Application of medicine composition containing anti-CD20 antibody medicine conjugate in preparation of medicine for treating NHL

Abstract

The invention discloses an application of a combination of an anti-CD20 antibody drug conjugate and at least one therapeutic agent in preparation of a drug for treating recurrent or refractory non-Hodgkin lymphoma after receiving at least one standard therapeutic schedule. The combined therapy of the anti-CD20 antibody drug conjugate and at least one therapeutic agent has a better curative effect than the existing clinical second-line standard therapy.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmacy and pharmaceutical combination technology, and in particular to the use of a pharmaceutical combination containing an anti-CD20 antibody drug conjugate in the preparation of a medicament for treating NHL. BACKGROUND

[0002] Non-Hodgkin lymphoma (NHL) is the seventh most common type of cancer worldwide, accounting for about 4-5% of new cancer cases and 3-4% of cancer-related deaths, affecting about 1.5 million people worldwide.

[0003] NHL is a group of malignant proliferative diseases of the lymphatic system, including numerous types of lymphocytic tumors, which mainly originate from B lymphocytes (>85%), and a small number of T cells and natural killer cells. It is usually classified as slow progression or indolent NHL (iNHL) and rapid progression or aggressive NHL (aNHL) according to prognosis; follicular lymphoma (FL) is the most common iNHL, accounting for about 1 / 5 of all NHL patients, while diffuse large B-cell lymphoma (DLBCL) is the most common aNHL, accounting for about 1 / 3 of all NHL patients.

[0004] 30-35% of DLBCL express MYC protein, 20-35% express BCL2, called "double-expressed lymphoma", and some DLBCL express MYC, BCL2 and BCL6 simultaneously, called "triple-expressed lymphoma", which indicates poor prognosis.

[0005] The current clinical guidelines recommend the first-line standard treatment regimen for DLBCL, including R-CHOP regimen, R-CHOEP regimen, R-miniCHOP regimen, DA-EPOCH-R regimen and Pola-R-CHP regimen, etc. R-CHOP regimen uses rituximab (R), cyclophosphamide (C), vincristine (H), doxorubicin (O) and prednisone (P) in combination; R-CHOEP regimen uses rituximab (R), cyclophosphamide (C), vincristine (H), doxorubicin (O), etoposide (E) and prednisone (P) in combination; R-miniCHOP regimen uses rituximab (R), cyclophosphamide (C), vincristine (H), doxorubicin (O) and prednisone (P) in combination, with low-dose CHOP; DA-EPOCH-R uses etoposide (E), prednisone (P), doxorubicin (O), cyclophosphamide (C), vincristine (H) and rituximab (R) in combination, and dose adjustment (DA) is performed after each chemotherapy cycle according to the patient's response to chemotherapy; Pola-R-CHP uses Polatuzumab vedotin (an ADC targeting CD79b, trade name Polivy) in combination with rituximab (R), cyclophosphamide (C) and hydroxycarbamide (H). ), rituximab (R), cyclophosphamide (C), vincristine (H) and prednisone (P). Although the patients get different degrees of remission after the first-line therapy, 40%-50% of them are still prone to relapse or refractory, especially for "double expression lymphoma" or "three expression lymphoma", which shows poor prognosis.

[0006] The second-line standard therapy for relapsed or refractory DLBCL after the first-line standard treatment includes R-GemOx (rituximab (R), gemcitabine (Gem) and oxaliplatin (Ox) combination), R 2 (rituximab (R) and lenalidomide (R) combination), BR (bendamustine (B) and rituximab (R) combination), R-ICE (rituximab, ifosfamide, carboplatin and etoposide combination), R-DHAP (rituximab, cisplatin, cytarabine and dexamethasone combination), R-GDP (rituximab, gemcitabine, cisplatin and dexamethasone combination), R-MINE (rituximab, mesna, ifosfamide, mitoxantrone and etoposide combination), R-ESHAP (rituximab, etoposide, methylprednisolone, cisplatin and cytarabine combination), DA-EPOCH-R (rituximab, etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin combination). Although the patients get a certain degree of remission after the second-line standard therapy, there is still room for further improvement in clinical benefit, and therefore, there is still a need to find more effective treatment or combination therapy drugs and treatment regimens for relapsed or refractory non-Hodgkin's lymphoma after receiving at least one standard treatment. SUMMARY

[0007] The purpose of the present application is to provide a drug product and its use in the preparation of a drug for treating non-Hodgkin's lymphoma, which has a better efficacy than the existing clinical second-line standard therapy.

[0008] The first aspect of the present application discloses the use of a combination of an anti-CD20 antibody drug conjugate and at least one therapeutic agent in the preparation of a drug for treating relapsed or refractory non-Hodgkin's lymphoma after receiving at least one standard treatment regimen.

[0009] The anti-CD20 antibody drug conjugate has the following structural formula:

[0010] mAb-(L-D)n;

[0011] Wherein, mAb represents a recombinant anti-CD20 monoclonal antibody, D represents a small molecule toxin; L is a linker connecting the monoclonal antibody and the small molecule toxin; n is the average number of conjugated small molecule toxins to the monoclonal antibody; "-" is a bond.

[0012] Preferred said recombinant anti-CD20 mAb include, but are not limited to, Rituximab or biosimilars thereof, Ofatumumab or biosimilars thereof, Obinutuzumab or biosimilars thereof, Ocrelizumab or biosimilars thereof.

[0013] More preferred said recombinant anti-CD20 mAb is preferably Rituximab or biosimilars thereof.

[0014] Preferred D is one or more monomethyl auristatin, including but not limited to monomethyl auristatin-E (MMAE), monomethyl auristatin-D (MMAD), or monomethyl auristatin-F (MMAF); further said monomethyl auristatin is monomethyl auristatin-E (MMAE).

[0015] L is a cleavable linker or a non-cleavable linker, including but not limited to a thioether linker, said thioether linker comprising a maleimide group, preferably said maleimide group further comprises hexanoic acid, forming a maleimidocaproyl (mc); preferably said maleimide group comprises a maleimidomethyl, such as succinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sMCC) or sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-sMCC).

[0016] Said cleavable linker includes but is not limited to a hydrazone linker, a disulfide linker, a peptide linker; said peptide linker comprises valine-citrulline (Val-Cit or VC), phenylalanine-lysine (Phe-Lys), valine-alanine (Val-Ala), or valine-lysine (Val-Lys). Preferred said peptide linker is valine-citrulline (Val-Cit).

[0017] Further, linker moiety further comprises p-aminobenzyl alcohol (PAB), p-aminobenzyloxycarbonyl (PABC), or derivatives or analogs thereof.

[0018] Further, L is preferably MC-VC-PAB.

[0019] Said n is an integer or non-integer from 1 to 8; preferably n is 4.2±1, further preferably 4.2±0.5, and more further preferably 4.2±0.3.

[0020] Said anti-CD20 antibody drug conjugate further has the following structure:

[0021]

[0022] wherein mAb represents a recombinant anti-CD20 monoclonal antibody, n is the average number of conjugations of small molecule toxin to the antibody, and n is 1-8; preferably n is 4.2±1, further preferably n is 4.2±0.5, and more preferably n is 4.2±0.3.

[0023] The anti-CD20 antibody drug conjugate of the present application can be a pharmaceutical preparation containing the anti-CD20 antibody drug conjugate and a carrier or excipient, and the pharmaceutical preparation is a liquid preparation or a lyophilized preparation.

[0024] The carrier or excipient is selected from the group consisting of a pH buffer, an osmotic pressure regulator, a lyophilized powder excipient, a protein protective agent, a solubilizer, and water for injection.

[0025] The pH buffer includes a histidine hydrochloride buffer, an acetic acid buffer, a phosphate buffer, a citric acid buffer, or a Tris buffer, and preferably the pH buffer is a histidine hydrochloride buffer.

[0026] The protein protective agent includes trehalose, sucrose, lactose, or glucose, and preferably the protein protective agent is trehalose.

[0027] The osmotic pressure regulator includes mannitol or sodium chloride, and preferably the osmotic pressure regulator is mannitol.

[0028] The solubilizer includes polysorbate 80, polysorbate 20, or poloxamer 188, and preferably the solubilizer is polysorbate 80.

[0029] Further, the liquid or lyophilized preparation includes the above-mentioned anti-CD20 antibody drug conjugate, histidine hydrochloride, trehalose, mannitol, and polysorbate 80.

[0030] In some embodiments, the recombinant anti-CD20 monoclonal antibody is selected from Rituximab (Rituxan®) or a biosimilar thereof, Ofatumumab (Arzerra®) or a biosimilar thereof, Ocrelizumab (Ocrevus®) or a biosimilar thereof, and Obinutuzumab (Gazyva®) or a biosimilar thereof.

[0031] Further, the recombinant anti-CD20 monoclonal antibody is selected from Rituximab (Rituxan®) or a biosimilar thereof.

[0032] In some embodiments, the at least one therapeutic agent is selected from one or more of a hormonal agent, a platinum agent, and an antimetabolite agent; the hormonal agent is selected from one or more of prednisone, dexamethasone, and methylprednisolone; the platinum agent is selected from one or more of carboplatin, cisplatin, and oxaliplatin; the antimetabolite agent is selected from one or more of pemetrexed, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, and thioguanine.

[0033] Further, the at least one therapeutic agent is gemcitabine, dexamethasone, and cisplatin.

[0034] In some embodiments, the non-Hodgkin lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocytic leukemia, or anaplastic large cell lymphoma.

[0035] Further, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

[0036] Further, the diffuse large B-cell lymphoma is CD20-positive diffuse large B-cell lymphoma.

[0037] Further, the CD20-positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

[0038] In some embodiments, the at least one standard treatment regimen comprises at least anti-CD20 antibody monotherapy or anti-CD20 antibody combination therapy.

[0039] Further, the at least one standard treatment regimen comprises at least one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R, and Pola-R-CHP.

[0040] Further, the at least one standard treatment regimen is R-CHOP.

[0041] A second aspect of the present application discloses a pharmaceutical product for treating relapsed or refractory non-Hodgkin lymphoma after receiving at least one standard treatment regimen

[0042] The pharmaceutical product comprises an anti-CD20 antibody drug conjugate and at least one therapeutic agent, the anti-CD20 antibody drug conjugate has the following structure:

[0043]

[0044] wherein mAb represents a recombinant anti-CD20 mAb, the drug antibody ratio (DAR) is 1-8, preferably the DAR is 4.2±1, further preferably the DAR is 4.2±0.5, and more further preferably the DAR is 4.2±0.3.

[0045] wherein the at least one therapeutic agent is selected from one or more of a hormone drug, a platinum drug, and an antimetabolite drug;

[0046] the hormone drug is selected from one or more of prednisone and dexamethasone;

[0047] the platinum drug is selected from one or more of carboplatin, cisplatin, and oxaliplatin;

[0048] the antimetabolite drug is selected from one or more of pemetrexed, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, and thioguanine.

[0049] In some embodiments, the recombinant anti-CD20 mAb is selected from Rituximab or a biosimilar thereof, Ofatumumab or a biosimilar thereof, Ocrelizumab or a biosimilar thereof, and Obinutuzumab or a biosimilar thereof.

[0050] Further, the recombinant anti-CD20 mAb is selected from Rituximab or a biosimilar thereof.

[0051] In some embodiments, the at least one therapeutic agent is gemcitabine, dexamethasone, and cisplatin.

[0052] In some embodiments, the pharmaceutical product of the present application is a combination of the anti-CD20 antibody drug conjugate, gemcitabine, dexamethasone, and cisplatin.

[0053] The combination of the anti-CD20 antibody drug conjugate and the at least one therapeutic agent is only an exemplary combination and does not constitute a limitation on the anti-CD20 antibody drug conjugate of the present application and other drugs to be combined.

[0054] The pharmaceutical product of the present application is composed of a first pharmaceutical product comprising the anti-CD20 antibody drug conjugate and a carrier or excipient thereof and a second pharmaceutical product comprising the at least one therapeutic agent and a carrier or excipient thereof.

[0055] The first pharmaceutical product and the second pharmaceutical product of the present application can be packaged independently or co-packaged.

[0056] The present application also discloses a kit comprising the anti-CD20 antibody drug conjugate and the at least one therapeutic agent.

[0057] Further, the anti-CD20 antibody drug conjugate and the at least one therapeutic agent are independently packaged and disposed in the kit.

[0058] Further, the kit comprises the anti-CD20 antibody drug conjugate, gemcitabine, dexamethasone and cisplatin.

[0059] The third aspect of the present application discloses a combination therapy for treating relapsed or refractory non-Hodgkin lymphoma after receiving at least one standard treatment regimen.

[0060] The combination therapy comprises administering an effective amount of the pharmaceutical product disclosed in the second aspect of the present application for treating relapsed or refractory non-Hodgkin lymphoma after receiving at least one standard treatment regimen.

[0061] In some embodiments, the combination therapy comprises administering an effective amount of the anti-CD20 antibody drug conjugate, gemcitabine, dexamethasone and cisplatin in combination.

[0062] In some embodiments, the non-Hodgkin lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocyte leukemia or anaplastic large cell lymphoma.

[0063] Further, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

[0064] Further, the diffuse large B-cell lymphoma is CD20 positive diffuse large B-cell lymphoma.

[0065] Further, the CD20 positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

[0066] In some embodiments, the at least one standard treatment regimen comprises at least anti-CD20 antibody monotherapy or anti-CD20 antibody combination therapy.

[0067] Further, the at least one standard treatment regimen comprises at least one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R and Pola-R-CHP.

[0068] Further, the at least one standard treatment regimen is R-CHOP.

[0069] In some embodiments, the anti-CD20 antibody drug conjugate is administered prior to, concurrently with, and / or after the administration of the at least one therapeutic agent.

[0070] In some embodiments, the anti-CD20 antibody drug conjugate and the at least one therapeutic agent can be administered in a single dose or multiple doses. For example, the anti-CD20 antibody drug conjugate can be administered in a single dose, or in multiple doses, for which the frequency of administration can be, for example, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks, etc.; or in a cycle of one day, one week, two weeks, three weeks, four weeks, one month, two months, three months, six months, etc., with one, two, three, four, five, six, etc. doses per cycle, for an appropriate cycle and frequency of administration until the patient's disease progresses, dies, or is cured.

[0071] For the at least one therapeutic agent, such as gemcitabine, dexamethasone, and cisplatin, etc., can be administered in a single dose or multiple doses. For multiple doses, the frequency of administration can be, for example, three times a day, twice a day, once a day, once every two days, once a week, once every two weeks, once every three weeks, once every four weeks, etc.; or in a cycle of one day, one week, two weeks, three weeks, four weeks, one month, two months, three months, six months, etc., with one, two, three, four, five, six, etc. doses per cycle, for an appropriate cycle and frequency of administration until the patient's disease progresses, dies, or is cured.

[0072] The combination drug of the present application can be administered by any suitable means, including gastrointestinal, parenteral, intrapulmonary, and intranasal, etc. Parenteral infusion includes intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration, etc.

[0073] The fourth aspect of the present application discloses a non-therapeutic method for inhibiting non-Hodgkin lymphoma cells.

[0074] The method comprises adding an effective dose of the drug product of the second aspect of the present application to a system of relapsed or refractory non-Hodgkin lymphoma cells receiving at least one inhibitory treatment.

[0075] In some embodiments, the method comprises administering an effective dose of the anti-CD20 antibody drug conjugate, gemcitabine, dexamethasone, and cisplatin to the system of relapsed or refractory non-Hodgkin lymphoma cells receiving at least one inhibitory treatment.

[0076] In some embodiments, the non-Hodgkin lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocyte leukemia, or anaplastic large cell lymphoma.

[0077] Further, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

[0078] Further, the diffuse large B-cell lymphoma is CD20-positive diffuse large B-cell lymphoma.

[0079] Further, the CD20-positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

[0080] In some embodiments, the at least one inhibitory treatment comprises at least a single-agent inhibitory treatment with an anti-CD20 antibody or a combination inhibitory treatment with an anti-CD20 antibody and at least one therapeutic agent.

[0081] Further, the at least one inhibitory treatment comprises at least one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R, and Pola-R-CHP.

[0082] Further, the at least one inhibitory treatment is R-CHOP.

[0083] For relapsed or refractory non-Hodgkin lymphoma, especially CD20-positive diffuse large B-cell lymphoma with double expression of BCL2 and MYC, after receiving at least one standard treatment regimen, the anti-CD20 antibody drug conjugate combination regimen of the present application shows better tumor inhibition effect and better treatment potential compared with the existing second-line standard therapy, while having good safety. BRIEF DESCRIPTION OF DRAWINGS

[0084] Hereinafter, embodiments of the present application will be described in detail with reference to the accompanying drawings, in which:

[0085] Figure 1 Tumor volume change trend of each administration group of mice in WSU-DLCL2 / R-CHOP (relapse model);

[0086] Figure 2 Body weight change trend of each administration group of mice in WSU-DLCL2 / R-CHOP (relapse model). DETAILED DESCRIPTION

[0087] The present application will be described in detail below with reference to specific examples. Those skilled in the art will understand that these examples are only used to illustrate the present application, and do not limit the scope of the present application in any way.

[0088] The experimental methods in the following examples are all conventional methods unless otherwise specified. The raw materials, reagents and materials used in the following examples are all commercially available products unless otherwise specified.

[0089] Definitions:

[0090] "Rituximab" refers to: a CD20-targeted monoclonal antibody drug developed by Roche and approved for marketing by drug regulatory agencies with the trade name "Mabthera". Rituximab is its generic name, and only the original drug can be called rituximab.

[0091] "Rituximab biosimilar" refers to: in addition to the original rituximab, other enterprises develop monoclonal antibody drugs with the same amino acid sequence as rituximab, and the physicochemical properties, efficacy, pharmacokinetics and safety of the original rituximab are similar to those of the original rituximab.

[0092] "High expression" refers to: the recognition of the high expression of antigen or gene by the technical personnel according to the tumor tissue or cell antigen or gene expression level detection results according to the conventional evaluation standard higher than a certain expression level or relatively higher expression level, for example, the strong positive (+++) and / or positive (++) determined according to the proportion of immunohistochemical colored cells and staining intensity can be determined as the high expression of antigen or gene.

[0093] "Low expression" refers to: the recognition of the low expression of antigen or gene by the technical personnel according to the tumor tissue or cell antigen or gene expression level detection results according to the conventional evaluation standard lower than a certain expression level or relatively lower expression level, for example, the weak positive (+) determined according to the proportion of immunohistochemical colored cells and staining intensity can be determined as the low expression of antigen or gene.

[0094] "Effective dose" refers to the amount effective to achieve the desired therapeutic result at the required dose and time period. The 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 the desired response in the individual.

[0095] The "standard treatment" referred to in the present application is not limited to the standard treatment regimen determined in the general sense of clinical practice, but also includes clinical recommended treatment regimen, clinical trial treatment regimen and other treatment regimens.

[0096] Although the present application has been described generally, embodiments of the present application will be further disclosed in the following examples, which should not be construed as limiting the scope of the claims.

[0097] Example 1: Preparation of anti-CD20 ADC (TRS005)

[0098] The preparation method of the exemplary anti-CD20 ADC (TRS005) is specifically described in Chinese Patent CN108452318B, which is incorporated herein in its entirety.

[0099] The structure of TRS005 is as follows:

[0100]

[0101] wherein mAb is rituximab or a rituximab biosimilar, and the drug-antibody ratio (DAR) is 4.2±0.5.

[0102] Example 2: Anti-tumor efficacy evaluation of TRS005 alone or in combination in a human lymphoma WSU-DLCL2 / R-CHOP relapse model

[0103] (I) Model establishment

[0104] The establishment of the relapse model uses conventional methods in the art, for example, WSU-DLCL2 cells are inoculated into mice, treated with R-CHOP, defined as P1; tumor tissues with good growth state of WSU-DLCL2 / R-CHOP (P1) are selected, the fascia and internal necrotic tissues of the mice are removed, and then the mice are inoculated with the tissues under sterile conditions, treated with R-CHOP, defined as P2; tumor tissues with good growth state of WSU-DLCL2 / R-CHOP (P2) are selected, the fascia and internal necrotic tissues of the mice are removed, and then the mice are inoculated with the tissues under sterile conditions, treated with R-CHOP, defined as P3; the R-CHOP relapse model is constructed by P1-P3 passages through R-CHOP treatment.

[0105] The tumor tissues with good growth state of WSU-DLCL2 / R-CHOP (P3) are selected, the fascia and internal necrotic tissues of the mice are removed, and then the tissues are cut into 2x2x2mm 3 pieces and stored in RPMI 1640 basic medium for standby. After the animals are anesthetized with isoflurane, the tissue pieces are inoculated into the right subcutaneous tissue of the mice under sterile conditions using an 11G cannula needle.

[0106] (II) Grouping and administration

[0107] When the average tumor volume reaches 120-150mm 3 , the animals are randomly grouped according to the tumor volume, so that the difference in tumor volume between groups is less than 10% of the average value. In this experiment, 48 animals are grouped, divided into 8 groups, 6 animals in each group. The day of grouping is recorded as Day0, and the animals are immediately administered after grouping according to their body weight. The grouping and administration scheme is shown in Table 2.

[0108] Table 2. Grouping and administration scheme

[0109]

[0110]

[0111] IV indicates intravenous injection; IP indicates intraperitoneal injection; and PO indicates oral administration.

[0112] Animal body weight and tumor volume were measured twice weekly during the experiment. Clinical symptoms were observed and recorded daily during the experiment. Clinical observation included overall animal health, abnormal weight, behavioral abnormalities, and other drug-related adverse reactions.

[0113] (III) Evaluation Indicators and Statistical Analysis

[0114] Tumor growth inhibition rate (%TGI) TV The calculation formula is: (1-TV) T / TV C )×100%, TV C The mean tumor volume of the negative control group, TV T The average tumor volume is for the treatment group.

[0115] The formula for calculating relative tumor volume (RTV) is: Vt / V0, where V0 is the tumor volume at the time of grouping and Vt is the tumor volume at each measurement.

[0116] Relative tumor proliferation rate (%T / C) RTV The calculation formula is: T RTV / C RTV ×100%, where T RTV For the treatment group RTV, C RTV This serves as the negative control group for RTV.

[0117] The formula for calculating the rate of change in animal body weight (%BWC) is: (BWt-BW0) / BW0×100%, where BWt is the animal's body weight at each measurement and BW0 is the animal's body weight at the time of grouping.

[0118] According to the "Technical Guidelines for Non-Clinical Studies of Cytotoxic Antitumor Drugs" issued by the China National Medical Products Administration (NMPA) in November 2006, %T / C RTV A drug is considered effective if the mortality rate is ≤40% and statistical analysis shows a p-value <0.05. If the number of animal deaths related to the drug exceeds 20%, the drug dose is considered to be severely toxic.

[0119] Experimental data are expressed as mean ± SEM. Two-tailed t-tests were used for comparisons between groups. P < 0.05 was considered statistically significant, and P < 0.01 was considered highly statistically significant (Microsoft Excel 2007, Redmond, WA, USA).

[0120] (iv) Test Results

[0121] 1. Inhibition of tumor volume by test substance

[0122] The experimental period was 35 days, and on Day 25, the vehicle control group animals began to have tumor volumes greater than 2000 mm 3 , and the experiment was terminated, and the animals were euthanized. Statistical analysis was performed using data from Day 25, and the results of the study of the anti-tumor activity of TRS005 in combination with GDP in the relapsed model of human lymphoma WSU-DLCL2 / R-CHOP are shown in Tables 4-5 and Figure 1 .

[0123] Referring to Tables 4 and Figure 1 , in the single administration group:

[0124] Group 5 TRS005 low, the average tumor volume was 963.43 ± 88.63 mm 3 , the tumor growth inhibition rate %TGI TV was 40.51% (P < 0.01); and the relative tumor proliferation rate %T / C RTV was 60.59% (P < 0.001).

[0125] Group 6 TRS005 high, the average tumor volume was 564.28 ± 92.11 mm 3 , the tumor growth inhibition rate %TGI TV was 65.16% (P < 0.001); and the relative tumor proliferation rate %T / C RTV was 36.02% (P < 0.001).

[0126] In the combination administration group:

[0127] Group 2 R-CHOP administration group, the average tumor volume was 1024.81 ± 85.61 mm 3 , the tumor growth inhibition rate %TGI TV was 36.72% (P < 0.05); and the relative tumor proliferation rate %T / C RTV was 64.15% (P < 0.001).

[0128] Group 3 R low + GDP administration group, the average tumor volume was 507.68 ± 96.44 mm 3 , the tumor growth inhibition rate %TGI TV was 68.65% (P < 0.001); and the relative tumor proliferation rate %T / C RTV was 31.53% (P < 0.001).

[0129] Group 4 R high + GDP administration group, the average tumor volume was 252.57 ± 82.91 mm 3 , the tumor growth inhibition rate %TGI TV was 84.40% (P < 0.001); the relative tumor proliferation rate %T / C RTV was 14.66% (P < 0.001).

[0130] Group 7 TRS005 low + GDP administration group, the average tumor volume was 42.93 ± 23.77 mm 3 , the tumor growth inhibition rate %TGI TV was 97.35% (P < 0.001); the relative tumor proliferation rate %T / C RTV was 2.29% (P < 0.001).

[0131] Group 8 TRS005 high + GDP administration group, the average tumor volume was 7.69 ± 7.69 mm 3 , the tumor growth inhibition rate %TGI TV was 99.53% (P < 0.001); the relative tumor proliferation rate %T / C RTV was 0.42% (P < 0.001).

[0132] Table 4. Anti-tumor activity of TRS005 in combination with GDP

[0133]

[0134]

[0135] *: P < 0.05 compared with the vehicle group.

[0136] **: P < 0.01 compared with the vehicle group.

[0137] ***: P < 0.001 compared with the vehicle group.

[0138] As shown in Table 5, the significant analysis of the anti-tumor activity showed that there was a very significant difference (P < 0.001) between the TRS005 low + GDP administration group and the TRS005 low dose administration group alone. There was a very significant difference (P < 0.001) between the TRS005 high + GDP administration group and the TRS005 high dose administration group alone.

[0139] There was a very significant difference (P < 0.01) between the TRS005 low + GDP administration group and the R low + GDP administration group. There was a significant difference (P < 0.05) between the TRS005 high + GDP administration group and the R high + GDP administration group.

[0140] Table 5. Significance analysis of anti-tumor activity of TRS005 monotherapy or in combination with Gemox

[0141]

[0142] The above results show that the anti-CD20 antibody drug conjugate of the present application in combination with GDP significantly improves the tumor inhibition rate compared with the anti-CD20 antibody drug conjugate monotherapy and the second-line standard therapy R+GDP, and achieves excellent efficacy.

[0143] 2. Effects of test substances on body weight of tumor-bearing animals

[0144] The effects of each test substance on the body weight of tumor-bearing animals in the WSU-DLCL2 / R-CHOP relapse model after administration are shown in Table 6 and Figure 2 The results show that the average body weight of animals in each group changed by -2.01% to 6.78% (-0.49g to 1.52g) compared with Day 0 when the experiment started. The body weight changes of mice in each treatment group were within the normal range, no drug-related mouse deaths occurred, and no other obvious drug-related adverse reactions were observed, indicating that the TRS005 monotherapy and each TRS005 combination administration scheme of the present application have good safety.

[0145] Table 6. Effects of administration of each group on the body weight of tumor-bearing animals

[0146]

[0147]

[0148] In summary, for the WSU-DLCL2 / R-CHOP relapse model, the TRS005 high+GDP and TRS005 low+GDP dose groups of the present application both significantly improve the tumor inhibition rate compared with the corresponding second-line standard therapy R high+GDP and R low+GDP dose groups; the TRS005 high+GDP and TRS005 low+GDP dose groups both significantly improve the tumor inhibition rate compared with the corresponding TRS005 high and TRS005 low monotherapy dose groups; no animal deaths and other drug-related adverse reactions were observed during the experiment, and the TRS005 combination with GDP scheme of the present application has good safety.

[0149] The above description of specific embodiments of the present application does not limit the present application, and those skilled in the art can make various changes or modifications to the present application without departing from the spirit of the present application, and all such changes or modifications shall fall within the scope of the appended claims of the present application.

Claims

1. Use of an anti-CD20 antibody drug conjugate and at least one therapeutic agent in the manufacture of a medicament for treating relapsed or refractory non-Hodgkin's lymphoma after receiving at least one standard treatment regimen, characterized in that, The anti-CD20 antibody drug conjugate has the following structure: wherein mAb represents a recombinant anti-CD20 monoclonal antibody, the drug-to-antibody ratio (DAR) is 1-8, preferably the DAR is 4.2±1, further preferably the DAR is 4.2±0.5, and more preferably the DAR is 4.2±0.3; wherein the at least one therapeutic agent is selected from one or more of a hormone drug, a platinum drug, and an antimetabolite drug; the hormone drug is selected from one or more of prednisone, dexamethasone, and methylprednisolone; the platinum drug is selected from one or more of carboplatin, cisplatin, and oxaliplatin; the antimetabolite drug is selected from one or more of pemetrexed, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, and thioguanine.

2. Use according to claim 1, wherein The recombinant anti-CD20 monoclonal antibody is selected from Rituximab or a biosimilar thereof, Ofatumumab or a biosimilar thereof, Ocrelizumab or a biosimilar thereof, and Obinutuzumab or a biosimilar thereof.

3. Use according to claim 2, wherein the compound is ###0002### The recombinant anti-CD20 monoclonal antibody is selected from Rituximab or a biosimilar thereof.

4. Use according to any one of claims 1 to 3, wherein The at least one therapeutic agent is gemcitabine, dexamethasone, and cisplatin.

5. Use according to any one of claims 1 to 4, wherein The non-Hodgkin's lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocyte leukemia, or anaplastic large cell lymphoma.

6. The use according to claim 5, wherein the compound is ###0002### The non-Hodgkin's lymphoma is diffuse large B-cell lymphoma.

7. Use according to claim 6, wherein The diffuse large B-cell lymphoma is CD20-positive diffuse large B-cell lymphoma.

8. Use according to claim 7, wherein the compound is ###0002### The CD20-positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

9. Use according to any one of claims 1 to 8, wherein The at least one standard treatment regimen at least includes anti-CD20 antibody monotherapy or anti-CD20 antibody combination therapy.

10. Use according to claim 9, wherein The at least one standard treatment regimen at least includes one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R, and Pola-R-CHP.

11. Use according to claim 10, wherein the compound is ###00003### or a pharmaceutically acceptable salt thereof. The at least one standard treatment regimen is R-CHOP.

12. A pharmaceutical product for the treatment of relapsed or refractory non-Hodgkin's lymphoma after having received at least one standard treatment regimen, characterized in that, The drug product comprises an anti-CD20 antibody drug conjugate and at least one therapeutic agent, the anti-CD20 antibody drug conjugate has the following structure: wherein mAb represents a recombinant anti-CD20 monoclonal antibody, the drug-to-antibody ratio (DAR) is 1-8, preferably the DAR is 4.2±1, further preferably the DAR is 4.2±0.5, and more preferably the DAR is 4.2±0.

3. wherein the at least one therapeutic agent is selected from one or more of a hormone drug, a platinum drug, and an antimetabolite drug; the hormone drug is selected from one or more of prednisone, dexamethasone; the platinum drug is selected from one or more of carboplatin, cisplatin, and oxaliplatin; the antimetabolite drug is selected from one or more of pemetrexed, methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine, 6-mercaptopurine, and thioguanine. The anti-metabolite is selected from one or more of Pemetrexed, Methotrexate, Fluorouracil, Capecitabine, Cytarabine, Gemcitabine, 6-Mercaptopurine, and Thioguanine.

13. The pharmaceutical product according to claim 12, characterized in that The recombinant anti-CD20 mAb is selected from Rituximab (Rituxan®) or a biosimilar thereof, Ofatumumab (Arzerra®) or a biosimilar thereof, Ocrelizumab (Ocrevus®) or a biosimilar thereof, and Obinutuzumab (Gazyva®) or a biosimilar thereof.

14. The pharmaceutical product according to claim 13, characterized in that The recombinant anti-CD20 mAb is selected from Rituximab (Rituxan®) or a biosimilar thereof.

15. Pharmaceutical product according to any one of claims 12 to 14, characterized in that The at least one therapeutic agent is Gemcitabine, Dexamethasone, and Cisplatin.

16. Pharmaceutical product according to any one of claims 12 to 15, characterized in that The non-Hodgkin lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocyte leukemia, or anaplastic large cell lymphoma.

17. The pharmaceutical product according to claim 16, characterized in that The non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

18. The pharmaceutical product according to claim 17, characterized in that The diffuse large B-cell lymphoma is CD20-positive diffuse large B-cell lymphoma.

19. The pharmaceutical product according to claim 18, characterized in that The CD20-positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

20. The pharmaceutical product according to any one of claims 12 to 19, characterized in that, The at least one standard treatment regimen comprises at least anti-CD20 antibody monotherapy or anti-CD20 antibody combination therapy.

21. The pharmaceutical product according to claim 20, characterized in that The at least one standard treatment regimen comprises at least one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R, and Pola-R-CHP.

22. The pharmaceutical product according to claim 21, characterized in that The at least one standard treatment regimen is R-CHOP.

23. A combination therapy for the treatment of relapsed or refractory non-Hodgkin's lymphoma after at least one standard treatment regimen, comprising, The subject is administered an effective dose of the pharmaceutical product of any one of claims 12-22.

24. The combination therapy of claim 23, wherein, The non-Hodgkin lymphoma is selected from small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia, marginal zone B-cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma, precursor (peripheral) large granular lymphocyte leukemia, or anaplastic large cell lymphoma.

25. The combination therapy of claim 24, wherein, The non-Hodgkin lymphoma is diffuse large B-cell lymphoma.

26. The combination therapy of claim 25, wherein, The diffuse large B-cell lymphoma is CD20-positive diffuse large B-cell lymphoma.

27. The combination therapy of claim 26, wherein, The CD20-positive diffuse large B-cell lymphoma is MYC and BCL2 double-expressed diffuse large B-cell lymphoma.

28. The combination therapy of any of claims 23-27, wherein, The at least one standard treatment regimen comprises at least anti-CD20 antibody monotherapy or anti-CD20 antibody combination therapy.

29. The combination therapy of claim 28, wherein the anti-VEGF antibody is administered intravitreally. The at least one standard treatment regimen comprises at least one selected from R-CHOP, R-CHOEP, R-miniCHOP, DA-EPOCH-R, and Pola-R-CHP.

30. The combination therapy of claim 29, wherein the anti-VEGF antibody is administered intravitreally. The at least one standard treatment regimen is R-CHOP.

31. The combination therapy of any of claims 23-30, wherein, The anti-CD20 antibody drug conjugate is administered prior to, concurrently with, and / or after administration of the at least one additional therapeutic agent.

32. A non-therapeutic method of inhibiting non-Hodgkin's lymphoma cells, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-31. administering an effective amount of the pharmaceutical product of any one of claims 12-22 to a non-Hodgkin's lymphoma cell system, wherein the non-Hodgkin's lymphoma cell is a relapsed or refractory non-Hodgkin's lymphoma cell after receiving at least one inhibitory treatment.

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