Use of anti-CD20 antibody-drug conjugates in the manufacture of therapeutic agents for non-Hodgkin's lymphoma

Abstract

Disclosed herein is the use of an anti-CD20 antibody-drug conjugate in the manufacture of an NHL therapeutic agent that has good clinical efficacy and safety in the treatment of relapsed or refractory NHL after at least two standard therapies.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims priority from Chinese Patent Application No. CN202310223225.2, filed on March 9, 2023, the entire contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to the pharmaceutical arts, and in particular to the use of anti-CD20 antibody-drug conjugates in the manufacture of medicaments for the treatment of patients with non-Hodgkin's lymphoma. [Background technology]

[0003] Non-Hodgkin lymphoma (NHL) is the seventh most common cancer worldwide, accounting for approximately 4% to 5% of new cases and 3% to 4% of deaths. Approximately 1.5 million people worldwide suffer from this disease. NHL is a general term for malignant proliferative disorders of the lymphatic system and includes various types of lymphoma. These tumors are primarily derived from B lymphocytes (>85%), with some derived 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).

[0004] Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL and is clinically classified into germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) subtypes, typically classified according to the Hans classification. Currently, recommended first-line therapy includes R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). For relapsed or refractory DLBCL, second-line therapy, i.e., other chemotherapy drugs not cross-resistant to CHOP with or without rituximab, or individualized therapy, can be selected. Patients who are transplant-eligible and achieve a complete or partial response (CR) or partial response (PR) can undergo chemotherapy followed by hematopoietic stem cell transplantation (HSCT) with or without local radiation therapy (RT, 30–40 Gy) or participate in a clinical trial. Patients who are not transplant-eligible or whose disease remains stable or progresses after treatment are considered for clinical trials or best supportive care.

[0005] However, approximately 10–15% of patients treated with R-CHOP develop primary refractory disease (i.e., incomplete response or relapse within 6 months of treatment initiation). Furthermore, approximately 20–25% of patients progress within 2 years after initial response (POD 24). These patients have been shown to have relatively poor treatment outcomes. While patients with late relapse (relapse >2 years after treatment) have a relatively good outcome, relapse remains a possibility in low-grade lymphoma. For chemotherapy-sensitive relapsed / refractory patients, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) may result in a cure. However, due to advanced age and comorbidities, only half of relapsed / refractory patients are suitable for ASCT.

[0006] A study by Crump M et al. showed that approximately 73% of patients with relapsed / refractory DLBCL fail to achieve a response even after second-line therapy. The SCHOLAR-1 study evaluated the prognosis of relapsed / refractory DLBCL patients in 603 patients. The results showed an unfavorable objective response rate (ORR) of 26% and a median OS of only 6.3 months (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).

[0007] The multicenter real-world (REAL-TREND) study conducted in China also showed similar results to those of Crump et al. [1]. This study enrolled 2,778 DLBCL patients over a 5-year period and estimated the cumulative incidence of refractory DLBCL patients over the 5-year period to be 20%. The response rate and overall survival (OS) of these refractory DLBCL patients were very low, with an objective response rate (ORR) of 30%, including a complete response rate (CR) of 9%. Furthermore, the median OS was only 5.9 months, and the 2-year OS rate was 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.). Summary of the Invention [Problem to be solved by the invention]

[0008] Therefore, there is a need to explore more effective drugs and therapies to treat relapsed / refractory DLBCL. [Means for solving the problem]

[0009] Summary of the Invention An object of the present invention is to provide use of an anti-CD20 antibody-drug conjugate that has good clinical efficacy and safety in the treatment of relapsed / refractory non-Hodgkin's lymphoma, particularly diffuse large B-cell lymphoma, which has undergone at least two standard therapies, in the manufacture of a therapeutic agent for non-Hodgkin's lymphoma.

[0010] A first aspect of the present invention discloses the use of an anti-CD20 antibody-drug conjugate in the manufacture of a medicament for the treatment of patients with non-Hodgkin's lymphoma.

[0011] The anti-CD20 antibody-drug conjugate has the following structure: [ka]

[0012] Here, the mAb is a rituximab antidrug or a biological analog thereof, and the antibody molecule to small molecule drug binding ratio (DAR) is 1 to 8. The preferred DAR is 4.2±1, more preferably 4.2±0.5, and even more preferably 4.2±0.3.

[0013] According to a specific embodiment of the present invention, the anti-CD20 antibody-drug conjugate may be the anti-CD20 ADC "TRS005", the preparation method of which is described in patent application publication CN108452319A, the entire text of which is incorporated herein by reference.

[0014] The therapeutic agent for non-Hodgkin's lymphoma patients of the present invention can also be produced from a pharmaceutical product containing the anti-CD20 antibody-drug conjugate and a carrier or excipient, and the pharmaceutical product is a liquid or lyophilized preparation.

[0015] The carrier or excipient is selected from the group consisting of a pH buffering agent, an osmolality adjusting agent, a lyophilized powder excipient, a protein protecting agent, a solubilizing agent, and water for injection.

[0016] Examples of the pH buffer include histidine hydrochloride buffer, acetate buffer, phosphate buffer, citrate buffer, and Tris buffer, and a preferred pH buffer is histidine hydrochloride buffer.

[0017] The protein protecting agent includes trehalose, sucrose, lactose, or glucose, and a preferred protein protecting agent is sucrose.

[0018] The osmolality adjuster includes mannitol or sodium chloride, and a preferred osmolality adjuster is mannitol.

[0019] The solubilizing agent may be polysorbate 80, polysorbate 20, or poloxamer 188, and a preferred solubilizing agent is polysorbate 80.

[0020] The liquid or lyophilized formulation further comprises the anti-CD20 antibody-drug conjugate, histidine hydrochloride, trehalose, mannitol, and polysorbate 80.

[0021] In the present invention, non-Hodgkin's lymphoma patients are relapsed / refractory non-Hodgkin's lymphoma patients after receiving at least two standard therapies, including, but not limited to, follicular lymphoma patients, marginal zone lymphoma patients, diffuse large B-cell lymphoma patients, mantle cell lymphoma patients, small lymphocytic lymphoma patients, or chronic lymphocytic leukemia patients.

[0022] In some embodiments, the non-Hodgkin's lymphoma patients described herein are patients with relapsed or refractory diffuse large B-cell lymphoma who have received at least two standard therapies.

[0023] 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.

[0024] Furthermore, the diffuse large B-cell lymphoma patient is a non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB) patient.

[0025] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline LDH of 250 or greater and / or a baseline LDH of less than 250.

[0026] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH of 250 or greater.

[0027] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline age of 60 years or older and / or younger than 60 years.

[0028] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older.

[0029] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline clinical stage of diffuse large B-cell lymphoma at or above stage III and / or at or below stage II.

[0030] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient whose baseline clinical stage is stage III or higher.

[0031] A second aspect of the present invention discloses a method for treating patients with non-Hodgkin's lymphoma.

[0032] The method includes administering to the patient an effective dose of an anti-CD20 antibody-drug conjugate, wherein the anti-CD20 antibody-drug conjugate has the following structure:

[0033] [ka]

[0034] Here, the mAb is a rituximab antidrug or a biological analog thereof, and the antibody molecule to small molecule drug binding ratio (DAR) is 1 to 8. The preferred DAR is 4.2±1, more preferably 4.2±0.5, and even more preferably 4.2±0.3.

[0035] According to a specific embodiment of the present invention, the anti-CD20 antibody-drug conjugate may be the anti-CD20 ADC "TRS005", the preparation method of which is described in patent application publication CN108452319A, the entire text of which is incorporated herein by reference.

[0036] When the anti-CD20 drug conjugates described herein are administered to patients with non-Hodgkin's lymphoma, they may be administered in the form of a pharmaceutical preparation comprising the anti-CD20 drug conjugate and a carrier or excipient, the pharmaceutical preparation being a liquid formulation or a lyophilized formulation.

[0037] The carrier or excipient is selected from the group consisting of a pH buffering agent, an osmolality adjusting agent, a lyophilized powder excipient, a protein protecting agent, a solubilizing agent, and water for injection.

[0038] Examples of the pH buffer include histidine hydrochloride buffer, acetate buffer, phosphate buffer, citrate buffer, and Tris buffer, and a preferred pH buffer is histidine hydrochloride buffer.

[0039] The protein protecting agent includes trehalose, sucrose, lactose, or glucose, and a preferred protein protecting agent is sucrose.

[0040] The osmolality adjuster includes mannitol or sodium chloride, and a preferred osmolality adjuster is mannitol.

[0041] The solubilizing agent may be polysorbate 80, polysorbate 20, or poloxamer 188, and a preferred solubilizing agent is polysorbate 80.

[0042] The liquid or lyophilized formulation further comprises the anti-CD20 antibody-drug conjugate, histidine hydrochloride, trehalose, mannitol, and polysorbate 80.

[0043] In some embodiments, the dose of the anti-CD20 antibody-drug conjugate is 0.05 mg / kg to 2.7 mg / kg.

[0044] Preferably, the dose of the anti-CD20 antibody-drug conjugate is 0.1 mg / kg to 2.3 mg / kg.

[0045] 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, or 2.3 mg / kg.

[0046] More preferably, the dose 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.

[0047] Most preferably, the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

[0048] The non-Hodgkin's lymphoma patients are relapsed / refractory patients after at least two standard therapies, including follicular lymphoma patients, marginal zone lymphoma patients, diffuse large B-cell lymphoma patients, mantle cell lymphoma patients, small lymphocytic lymphoma patients, or chronic lymphocytic leukemia patients.

[0049] In some embodiments, the non-Hodgkin's lymphoma patients described herein are patients with relapsed or refractory diffuse large B-cell lymphoma who have received at least two standard therapies.

[0050] 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.

[0051] Furthermore, the diffuse large B-cell lymphoma patient is 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, and the dose of the anti-CD20 antibody-drug conjugate is 1.5 mg / kg or 1.8 mg / kg.

[0053] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline LDH of 250 or greater and / or a baseline LDH of less than 250.

[0054] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH of 250 or greater.

[0055] Furthermore, the diffuse large B-cell lymphoma patient has a baseline LDH of 250 or greater, and the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

[0056] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline age of 60 years or older and / or younger than 60 years.

[0057] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older.

[0058] Furthermore, the diffuse large B-cell lymphoma patient has a baseline age of 60 years or older, and the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

[0059] In some embodiments, the diffuse large B-cell lymphoma patient has a baseline clinical stage of diffuse large B-cell lymphoma at or above stage III and / or at or below stage II.

[0060] Furthermore, the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient whose baseline clinical stage is stage III or higher.

[0061] Furthermore, the patient with diffuse large B-cell lymphoma has a baseline clinical stage of stage III or higher, and the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

[0062] In some embodiments, the anti-CD20 antibody-drug conjugate may be administered in a single dose or multiple doses.

[0063] Preferred anti-CD20 antibody-drug conjugates are administered repeatedly, and the administration frequency may be once per week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

[0064] Preferably, the dosing frequency is once every three weeks (Q3W). Studies have demonstrated that the anti-CD20 antibody-drug conjugates of the present invention have similar pharmacokinetic (PK) properties after a single dose and after four cycles of dosing, and are almost completely metabolized in the blood by day 21. These results support a preferred dosing frequency of once every three weeks.

[0065] In some embodiments, the interval between each administration is one treatment cycle, and the administration period may range from 1 to 20 treatment cycles. Preferably, the administration period is 6 treatment cycles.

[0066] In some embodiments, the anti-CD20 antibody-drug conjugate is administered every three weeks (Q3W) and continues until the patient is cured, the disease progresses, or the patient dies.

[0067] In some embodiments, the method of administration may be intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous, with intravenous administration being preferred.

[0068] It should be understood that one, some, or all of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other embodiments of the present invention are further described in the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0069] Best Mode for Carrying Out the Invention The present invention will now be described with reference to specific examples, which should be understood by those skilled in the art as being illustrative of the present invention and not limiting the scope of the present invention in any way.

[0070] The experimental methods in the following examples are conventional methods unless otherwise specified. Raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0071] Definition:

[0072] "Rituximab" refers to a monoclonal antibody drug targeting CD20, developed by Roche and approved by the National Medical Products Regulatory Authority and marketed under the trade name "Mei Luohua." Rituximab is its generic name; only the original drug can be called rituximab.

[0073] "Biologically similar drugs to rituximab" refers to monoclonal antibody drugs, excluding the original drug rituximab, that have been developed by other companies to imitate rituximab, whose amino acid sequence is identical to that of rituximab and whose physicochemical properties, therapeutic effects, pharmacokinetics and safety are similar to those of the original drug rituximab.

[0074] "Complete Response (CR)" refers to the complete disappearance of target lesions or the reduction of all target nodules to normal size (minor axis < 10 mm) that lasts for 4 weeks or more.

[0075] "Partial Response (PR)" refers to a reduction of 50% or more (in hematomas) in the sum of the measurable diameters of all target lesions (the longest diameter is selected for target lesions, and the shortest diameter is selected for target nodules) compared to baseline, and the reduction lasts for 4 weeks or more.

[0076] "Progressive Disease (PD)" refers to the condition in which the minimum sum of the diameters of all target lesions measured during the entire tumor treatment period is taken as the reference value, and the sum of the diameters of the target lesions 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 or partial response is not achieved before the volume or number of lesions increases.

[0077] "Stable disease (SD)" refers to a state in which the change in the volume and number of lesions is between partial response and disease progression.

[0078] "Overall Survival (OS)" refers to the time from randomization (receiving treatment in the assigned group) to the time the subject died or was lost to follow-up due to any cause.

[0079] "Progression-Free Survival (PFS)" refers to the time from randomization to first tumor recurrence / metastasis or death of the subject due to any other cause.

[0080] "Median Progression-Free Survival (mPFS)" refers to the progression-free survival achieved by 50% of evaluable patients.

[0081] "Objective Response Rate (ORR)" refers to the sum of the Complete Response Rate (CRR) and the Partial Response Rate, i.e., the proportion of patients who achieved a complete or partial response among all evaluable patients.

[0082] "Disease control rate (DCR)" refers to the sum of the complete response rate, partial response rate, and stable disease rate, i.e., the proportion of patients who achieved a complete response, partial response, or stable disease among all evaluable patients.

[0083] "Refractory" refers to failure to achieve a partial response (PR) after two treatment cycles or a complete response (CR) after four treatment cycles.

[0084] An "effective dose" refers to an amount effective, at a desired dosage and for a desired period of time, to achieve a desired therapeutic result. An effective dose can vary depending on 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.

[0085] "Standard treatment": In the present invention, "standard treatment" is not limited to standard treatments established in the clinically usual sense, but also includes treatments recommended in clinical trials, treatments in clinical trials, and other treatments. [Example]

[0086] Having generally described the present invention, the following examples further disclose embodiments of the invention and are not to be construed as limiting the scope of the claims.

[0087] Example 1: Preparation of anti-CD20 antibody-drug conjugate (TRS005)

[0088] For the preparation method of TRS005, please refer to the published patent application CN108452319A, the entire text of which is incorporated herein by reference.

[0089] The structure of TRS005 is as follows: [ka]

[0090] Here, the mAb is rituximab or a biosimilar thereof with a drug-antibody ratio (DAR) of 4.2±0.5.

[0091] Example 2 : A study to evaluate the safety, tolerability, pharmacokinetic properties, and efficacy of TRS005 for relapsed or refractory non-Hodgkin's lymphoma

[0092] The clinical efficacy data for TRS005 are derived from an open-label, multicenter, first-in-human, dose-escalation and dose-expansion Phase I clinical study of TRS005 treatment in CD20-positive late relapsed or refractory B-cell non-Hodgkin's lymphoma (B-NHL). The study enrolled a total of 128 subjects from August 24, 2020 to October 20, 2023, and treatment efficacy analysis was performed on 96 subjects (data up to October 20, 2023). (1) Subject baseline information

[0093] Baseline information for the 128 subjects is shown in Table 1.

[0094] Table 1. Baseline information for R / R NHL subjects

[0095] [Table 1]

[0096] (2) Administration method The doses 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 dose-expansion phase was 1.5 mg / kg and 1.8 mg / kg. Patients received TRS005 intravenously on day 1 of each cycle (21 days per cycle, for a total of six cycles; patients who demonstrated clinical benefit continued treatment until cure, disease progression, or death).

[0097] (3) Treatment effect data Of the 128 subjects enrolled in the Phase I clinical study (dose groups: 0.1-2.1 mg / kg), 96 patients underwent post-treatment efficacy analysis. Overall, 17 subjects achieved complete response and 26 subjects achieved partial response, resulting in an ORR of 44.8% (43 / 96). Overall, TRS005 demonstrated excellent clinical efficacy in patients with relapsed or refractory non-Hodgkin's lymphoma after at least two prior standard therapies.

[0098] Based on 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. TRS005 demonstrated excellent therapeutic effects in the treatment of relapsed or refractory DLBCL and MCL after second-line therapy, and this superior efficacy in both DLBCL and MCL was unexpected. Data are shown in Table 2.

[0099] Table 2 Treatment efficacy data in R / R NHL subjects by pathological subtype

[0100] [Table 2]

[0101] Abbreviation: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease ORR: Objective response rate; DCR: Disease control rate

[0102] Looking at each dose group, 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 indicates that therapeutic efficacy was observed even in the lower dose groups, with the 1.8 mg / kg group showing the best therapeutic efficacy signal. The data are shown in Table 3.

[0103] Table 3. Treatment Efficacy Data in R / R NHL Subjects by Dose Group

[0104] [Table 3]

[0105] Abbreviation: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease ORR: Objective response rate; DCR: Disease control rate

[0106] (4) Safety All treatment-emergent adverse events (data cutoff: September 18, 2023): 1,535 events occurred in 93 (83.0%) subjects. Treatment-related adverse events (TRAEs): 1,303 events occurred in 91 (81.3%) subjects. Grade 3 or higher TEAEs: 204 events occurred in 68 (60.7%) subjects, of which 64 (57.1%), or 186 events, were determined to be related to the study drug.

[0107] During the study, adverse events with an incidence of 10% or higher were primarily hematological toxicities (including leukopenia, neutropenia, anemia, lymphopenia, and thrombocytopenia) and non-hematological toxicities (including elevated AST and ALT, fever, weakness, nausea, vomiting, and hypokalemia). Grade 3 or higher TRAEs were primarily hematological toxicities. No adverse events with an incidence of 10% or higher were observed for cardiac, renal, hepatic, gastrointestinal, cutaneous, neurological, or pulmonary toxicities.

[0108] Based on the above, the safety profile of TRS005 in the Phase I clinical study was similar to that of the already approved comparator drug rituximab, with no significant differences in the types and frequency of onset. The overall evaluation showed that TRS005 had good safety and tolerability.

[0109] Example 3: Efficacy analysis of TRS005 1.5mg / kg and 1.8mg / kg dose groups in relapsed or refractory diffuse large B-cell lymphoma.

[0110] (1) Subject baseline information Baseline information for the 50 subjects is shown in Table 4.

[0111] Table 4. Baseline information for R / R DLBCL subjects in the 1.5 mg / kg and 1.8 mg / kg treatment groups

[0112] [Table 4]

[0113] Data collection will continue until October 20, 2023.

[0114] (2) Overall treatment effect data The dose expansion phases in this study were 1.5 mg / kg and 1.8 mg / kg. A total of 50 evaluable DLBCL patients were included in the two dose groups. The ORR was 42.9% and DCR was 71.4% in the 1.5 mg / kg group, and the ORR was 58.6% and DCR was 89.7% in the 1.8 mg / kg group. The overall ORR was 52.0% and DCR was 82.0%. As can be seen from the above data, TRS005 demonstrated excellent efficacy in DLBCL patients, demonstrating a dose-dependent response. In particular, at the 1.8 mg / kg dose group, the recommended phase II dose (RP2D), the ORR reached 58.6%, significantly superior to the results of Crump et al. and Wang et al. (ORRs of 26% and 30%, respectively). The data are shown in Table 5.

[0115] Table 5. Treatment effects of 1.5 mg / kg and 1.8 mg / kg dose groups on R / R DLBCL subjects

[0116] [Table 5]

[0117] (3) Stratified analysis of treatment effects Baseline molecular type DLBCL can be divided into germinal center B-cell-like (GCB) and non-germinal center B-cell-like (non-GCB) subtypes according to the Hans classification, which is currently the most commonly used classification. The prognosis for non-GCB DLBCL patients is poorer, and the need for clinical drug use is increasing. Therefore, the development of more effective clinical drugs and treatments is required.

[0118] A total of 49 patients were included in the Hans classification analysis. The study results showed that TRS005 demonstrated excellent therapeutic efficacy in both GCB and non-GCB subtypes. Surprisingly, TRS005 demonstrated even better efficacy in the non-GCB subtype, demonstrating a dose-dependent relationship. The overall ORR for non-GCB subtypes was 55.9%, while that for GCB subtypes was 40%. Non-GCB subtypes typically have a poorer prognosis than GCB subtypes. Contrary to expectations, the above results indicated that TRS005 demonstrated superior therapeutic efficacy in non-GCB subtypes compared with GCB subtypes, resulting in a better prognosis. This suggests that TRS005 may provide superior therapeutic efficacy and treatment options for clinical use, potentially addressing unmet clinical needs. The data are shown in Table 6.

[0119] Table 6 Treatment efficacy in R / R DLBCL subjects by Hans classification subtype

[0120] [Table 6]

[0121] b. Baseline LDH Relatively high lactic dehydrogenase (LDH) levels play an important role in tumor metabolism, growth, invasion, and metastasis, and patients with low baseline LDH levels generally have a higher objective response rate (ORR) than patients with high baseline LDH levels.

[0122] The study results showed that TRS005 demonstrated excellent therapeutic efficacy in both patients with baseline LDH levels of 250 or higher (high group) and those with LDH levels below 250 (low group). Unexpectedly, TRS005 demonstrated a higher therapeutic effect in subjects with high baseline LDH levels than in subjects with low baseline LDH levels, demonstrating a dose-dependent relationship. The overall ORR for patients with baseline LDH levels ≥ 250 was 56.3%, while the ORR for patients with baseline LDH < 250 was 44.4%. In particular, in the 1.8 mg / kg dose group, the ORR for subjects with high baseline LDH levels reached 65% and for subjects with low baseline LDH levels reached 44.4%. These results unexpectedly demonstrated that TRS005 demonstrated superior therapeutic efficacy in DLBCL patients with high baseline LDH levels. The data are shown in Table 7.

[0123] Table 7. Treatment effect in R / R DLBCL subjects by baseline LDH level

[0124] [Table 7]

[0125] c. Baseline age (≥60 vs <60) The study results showed that TRS005 demonstrated superior therapeutic efficacy in both patients aged 60 years and younger. Unexpectedly, the therapeutic efficacy of TRS005 in patients aged 60 years and older was superior to that in patients younger than 60 years. This demonstrated a dose-related relationship, with the ORR in patients aged 60 years and older being 60.9% compared with 44.4% in patients younger than 60 years. In particular, in the 1.8 mg / kg dose group, the ORR in patients aged 60 years and older was 72.7% with a CRR of 54.6% compared with 50.0% with a CRR of 11.1% in patients younger than 60 years. These results unexpectedly demonstrated that TRS005 demonstrated superior therapeutic efficacy in older DLBCL patients. The data are shown in Table 8.

[0126] Table 8. Treatment effect in R / R DLBCL subjects by baseline age

[0127] [Table 8]

[0128] d. Baseline clinical stage (≥stage III vs. ≤stage II) The study results showed that in the 1.8 mg / kg dose group, the ORR was 70% in patients with clinical stage III or higher, but only 20% in patients with clinical stage II or lower. Therefore, it was unexpectedly discovered that at the 1.8 mg / kg dose, TRS005 had a significantly higher therapeutic effect in patients with higher clinical stage disease than in patients with lower clinical stage disease. The data are shown in Table 9.

[0129] Table 9. Treatment effect in R / R DLBCL subjects by baseline clinical stage

[0130] [Table 9]

[0131] e. Number of previous lines of treatment The study results showed that TRS005 did not significantly affect the overall therapeutic effect of patients with different prior lines of therapy, and the data are shown in Table 10.

[0132] Table 10. Treatment effect in R / R DLBCL subjects by number of prior lines of treatment at baseline

[0133] [Table 10]

[0134] As shown above, TRS005 demonstrated excellent clinical efficacy overall among DLBCL patients who had received at least two standard therapies, with more pronounced efficacy in non-GCB subtypes, patients with relatively high baseline LDH levels, and elderly DLBCL patients. The efficacy was superior in patients receiving the 1.8 mg / kg dose compared to the 1.5 mg / kg dose.

[0135] In conclusion, TRS005 has demonstrated favorable clinical efficacy and safety in the treatment of non-Hodgkin's lymphoma, particularly DLBCL, after at least two standard therapies, making it a potentially excellent drug candidate.

[0136] The above description of the specific embodiments of the present invention is not intended to limit the present invention, and those skilled in the art may make various modifications or variations based on the present invention without departing from the spirit of the present invention, all of which are within the scope of the claims of the present invention.

Claims

1. 1. Use of an anti-CD20 antibody-drug conjugate in the manufacture of a medicament for treating a patient with non-Hodgkin's lymphoma, wherein the anti-CD20 antibody-drug conjugate has the following structure: 【Chemistry 1】 Here, the mAb is a rituximab antidrug or its biosimilar, and the antibody molecule to small molecule drug binding ratio (DAR) is 1-8.

2. 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 is 4.2±0.

3.

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

5. The use according to claim 4, characterized in that the non-Hodgkin's lymphoma patient is a relapsed or refractory diffuse large B-cell lymphoma patient who has received at least two standard therapies.

6. The use according to claim 5, wherein the patient with diffuse large B-cell lymphoma is a patient with germinal center B-cell-like diffuse large B-cell lymphoma (GCB) and / or a patient with non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB).

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

8. The use according to claim 5, characterized in that the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH of 250 or more and / or a baseline LDH of less than 250.

9. The use according to claim 8, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH of 250 or more.

10. The use according to claim 5, characterized in that the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older and / or younger than 60 years.

11. The use according to claim 10, characterized in that the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older.

12. The use according to claim 5, characterized in that the patient with diffuse large B-cell lymphoma is a patient with diffuse large B-cell lymphoma whose baseline clinical stage is stage III or higher and / or stage II or lower.

13. The use according to claim 12, wherein the patient with diffuse large B-cell lymphoma is a patient with diffuse large B-cell lymphoma whose baseline clinical stage is stage III or higher.

14. 1. A method of treating a patient 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, wherein the anti-CD20 antibody-drug conjugate has the following structure: 【Chemistry 2】 Here, the mAb is a rituximab antidrug or a biological analog thereof, and the antibody molecule to small molecule drug binding ratio (DAR) is 1 to 8, with a preferred DAR being 4.2±1, a more preferred DAR being 4.2±0.5, and an even more preferred DAR being 4.2±0.

3.

15. The method of claim 14, wherein the dose of the anti-CD20 antibody-drug conjugate is 0.05 mg / kg to 2.7 mg / kg, preferably 0.1 mg / kg to 2.3 mg / kg, preferably 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, preferably 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.8 mg / kg, or 2.1 mg / kg, and more preferably 1.8 mg / kg.

16. 16. The method of claim 15, wherein the non-Hodgkin's lymphoma patient is a relapsed / refractory patient after at least two standard therapies, including follicular lymphoma patient, marginal zone lymphoma patient, diffuse large B-cell lymphoma patient, mantle cell lymphoma patient, small lymphocytic lymphoma patient, or chronic lymphocytic leukemia patient.

17. 17. The method of claim 16, wherein the non-Hodgkin's lymphoma patient is a relapsed or refractory diffuse large B-cell lymphoma patient who has received at least two standard therapies.

18. The method according to claim 17, wherein the diffuse large B-cell lymphoma patient is a patient with germinal center B-cell-like diffuse large B-cell lymphoma (GCB) and / or a patient with non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB).

19. The method according to claim 18, wherein 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 dose of the anti-CD20 antibody-drug conjugate is 1.5 mg / kg or 1.8 mg / kg.

21. 18. The method of claim 17, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline LDH of 250 or more and / or a baseline LDH of less than 250.

22. 22. The method of claim 21, wherein the diffuse large B-cell lymphoma patient has a baseline LDH of 250 or greater.

23. 23. The method of claim 22, wherein the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

24. 18. The method of claim 17, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older and / or younger than 60 years.

25. 25. The method of claim 24, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline age of 60 years or older.

26. 26. The method of claim 25, wherein the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

27. The method of claim 17, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient whose baseline clinical stage is stage III or higher and / or stage II or lower.

28. 28. The method of claim 27, wherein the diffuse large B-cell lymphoma patient is a diffuse large B-cell lymphoma patient with a baseline clinical stage of stage III or higher.

29. 29. The method of claim 28, wherein the dose of the anti-CD20 antibody-drug conjugate is 1.8 mg / kg.

30. The method of any one of claims 14 to 29, wherein the anti-CD20 antibody-drug conjugate may be administered once or repeatedly, preferably the anti-CD20 antibody-drug conjugate is administered repeatedly, and the administration frequency may be once a week (QW), once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W), more preferably once every three weeks (Q3W).

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

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