely metabolized in the blood after 21 days, supporting the preferred dosing frequency of once every three weeks.

[0066] In some embodiments, the interval between each administration is one treatment cycle, and the administration time can be 1-20 treatment cycles, preferably 6 treatment cycles.

[0067] In some embodiments, the anti-CD20 antibody drug conjugate is administered once every three weeks (Q3W) and continues to be administered until the patient is cured, the disease progresses, or the patient dies.

[0068] In some embodiments, the administration can be intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous, with intravenous administration being preferred.

[0069] It should be understood that one, some or all of the various embodiments described herein can be combined to form other embodiments of the present invention. These and other embodiments of the present invention are further described by the following detailed description.

[0070] Best Mode for Carrying Out the Invention

[0071] The present invention is described below with reference to specific examples. Those skilled in the art will appreciate that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0072] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0073] definition:

[0074] "Rituximab" refers to a CD20-targeting monoclonal antibody developed by Roche and approved by drug regulatory authorities under the trade name "MabThera." Rituximab is its generic name; only brand-name drugs can be called rituximab.

[0075] "Rituximab biosimilars" refer to monoclonal antibody drugs developed by other companies that imitate rituximab, in addition to the original rituximab, with the same amino acid sequence as rituximab and similar physical and chemical properties, efficacy, pharmacokinetics and safety as the original rituximab.

[0076] "Complete response (CR)" means that the target lesion (target lesion) completely disappears, or all target nodules (target nodules) are reduced to normal size (short axis <10mm) and lasts for 4 weeks or more.

[0077] "Partial response (PR)" means that the sum of the diameters of all measurable target lesions (the long diameter of target lesions and the short diameter of target nodules) is reduced by ≥50% (in hematological tumors) compared with the baseline and lasts for 4 weeks or more.

[0078] "Progressive Disease (PD)" means: taking the minimum value of the sum of all target lesion diameters measured during the entire tumor treatment process as the reference value, the sum of the target lesion diameters exceeds the reference value by 20% or more, and the absolute value increases by 5 mm or more, or one or more new lesions appear, and complete remission and partial remission are not achieved before the lesions increase in volume or number.

[0079] "Stable disease (SD)" means that the changes in the volume and number of lesions are between partial remission and disease progression.

[0080] Overall survival (OS) refers to the time from randomization (acceptance of group treatment) to death of the patient for any reason or loss of follow-up.

[0081] "Progression-free survival (PFS)" refers to the time from randomization to the first recurrence / metastasis of the tumor, or the death of the patient due to any other reason.

[0082] "Median Progression-Free Survival (mPFS)" refers to the progression-free survival achieved by 50% of evaluable patients.

[0083] "Objective Response Rate (ORR)" refers to the sum of the complete response rate (CRR) and the partial response rate, that is, the ratio of patients who achieved complete response and partial response to all evaluable patients.

[0084] "Disease control rate (DCR)" refers to the sum of complete remission rate, partial remission rate and disease stabilization rate, that is, the ratio of patients who achieved complete remission, partial remission and disease stabilization to all evaluable patients.

[0085] "Refractory" means: no partial remission (PR) after two treatment cycles or no complete remission (CR) after four treatment cycles.

[0086] An "effective dose" refers to an amount effective to achieve the desired therapeutic result, at dosages and for periods of time necessary. An effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the therapeutic agent or combination of therapeutic agents to elicit a desired response in the individual.

[0087] “Standard treatment”: The “standard treatment” referred to in the present invention is not limited to the standard treatment regimen determined in the usual clinical sense, but also includes clinically recommended treatment regimens, clinical trial treatment regimens and other treatment regimens.

[0088]

[0066] While the present invention has been generally described, embodiments of the invention will be further disclosed in the following examples, which should not be construed as limiting the scope of the claims.

[0089] Example 1: Preparation of anti-CD20 antibody drug conjugate (TRS005)

[0090] For details on the preparation method of TRS005, please refer to patent application publication CN108452319A, the full text of which is incorporated herein by reference.

[0091] The structure of TRS005 is as follows:

[0092] Among them, the mAb is rituximab or its biosimilar, and the drug-antibody ratio (DAR) is 4.2±0.5.

[0093] Example 2: Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TRS005 in the Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma

[0094] The clinical efficacy data of TRS005 comes from an ongoing open, multicenter, first-in-human, dose-escalation and dose-expansion Phase I clinical study of TRS005 for the treatment of CD20-positive advanced relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL). The study was conducted from August 24, 2020 to October 20, 2023, with a total of 128 subjects enrolled and 96 subjects underwent efficacy analysis (data updated to October 20, 2023).

[0095] (1) Subject baseline information

[0096] The baseline information of the 128 enrolled subjects is shown in Table 1.

[0097] Table 1 Baseline information of R / R NHL subjects

[0098] (2) Dosage regimen

[0099] The doses administered in the dose-escalation phase of this study were 0.1 mg / kg, 0.5 mg / kg, 1.0 mg / kg, 1.5 mg / kg, 1.8 mg / kg and 2.1 mg / kg, and the doses administered in the dose-expansion phase were 1.5 mg / kg and 1.8 mg / kg. Patients received TRS005 intravenously on the first day of each cycle (one cycle was 21 days, for a total of 6 cycles. Patients with clinical benefit will continue to receive the drug until the patient is cured, the disease progresses or the patient dies).

[0100] (3) Efficacy data

[0101] Of the 128 subjects enrolled in Phase I (dose groups: 0.1-2.1 mg / kg), 96 patients underwent post-treatment efficacy analysis. The overall efficacy of the study was 17 subjects evaluated as CR and 26 subjects evaluated as PR, with an ORR of 44.8% (43 / 96). Overall, TRS005 achieved excellent clinical efficacy in patients with relapsed or refractory non-Hodgkin's lymphoma who had received at least two standard therapies.

[0102] By histological subtype, the ORR for DLBCL was 48.2% (27 / 56), including 12 CRs and 15 PRs; the ORR for MCL was 55.6% (5 / 9), including 2 CRs and 3 PRs; and the ORR for FL was 29.4% (5 / 17), including 2 CRs and 3 PRs. This demonstrates that TRS005 demonstrates excellent efficacy in the treatment of relapsed or refractory DLBCL and MCL after second-line therapy. This superior performance in DLBCL and MCL was unexpected. The data are shown in Table 2.

[0103] Table 2 Efficacy data of R / R NHL subjects with different pathological subtypes

[0104] Abbreviations:

[0105] CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease

[0106] ORR: objective response rate; DCR: disease control rate

[0107] Across dose groups, the ORR was 42.9% in the 0.5 mg / kg group, 41.4% in the 1.5 mg / kg group, and 50.0% in the 1.8 mg / kg group. This demonstrates efficacy in the lower dose groups, with the 1.8 mg / kg group showing the strongest efficacy signal. Table 3 shows these data.

[0108] Table 3 Efficacy data of R / R NHL subjects in different dose groups

[0109] Abbreviations:

[0110] CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease

[0111] ORR: objective response rate; DCR: disease control rate

[0112] (4) Security

[0113] All-treatment adverse events (data cutoff: September 18, 2023): 93 patients (83.0%), 1535 events. Treatment-related adverse events (TRAEs): 91 patients (81.3%), 1303 events. Grade ≥ 3 TEAEs: 68 patients (60.7%), 204 events, of which 64 patients (57.1%), 186 events, were judged to be related to study drug.

[0114] Adverse reactions with an incidence of ≥10% during the trial were primarily hematologic toxicities (including decreased white blood cell count, decreased neutrophil count, anemia, decreased lymphocyte count, and decreased platelet count) and non-hematologic toxicities (including increased AST, increased ALT, fever, fatigue, nausea, vomiting, and hypokalemia). Grade 3 or higher TRAEs were primarily hematologic toxicities. No grade 3 or higher adverse reactions with an incidence of ≥10% were observed for cardiac, renal, hepatic, gastrointestinal, skin, neurologic, or pulmonary toxicities.

[0115] In summary, the safety profile of TRS005 in the Phase I clinical study suggests that it is similar to the safety profile of the approved control drug rituximab, with no significant difference in the type and frequency of occurrence. A comprehensive assessment shows that TRS005 is safe and well tolerated.

[0116] Example 3: Analysis of the effectiveness of TRS005 1.5 mg / kg and 1.8 mg / kg dose groups in the treatment of relapsed or refractory diffuse large B-cell lymphoma.

[0117] (1) Subject baseline information

[0118] The baseline information of the 50 enrolled subjects is shown in Table 4.

[0119] Table 4 Baseline information of R / R DLBCL subjects in the 1.5 mg / kg and 1.8 mg / kg dose groups

[0120] Data statistics are as of October 20, 2023.

[0121] (2) Overall efficacy data

[0122] In the dose expansion phase of this study, 50 evaluable subjects with DLBCL were enrolled at doses of 1.5 mg / kg and 1.8 mg / kg. The 1.5 mg / kg dose group achieved an ORR of 42.9% and a DCR of 71.4%, while the 1.8 mg / kg dose group achieved an ORR of 58.6% and a DCR of 89.7%. Overall, the ORR was 52.0% and the DCR was 82.0%. These data demonstrate that TRS005 achieved excellent efficacy in DLBCL subjects, with a dose-dependent response. In particular, the 1.8 mg / kg dose group, at the proposed Phase II recommended dose (RP2D), achieved an ORR of 58.6%, significantly superior to the results of studies by Crump M et al. and Wang et al. (ORRs of 26% and 30%, respectively). The data are shown in Table 5.

[0123] Table 5 Efficacy of R / R DLBCL subjects in the 1.5 mg / kg and 1.8 mg / kg dose groups

[0124] (3) Stratified analysis of efficacy

[0125] a. Baseline molecular typing

[0126] According to the most commonly used Han's classification, DLBCL can be divided into germinal center B cell-like (GCB) and non-germinal center B cell-like (non-GCB) subtypes. Patients with non-GCB DLBCL have a worse prognosis and a greater need for clinical medication, necessitating better clinical drugs and treatment options.

[0127] A total of 49 patients were included in the Han's classification analysis. The results showed that TRS005 demonstrated excellent efficacy in both GCB and non-GCB subtypes. Surprisingly, TRS005 was found to be more effective in the non-GCB subtype and showed a dose-related effect. The overall ORR for the non-GCB subtype was 55.9%, while the ORR for the GCB subtype was 40%. Non-GCB generally has a worse prognosis than GCB. Surprisingly, these results showed that TRS005 has better efficacy in non-GCB compared to GCB, which will correspondingly achieve a better prognosis. This could provide clinically optimized drugs and treatment options to address existing unmet clinical needs. The data are shown in Table 6.

[0128] Table 6 Efficacy of R / R DLBCL subjects with different Han's classification subtypes

[0129] b. Baseline LDH

[0130] Higher lactate dehydrogenase (LDH) levels play an important role in tumor metabolism, proliferation, invasion, and metastasis. Generally, patients with low baseline LDH levels have a higher objective response rate (ORR) than those with high baseline LDH levels.

[0131] The study results showed that TRS005 achieved excellent efficacy in both patients with a baseline LDH ≥ 250 (high group) and LDH < 250 (low group). Surprisingly, TRS005 demonstrated superior efficacy in patients with high baseline LDH levels compared to those with low baseline LDH levels, demonstrating a dose-dependent relationship. The overall ORR for patients with a baseline LDH ≥ 250 was 56.3%, while that for patients with a baseline LDH < 250 was 44.4%. Specifically, at the 1.8 mg / kg dose, the ORR for patients with high baseline LDH levels reached 65%, compared to 44.4% for those with low baseline LDH levels. These results demonstrate, unexpectedly, that TRS005 exhibited superior efficacy in DLBCL patients with high baseline LDH levels. The data are shown in Table 7.

[0132] Table 7 Efficacy of R / R DLBCL subjects with different baseline LDH levels

[0133] c. Baseline age (≥60 vs <60)

[0134] Study results showed that TRS005 achieved excellent efficacy in both subjects aged 60 years and younger. Surprisingly, TRS005 demonstrated superior efficacy in subjects aged 60 years and older compared to those younger than 60 years, demonstrating a dose-dependent response. The ORR for subjects aged 60 years and older was 60.9%, while the ORR for subjects younger than 60 years was 44.4%. Specifically, at the 1.8 mg / kg dose, subjects aged 60 years and older achieved an ORR of 72.7% and a CRR of 54.6%, while subjects younger than 60 years achieved an ORR of 50.0% and a CRR of 11.1%. These results demonstrate, unexpectedly, that TRS005 exhibits superior efficacy in older patients with DLBCL. The data are shown in Table 8.

[0135] Table 8 Efficacy of R / R DLBCL subjects at different baseline ages

[0136] d. Baseline clinical stage (≥III vs ≤II)

[0137] The study results showed that in the 1.8 mg / kg dose group, the ORR was 70% for subjects with clinical stage III or higher, while the ORR was only 20% for subjects with clinical stage II or lower. Therefore, it was unexpected that TRS005, at a dose of 1.8 mg / kg, was significantly more effective in subjects with higher clinical stages than in those with lower clinical stages. The data are shown in Table 9.

[0138] Table 9 Efficacy of R / R DLBCL subjects at different baseline clinical stages

[0139] e. Number of previous treatment lines

[0140] The study results showed that there was no significant difference in the overall efficacy of TRS005 for patients with different previous lines of treatment. The data are shown in Table 10.

[0141] Table 10 Efficacy of R / R DLBCL subjects with different baseline and previous treatment lines

[0142] As shown above, TRS005 showed excellent overall clinical efficacy in DLBCL subjects who had received at least two standard treatments, especially for subjects with non-GCB subtype, high baseline LDH levels, and elderly DLBCL. Compared with the 1.5 mg / kg dose group, the 1.8 mg / kg dose group had better efficacy for the subjects.

[0143] In summary, TRS005 has shown good clinical efficacy and safety in the treatment of non-Hodgkin's lymphoma, especially DLBCL, after at least two standard treatments, and has excellent drug potential.

[0144] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should fall within the scope of the claims attached to the present invention.

Claims

1. Use of an anti-CD20 antibody-drug conjugate in the preparation of a drug for treating patients with non-Hodgkin's lymphoma, characterized in that: The anti-CD20 antibody-drug conjugate has the following structure: Among them, mAb is rituximab or its biosimilar, and the drug-antibody ratio (DAR) is 1-8.

2. The use according to claim 1, characterized in that The DAR is 4.2±1, preferably 4.2±0.

5.

3. The use according to claim 1, characterized in that The DAR was 4.2±0.

3.

4. The use according to any one of claims 1 to 3, characterized in that The non-Hodgkin's lymphoma patients are patients whose disease has relapsed or is refractory after at least two standard treatments, including patients with follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma or chronic lymphocytic leukemia.

5. The use according to claim 4, characterized in that The non-Hodgkin's lymphoma patients are patients with relapsed or refractory diffuse large B-cell lymphoma after receiving at least two standard treatments.

6. The use according to claim 5, characterized in that The diffuse large B-cell lymphoma patients are patients with germinal center B-cell-like diffuse large B-cell lymphoma (GCB) and / or patients with non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB).

7. The use according to claim 6, characterized in that The diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

8. The use according to claim 5, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with baseline LDH ≥ 250 and / or baseline LDH < 250.

9. The use according to claim 8, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline LDH ≥ 250.

10. The use according to claim 5, characterized in that The diffuse large B-cell lymphoma patients are patients with diffuse large B-cell lymphoma whose baseline age is ≥60 years old and / or <60 years old.

11. The use according to claim 10, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline age of ≥60 years old.

12. The use according to claim 5, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline clinical stage ≥III and / or ≤II.

13. The use according to claim 12, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline clinical stage ≥ III.

14. A method for treating patients with non-Hodgkin's lymphoma, characterized in that: The method comprises administering to the patient an effective dose of an anti-CD20 antibody-drug conjugate having the following structure: Wherein, mAb is rituximab or a biosimilar thereof, and the drug-antibody ratio (DAR) is 1-8; the preferred DAR is 4.2±1, the further preferred DAR is 4.2±0.5, and the further preferred DAR is 4.2±0.

3.

15. The method according to claim 14, characterized in that The dosage of the anti-CD20 antibody drug conjugate is 0.05 mg / kg-2.7 mg / kg; preferably, the dosage of the anti-CD20 antibody drug conjugate is 0.1 mg / kg-2.3 mg / kg; preferably, the dosage of the anti-CD20 antibody drug conjugate is 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.3 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2.1 mg / kg, 2.3 mg / kg; preferably, the dosage of the anti-CD20 antibody drug conjugate is 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.8 mg / kg, 2.1 mg / kg; more preferably, the dosage of the anti-CD20 antibody drug conjugate is 1.8 mg / kg.

16. The method according to claim 15, characterized in that The non-Hodgkin's lymphoma patients are patients whose disease has relapsed or is refractory after at least two standard treatments, including patients with follicular lymphoma, marginal zone lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma or chronic lymphocytic leukemia.

17. The method according to claim 16, characterized in that The non-Hodgkin's lymphoma patients are patients with relapsed or refractory diffuse large B-cell lymphoma after receiving at least two standard treatments.

18. The method according to claim 17, characterized in that The diffuse large B-cell lymphoma patients are patients with germinal center B-cell-like diffuse large B-cell lymphoma (GCB) and / or patients with non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB).

19. The method according to claim 18, characterized in that The diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

20. The method of claim 19, wherein: The administration amount of the anti-CD20 antibody drug conjugate is 1.5 mg / kg or 1.8 mg / kg.

21. The method of claim 17, wherein: The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with baseline LDH ≥ 250 and / or baseline LDH < 250.

22. The method according to claim 21, characterized in that The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline LDH ≥ 250.

23. The method of claim 22, wherein: The administration amount of the anti-CD20 antibody drug conjugate was 1.8 mg / kg.

24. The method of claim 17, wherein: The diffuse large B-cell lymphoma patients are patients with diffuse large B-cell lymphoma whose baseline age is ≥60 years old and / or <60 years old.

25. The method of claim 24, wherein: The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline age of ≥60 years old.

26. The method of claim 25, wherein: The administration amount of the anti-CD20 antibody drug conjugate was 1.8 mg / kg.

27. The method of claim 17, wherein: The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline clinical stage ≥III and / or ≤II.

28. The method of claim 27, wherein: The diffuse large B-cell lymphoma patients are diffuse large B-cell lymphoma patients with a baseline clinical stage ≥ III.

29. The method of claim 28, wherein: The administration amount of the anti-CD20 antibody drug conjugate was 1.8 mg / kg.

30. The method according to any one of claims 14 to 29, characterized in that The anti-CD20 antibody drug conjugate can be administered once or multiple times; preferably, the anti-CD20 antibody drug conjugate is administered multiple times, and the administration frequency can be once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W) or once every four weeks (Q4W); more preferably, the administration frequency is once every three weeks (Q3W).

31. The method of claim 30, wherein: The anti-CD20 antibody drug conjugate is administered once every three weeks (Q3W) and continues to be administered until the patient is cured, the disease progresses, or he dies.