Treatment of B-cell malignancies

Abstract

The present disclosure relates to anti-BAFFR antibodies and binding fragments thereof, alone or in combination with additional agents, for use in the treatment of B-cell malignancies, such as B-cell non-Hodgkin's lymphoma.

Description

Technical Field

[0001] 1. Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 060,786, filed on August 4, 2020; U.S. Provisional Patent Application No. 63 / 114,363, filed on November 16, 2020; and U.S. Provisional Patent Application No. 63 / 147,507, filed on February 9, 2021, the contents of each of which are hereby incorporated herein by reference in their entirety.

[0002] 2. Sequence listing This application includes a sequence listing submitted electronically in ASCII format, which is hereby incorporated herein by reference in its entirety. The ASCII copy created on July 26, 2021, is named PAT059003 - WO - PCT_SL.txt and is 13,921 bytes in size.

[0003] The present disclosure generally relates to anti - BAFFR antibodies and binding fragments thereof for use in the treatment of B - cell malignancies, such as B - cell non - Hodgkin lymphoma, as a monotherapy or as a "backbone" agent in combination with one or more additional agents.

Background Art

[0004] B - cell malignancies include non - Hodgkin lymphoma (NHL), Hodgkin lymphoma, leukemia, and myeloma.

[0005] NHL accounts for approximately 4% of all cancers, with an estimated 74,200 new cases diagnosed and approximately 19,970 deaths in the United States in 2019 (www.cancer.org). NHL is classified by the WHO into immature lymphoid neoplasms, mature B-cell neoplasms, T-cell and NK-cell neoplasms, and post-transplant lymphoproliferative disorders (PTLD). Mature B-cell lymphomas are further classified into painless lymphomas (e.g., follicular lymphoma, small lymphocytic lymphoma) and invasive lymphomas (e.g., diffuse large B-cell lymphoma, mantle cell lymphoma).

[0006] Diffuse large B-cell lymphoma (DLBCL) is the most common invasive lymphoma subtype, accounting for 30–35% of all NHLs (Ghielmini et al 2013). Approximately one-third of DLBCL patients will develop relapsed and / or refractory (r / r) disease, which is a major cause of morbidity and mortality. Patients with relapsed and / or refractory disease have a poor prognosis. Approximately 60% of patients with r / r DLBCL maintain sensitivity to conventional second-line salvage immunochemotherapy, while less than 10% have extended disease-free survival (Gisselbrecht et al 2010). In the recently reported SCHOLAR-1 trial, which combined data from two clinical trials and two academic databases, the median overall survival for 636 patients with refractory DLBCL was only 6.3 months, while only 20% of patients survived for two years (Crump et al 2017). The prognosis is poor for transplant candidates who have failed second-line therapy or who have relapsed after transplantation. Novel therapies that showed promising activity include the BTK inhibitor ibrutinib (ORR of 25% in DLBCL patients) (Wilson et al 2015), monoclonal antibodies (e.g., immune checkpoint inhibitors with an ORR of approximately 40% in DLBCL (Lesokhin et al 2016; Zinzani et al 2017)), bispecific antibodies such as blinatumomab with an ORR of 35-50% (Viardot et al 2016), ADCs (ORR of brentuximab vedotin with 44% in CD30+ relapsed DLBCL (Jacobsen et al 2015), ORR of polatuzumab vedotin in combination with rituximab and bendamustine with 70% (Sehn et al 2017)), and cell therapies (e.g., CAR-T therapy with an ORR of 53-82% (Neelapu et al 2017; Schuster)). This includes oral targeted therapies such as those described in et al 2017). CAR-T therapy appears to result in long-term remission in approximately one-third of r / r DLBCL patients.Most recently, in 2020, tafacitamab-cxix (MOR208, MONJUVI®) + lenalidomide (ORR 55%, CR 37%) received initial FDA approval for patients with relapsed or refractory DLBCL who are unsuitable for transplantation (Tafacitamab-cxix prescribing information).

[0007] Mantle cell lymphoma (MCL) is an invasive mature B-cell non-Hodgkin lymphoma associated with poor long-term survival. Treatment consists primarily of immunochemotherapy; the choice of treatment strategy and regimen is variable and depends on symptoms and patient fitness (Schieber et al 2018). Despite a high initial response rate (ORR > 90% with invasive therapy), MCL remains an incurable disease. The 5-year overall survival rate in low-risk patients is approximately 80%, compared to 34% in high-risk patients (Hoster et al 2014). The median survival rate for relapsed MCL has historically been less than 3 years. Targeted therapies such as bortezomib (Fisher et al 2006) and temsirolimus (Hess et al 2009) have improved response rates. Lenalidomide showed promising activity (28% ORR) in a heavily pre-treated population in the Phase II EMERGE trial, leading to its approval in the United States (Goy et al 2013). In a Phase III trial, the Bruton's tyrosine kinase ibrutinib demonstrated a significant improvement in progression-free survival (PFS) compared to temsirolimus, and showed few treatment-related adverse effects (Dreyling et al 2016). Phase II data for ibrutinib combined with the Bcl-2 inhibitor venetoclax achieved a complete remission rate (CRR) of 42% compared to 9% in historical controls (Tam et al 2018). More recently, data from a phase II trial of acalabrutinib monotherapy for relapsed / refractory MCL (ACE-LY-004 trial) showed a median PFS of 20 months, an 81% ORR, and a 43% CR rate (Wang et al 2019). Despite promising developments over the past decade, assuming a 1-year overall survival rate of approximately 70% in the ibrutinib era, patients with r / r MCL require novel treatment options (Schieber et al 2018).

[0008] Despite the introduction of newer therapies for the treatment of B-cell malignancies, including relapsed / refractory NHL such as DLBCL and MCL, there remains a significant unmet medical need for patients with B-cell malignancies, such as those with relapsed / refractory NHL. These patients have few effective treatment options and suffer from significantly reduced overall survival. [Overview of the Initiative]

[0009] This disclosure relates to an anti-B cell activator receptor antibody (anti-BAFFR antibody) and its conjugate fragment for use in the treatment of B cell malignancies (e.g., non-Hodgkin lymphomas such as DLBCL or MCL) as monotherapy or as a “skeleton” agent in combination with one or more additional agents, such as an immunomodulatory imide (IMiD) such as lenalidomide. BAFFR is widely expressed in B cell malignancies such as NHL and CLL, and preclinical and clinical trials using the anti-BAFFR antibody ianarumab (VAY736), as reported in the examples of this application, support the use of an anti-BAFFR antibody and its conjugate fragment for the treatment of B cell malignancies as monotherapy or in combination with one or more additional agents.

[0010] Accordingly, in one embodiment, the present disclosure provides an anti-BAFFR antibody (e.g., ianarumab) or a conjugated fragment thereof for use in the treatment of B-cell malignancies in subjects requiring such use, wherein the anti-BAFFR antibody or conjugated fragment thereof is to be administered in a therapeutically effective dose.

[0011] In some embodiments, the anti-BAFFR antibody or its conjugated fragment should be administered in combination with one or more additional agents. In some embodiments, one or more additional agents include immunomodulatory imide drugs (IMiDs), such as lenalidomide.

[0012] In another aspect, the present disclosure provides a novel dosing regimen for an anti-BAFFR antibody (e.g., ianarumab) and its conjugate fragments that can be used in methods for treating B-cell malignancies.

[0013] Exemplary anti-BAFFR antibodies and administration regimens for use in the treatment of B-cell malignancies are described in Section 7.2 and specific embodiments 1-32 below. Exemplary additional agents are described in Section 7.3 and specific embodiments 33-49 below. Exemplary B-cell malignancies and patient populations suitable for treatment using the methods and compositions described herein are described in Section 7.4 and specific embodiments 116-166.

[0014] In another aspect, the present disclosure provides a method for treating subjects with B-cell malignancies using an anti-BAFFR antibody (e.g., ianarumab) or a conjugate thereof, either as monotherapy or in combination with one or more additional agents. Exemplary therapeutic methods are described in the specific embodiments 50–100 below.

[0015] In another embodiment, the present disclosure provides combinations comprising an anti-BAFFR antibody (e.g., ianarumab) or a conjugate thereof with one or more additional agents, such as immunomodulatory imide drugs (IMiDs). Such combinations can be used, for example, in methods of treating subjects having B-cell malignancies, as described herein. In some embodiments, the combinations include ianarumab and lenalidomide. Exemplary combinations are described in the specific embodiments 101-111 below.

[0016] In another embodiment, the disclosure provides the use of anti-BAFFR antibodies (e.g., ianarumab) and their conjugate fragments, as well as additional agents, in the manufacture of agents for treating subjects having NHLs such as DLBCL or MCL. In some embodiments, the subjects have an NHL, e.g., DLBCL or MCL, and (i) have failed at at least one prior line (and optionally up to five prior lines) of standard therapeutic therapy, e.g., anti-CD20 therapy such as rituximab, and / or (ii) are intolerant to or unsuitable for one or more other approved therapies, e.g., autologous stem cell transplantation (ASCT), and / or (iii) are unresponsive to chimeric antigen receptor (CAR) T-cell therapy. The NHL may be relapsed and / or refractory.

[0017] In some embodiments, the agent comprising an anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is for administration in combination with an additional agent, e.g., an additional agent described herein, and / or for administration in a therapeutic method described herein. Exemplary uses of the anti-BAFFR antibody and its conjugate fragment, as well as the additional agent, in the manufacture of the agent are described in specific embodiments 112-115 below.

[0018] In a further embodiment, the Disclosure provides anti-BAFFR antibodies and their conjugates for use in the treatment of subjects having or at risk of cytokine release syndrome (CRS), a method for reducing the severity of one or more symptoms of CRS in a subject by administering the anti-BAFFR antibody or its conjugate to the subject, and the use of anti-BAFFR antibodies and their conjugates in the manufacture of agents for treating subjects having or at risk of CRS. Where theories are not constrained, cytokine release by normal B cells is considered to be a key driver in CRS, and depletion of normal B cells in a subject by anti-BAFFR antibodies or their conjugates is considered to reduce the severity of CRS experienced by the subject and / or reduce the likelihood of developing CRS. Exemplary anti-BAFFR antibodies and their conjugates for use in the treatment of subjects having or at risk of cytokine release syndrome (CRS), methods for using anti-BAFFR antibodies or their conjugates to reduce the severity of one or more symptoms of CRS in subjects, and the use of anti-BAFFR antibodies and their conjugates in the manufacture of agents for treating subjects having or at risk of CRS are described in specific embodiments 167-170 below. [Brief explanation of the drawing]

[0019] [Figure 1-1] Figure 1: Tumor growth in an in vivo model of DLBCL in animals treated with solvent (Figure 1A), 5 mg / kg VAY736 (Figure 1B), 50 mg / kg VAY736 (Figure 1C), or rituximab (Figure 1D). [Figure 1-2] (As stated above.) [Figure 1-3] (As stated above.) [Figure 1-4] (As stated above.) [Figure 2-1]Figure 2: Percent specific lysis of SUDHL4 cells in the presence of VAY736 by NK3.3 cells treated with lenalidomide (L) for 72 hours. NK3.3 cells were treated with lenalidomide or DMSO for 72 hours and then added to calcein AM-labeled SUDHL4 cells for 2 hours at an E:T ratio of 10:1 (Figure 2A) or 20:1 (Figure 2B) in the presence of a dose curve of VAY736. A total of 7.5e3 SUDHL4 cells were seeded. The x-axis is the concentration of VAY736 (ng / ml). [Figure 2-2] (As described above.) [Figure 3-1] Figure 3: Percent specific lysis of SUDHL4 cells in the presence of VAY736 by PBMC treated with lenalidomide (L) for 24 hours. Unstimulated PBMC were treated with lenalidomide or DMSO for 24 hours and then added to calcein AM-labeled SUDHL4 cells for 4 hours at an E:T ratio of 2:1 (Figure 3A), 10:1 (Figure 3B), or 20:1 (Figure 3C) in the presence of a dose curve of VAY736. A total of 7.5e3 SUDHL4 cells were seeded. The x-axis is the concentration of VAY736 (ng / ml). [Figure 3-2] (As described above.) [Figure 3-3] (As described above.) [Figure 4-1] Figure 4: Percent specific lysis of SUDHL4 cells in the presence of VAY736 by pNK cells treated with lenalidomide (L) for 24 hours. Unstimulated PBMC cells were treated with lenalidomide or DMSO for 24 hours and then NK cells isolated from the PBMC were added to calcein AM-labeled SUDHL4 cells for 4 hours at an E:T ratio of 2:1 (Figure 4A), 10:1 (Figure 4B), or 20:1 (Figure 4C) in the presence of a dose curve of VAY736. A total of 7.5e3 SUDHL4 cells were seeded. The x-axis is the concentration of VAY736 (ng / ml). [Figure 4-2] (As described above.) [Figure 4-3] (As described above.) [Figure 5-1]Figure 5: Percent specific lysis of SUDHL4 cells in the presence of VAY736 by NK3.3 cells treated with lenalidomide (L) for 24 or 72 hours. NK3.3 cells were treated with lenalidomide or DMSO for 48 hours (Figure 5B and Figure 5D) or 72 hours (Figure 5A and Figure 5C), then added to calcein AM-labeled SUDHL4 cells for 2 hours at an E:T of 20:1 (Figure 5A and Figure 5B) or 7:1 (Figure 5C and Figure 5D) in the presence of a dose curve of VAY736 or isotype control antibody. A total of 7.5e3 SUDHL4 cells were seeded. The x-axis is the concentration (ng / ml) of VAY736 or isotype control antibody. [Figure 5-2] (As described above.) [Figure 5-3] (As described above.) [Figure 5-4] (As described above.) [Figure 6-1] Figure 6: Percent specific lysis of SUDHL4 cells in the presence of VAY736 by NK3.3 cells treated with lenalidomide (L) for 48 or 72 hours, with isotype control subtracted. The data correspond to the data shown in Figures 5A - 5D, where the signal from the isotype control was subtracted from the VAY736 conditions. NK3.3 cells were treated with lenalidomide or DMSO for 48 hours (Figure 6B and Figure 6D) or 72 hours (Figure 6A and Figure 6C), then added to calcein AM-labeled SUDHL4 cells for 2 hours at an E:T of 20:1 (Figure 6A and Figure 6B) or 7:1 (Figure 6C and Figure 6D) in the presence of a dose curve of VAY736 or isotype control antibody. A total of 7.5e3 SUDHL4 cells were seeded. The x-axis is the concentration (ng / ml) of VAY736 or isotype control antibody. [Figure 6-2] (As described above.) [Figure 6-3] (As described above.) [Figure 6-4] (As described above.) [Figure 7-1]Figure 7: Percentage-specific lysis of SUDHL4 cells in the presence of VAY736 by unstimulated or stimulated PBMCs treated with lenalidomide (LEN) for 72 hours. Unstimulated (Figures 7A and 7C) or 24-hour IL2-stimulated (Figures 7B and 7D) PBMCs were treated with lenalidomide or DMSO for 72 hours and then added to calcein AM-labeled SUDHL4 cells for 3 hours in a 3:1 E:T ratio in the presence of a dose curve of VAY736 or isotype control. A total of 10e3 SUDHL4 cells were seeded. Figures 7A and 7B show the isotype control signal subtracted from the signal from VAY736. The X-axis is the concentration (ng / ml) of VAY736 (Figures 7A and 7B) or isotype control antibody or VAY736 (Figures 7C and 7D). SVC = solvent control (DMSO). [Figure 7-2] (As stated above.) [Figure 7-3] (As stated above.) [Figure 7-4] (As stated above.) [Figure 8] The effect of lenalidomide (LEN) on IL2 production in PBMCs in the presence and absence of CD3+ cells. Unstimulated PBMCs or PBMCs with depleted positive CD3+ cells were treated with lenalidomide or DMSO for 72 hours, and the supernatant was then isolated and analyzed for IL2 protein, expressed in pg / ml units. [Figure 9-1] Figure 9: Percentage-specific lysis of SUDHL4 cells in the presence of VAY736 by PBMCs treated with lenalidomide (LEN) for 72 hours, in the presence and absence of CD3+ cells. PBMCs were treated with lenalidomide or DMSO for 72 hours, and then PBMCs (Figure 9A), pNK cells isolated from PBMCs (Figure 9B), or CD3+-depleted PBMCs (Figure 9C) were added to calcein AM-labeled SUDHL4 cells for 4 hours in E:T ratios of 2:1, 6:1 (PBMC), 1:1, 1:3, 1:10 (pNK), or 2:1, 6:1, 15:1 (CD3+-depleted PBMC), in the presence of a dose curve of VAY736. A total of 7.5e3 SUDHL4 cells were seeded. Figure 9D is an edited compilation of data from Figures 9A-9C. The X-axis represents the concentration of VAY736 (ng / ml). [Figure 9-2] (As stated above.) [Figure 9-3] (As stated above.) [Figure 9-4] (As stated above.) [Figure 10] Presentation of a schematic diagram of the treatment plan for Example 3. [Figure 11] Percentage change from baseline in blood MRD of patients treated as in Example 3. [Modes for carrying out the invention]

[0020] In one embodiment, the disclosure provides an anti-BAFFR antibody (e.g., ianarumab) or a conjugate thereof for use in the treatment of B-cell malignancies in subjects requiring such use. For example, B-cell malignancies may be non-Hodgkin lymphoma (NHL), e.g., chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), MALT lymphoma (mucosa-associated lymphoid tissue lymphoma) or marginal zone lymphoma (MZL), leukemia, or multiple myeloma.

[0021] Anti-BAFFR antibodies or fragments thereof can be administered as monotherapy or in combination with one or more additional drugs.

[0022] In another embodiment, the Disclosure provides a method for treating a subject having a B-cell malignancy with an anti-BAFFR antibody (e.g., ianarumab) or a conjugate thereof, either as monotherapy or in combination with one or more additional agents. In some embodiments, the subject has an NHL, e.g., DLBCL or MCL, and (i) has failed at at least one prior line (and optionally up to five prior lines) of standard therapy, e.g., anti-CD20 therapy such as rituximab, and / or (ii) is intolerant to or unsuitable for one or more other approved therapies, e.g., autologous stem cell transplantation (ASCT), and / or (iii) is unresponsive to chimeric antigen receptor (CAR) T-cell therapy. The NHL may be relapsed and / or refractory.

[0023] In another embodiment, the disclosure provides a combination comprising an anti-BAFFR antibody (e.g., ianarumab) or a conjugate thereof, and one or more additional agents, such as immunomodulatory imide drugs (IMiDs). In some embodiments, the combination comprises ianarumab and lenalidomide.

[0024] In another embodiment, the disclosure provides the use of anti-BAFFR antibodies (e.g., ianarumab) and their conjugate fragments, as well as additional agents, in the manufacture of agents for treating subjects having NHLs such as DLBCL or MCL. In some embodiments, the subjects have an NHL, e.g., DLBCL or MCL, and (i) have failed at at least one prior line (and optionally up to five prior lines) of standard therapeutic therapy, e.g., anti-CD20 therapy such as rituximab, and / or (ii) are intolerant to or unsuitable for one or more other approved therapies, e.g., autologous stem cell transplantation (ASCT), and / or (iii) are unresponsive to chimeric antigen receptor (CAR) T-cell therapy. The NHL may be relapsed and / or refractory.

[0025] In a further embodiment, the Disclosure provides anti-BAFFR antibodies and their conjugates for use in the treatment of subjects having or at risk of cytokine release syndrome (CRS), a method for reducing the severity of one or more symptoms of CRS in a subject by administering the anti-BAFFR antibody or its conjugates to the subject, and the use of anti-BAFFR antibodies and their conjugates in the manufacture of agents for treating subjects having or at risk of CRS.

[0026] Exemplary anti-BAFFR antibodies and conjugate fragments are described in Section 7.2. Exemplary administration schemes for the use of exemplary anti-BAFFR antibodies or conjugate fragments in the treatment of B-cell malignancies are described in Section 7.2. Exemplary additional agents are described in Section 7.3. Exemplary B-cell malignancies are described in Section 7.4. Exemplary characteristics of pharmaceutical compositions are described in Section 7.5.

[0027] 7.1.Definition As used herein, the following terms are intended to have the following meanings:

[0028] A, An, The: When used herein, the terms “a,” “an,” “the” and similar terms used in connection with this disclosure (in particular with the claims) should be construed to encompass both singular and plural unless otherwise indicated herein or explicitly denied by the context. Thus, the terms “a” (or “an”), “one or more,” and “at least one” may be used interchangeably herein.

[0029] and / or: The term "and / or" means that each, both, or all of the components or features of the list, especially two or more of them in an alternative or cumulative form, are possible alternative spellings.

[0030] Additional drugs: For convenience, drugs used in combination with anti-BAFFR antibodies or their conjugated fragments are referred to herein as “additional” drugs.

[0031] Antibody: The term “antibody” refers to a protein, such as an immunoglobulin chain or a fragment thereof, that contains at least one immunoglobulin variable domain sequence. The term “antibody” includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). An antibody includes a full-length antibody, or a full-length immunoglobulin chain, or an antigen-binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. An antibody may also be a multiselective antibody, for example, that contains multiple immunoglobulin variable domain sequences, where the majority of first immunoglobulin variable domain sequences have binding specificity to a first epitope, and the majority of second immunoglobulin variable domain sequences have binding specificity to a second epitope. The term “binding fragment,” as used herein, refers to a portion of an antibody that has the ability to bind to a BAFFR epitope.

[0032] Anti-BAFFR antibody: The term "anti-BAFFR antibody or its conjugated fragment" as used herein refers to an antibody or its conjugated fragment containing a BAFFR-binding domain. Binding of the antibody (or its conjugated fragment) to BAFFR inhibits the binding of BAFFR to BAFF, thereby reducing the formation of the BAFF / BAFFR complex and / or decreasing the activation of BAFFR. Preferably, the anti-BAFFR antibody or its conjugated fragment can reduce the formation of the BAFF / BAFFR complex and / or decrease the activation of BAFFR by at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more compared to a suitable control (e.g., a sample without the anti-BAFFR antibody or its conjugated fragment). Additionally or alternatively, the anti-BAFFR antibody or its binding can dissociate pre-formed BAFF / BAFFR complexes. In preferred embodiments, the antibody or its binding fragment can dissociate at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more of the pre-formed BAFF / BAFFR complex. As described above, this property can be compared to a suitable control (e.g., a sample without the presence of an anti-BAFFR antibody or its binding fragment).

[0033] BAFFR: The term "BAFFR" refers to the B cell activator receptor protein. BAFFR is also known as TNF receptor superfamily member 13C (TNFRSF13C). The amino acid and nucleic acid sequences of human and mouse BAFFR can be found in public databases such as GenBank, UniProt, and Swiss-Prot. For example, the amino acid sequence of human BAFFR can be found as acceptance number Q96RJ3 in UniProt / Swiss-Prot, and the nucleotide sequence encoding human BAFFR can be found as acceptance number NM_052945.4. It is primarily expressed in subsets of B lymphocytes and T cells.

[0034] B-cell malignancies: As used herein, B-cell malignancies refer to the uncontrolled proliferation of B cells. Examples of B-cell malignancies include non-Hodgkin lymphoma (NHL), such as diffuse large B-cell lymphoma (DLBCL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma, mantle cell lymphoma (MCL), follicular lymphoma, mucosa-associated lymphoid tissue lymphoma (MALT), and Burkitt lymphoma; precursor B-lymphoblastic leukemia; chronic lymphocytic leukemia; and multiple myeloma.

[0035] Chimeric Antigen Receptor: The term “chimeric antigen receptor” or alternatively “CAR” refers, in the case of an immune effector cell, to a set of two polypeptides that, in its simplest embodiment, provide the cell with specificity to target cells, typically cancer cells, and intracellular signaling. In some embodiments, the CAR comprises at least an extracellular antigen-binding domain, a transmembrane domain, and a cytoplasmic signaling domain (also referred to herein as the “intracellular signaling domain”) which includes a functional signaling domain derived from stimulating and / or co-stimulating molecules as defined below. The set of polypeptides may be adjacent or non-adjacent to each other. If the polypeptides are not adjacent to each other, the set of polypeptides may include a dimerization switch that can couple the polypeptides to each other in the presence of a dimerizing molecule, for example, a dimerization switch that can couple the antigen-binding domain to the intracellular signaling domain. The CAR molecule is typically administered to a subject through the administration of immune effector cells (e.g., preferably autologous T cells to the subject) that have been modified to express the CAR molecule.

[0036] Combinations: The terms “combinations” or “combined with” are not intended to imply that the therapies or therapeutic agents must be administered simultaneously and / or formulated for joint delivery, although such delivery methods are included within the scope described herein. A combined therapeutic agent may be administered simultaneously with, before, or after, one or more other additional therapies or therapeutic agents. The therapeutic agents or treatment protocols may be administered in any order. Generally, each agent will be administered in the dose and / or time schedule determined for that agent. Furthermore, it will be understood that the additional therapeutic agents used in this combination may be administered together or separately in different compositions. Generally, it is assumed that the additional therapeutic agents used in a combination are utilized at levels not exceeding those at which they are used individually. In some embodiments, the levels at which they are used in combination are lower than those at which they are used individually.

[0037] Drugs, active substances, active ingredients, etc.: The terms “drug,” “active substance,” “active ingredient,” “pharmaceutical active ingredient,” “active drug,” “therapeutic drug,” or “drug” should be understood to mean a compound in its free form or in the form of a pharmaceutically acceptable salt.

[0038] Effective dose: The terms “effective dose,” “therapeutic effective dose,” or “pharmaceutical effective dose” mean the amount or content of an active agent that is sufficient to induce a requested or desired response, or in other words, the amount that, when administered to a subject, is sufficient to induce a clear biological response. The amount preferably relates to the amount that is therapeutically, or more broadly, prophylactically effective against the progression of a disease or disorder as disclosed herein. It is understood that the “effective dose” or “therapeutic effective dose” may vary among subjects due to variations in drug metabolism, age, weight, the subject’s overall condition, the condition under treatment, the severity of the condition under treatment, and the judgment of the prescribing physician.

[0039] Patient / Subject: As used herein, the terms “patient” or “subject” shall be interpreted as meaning a human being. Unless otherwise specified, the terms “patient” or “subject” shall be used interchangeably herein.

[0040] ~to need: As used herein, an object "needs" such treatment if such object derives a biological, medical, or quality of life benefit from such treatment.

[0041] Pharmaceutically acceptable: The term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that falls within the bounds of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable risk-benefit ratio.

[0042] pharmaceutically acceptable salts: The term “pharmaceutically acceptable salt” can be, for example, formed as an acid addition salt with an organic or inorganic acid. Suitable inorganic acids are halogen acids, such as hydrochloric acid. Suitable organic acids are carboxylic acids or sulfonic acids, such as fumaric acid or methanesulfonic acid. For isolation or purification purposes, pharmaceutically acceptable salts, such as picrates or perchlorates, may also be used. For therapeutic applications, only pharmaceutically acceptable salts or free compounds are used (where applicable in the form of a formulation), and therefore these are preferred. Any reference to free compounds herein should be understood to also refer to the corresponding salts, for appropriate and convenient reasons. Salts of pharmaceuticals are, as described herein, preferably pharmaceutically acceptable salts; suitable counterions for forming pharmaceutically acceptable salts are known in the art.

[0043] To treat, to treat, treatment: As used herein, the terms “to treat,” “to treat,” or “treatment” for any disease or disorder mean, in one embodiment, to bring the disease or disorder into remission (e.g., to slow, stop, or reduce the manifestation of the disease or at least one clinical symptom or its pathological feature). In another embodiment, “to treat,” “to treat,” or “treatment” means to reduce or bring into remission at least one physical parameter or pathological feature of the disease, including, for example, cases that may not be identifiable by the subject. In yet another embodiment, “to treat,” “to treat,” or “treatment” means to modulate the disease or disorder by physical means (e.g., stabilization of at least one identifiable or unidentifiable symptom), physiological means (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “to treat,” “to treat,” or “treatment” means to prevent or delay the onset, manifestation, or progression of at least one symptom or pathological feature of, or associated with, the disease or disorder. In yet another embodiment, “to treat,” “to cure,” or “to treat” refers to preventing the progression of a disease or delaying it to a more advanced stage or a more severe condition. The benefit to the patient being treated is statistically significant or at least recognizable to the patient or the physician. However, it will be understood that when a drug is administered to a patient to treat a disease, the outcome may not always be an effective treatment.

[0044] The following abbreviations will be used throughout this disclosure. ADCC antibody-dependent cytotoxicity Adverse events (AEs) ANC Absolute Neutral Count BAFF B cell activating factor BAFF-R B-cell activator receptor BHLRM Bayesian Hierarchical Logistic Regression Model BOR Best Overall Effect BTK Bruton's tyrosine kinase BTKi Bruton's tyrosine kinase inhibitors CI confidence interval CLL (Chronic Lymphocytic Leukemia) CR (Complete Remission) General Terminology Criteria for CTCAE Adverse Events DLBCL (Diffuse Large B-Cell Lymphoma) DLT dose-limiting toxicity ECOG (East Coast Cancer Clinical Trials Group) EWOC (Endowment of Overdose) Gradual Increase FDA (Food and Drug Administration) Hgb (hemoglobin) HIV (Human Immunodeficiency Virus) Ig immunogenicity IgG (Immunoglobulin G) IgG1 Immunoglobulin G1 IUD (Intrauterine Device) IUS (Intrauterine System) iv Intravenous mAb monoclonal antibody MRD (Minimal Residual Disease) MTD maximum tolerated dose NHL Non-Hodgkin Lymphoma NK Natural Killer NYHA (New York Heart Association) ORR performance efficiency PD Pharmacodynamics PFS-free survival PK (Pharmacokinetics) PO (Oral Administration) PR (Partial Remission) QD once a day Q2W: Once every two weeks Q4W: Once every 4 weeks RD Recommended Dose SAE (Serious Adverse Event) SD Stable State Time until TTP proceeds ULN normal upper limit WHO (World Health Organization)

[0045] 7.2. Anti-BAFFR antibody Antibodies against BAFFR ("anti-BAFFR antibodies") are known, for example, by International Publication No. 2010 / 007082, and include antibodies characterized by having a VH domain having the amino acid sequence of SEQ ID NO: 1 and a VL domain having the amino acid sequence of SEQ ID NO: 2. Antibody MOR6654 is one such antibody (IgG1 kappa). It has the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10. The antibody, from SEQ ID NOs: 13 and 14, can be expressed preferably in host cells lacking fucosyl-transferase, for example in mammalian cell lines having an inactive FUT8 gene (e.g., FUT8- / -), and may provide ADCC enhanced to a functional non-fucosylated anti-BAFFR antibody. This antibody will hereafter be referred to as MOR6654B or VAY736, or ianarumab under its international non-trademark designation. Alternative methods for producing non-fucosylated antibodies are known in the art. The amino acid sequence of ianarumab, along with the nucleic acid sequences encoding the ianarumab heavy and light chains, is shown in Table 1.

[0046] [Table 1]

[0047] [Table 2]

[0048] [Table 3]

[0049] [Table 4]

[0050] In some embodiments, the anti-BAFFR antibody or its conjugated fragment includes a heavy chain variable region comprising three CDRs having the sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and a light chain variable region comprising three CDRs having the sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. In preferred embodiments, the anti-BAFFR antibody or its conjugated fragment includes a heavy chain variable region consisting of the sequence of SEQ ID NO: 1 and a light chain variable region consisting of the sequence of SEQ ID NO: 2. In more preferred embodiments, the anti-BAFFR antibody or its conjugated fragment is ianarumab or its conjugated fragment.

[0051] In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered in doses of 0.1 mg / kg to 20 mg / kg (e.g., 1 mg / kg to 10 mg / kg, 5 mg / kg to 15 mg / kg, or 10 mg / kg to 20 mg / kg). In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered in doses of 1 mg / kg to 10 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered in doses of 10 mg / kg to 20 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered in doses of approximately 1 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered in doses of approximately 3 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered at a dose of approximately 6 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered at a dose of approximately 9 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered at a dose of approximately 12 mg / kg. In some embodiments, the anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment is administered at a dose of approximately 20 mg / kg.

[0052] An anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment may be administered to the subject once every two weeks in some embodiments. For example, an anti-BAFFR antibody (e.g., ianarumab) may be administered to the subject on days 1 and 15 of a 28-day administration cycle. An administration window around every other week (e.g., + / - 3 days, + / - 2 days, or + / - 1 day) may be used.

[0053] Alternatively, an anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment may be administered more or less frequently, for example, once a week (e.g., on days 1, 8, 15, and 22 of a 28-day cycle) or once every four weeks (e.g., on day 1 of a 28-day cycle). A dosing window (e.g., + / - 3 days, + / - 2 days, or + / - 1 day) before or after the once-weekly or once-every-four-weeks administration is available.

[0054] In one embodiment, the anti-BAFFR antibody or its conjugate fragment is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg. In a preferred embodiment, ianarumab or its conjugate fragment is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg.

[0055] In one embodiment, the anti-BAFFR antibody or its conjugate fragment is administered once every four weeks (+ / - 3 days) at a dose of approximately 9 mg / kg. In a preferred embodiment, ianarumab or its conjugate fragment is administered once every four weeks (+ / - 3 days) at a dose of approximately 9 mg / kg.

[0056] An anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment may be administered over multiple cycles, for example, multiple 28-day cycles. In some embodiments, an anti-BAFFR antibody (e.g., ianarumab) or its conjugate fragment may be administered over 12 or more cycles.

[0057] The anti-BAFFR antibody (e.g., ianarumab) or its conjugated fragment is preferably administered to the subject by intravenous administration.

[0058] 7.3. Additional medications An anti-BAFFR antibody or its conjugate fragment (e.g., ianarumab) may be administered in combination with one or more additional agents, such as immunomodulatory imide drugs (IMiDs), such as lenalidomide or a pharmaceutically acceptable salt thereof, and / or one or more adjuvants.

[0059] In some embodiments, an anti-BAFFR antibody (e.g., ianarumab) is administered in combination with an immunomodulatory imide (IMiD), such as lenalidomide or a pharmaceutically acceptable salt thereof. Lenalidomide is marketed as REVLIMID® (Celgene) and is available in dosage forms of 2.5 mg, 5 mg, 15 mg, 20 mg, and 25 mg. Lenalidomide may be administered daily (e.g., on days 1 to 21 of a 28-cycle) at a daily dose of, for example, 2.5 mg to 25 mg (e.g., 2.5 mg, 5 mg, 15 mg, 20 mg, or 25 mg). In some embodiments, lenalidomide may be administered to the subject for up to 12 cycles, after which treatment with an anti-BAFFR antibody (e.g., ianarumab) may be continued as monotherapy.

[0060] Other IMiDs include thalidomide, pomalidomide, and iverdamide. Lenalidomide, pomalidomide, and iverdamide are thalidomide analogs.

[0061] Available adjuvants include antiemetics (e.g., phenothiazines such as prochlorperazine and chlorpromazine, 5-HT3 receptor selective antagonists such as ondansetron, granisetron, and tropisetron) and antidiarrheal agents (e.g., loperamide).

[0062] The anti-BAFFR antibody or its conjugated fragment and the additional drug may be administered simultaneously, in the same or different compositions, or sequentially. In the case of sequential administration, the anti-BAFFR antibody or its conjugated fragment may be administered first, followed by the additional drug, or the order of administration may be reversed.

[0063] 7.4. B-cell malignancies and patient populations Anti-BAFFR antibodies (e.g., ianarumab) and their conjugate fragments can be used to treat subjects with B-cell malignancies.

[0064] In some embodiments, B-cell malignancies are blood cancers.

[0065] In some embodiments, B-cell malignancies are malignant lymphoproliferative states.

[0066] In some embodiments, B-cell malignancies are plasma cell cachexia.

[0067] In some embodiments, the B-cell malignancy is acute leukemia. In some embodiments, the B-cell malignancy is B-cell acute lymphoblastic leukemia (also known as B-cell acute lymphoblastic leukemia or B-cell acute lymphoblastic leukemia) (ALL or B-ALL), for example, relapsed and / or refractory B-ALL.

[0068] In some embodiments, B-cell malignancies include non-Hodgkin lymphoma (NHL), such as chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), MALT lymphoma (mucosa-associated lymphoid tissue lymphoma), and marginal zone lymphoma (MZL) (for example, extranodal marginal zone lymphoma (EMZL) or nodular marginal zone B-cell lymphoma (NZML)).

[0069] In some embodiments, the B-cell malignancy is relapsed and / or refractory non-Hodgkin lymphoma (NHL).

[0070] In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), for example, relapsed and / or refractory CLL / SLL.

[0071] In some embodiments, the B-cell malignancy is follicular lymphoma (FL), for example, relapsed and / or refractory FL. In some embodiments, FL is small cell FL. In other embodiments, FL is large cell FL.

[0072] In some embodiments, the B-cell malignancy is mantle cell lymphoma (MCL), for example, relapsed and / or refractory MCL.

[0073] In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), for example, relapsed and / or refractory DLBCL.

[0074] In some embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the anti-BAFFR antibody or its conjugate is administered once every four weeks (+ / - 3 days) at a dose of approximately 9 mg / kg. In preferred embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the ianarumab or its conjugate is administered once every four weeks (+ / - 3 days) at a dose of approximately 9 mg / kg.

[0075] In some embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the anti-BAFFR antibody or its conjugate is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg. In preferred embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the ianarumab or its conjugate is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg.

[0076] In some embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the anti-BAFFR antibody or its conjugate is administered in combination with IMiD, where the anti-BAFFR antibody or its conjugate is administered once every 4 weeks (+ / - 3 days) at a dose of approximately 9 mg / kg. In preferred embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the ianarumab or its conjugate is administered in combination with IMiD, where the ianarumab or its conjugate is administered once every 4 weeks (+ / - 3 days) at a dose of approximately 9 mg / kg. In some embodiments, IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is thalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is pomalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is iverdimide or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the anti-BAFFR antibody or its conjugate is administered in combination with IMiD, where the anti-BAFFR antibody or its conjugate is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg. In preferred embodiments, the B-cell malignancy is DLBCL, e.g., relapsed and / or refractory DLBCL, and the ianarumab or its conjugate is administered in combination with IMiD, where the ianarumab or its conjugate is administered once every two weeks (+ / - 3 days) at a dose of approximately 3 mg / kg. In some embodiments, IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is thalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is pomalidomide or a pharmaceutically acceptable salt thereof. In other embodiments, IMiD is iverdimide or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the B-cell malignancy is Burkitt lymphoma.

[0079] In some embodiments, the B-cell malignancy is lymphoplasmacytic lymphoma (Waldenström macroglobulinemia).

[0080] In some embodiments, the B-cell malignancy is MALT lymphoma (mucosal-associated lymphoid tissue lymphoma).

[0081] In some embodiments, the B-cell malignancy is marginal zone lymphoma (MZL).

[0082] In some embodiments, the B-cell malignancy is extranodal marginal zone lymphoma (EMZL).

[0083] In some embodiments, the B-cell malignancy is nodular marginal zone B-cell lymphoma (NZML).

[0084] In some embodiments, the B-cell malignancy is splenic marginal zone B-cell lymphoma (SMZL).

[0085] In some embodiments, the B-cell malignancy is Hodgkin lymphoma.

[0086] In some embodiments, the B-cell malignancy is multiple myeloma.

[0087] In some embodiments, the B-cell malignancy is hairy cell leukemia.

[0088] In some embodiments, the B-cell malignancy is a primary exudative lymphoma.

[0089] In some embodiments, B-cell malignancies are B-cell prelymphocytic leukemias.

[0090] In some embodiments, the B-cell malignancy is plasmablastic lymphoma.

[0091] In some embodiments, the B-cell malignancy is follicular lymphoma.

[0092] In some embodiments, the B-cell malignancy is a precursor B-lymphoblastic leukemia.

[0093] In some embodiments, the B-cell malignancy is a high-grade B-cell lymphoma.

[0094] In some embodiments, the B-cell malignancy is primary mediastinal large B-cell lymphoma.

[0095] Certain aspects of the embodiments described above relate to subjects having NHL and who (i) have failed at at least one prior line (and optionally up to five prior lines) of standard therapeutic therapy, such as anti-CD20 therapy including rituximab, and / or (ii) are intolerant to or unsuitable for one or more other approved therapies, such as autologous stem cell transplantation (ASCT), and / or (iii) are unresponsive to chimeric antigen receptor (CAR) T-cell therapy. NHL can be chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), MALT lymphoma (mucosa-associated lymphoid tissue lymphoma), or marginal zone lymphoma (MZL) (e.g., extranodal marginal zone lymphoma (EMZL) or nodular marginal zone B-cell lymphoma (NZML)). In some embodiments, NHL may be relapsed and / or refractory, such as relapsed and / or refractory DLBCL or MCL.

[0096] Therefore, in certain embodiments, subjects with NHL who are administered an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment, or a combination including an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment (e.g., a combination including any anti-BAFFR antibody and an IMiD such as lenalidomide), have failed at least one preceding line of standard therapy, and optionally, up to five standard therapy treatments. In various embodiments, subjects have failed one, two, three, four, or five standard therapy treatments. Exemplary standard therapy treatments for B-cell malignancies include anti-CD20 therapy such as rituximab.

[0097] In a further embodiment, subjects with NHL who are administered an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment, or a combination including an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment (e.g., a combination including any anti-BAFFR antibody and an IMiD such as lenalidomide), are intolerant to or unsuitable for one or more other approved therapies, such as autologous stem cell transplantation (ASCT).

[0098] In further embodiments, subjects having NHL are administered an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment, or a combination containing an anti-BAFFR antibody (e.g., ianarumab) or a conjugate fragment (e.g., a combination containing any anti-BAFFR antibody and an IMiD such as lenalidomide), such as a chimeric antigen receptor (CAR) T-cell therapy composition ("CAR composition"), e.g., an anti-CD19 CAR composition. In certain embodiments, the CAR composition contains CTL019. In other embodiments, the CAR composition contains tisagenlecleucel, named USAN or INN. Tisagenlecleucel is commercially available as KYMRIAH®. See, for example, the KYMRIAH® formulation information available at www.pharma.us.novartis.com / sites / www.pharma.us.novartis.com / files / kymriah.pdf. In other embodiments, the CAR composition contains axicapbutagensiloleucel, named USAN or INN. Axicapbutagen siroleucel is marketed as Yescarta®. See, for example, the Yescarta® formulation information available at www.yescarta.com / files / yescarta-pi.pdf. In other embodiments, the CAR composition contains brexcapbutagen autol-ucell, named USAN. Brexcapbutagen autol-ucell is marketed as TECARTUS®. See, for example, the TECARTUS® formulation information available at www.gilead.com / - / media / files / pdfs / medicines / oncology / tecartus / tecartus-pi.pdf. In yet another embodiment, the CAR composition contains lysocabbutagen maral-ucell, named USAN or INN. Lysocabbutagen maral-ucell is marketed as BREYANZI®. For example, please refer to the prescription information for BREYANZI® available at packageinserts.bms.com / pi / pi_breyanzi.pdf.

[0099] 7.5. Pharmaceutical Compositions Anti-BAFFR antibodies and their fragments, as well as additional agents, can be formulated as pharmaceutical compositions containing one or more pharmaceutically acceptable excipients or carriers. For the preparation of pharmaceutical or sterile compositions, the formulations can be combined with one or more pharmaceutically acceptable excipients and / or carriers. In combination therapy, the anti-BAFFR antibodies or their fragments and additional agents are typically formulated as separate pharmaceutical compositions. Each can be provided, for example, in single-dose or multi-dose containers.

[0100] For example, formulations of anti-BAFFR antibodies and additional drugs can be prepared by mixing the drugs with physiologically acceptable carriers, excipients, or stabilizers in the form of, for example, lyophilized powder, slurry, aqueous solution, lotion, or suspension (e.g., Hardman et al., 2001, Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro, 2000, Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.), 1993, Pharmaceutical Dosage Forms: General Medications, Marcel Dekker, NY; Lieberman, et al. (eds.), 1990, Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. See also: al. (eds.), 1990, Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie, 2000, Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY). Anti-BAFFR antibody preparations are described in International Publication No. 2012 / 076670 and International Publication No. 2013 / 186700 (their contents are incorporated herein by reference in their entirety). [Examples]

[0101] Ianarumab (VAY736) is a human IgG1 / κ mAb designed to block BAFF-R-mediated signaling in B cells by targeting human BAFF-R and competitively inhibiting the binding of BAFF to BAFF-R. Furthermore, Ianarumab has been modified to effectively remove B cells from circulation by ADCC in vivo. Therefore, Ianarumab blocks BAFF-R + Mature and immature B cells are eliminated through a dual mechanism: (1) antibody-dependent cytotoxicity (ADCC) and (2) induction of B cell apoptosis by blocking BAFF:BAFF-R interactions and downstream survival pathways in B cells.

[0102] Example 1 below demonstrates that ianarumab reduces tumor growth in a DLBCL model. Example 2 below demonstrates that lenalidomide enhances ianarumab-induced ADCC in DLBCL cell lines in vitro. Example 3 below presents preliminary safety and activity data from clinical trials of ianarumab in combination with ibrutinib in subjects with relapsed / refractory CLL. In summary, the data support the use of VAY736 in patients with NHL, either as a monotherapy or as a "skeleton" agent in combination with additional agents, as described in Example 4.

[0103] Examples 4-5 below demonstrate that the anti-BAFFR antibody VAY736 has the ability to deplete healthy B cells in vivo in both mice and cynomolgus monkeys. Unless constrained by theory, cytokine release by normal B cells is considered a key driver in CRS, and depletion of normal B cells in subjects by VAY736 may reduce the severity of CRS experienced by those subjects.

[0104] 8.1. Example 1: VAY736 slows tumor growth in a DLBCL model. A study was conducted to evaluate the efficacy of VAY736 in an in vivo DLBCL model. Specifically, DLBCL cell line SUDHL4 was subcutaneously transplanted into SCID mice, which were then treated weekly with 5 mg / kg or 50 mg / kg of VAY736 intravenously. The solvent and rituximab were used as controls. As shown in Figures 1A-1C, VAY736 treatment significantly slowed tumor growth in the model compared to the solvent control, as assessed by tumor volume measurements collected over time.

[0105] 8.2. Example 2: VAY736 combined with lenalidomide enhances VAY736-induced ADCC in vitro. The tests described in this example were conducted to determine whether lenalidomide can enhance the ADCC capacity of various effector cell lines in vitro using VAY736 in NHL cell lines (SUDHL4, a DLBCL cell line). Several different effector cell lines were used, including PBMCs, pNK cells, and NK3.3 cell lines.

[0106] 8.2.1. Materials and Methods 8.2.1.1. Preparation of Effector Cells 8.2.1.1.1.NK3.3 cells NK3.3 cells were collected, washed once, and incubated in starvation medium in or without 3 μM lenalidomide. Cells were incubated for 48 or 72 hours, collected, centrifuged, and resuspended in assay buffer. 100 μl of NK3.3 cells at the specified E:T ratio were transferred to a 96-well plate containing SUDHL4 cells and antibodies. The co-culture was incubated for 2 hours.

[0107] 8.2.1.1.2.PBMC / pNK cells Frozen PBMCs were thawed, or new PBMCs were isolated. If T cells were depleted, CD3 beads (Miltenyi #130-050-101) were used, and PBMCs were used for CD3-positive depletion. Cells were washed once and incubated in non-stimulating medium (phenol red-free / glutamax / hepes / anti-penicillin anti-streptomycin / FBS) in or without 3 μM, 1 μM, or 10 μM lenalidomide. Cells were incubated for 24 hours or 72 hours. Supernatants were collected, frozen, and IL2 analysis was performed. In one test, for 72-hour cultures, 100 pg / ml of IL2 was added to the culture in the most recent 24 hours. Primary NK cells were isolated on the day of co-culture setup. 100 μl of PBMCs or pNK cells at the specified E:T ratio were transferred to a 96-well plate containing SUDHL4 cells and antibodies. The co-culture was incubated for 3 or 4 hours.

[0108] 8.2.1.2. Co-culture setup and ADCC assay interpretation A total of 10e6 or 4e6 SUDHL4 cells were incubated with calcein AM for 60 minutes. The cells were then washed twice with 30 ml of medium. The cells were counted and resuspended at 0.15e6 cells / ml or 0.2e6 cells / ml, and 40 ng / ml of IL2 was added to one test. A total of 50 μl of cells was then transferred to a 96-well plate. A diluted VAY736 or defucosylated isotype control was then added to the cells, and 50 μl was incubated at RT for 20 minutes. Effector cells were then added to the 96-well plate. The plate was then centrifugated at 200 × g without a brake for 4 minutes, and the coculture was incubated for 2, 3, or 4 hours. The plate was then centrifugated at 1500 RPM without a brake for 4 minutes. 100 μl of the supernatant was transferred to a black 96-well plate (Corning, #3904), and fluorescence was recorded using a PerkinElmer Envision plate reader.

[0109] 8.2.2.Results In vitro ADCC assays using the SUDHL4 cell line, as well as various effector cells including PBMCs, pNK cells, and NK3.3 cell lines, showed potent ADCC in the presence of VAY736. The data generally demonstrated dose-dependent VAY736-dependent specific lysis of SUDHL4 cells. The addition of lenalidomide generally resulted in enhanced VAY736-dependent percent-specific lysis of SUDHL4 cells under several cultures and treatment conditions, yielding greater enhancement compared to others.

[0110] Figures 2A-2B, 5A-5D, and 6A-6D show the results when NK3.3 cells were included as effector cells. The addition of lenalidomide resulted in an increase in VAY736-induced ADCC, which was more pronounced with 72-hour pretreatment with lenalidomide at an E:T ratio of 20:1, as shown in Figures 2A-2B. With lenalidomide pretreatment, a slight increase in ADCC was observed at E:T ratios of 20:1 and 7:1, and with 72-hour and 48-hour lenalidomide pretreatment (Figures 5A-5D and 6A-6D).

[0111] Figures 3A–3C, 7A–7D, and 9A, 9C, and 9D show the results when PBMCs were included as effector cells. 24-hour pretreatment of PBMCs with lenalidomide resulted in enhanced VAY736-induced ADCC at an E:T ratio of 10:1, where 2:1 simply showed enhancement at the highest concentration, and 20:T showed only slight enhancement (Figures 3A–3C). Figures 7A–7D show that lenalidomide increased VAY736-induced ADCC at a 3:1 ratio, and this increase was mainly dose-independent and inhibited by IL2 stimulation of PBMCs. The improvement of VAY736-induced ADCC by lenalidomide was not very evident at 6:1 after 72 hours of lenalidomide treatment, but was evident at 2:1 (Figure 9A). This enhancement was likely due to IL2 produced by T cells through lenalidomide treatment. (Figure 8) This was dependent on the presence of CD3+ T cells (Figures 9A, 9C, and 9D).

[0112] Figures 4A–4C and 9B and 9D show the results when isolated pNK cells were included as effector cells. Pretreatment of PBMCs with lenalidomide for 24 hours, followed by isolation of pNK cells, resulted in enhancement of VAY736-induced ADCC, with further enhancement under 10:1 and 20:1 conditions (Figures 4A–4C), and under 72-hour Len pretreatment at 1:1 and 1:3 (Figure 9B).

[0113] 8.2.3. Discussion The in vitro ADCC assay used in this example included various effector cell types, and VAY736-induced enhancement of ADCC was observed in all effector cell types under various culture conditions. Interestingly, CD3+ cells were found to be required for this lenalidomide-induced enhancement of ADCC. Unless constrained by theory, this observation may be attributable to the positive effect that lenalidomide has on T-cell IL2 secretion; if so, IL2 would provide a positive activation signal to NK cells. In conclusion, these in vitro studies support the combination of VAY736 and lenalidomide for the treatment of B-cell malignancies such as DLBCL.

[0114] 8.3. Example 3: Phase Ib open-label trial of VAY736 and ibrutinib in patients with chronic lymphocytic leukemia (CLL) A clinical trial (CVAY736Y2102) is underway to determine a safe and tolerable dose of VAY736 for use in combination with ibrutinib to treat chronic lymphocytic leukemia (CLL) and to investigate the preliminary efficacy of the combination. The treatment plan in the trial is schematically shown in Figure 10 and includes dose levels of 0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 9 mg / kg for VAY736.

[0115] A total of 15 patients (median age: 65 years; ECOG PS 0: 93%) were treated according to the data cutoff. Eleven patients completed combination therapy, three discontinued (primarily due to disease progression), and one remained in treatment. The majority of patients (73%) had ibrutinib-resistant mutations at baseline (primarily [82%]BTKC481), and 33% had received ≥4 prior regimens (median: 3, range: 1–5); the median duration of prior ibrutinib treatment was 4.1 years (range: 0.2–8.3). Baseline cytogenetics (non-mutually exclusive) included: 27% del(17)(p13.1), 80% non-mutant IGHV, 80% stimulated complex karyotypes (≥3 abnormalities), 60% del(13)(q14), and 7%+12.

[0116] No dose-limiting toxicities were observed, and the MTD was not reached. A total of 14 patients (93%) experienced an adverse event (AE) unrelated to the cause. Four patients (27%) experienced grade ≥ 3 AEs, including neutropenia (n=3), hypophosphatemia (n=2), leukopenia, leukocytosis, lymphocyte erythrocytes, hypertension, hypokalemia, and hypomagnesemia (n=1 each).

[0117] The overall response on cycle 9, day 1 (C9D1) was complete response (CR) in 6 patients (40%), stable disease (SD) in 4 patients (27%), progressive disease (PD) in 4 patients (27%), and unassessed (continuing treatment) in 1 patient (7%). The mean baseline CLL cell counts in the bone marrow of the CR, SD, and PD groups were 27% (range: 0.8–60.6%), 13% (range: 2.5–27%), and 66% (range: 47–77.9%), respectively. Three patients (20%) with CR achieved MRD negativity and were able to discontinue CLL-targeted therapy including ibrutinib; they maintained CR for 1–16 months after ibrutinib discontinuation. The median percentage change from baseline was -92.8% (range: -100%; -16.7%; Figure 11) for blood MRD and -89.6% (range: -100%; -32.6%) for bone marrow MRD. Among patients with baseline ibrutinib-resistant mutations and C9D1 evaluation, one patient (1 / 6) was negative for ibrutinib-resistant mutations at C9D1. Among patients who were negative for ibrutinib-resistant mutations at baseline (4 / 4), no patients developed mutations by C9D1.

[0118] VAY736 concentrations increased with dose and accumulated after repeated administration in combination with ibrutinib, achieving linear pharmacokinetics at 3 mg / kg or higher. Tissue receptor occupancy was >99% for VAY736 doses of 3 mg / kg or higher. Free BAFF accumulated to a steady state, but no dose-related relationship was observed.

[0119] VAY736 + ibrutinib exhibits acceptable safety characteristics, shows promising preliminary activity compared to ibrutinib in patients with R / R CLL, and provides clinical evidence of the ability of VAY736 add-on therapy to discontinue ibrutinib. Further investigation of this combination is underway, for example, in combination with other ibrutinibs as first-line treatment in patients.

[0120] 8.4. Example 4: Phase Ib open-label study of VAY736 and lenalidomide in patients with B-cell non-Hodgkin lymphoma (NHL) Preclinical data on VAY736 (see, e.g., Examples 1 and 2), along with promising ORR and PFS in patients with severely pre-treated CLL (see, e.g., Example 3), support the trial of VAY736 in the NHL population, either as a monotherapy or as a "skeleton" agent in combination with additional agents. This example evaluates the safety and tolerability of VAY736 in combination with lenalidomide (IMiD, which has direct and indirect effects on NHL cells and monotherapy activity in relapsed / refractory B-cell NHL), as well as the antitumor activity of VAY736, both as a monotherapy and in combination with lenalidomide.

[0121] 8.4.1. Materials and Methods This is a Phase Ib, multicenter, open-label trial with multiple treatment arms. The trial consists of a dose-escalation part and a dose-expansion part.

[0122] In this trial, VAY736 is considered the “skeleton.” The combination of the skeleton and lenalidomide as a partner therapy constitutes a treatment arm. VAY736 is used as the initial skeleton monotherapy with the lenalidomide partner added, including a dual treatment arm. During the dose-escalation part of each treatment arm, patients are treated with VAY736 alone or in combination with the partner investigational drug lenalidomide.

[0123] Each treatment arm will enroll a cohort of 3-6 patients with NHL (or a specific NHL subtype such as DLBCL) who have been treated until they reach MTD or a lower RD is established.

[0124] The platform study design methodology has been successfully applied as a facilitating mechanism for evaluating multiple compounds in various diseases and has been extensively implemented in recent clinical trials (Ventz et al. 2017, Saville et al. 2016, Renfro et al. 2017, Berry et al. 2015, Woodcock et al. 2017).

[0125] The dose escalation and determination of MTD / RD are guided by a Bayesian Hierarchical Logistic Regression Model (BHLRM) using an overdose control (EWOC) criterion.

[0126] Each dose expansion arm will enroll approximately 20 patients. In the expansion part of a given combination therapy, additional patients may be enrolled depending on the antitumor activity.

[0127] Multiple combination treatment arms, for example, Arm 1A: Dosage escalation of VAY736 monotherapy. Arm 1B: Dose expansion of VAY736 monotherapy. Arm 2A: Gradual dose increase of VAY736 + lenalidomide. Arm 2B: VAY736 + increased dosage of lenalidomide, etc. The search is conducted over time.

[0128] 8.4.1.1. Dosage Plan The administration cycle is 28 days. In VAY736 monotherapy dose escalation, patients receive VAY736 intravenously (iv) once every two weeks (on days 1 and 15 of each cycle) (Q2W). In VAY736 + lenalidomide dose escalation, lenalidomide is administered at a QD PO of 25 mg on days 1-21 of the 28-day cycle for up to 12 cycles; the patient then continues VAY736 monotherapy. Alternative dosing schedules (e.g., once weekly (QW) or once every four weeks (Q4W)) may also be evaluated if supported by the evolving clinical data. During the dose expansion part of the study, lenalidomide will continue on the same dosing schedule as determined in the dose escalation part.

[0129] The tolerated dose of lenalidomide during dose expansion is 25 mg or more.

[0130] The doses of VAY736 during dose escalation are 1 mg / kg iv, 3 mg / kg iv, 6 mg / kg iv, 12 mg / kg iv, and 20 mg / kg iv.

[0131] In general, supportive care for the patient (e.g., antiemetics, antidiarrheals, etc.) and concomitant medications and therapies deemed necessary for safety are acceptable. Limited-area symptomatic radiotherapy for non-target lesions is acceptable.

[0132] 8.4.1.2. Inclusion criteria applicable to all treatment arms 1. Histologically definitive diagnosis of B-non-Hodgkin lymphoma (NHL), including all subtypes of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL), based on the WHO 2016 criteria (Swerdlow et al 2016). 2. Patients with NHL must have failed standard treatment (at least one preceding line of systemic therapy, including anti-CD20 therapy for NHL, but no more than five preceding lines of therapy), or be intolerant to or ineligible for other approved treatments, including autologous stem cell transplantation (ASCT). Patients with painless lymphoma must have failed standard treatment, or be intolerant to or ineligible for approved treatments, and require therapeutic intervention. 3. Patients who are refractory to prior CAR T-cell therapy or who have subsequently relapsed will be accepted in this trial 30 days after CART infusion and will meet the inclusion / exclusion criteria defined in the protocol. Treatment will be accepted after confirmation of disease progression following CAR T-cell therapy. 4. Activity status of the East Coast Cancer Clinical Group (ECOG) ≤ 2 5. Diseases measurable at registration: a. Nodular lesions ≥ 15 mm in the long axis (unrelated to the length in the short axis) and / or b. Extranodal lesions ≥ 10 mm in both the long and short axes

[0133] 8.4.1.3. Exclusion criteria applicable to all treatment arms Patients who meet any of the following criteria are not eligible for enrollment in this study: 1. Patients whose clinical laboratory values ​​fall outside the range defined below: • Serum creatinine > 1.5 × upper limit of normal (ULN) and / or calculated creatinine clearance < 45 mL / min in the case of the VAY736 monotherapy arm using the Cockcroft-Gault formula (for the lenalidomide arm, see section 8.4.1.4). Patients with hepatic impairment are excluded if their aspartate transaminase (AST) level is >3.0 × ULN, except in cases where (AST) >5.0 × ULN. Patients with hepatic impairment are excluded if their alanine transaminase (ALT) level is >3.0 × ULN, except in cases where the ALT level is >5.0 × ULN. Patients with Gilbert's syndrome are excluded if total bilirubin > 1.5 × ULN (however, if total bilirubin > 3.0 × ULN or direct bilirubin > 1.5 × ULN). • Hemoglobin (Hgb) < 8 g / dL (Blood transfusion support does not need to be used within 7 days prior to the first dose of the study drug) • Independent of growth factor support within 7 days prior to the first dose of the investigational drug, absolute neutrophil count (ANC) < 1.0 × 10⁻¹⁰ 9 / L • If transfusion support is not available within 7 days of the initial administration of the study drug, platelet count <75 × 10⁶ 9 / L. Patients with transfusion-dependent thrombocytopenia are excluded. 2. Presence or history of central nervous system disorders due to lymphoma. 3. Patients receiving anticancer therapy within the following time frame prior to the first dose of the investigational drug. • Conventional cytotoxic chemotherapy: ≤5 half-life or ≤4 weeks (whichever is longer) • Biological therapy (e.g., antibodies): ≤ 4 weeks • Non-cytotoxic small molecule therapeutics: Half-life ≤ 5 weeks or ≤ 2 weeks (whichever is longer) • Radiotherapy (symptomatic use is acceptable): ≤4 weeks: Symptomatic radiotherapy to a limited area, e.g., for the treatment of bone pain or localized painful lumps, is acceptable. To allow for evaluation of the response to treatment, the patient must maintain a measurable disease that has not been irradiated. • Major surgery: ≤2 weeks (Mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery) • Autologous stem cell transplantation within 12 weeks prior to the first dose of the investigational drug 4. Patients who have undergone allogeneic stem cell transplantation prior to the first dose of the investigational drug. 5. Before screening, within the last 30 days or 5 half-lives, or until the expected pharmacodynamic effect returns to baseline (e.g., for biologics), whichever is longer, or whichever is required by local regulations. 6. Ongoing immunosuppressive therapy, including systemic corticosteroids, for the treatment of lymphoma. Subjects may receive topical or inhaled corticosteroids as treatment for complications, and low-dose systemic corticosteroids (≤25 mg / day of prednisone or equivalent) for endocrine or rheumatic conditions. During study participation, subjects may receive systemic or other corticosteroids as necessary, either as a pre-treatment for VAY736 infusion or for emergent complications arising from treatment. 7. Administration of attenuated vaccine within 30 days prior to VAY736 treatment. 8. A history of hypersensitivity to VAY736 or any of its excipients, or to a similar class of chemical agents (e.g., mAbs). 9. Cardiac dysfunction or clinically significant heart disease, including any of the following: • Clinically significant heart disease and / or uncontrolled heart disease, such as congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension, or clinically significant arrhythmias. • QTcF > 480 milliseconds on screening ECG or congenital long QT syndrome • Acute myocardial infarction or unstable angina in less than 3 months prior to trial registration 10. Patients with a history of drug-induced interstitial pneumonia or current interstitial pneumonia. 11. Patients with hepatic impairment as defined by Childe-Pugh Class B or C. 12. History of stroke or intracranial hemorrhage within 6 months prior to the start of the study drug. 13. Evidence of active, ongoing systemic bacterial, mycobacterial, fungal, or viral infection at the time of trial enrollment. Subjects with localized fungal infections of the skin or nails are eligible. Subjects may, at the discretion of the principal investigator, be receiving prophylactic antiviral or antimicrobial therapy. 14. Malignant diseases other than those currently being treated in the trial. Exceptions include basal cell carcinoma or squamous cell carcinoma of the skin that may be undergoing curative treatment, or in-situ cervical cancer or other tumors that do not affect life expectancy. 15. Prior to trial registration, all acute toxic effects of any prior antitumor therapy (including lenalidomide) as defined in CTCAE v5.0 G1 (with the exception of alopecia, G2 neurotoxicity, or G2 or G3 bone marrow parameters) 16. The patient is aware of or has been tested for HIV infection and is HIV positive (the patient is positive for either HIV1 or HIV2 immunoassay and / or HIV RNA viral load). 17. Active hepatitis C infection as defined by RNA positivity in PCR testing and / or hepatitis B infection as defined below: • Serum-positive for hepatitis B surface antigen (HbsAg) • Serum-positive for hepatitis B core antibodies (HbcAb), except when all three of the following criteria are met: i.HBV DNA negative ii. Prophylactic treatment (nucleos / tide) was initiated on the most recent day 1 and continued for 12 months after the last treatment. iii. Hepatitis B monitoring is performed: HbsAg (and HBV DNA) is tested every four weeks until prophylactic treatment is completed. Patients whose disease is controlled under antiviral therapy should not be excluded. Patients who are HBsAb-positive on their own are eligible. 18. Patients who required treatment discontinuation due to treatment-related toxicity during prior therapy directed at the same target as the drug under investigation in this protocol. 19. Suspected or confirmed COVID-19 infection in the 30 days prior to signing informed consent for testing, without vaccination, serologically unpositive, or without appropriate treatment. COVID-19 testing is mandatory. 20. A serious and / or uncontrolled medical condition in the opinion of the principal investigator that could affect the safety of the individual or impair the evaluation of the study results. 21. Pregnant women or women who are breastfeeding. 22. Women of childbearing potential are defined as all women who are physiologically capable of becoming pregnant without the use of highly effective contraception (VAY736 single arm) or two reliable methods of contraception (highly effective contraception and another effective method of contraception (male latex or synthetic condom, diaphragm, or cervical cap), in the case of lenalidomide) during or for four months after discontinuation of the study drug. In the case of the lenalidomide arm, contraception must be initiated four weeks prior to day 1 of cycle 1. This duration may be increased based on the PK data being obtained. Highly effective contraception includes: • Complete abstinence (if this is consistent with the subject's preferred normal lifestyle). Periodic abstinence (e.g., calendar method, ovulation method, symptomatic basal body temperature method, post-ovulation method) and withdrawal are not acceptable methods of contraception. • Female contraception (including surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to taking the study drug. In the case of oophorectomy alone, the woman's reproductive status must be confirmed by follow-up hormone level assessment. • Male contraception (at least 6 months prior to screening). For female subjects in the trial, a vasectomized male partner must be the sole partner of that subject. • Oral use (estrogen and progesterone), injection, or implantation of hormonal contraception devices or intrauterine devices (IUDs) or intrauterine systems (IUSs), or other forms of hormonal contraception with equivalent effectiveness (failure rate <1%), such as hormonal vaginal rings or transdermal hormonal contraception. When using oral contraception, women must be stable with the same pill for at least three months prior to taking the test medication. A woman is considered postmenopausal and not fertile if she has 12 months of spontaneous amenorrhea with appropriate clinical characteristics (e.g., age-appropriate (generally 40-59 years), no history of vasomotor symptoms [e.g., hot flashes], and in the absence of other medical justifications), or if she has had a surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior. In the case of oophorectomy alone, she is not considered fertile only if her reproductive status has been confirmed by follow-up hormone level assessments. 23. Sexually active men who, even after a successful vasectomy, refrain from using latex or synthetic condoms during sexual intercourse while taking the study drug and for 150 days after discontinuation of the study drug (the five predicted half-lives of VAY736 + 90 days). This duration may increase based on the PK data being obtained. Condoms are required for all sexually active male patients to prevent them from becoming fathers and to prevent the delivery of the study drug to their partners via semen. Furthermore, male patients must not provide sperm for the periods specified above.

[0134] 8.4.1.4. Specific exclusion criteria for treatment arms including the lenalidomide arm. Patients who meet any of the following criteria are not eligible for inclusion in the lenalidomide treatment arm: 101. Ongoing or prior treatment with lenalidomide, thalidomide, or thalidomide analogues 102. Primary refractory DLBCL, defined as a response of less than PR (partial remission) to frontline therapy or first-line therapy, or progression during or within 6 months thereof. 103. If known, a history of double-hit or triple-hit DLBCL (simultaneous detection of MYC and BCL2 or BCL6 or both) 104. Known allergies to lenalidomide, or to compounds or derivatives having a chemical structure similar to lenalidomide (e.g., thalidomide, pomalidomide) and / or their excipients. 105. History of angioedema or severe skin reactions, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reactions with eosinophilia and systemic symptoms (DRESS), or G4 rash associated with lenalidomide or thalidomide treatment. 106. History of oncolytic syndrome due to lenalidomide or thalidomide treatment 107. Serum creatinine > 1.5 × upper limit of normal (ULN) and / or calculated creatinine clearance < 61 mL / min in the case of lenalidomide arm using the Cockcroft-Gault formula (or, according to the national prescribing information for lenalidomide, a QD dose of 25 mg but not lower than < 61 mL / min) 108. Patients at risk of thromboembolism who are not proactive in preventing it. 109. Gastrointestinal (GI) dysfunction or GI disease that may significantly alter the absorption of oral lenalidomide (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel resection, or presence of grade 2 or higher GI-related toxicity due to prior therapy). 110. (Based on the risk that blood may be supplied to pregnant patients whose fetuses should not be exposed to lenalidomide) I cannot agree or willingly agree not to donate blood during treatment with lenalidomide and for four weeks after discontinuing lenalidomide. 111. Unable to swallow or unwilling to swallow oral medications as prescribed by the administration plan.

[0135] 8.4.1.5. Purpose and Endpoints The objectives and endpoints for all arms are shown in the table below.

[0136] [Table 5]

[0137] 8.5. Example 5: Depletion of normal B cells by ianarumab in mice The effect of ianarumab on healthy B cell levels in mice was evaluated in a repeated dose-toxicity study.

[0138] 8.5.1. Materials and Methods CD-1 mice were administered ianarumab at a dose of 0 mg / kg or 100 mg / kg intravenously weekly for 13 weeks, followed by an 11-week recovery period.

[0139] 8.5.2.Results CD-1 mice administered 100 mg / kg of ianarumab showed 70-90% mature B cell depletion. B cell levels recovered during the recovery period.

[0140] 8.6. Example 6: Depletion of normal B cells by ianarumab in cynomolgus monkeys Increased single-dose intravenous dose-range (DRF), toxicity, and TK / PD studies, as well as three repeated dose-toxicity studies, were conducted with ianarumab in cynomolgus monkeys. B cell levels were assessed in the studies.

[0141] In single-dose studies, ianarumab at 0.4 mg / kg and higher doses induced B-cell depletion. Ianarumab was well-tolerated.

[0142] B-cell depletion was observed at all dose levels in three repeated-dose trials.

[0143] In summary, mouse and cynomolgus monkey studies demonstrate that ianarumab depletes healthy B cells in vivo. Similar effects of ianarumab on healthy B cells are expected in humans.

[0144] 9. Specific embodiments and references While various specific embodiments are illustrated and described, it will be understood that various modifications can be made without departing from the spirit and scope of this disclosure. This disclosure is illustrated by the numbered embodiments described below. 1. An anti-BAFFR antibody or its conjugate fragment for use in the treatment of B-cell malignancies in subjects requiring it, which should be administered in a therapeutically effective dose. 2. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 1, comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. 3. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 1 or Embodiment 2, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. 4. An anti-BAFFR antibody or its conjugate fragment, which is ianarumab or its conjugate fragment, for use according to any one of Embodiments 1 to 3. 5.0.An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 4, which should be administered in doses of 1 mg / kg to 20 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered in doses of 6.1 mg / kg to 10 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered in doses of 7.5 mg / kg to 15 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered in doses of 8.10 mg / kg to 20 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 9.1 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 10.3 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 11.6 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 12.9 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 13.12 mg / kg. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 5, which should be administered at a dose of 14.20 mg / kg. 15. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 14, which should be administered once every two weeks (+ / - 3 days) to a subject requiring it. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 15, which should be administered on day 1 + / - 3 and day 15 + / - 3 of a 16.28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 15, which should be administered on day 1 + / - 2 and day 15 + / - 2 of a 17.28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 15, which should be administered on day 1 + / - 1 and day 15 + / - 1 of a 18.28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 15, which should be administered on day 1 and day 15 of a 19.28-day administration cycle. 20. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 14, which should be administered once every week (+ / - 3 days) to a subject requiring it. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 20, which should be administered on day 1 + / - 3, day 8 + / - 3, day 15 + / - 3, and day 22 + / - 3 of a 21.28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 20, which should be administered on day 1 + / - 2, day 8 + / - 2, day 15 + / - 2, and day 22 + / - 2 of a 22.28-day administration cycle. 23. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 20, which should be administered on day 1 + / - 1, day 8 + / - 1, day 15 + / - 1, and day 22 + / - 1 of a 28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 20, which should be administered on days 1, 8, 15, and 22 of a 24-day administration cycle. 25. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 14, which should be administered once every four weeks (+ / - 3 days) to a subject requiring it. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 25, which should be administered on day 1 + / - 3 of a 26.28-day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 26, which should be administered on day 1 + / - 2 of a 27-28 day administration cycle. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 26, which should be administered on day 1 + / - 1 of a 28-day administration cycle. 29. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 20, which should be administered on day 1 of a 28-day administration cycle. 30. An anti-BAFFR antibody or its conjugated fragment for use according to any one of embodiments 15 to 29, which should be administered over a 28-day cycle of 30.12 or more. 31. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 30, which should be administered intravenously to a subject requiring it. 32. An anti-BAFFR antibody or its conjugate fragment for use according to any one of Embodiments 1 to 31, which should be administered as monotherapy for B-cell malignancies. 33. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 31, which should be administered in combination with one or more additional agents. 34. An anti-BAFFR antibody or a conjugated fragment thereof for use according to Embodiment 33, wherein one or more additional agents include an immunomodulatory imide drug (IMiD). 35. An anti-BAFFR antibody or a conjugate thereof for use according to Embodiment 34, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdamide or a pharmaceutically acceptable salt thereof. 36. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 34, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. 37. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 36, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered in a dose of 2.5 mg to 25 mg. 38. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 37, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered in a dose of 2.5 mg. 39. An anti-BAFFR antibody or a conjugated fragment thereof for use according to Embodiment 37, wherein lenalidomide or a pharmaceutically acceptable salt thereof is to be administered in a dose of 5 mg. 40. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 37, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered in a dose of 15 mg. 41. An anti-BAFFR antibody or its conjugate for use according to Embodiment 37, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered in a dose of 20 mg. 42. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 37, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered in a dose of 25 mg. 43. An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of embodiments 36 to 42, wherein lenalidomide or a pharmaceutically acceptable salt thereof is to be administered once daily to a subject requiring it. 44. An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of embodiments 36 to 43, wherein lenalidomide or a pharmaceutically acceptable salt thereof is to be administered orally to a subject requiring it. 45. An anti-BAFFR antibody or its conjugate for use according to any one of embodiments 36 to 44, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered on days 1 to 21 of a 28-day cycle. 46. ​​An anti-BAFFR antibody or its conjugate for use according to Embodiment 45, wherein lenalidomide or a pharmaceutically acceptable salt thereof should be administered for up to 12 cycles. 47. An anti-BAFFR antibody or its conjugated fragment for use according to Embodiment 46, to be administered as monotherapy after the final dose of lenalidomide or a pharmaceutically acceptable salt. 48. An anti-BAFFR antibody or its conjugated fragment for use according to any one of embodiments 33 to 47, wherein one or more additional agents include an antiemetic. 49. An anti-BAFFR antibody or its conjugated fragment for use according to any one of embodiments 33 to 48, wherein one or more additional agents include an antidiarrheal agent. 50. A method for treating a subject with a B-cell malignancy, comprising administering a therapeutically effective dose of an anti-BAFFR antibody or a conjugated fragment thereof to the subject. 51. The method of Embodiment 50, wherein the anti-BAFFR antibody or its conjugated fragment comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. 52. The method of Embodiment 50 or Embodiment 51, wherein the anti-BAFFR antibody or its conjugated fragment comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. 53. Any one of Embodiments 50 to 52, wherein the anti-BAFFR antibody or its conjugate fragment is ianarumab or its conjugate fragment. 54. Any one of embodiments 50 to 53, wherein an anti-BAFFR antibody or its conjugated fragment is administered at a dose of 0.1 mg / kg to 20 mg / kg. 55. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered at a dose of 1 mg / kg to 10 mg / kg. 56. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 5 mg / kg to 15 mg / kg. 57. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 10 mg / kg to 20 mg / kg. 58. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 1 mg / kg. 59. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 3 mg / kg. 60. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 6 mg / kg. 61. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 9 mg / kg. 62. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 12 mg / kg. 63. The method of Embodiment 54, wherein an anti-BAFFR antibody or its conjugated fragment is administered, and the anti-BAFFR antibody or its conjugated fragment is administered at a dose of 20 mg / kg. 64. Any one of embodiments 50 to 63, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered to the subject once every two weeks (+ / - 3 days). 65. The method of Embodiment 64, wherein an anti-BAFFR antibody or its conjugated fragment is administered on day 1 + / - 3 and day 15 + / - 3 of a 28-day administration cycle. 66. The method of Embodiment 64, wherein an anti-BAFFR antibody or its conjugated fragment is administered on day 1 + / - 2 and day 15 + / - 2 of a 28-day administration cycle. 67. The method of Embodiment 64, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 + / - 1 and day 15 + / - 1 of a 28-day administration cycle. 68. The method of Embodiment 64, wherein an anti-BAFFR antibody or its conjugated fragment is administered on day 1 and day 15 of a 28-day administration cycle. 69. Any one of embodiments 50 to 63, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered to the subject once every week (+ / - 3 days). 70. The method of Embodiment 69, wherein an anti-BAFFR antibody or its conjugated fragment is administered on day 1 + / - 3, day 8 + / - 3, day 15 + / - 3, and day 22 + / - 3 of a 28-day administration cycle. 71. The method of Embodiment 69, wherein an anti-BAFFR antibody or its conjugated fragment is administered on day 1 + / - 2, day 8 + / - 2, day 15 + / - 2, and day 22 + / - 2 of a 28-day administration cycle. 72. The method of Embodiment 69, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 + / - 1, day 8 + / - 1, day 15 + / - 1, and day 22 + / - 1 of a 28-day administration cycle. 73. The method of Embodiment 69, wherein an anti-BAFFR antibody or its conjugated fragment is administered on days 1, 8, 15, and 22 of a 28-day administration cycle. 74. Any one of embodiments 50 to 63, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered to the subject once every four weeks (+ / - 3 days). 75. The method of Embodiment 74, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 + / - 3 of a 28-day administration cycle. 76. The method of Embodiment 74, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 + / - 2 of a 28-day administration cycle. 77. The method of Embodiment 74, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 + / - 1 of a 28-day administration cycle. 78. The method of Embodiment 74, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered on day 1 of a 28-day administration cycle. 79. An anti-BAFFR antibody or its conjugated fragment is administered over 12 or more 28-day cycles. Any one of embodiments 64 to 78. 80. Any one of embodiments 50 to 79, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered intravenously to the target. 81. Any one of Embodiments 50 to 80, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered as monotherapy for B-cell malignancies. 82. Any one of Embodiments 50 to 80, wherein an anti-BAFFR antibody or a conjugated fragment thereof is administered in combination with one or more additional agents. 83. The method of Embodiment 82, wherein one or more additional agents include an immunomodulatory imide (IMiD). 84. The method of Embodiment 83, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdimide or a pharmaceutically acceptable salt thereof. 85. The method of Embodiment 84, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. 86. The method of Embodiment 85, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject in a dose of 2.5 mg to 25 mg. 87. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 2.5 mg. 88. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 5 mg. 89. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 10 mg. 90. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 15 mg. 91. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 20 mg. 92. The method of Embodiment 86, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject at a dose of 25 mg. 93. Lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject once daily. Any one of embodiments 85 to 92. 94. Any one of embodiments 85 to 93, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered orally to the subject. 95. Any one of embodiments 85 to 94, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered to the subject on days 1 to 21 of a 28-day cycle. 96. The method of Embodiment 95, wherein lenalidomide or a pharmaceutically acceptable salt thereof is administered for up to 12 cycles. 97. An anti-BAFFR antibody or its conjugated fragment is administered as monotherapy after the final dose of lenalidomide or a pharmaceutically acceptable salt. The method of Embodiment 96. 98. Any one of the embodiments 82 to 97, wherein one or more additional agents include an antiemetic. 99. Any one of embodiments 82 to 98, wherein one or more additional agents include an antidiarrheal agent. 100. Any one of the methods from Embodiments 82 to 99, comprising administering one or more additional drugs to a target. 101. A combination comprising (i) an anti-BAFFR antibody or a conjugated fragment thereof and (ii) one or more additional drugs. 102. A combination of Embodiment 101, wherein the anti-BAFFR antibody or its conjugated fragment comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. 103. A combination of Embodiment 101 or Embodiment 102, wherein the anti-BAFFR antibody or its conjugated fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. 104. Any one combination of Embodiments 101 to 103, wherein the anti-BAFFR antibody or its conjugate fragment is ianarumab or its conjugate fragment. 105. Any one combination of Embodiments 101 to 104, wherein an anti-BAFFR antibody or a conjugated fragment thereof and one or more additional agents are formulated in separate pharmaceutical compositions. 106. Any one combination of embodiments 101 to 105, wherein one or more additional agents include an immunomodulatory imide (IMiD). 107. The combination of Embodiment 106, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdimide or a pharmaceutically acceptable salt thereof. 108. The combination of Embodiment 107, wherein IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. 109. Any one combination of embodiments 101 to 108, wherein one or more additional agents include an antiemetic. 110. Any one combination of embodiments 101 to 109, wherein one or more additional drugs include an antidiarrheal agent. 111. Any combination of embodiments 101 to 110 for use in the treatment of B-cell malignancies in subjects requiring it. 112. Use of an anti-BAFFR antibody in the manufacture of a drug for treating a subject having a B-cell malignancy, wherein the drug is for administration in combination with one or more additional drugs, and optionally the one or more additional drugs is one or more additional drugs described in any one of embodiments 34 to 49. 113. Use of an additional agent in the manufacture of a drug for the treatment of a subject having a B-cell malignancy, wherein the agent is for administration in combination with an anti-BAFFR antibody or a conjugated fragment thereof, and optionally the additional agent is the agent described in any one of embodiments 34 to 49. 114. Use of Embodiment 112 or Embodiment 113, wherein the anti-BAFFR antibody or its conjugated fragment is the anti-BAFFR antibody or its conjugated fragment described in any one of Embodiments 2 to 4. 115. Use of any one of Embodiments 112 to 114, wherein an anti-BAFFR antibody and / or one or more additional agents are formulated for administration according to any one of Embodiments 50 to 100. 116. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a hematological cancer. 117. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a malignant lymphoproliferative disorder. 118. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is plasma cell cachexia. 119. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is acute leukemia. 120. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is B-cell acute lymphoblastic leukemia (B-ALL). 121. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory B-cell acute lymphoblastic leukemia (B-ALL). 122. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is non-Hodgkin lymphoma (NHL). 123. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory non-Hodgkin lymphoma (NHL). 124. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). 125. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). 126. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is follicular lymphoma (FL), and optionally the FL is small cell FL or large cell FL. 127. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory follicular lymphoma (FL), and optionally the FL is small cell FL or large cell FL. 128. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is mantle cell lymphoma (MCL). 129. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory mantle cell lymphoma (MCL). 130. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). 131. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is relapsed and / or refractory diffuse large B-cell lymphoma (DLBCL). 132. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is Burkitt lymphoma. 133. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is lymphoplasmacytic lymphoma (Waldenström macroglobulinemia). 134. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is MALT lymphoma (mucosal-associated lymphoid tissue lymphoma). 135. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is marginal zone lymphoma (MZL). 136. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is extranodal marginal zone lymphoma (EMZL). 137. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is nodular marginal zone B-cell lymphoma (NZML). 138. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is splenic marginal zone B-cell lymphoma (SMZL). 139. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to any one of embodiments 122 to 138, wherein the subject has failed at least one prior line of standard therapeutic therapy. 140. An anti-BAFFR antibody or conjugate fragment, method, combination, or use according to Embodiment 139, in which the subject has failed up to five prior lines of standard therapeutic therapy. 141. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to Embodiment 139 or Embodiment 140, in which the subject has failed one prior line of standard therapeutic therapy. 142. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to Embodiment 139 or Embodiment 140, in which the subject has failed two prior lines of standard therapeutic therapy. 143. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to Embodiment 139 or Embodiment 140, in which the subject has failed three prior lines of standard therapeutic therapy. 144. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to Embodiment 139 or Embodiment 140, in which the subject has failed four prior lines of standard therapeutic therapy. 145. An anti-BAFFR antibody or conjugated fragment, method, combination or use according to Embodiment 139 or Embodiment 140, in which the subject has failed five prior lines of standard therapeutic therapy. 146. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to any one of embodiments 139 to 145, wherein at least one preceding line of standard therapeutic therapy includes anti-CD20 therapy. 147. Anti-CD20 therapy is rituximab, anti-BAFFR antibody or conjugate fragment, method, combination or use according to Embodiment 146. 148. An anti-BAFFR antibody or conjugate fragment, method, combination or use according to any one of Embodiments 139-147, in which the subject is intolerant to or unsuitable for one or more other approved therapies. 149. An anti-BAFFR antibody or conjugated fragment, method, combination, or use according to Embodiment 148, in which one or more other approved therapies include autologous stem cell transplantation (ASCT). 150. An anti-BAFFR antibody or conjugated fragment, method, combination or use according to any one of Embodiments 139 to 149, wherein the subject is a non-responder to the CAR composition. 151. An anti-BAFFR antibody or conjugated fragment, method, combination or use according to Embodiment 150, wherein the CAR composition is an anti-CD19 CAR composition. 152. An anti-BAFFR antibody or conjugated fragment, method, combination or use according to Embodiment 150 or Embodiment 151, wherein the CAR composition comprises CTL019, tisagenlecleucel, axicapbutagensiloleucel, brexcapbutagenautolucel, or lysocabbutagenmaralucel. 153. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is Hodgkin lymphoma. 154. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is multiple myeloma. 155. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is hairy cell leukemia. 156. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a primary exudative lymphoma. 157. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a B-cell prelymphocytic leukemia. 158. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is plasmablastic lymphoma. 159. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is follicular central lymphoma. 160. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a precursor B-lymphoblastic leukemia. 161. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is a high-grade B-cell lymphoma. 162. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, or a use according to any one of Embodiments 112 to 115, wherein the B-cell malignancy is primary mediastinal large B-cell lymphoma. 163. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, a use according to any one of Embodiments 112 to 115, or an anti-BAFFR antibody or its conjugated fragment, method, combination for use, or use according to any one of Embodiments 116 to 162, for subjects who are not eligible for autologous stem cell transplantation (ASCT) therapy. 164. An anti-BAFFR antibody or its conjugated fragment for use according to any one of Embodiments 1 to 49, a method according to any one of Embodiments 50 to 100, a combination for use according to Embodiment 111, a use according to any one of Embodiments 112 to 115, or an anti-BAFFR antibody or its conjugated fragment, method, combination for use, or use according to any one of Embodiments 116 to 163, for subjects who are not eligible for CAR-T therapy. 165. Anti-BAFFR antibodies or their conjugated fragments for use according to any one of Embodiments 1 to 49, methods according to any one of Embodiments 50 to 100, combinations for use according to Embodiment 111, uses according to any one of Embodiments 112 to 115, or uses according to any one of Embodiments 116 to 164, the subject does not meet any of the exclusion criteria set out in Section 8.4.1.3. 166. Anti-BAFFR antibodies or their conjugates for use according to any one of Embodiments 1 to 49, any method from any one of Embodiments 50 to 100, any combination for use according to Embodiment 111, any use according to any one of Embodiments 112 to 115, or any anti-BAFFR antibodies or their conjugates, methods, combinations for use, or uses according to any one of Embodiments 116 to 165, if the subject does not meet any of the exclusion criteria set out in Section 8.4.1.4. 167. Anti-BAFFR antibodies or their conjugates for use in the treatment of subjects with cytokine release syndrome (CRS) or at risk of CRS. 168. A method for reducing the severity of one or more symptoms of cytokine release syndrome (CRS) in a subject, comprising administering a therapeutically effective dose of an anti-BAFFR antibody or a conjugated fragment thereof to the subject. 169. Use of anti-BAFFR antibodies or their conjugate fragments in the manufacture of drugs for the treatment of subjects with cytokine release syndrome (CRS) or at risk of CRS. 170. The use of the anti-BAFFR antibody or its conjugated fragment of Embodiment 167, the method of Embodiment 168, or Embodiment 169, wherein the anti-BAFFR antibody or its conjugated fragment is the anti-BAFFR antibody or its conjugated fragment described in any one of Embodiments 2 to 4.

[0145] 10. Incorporation by reference All publications, patents, patent applications and other documents cited herein are incorporated by reference in such a manner as if each individual publication, patent, patent application and other document were incorporated by reference for any purpose. To the same extent as otherwise indicated, these references are incorporated herein by reference in their entirety for all purposes. In the event of any conflict between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings herein shall prevail. The inventions described in the original claims of this application are listed below. [Invention 1] An anti-BAFFR antibody or its conjugated fragment for use in the treatment of B-cell malignancies in subjects requiring its administration, which should be administered in a therapeutically effective dose. [Invention 2] An anti-BAFFR antibody or its conjugated fragment for use according to Invention 1, comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. [Invention 3] An anti-BAFFR antibody or its conjugated fragment for use according to Invention 1 or Invention 2, comprising a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. [Invention 4] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 3, wherein ianarumab or a conjugated fragment thereof. [Invention 5] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 4, which should be administered in doses of 0.1 mg / kg to 20 mg / kg, 1 mg / kg to 10 mg / kg, 5 mg / kg to 15 mg / kg, or 10 mg / kg to 20 mg / kg. [Invention 6] An anti-BAFFR antibody or its conjugated fragment for use according to Invention 5, which should be administered in doses of 1 mg / kg, 3 mg / kg, 6 mg / kg, 9 mg / kg, 12 mg / kg, or 20 mg / kg. [Invention 7] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 6, which should be administered to a subject requiring it once every two weeks (+ / - 3 days), once every week (+ / - 3 days), or once every four weeks (+ / - 3 days). [Invention 8] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 7, which should be administered once every two weeks (+ / - 3 days) at a dose of 3 mg / kg. [Invention 9] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 7, which should be administered once every four weeks (+ / - 3 days) at a dose of 9 mg / kg. [Invention 10] An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of inventions 1 to 9, which should be administered intravenously to a subject requiring it. [Invention 11] An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of Inventions 1 to 10, which should be administered as monotherapy for the aforementioned B-cell malignant tumor. [Invention 12] An anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 10, which should be administered in combination with one or more additional agents. [Invention 13] An anti-BAFFR antibody or a conjugated fragment thereof for use according to Invention 12, wherein the one or more additional agents include an immunomodulatory imide (IMiD). [Invention 14] An anti-BAFFR antibody or its conjugate for use according to Invention 13, wherein the IMiD is lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdamide or a pharmaceutically acceptable salt thereof. [Invention 15] An anti-BAFFR antibody or its conjugated fragment for use according to Invention 14, wherein the IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. [Invention 16] An anti-BAFFR antibody or its conjugated fragment for use according to Invention 15, wherein the lenalidomide or a pharmaceutically acceptable salt thereof is to be administered in a dose of 2.5 mg to 25 mg. [Invention 17] The anti-BAFFR antibody or its conjugated fragment for use according to Invention 16, wherein the lenalidomide or a pharmaceutically acceptable salt thereof is to be administered in doses of 2.5 mg, 5 mg, 15 mg, 20 mg, or 25 mg. [Invention 18] An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of Inventions 15 to 17, wherein the lenalidomide or a pharmaceutically acceptable salt thereof is to be administered once daily to a subject requiring it. [Invention 19] An anti-BAFFR antibody or a conjugated fragment thereof for use according to any one of Inventions 15 to 18, wherein the lenalidomide or a pharmaceutically acceptable salt thereof is to be administered orally to a subject requiring it. [Invention 20] A method for treating a subject having a B-cell malignancy, comprising administering a therapeutically effective amount of an anti-BAFFR antibody or a conjugated fragment thereof to the subject. [Invention 21] (i) an anti-BAFFR antibody or a conjugated fragment thereof, and (ii) a combination comprising one or more additional drugs. [Invention 22] The combination according to Invention 21, wherein the anti-BAFFR antibody or its conjugated fragment comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively. [Invention 23] The combination according to Invention 21 or Invention 22, wherein the anti-BAFFR antibody or its conjugated fragment includes a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2. [Invention 24] The combination according to any one of Inventions 21 to 23, wherein the anti-BAFFR antibody or its conjugated fragment is ianarumab or its conjugated fragment. [Invention 25] The combination according to any one of inventions 21 to 24, wherein the anti-BAFFR antibody or its conjugated fragment and the one or more additional agents are formulated in separate pharmaceutical compositions. [Invention 26] The combination according to any one of inventions 21 to 25, wherein the one or more additional agents include an immunomodulatory imide (IMiD). [Discussion 27] The combination according to Invention 26, wherein the IMiD is lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdamide or a pharmaceutically acceptable salt thereof. [Invention 28] The combination according to Invention 27, wherein the IMiD is lenalidomide or a pharmaceutically acceptable salt thereof. [Invention 29] A combination of any one of inventions 21 to 28 for use in the treatment of B-cell malignancies in subjects requiring such treatment. [Invention 30] Use of an anti-BAFFR antibody in the manufacture of a drug for treating a subject having a B-cell malignancy, wherein, optionally, the drug is for administration in combination with one or more additional drugs, and optionally, the one or more additional drugs are one or more additional drugs described in any one of Inventions 13 to 15. [Invention 31] Use of an additional agent in the manufacture of a drug for treating a subject having a B-cell malignancy, wherein the agent is for administration in combination with an anti-BAFFR antibody or a conjugated fragment thereof, and optionally the additional agent is a drug described in any one of Inventions 13 to 15. [Invention 32] The use according to Invention 30 or Invention 31, wherein the anti-BAFFR antibody or its conjugated fragment is the anti-BAFFR antibody or its conjugated fragment described in any one of Inventions 2 to 4. [Invention 33] The use according to any one of Inventions 30 to 32, wherein the anti-BAFFR antibody and / or one or more additional agents are formulated for administration according to the method described in Invention 20. [Invention 34] The B-cell malignant tumor is a hematological cancer, and the use is one of the anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 19, the method according to Invention 20, the combination for use according to Invention 29, or one of Inventions 30 to 33. [Invention 35] The B-cell malignant tumor is a malignant lymphoproliferative disorder, and the use of an anti-BAFFR antibody or its conjugated fragment according to any one of Inventions 1 to 19, the method according to Invention 20, the combination for use according to Invention 29, or the use according to any one of Inventions 30 to 33. [Invention 36] The aforementioned B-cell malignancies include plasma cell cachexia, acute leukemia, B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, lymphoplasmacytic lymphoma (Waldenström macroglobulinemia), and MALT lymphoma (mucosa-associated lymphocytes). A BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 19, the method according to Invention 20, the combination for use according to Invention 29, or the use according to any one of Inventions 30 to 33, wherein the FL is either small cell FL or large cell FL, and the FL is either a tissue lymphoma, marginal zone lymphoma (MZL), extranodal marginal zone lymphoma (EMZL), nodular marginal zone B-cell lymphoma (NZML), or splenic marginal zone B-cell lymphoma (SMZL), and optionally the FL is either small cell FL or large cell FL. [Invention 37] The B-cell malignant tumor is diffuse large B-cell lymphoma (DLBCL), and the use is described in any one of Inventions 1 to 19, an anti-BAFFR antibody or its conjugated fragment for use, the method described in Invention 20, the combination for use described in Invention 29, or any one of Inventions 30 to 33. [Invention 38] The B-cell malignancy is relapsed and / or refractory diffuse large B-cell lymphoma (DLBCL), and the use of an anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 19, the method according to Invention 20, the combination for use according to Invention 29, or the use according to any one of Inventions 30 to 33. [Invention 39] The anti-BAFFR antibody or conjugated fragment, method, combination, or use according to Invention 38, wherein the subject has failed at least one prior line of standard therapeutic therapy. [Invention 40] The anti-BAFFR antibody or conjugated fragment, method, combination, or use according to Invention 39, wherein the aforementioned prior line of standard therapeutic therapy includes anti-CD20 therapy. [Invention 41] The anti-BAFFR antibody or conjugated fragment, method, combination or use according to any one of Inventions 39 to 40, wherein the subject is intolerant to or unsuitable for one or more other approved therapies. [Invention 42] The anti-BAFFR antibody or conjugated fragment, method, combination, or use described in Invention 41, wherein the one or more other approved therapies include autologous stem cell transplantation (ASCT). [Invention 43] The anti-BAFFR antibody or conjugated fragment, method, combination, or use according to any one of Inventions 39 to 42, wherein the subject is a non-responder to the CAR composition. [Invention 44] The anti-BAFFR antibody or conjugated fragment, method, combination or use according to Invention 43, wherein the CAR composition is an anti-CD19 CAR composition, and optionally the CAR composition comprises CTL019, tisagenlecleucel, axicapbutagensiloleucel, brexcapbutagenautolucel, or lysocabbutagenmaralucel. [Invention 45] The B-cell malignancy is Hodgkin lymphoma, multiple myeloma, hairy cell leukemia, primary exudative lymphoma, B-cell pre-lymphoblastic leukemia, plasmablastic lymphoma, follicular central lymphoma, precursor B-cell lymphoblastic leukemia, high-grade B-cell lymphoma, or primary mediastinal large B-cell lymphoma, and the use of an anti-BAFFR antibody or its conjugated fragment for use according to any one of Inventions 1 to 19, the method according to Invention 20, the combination for use according to Invention 29, or the use according to any one of Inventions 30 to 33. [Invention 46] The subject is not eligible for autologous stem cell transplantation (ASCT) therapy, and the anti-BAFFR antibody or its conjugated fragment for use as described in any one of Inventions 1 to 19, the method of Invention 20, the combination for use as described in Invention 29, the use as described in any one of Inventions 30 to 33, or the anti-BAFFR antibody or its conjugated fragment, method, combination for use, or use as described in any one of Inventions 34 to 45. [Invention 47] The subject is not eligible for CAR-T therapy and is an anti-BAFFR antibody or its conjugated fragment for use as described in any one of Inventions 1 to 19, the method of Invention 20, the combination for use as described in Invention 29, the use as described in any one of Inventions 30 to 33, or an anti-BAFFR antibody or its conjugated fragment, method, combination for use, or use as described in any one of Inventions 34 to 45. [Invention 48] Anti-BAFFR antibodies or their conjugates for use in the treatment of subjects with cytokine release syndrome (CRS) or at risk of CRS. [Invention 49] A method for reducing the severity of one or more symptoms of cytokine release syndrome (CRS) in a subject, comprising administering a therapeutically effective amount of anti-BAFFR antibody or a conjugated fragment thereof to the subject. [Invention 50] Use of anti-BAFFR antibodies or their conjugate fragments in the manufacture of drugs for the treatment of subjects with cytokine release syndrome (CRS) or at risk of CRS. [Invention 51] The anti-BAFFR antibody or its conjugated fragment described in Invention 48, the method described in Invention 49, or the use described in Invention 50, wherein the anti-BAFFR antibody or its conjugated fragment is the anti-BAFFR antibody or its conjugated fragment described in any one of Inventions 2 to 4.

Claims

1. A pharmaceutical composition comprising an anti-BAFFR antibody for use in the treatment of diffuse large B-cell lymphoma (DLBCL) in a subject requiring treatment for DLBCL, The aforementioned anti-BAFFR antibody is ianarumab. The pharmaceutical composition is used so that the anti-BAFFR antibody is administered in a dose of 3 mg / kg or 9 mg / kg. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the anti-BAFFR antibody is administered once every two weeks (+ / - 3 days) at a dose of 3 mg / kg.

3. The pharmaceutical composition according to claim 1, wherein the anti-BAFFR antibody is administered once every four weeks (+ / - 3 days) at a dose of 9 mg / kg.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition is used to be administered intravenously to the subject.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is used to be administered as monotherapy for DLBCL.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition is used to be administered in combination with one or more additional agents, the one or more additional agents comprising an immunomodulatory imide (IMiD), the IMiD being lenalidomide or a pharmaceutically acceptable salt thereof, thalidomide or a pharmaceutically acceptable salt thereof, pomalidomide or a pharmaceutically acceptable salt thereof, or iverdimide or a pharmaceutically acceptable salt thereof.

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