Treatment of AIHA with BAFF or BAFF receptor inhibitoring antibodies

Abstract

The present disclosure relates to molecules that inhibit the BAFF pathway, in particular antibodies or binding fragments thereof, in particular anti-BAFF-R antibodies, such as iliumekumab, for use in the treatment of autoimmune hemolytic anemia (AIHA), in particular warm-type autoimmune hemolytic anemia (wAIHA).

Description

Technical Field

[0001] The present invention relates to molecules that inhibit the BAFF pathway, which are used to treat autoimmune hemolytic anemia (AIHA), in particular warm autoimmune hemolytic anemia (wAIHA). The present invention relates to a method for treating AIHA, in particular a method for treating warm autoimmune hemolytic anemia (wAIHA), the method comprising administering a molecule that inhibits the BAFF pathway to a subject in need, usually in a therapeutically effective amount. Preferably, the molecule is an antibody or a binding fragment thereof that binds to BAFF or to BAFF-R, in particular ianalumab.

[0002] Sequence Listing

[0003] This application contains a Sequence Listing which has been submitted electronically in ASCII format and which is hereby incorporated by reference in its entirety. Background Art

[0004] Hemolytic anemia is an anemia based on hemolysis, the irregular destruction of red blood cells (RBCs) by autoantibodies directed against RBCs. The disease may be primary or secondary (drug-induced or related to lymphoproliferative disorders, autoimmune or infectious diseases, immunodeficiency, solid tumors, or transplantation).

[0005] Autoimmune hemolytic anemia (AIHA) is a heterogeneous group of disorders characterized by RBC destruction triggered by autoantibodies. AIHA can be classified according to the nature of the autoantibodies (see Berentsen S., Seminars in Hematology 55 (2018), 141-149).

[0006] (AIHA) can be found in two basic variants: Serologically, cases are usually classified as warm antibody- (wAIHA) or cold antibody-mediated AIHA (cAIHA). The first step in the autoimmune hemolytic process is an antigen-antibody reaction that results in the deposition of autoantibodies on the red blood cell surface with or without complement fixation.

[0007] In the variant cold agglutinin disease (CAD) of cAIHA, its pathogenesis has been shown to rely entirely on the classical complement pathway (Berentsen 2018). Antigen-binding IgM (cold agglutinin) on the RBC surface binds C1q and induces the classical complement pathway. Sequential reactions lead to the formation of C3b. After warming to 37°C, IgM dissociates from the cells, causing the agglutinated RBCs to dissociate. However, C3b remains bound. C3b-coated RBCs are sequestered by the mononuclear phagocytic system, mainly in the liver. On surviving RBCs, C3b is cleaved, leaving a large number of C3d molecules. In some cases, complement activation proceeds after the C3b step, with C5 cleavage, leading to terminal pathway activation and intravascular hemolysis. In CAD, the autoantibodies are mainly monoclonal, with over 90% being of the IgMκ class.

[0008] wAIHA accounts for 48%-70% of AIHA patients. wAIHA is characterized by the binding of mainly polyclonal immunoglobulins (mainly IgG) to RBC antigens (Rh proteins or glycoprotein A-D). This binding is termed "warm type" because it occurs at most temperatures but is maximal at 37°C. The density of these RBC antigens is usually not sufficient to fix complement, but in some cases, complement also attaches to the RBCs. The opsonized RBCs are then modified (to become spherocytes) and are ultimately cleared by FcγRIII or C3b receptors on macrophages / activated lymphocytes in the lymphoid organs and spleen (extravascular hemolysis) (Jager et al. 2020, Blood Rev).

[0009] It has been reported that the frequency of primary wAIHA is slightly lower compared to secondary wAIHA, with an assumption that 35%-50% of all wAIHA is primary (Lechner and 2010, Blood, pages 1831-8). Primary wAIHA is the most common type in children. For primary wAIHA, the main indication for medical treatment is symptomatic anemia. In patients with mild and partially compensated hemolytic anemia (e.g., hemoglobin (Hb) level >10 g / dL), after weighing its potential burden and benefits, patients are usually monitored without treatment, i.e., the "watch and wait" strategy. Spontaneous remission is very rare, and most patients require treatment because the disease is usually acute and severe. However, many treated patients do not achieve or maintain complete remission.

[0010] wAIHA can also be secondary to an underlying disease, or it can be caused by various medications as well as organ transplantation (Kalfa 2016). In adults, the most common underlying diseases associated with wAIHA are lymphoproliferative malignancies such as chronic lymphocytic leukemia (CLL) and connective tissue diseases, especially SLE. In children, the most commonly reported causes of secondary wAIHA are Evans syndrome (ES), autoimmune diseases, and infections. The management of secondary wAIHA depends on the underlying cause. While secondary wAIHA associated with autoimmune diseases such as SLE or ES is managed using a similar approach with the use of steroids and immunosuppressants, secondary wAIHA associated with lymphoproliferative disorders, immunodeficiency, and other conditions should be treated with targeted therapies based on age and underlying disease according to current guidelines.

[0011] To date, there are no approved therapies for the treatment of AIHA, especially wAIHA. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 : Simulations of ibrutinib PK (upper panel) and B cell counts (middle panel) were obtained from the data-driven PK / PD model, and simulations of the lower panel were obtained from the hypothesis-driven tissue RO model. The shaded area is the 90% prediction interval (5th to 95th percentile), and the bold line is the predicted median. The black dashed line in the upper panel represents the trough concentration of 1.8 μg / mL for 300 mg q4w sc as determined in patients with primary Sjögren's syndrome in study CVAY736A2201. The gray dashed line represents the LLOQ of 0.025 μg / mL, the B cell depletion threshold of 10 cells / μL, and the 90% tissue receptor occupancy (RO).

[0013] Figure 2: Autoantibody reduction from baseline at Week 12 and Week 24 in patients participating in the primary Sjögren's syndrome trial (expressed as geometric mean ratio relative to baseline): SSAro52 ( Figure 2A )、SSAro60 ( Figure 2B ) and SSB autoantibodies ( Figure 2C ) .

[0014] Figure 3: Autoantibody reduction from baseline at Week 12 and Week 24 in patients participating in a systemic lupus erythematosus (SLE) trial (expressed as geometric mean ratio relative to baseline): C1q( Figure 3A ) and anti-dSDNA( Figure 3B ). DETAILED DESCRIPTION

[0015] In the absence of approved therapies for AIHA (e.g., wAIHA), existing treatment options are limited. Available therapies are mostly symptomatic, have limited efficacy, responses are often not durable / sustained after treatment cessation, and can be associated with significant side effects and negative impacts on quality of life. This highlights the need for new therapies for AIHA (e.g., wAIHA) that can induce durable or complete responses, allow treatment cessation, and maintain patients' hemoglobin levels within the normal range or at least above 10 g / dL (treatment-free remission [TFR]).

[0016] It has now been found that inhibition of the BAFF pathway can lead to the treatment of AIHA (eg wAIHA).Thus in one aspect, the invention provides molecules that inhibit the BAFF pathway for use in the treatment of human autoimmune hemolytic anemias, such as wAIHA.

[0017] The molecule is a small chemical molecule or a large biological molecule, such as an antibody or a binding fragment thereof. The molecule can also be an RNA molecule that interferes with the expression of BAFF pathway proteins. In addition, the molecule can be a peptide, such as a BAFF antagonist, such as a BAFF analog that binds to BAFF-R but does not activate BAFF-R.

[0018] In one embodiment, the molecule is a BAFF inhibitor. Typically, a BAFF inhibitor binds to BAFF and prevents BAFF from binding to its receptor BAFF-R. Alternatively or additionally, a BAFF inhibitor binds to BAFF and accelerates the clearance of BAFF from the bloodstream.

[0019] In one embodiment, the molecule is a BAFF-R inhibitor. Typically, a BAFF-R inhibitor binds to BAFF-R and prevents BAFF-R from binding to BAFF. Alternatively, a BAFF-R inhibitor binds to BAFF-R and, while not preventing BAFF-R from binding to BAFF, changes the conformation of BAFF-R, thereby preventing or reducing BAFF-R activation triggered by BAFF binding (allosteric inhibition).

[0020] In one embodiment, the molecule is an antibody or a binding fragment thereof.

[0021] In one embodiment, the antibody or its binding fragment is a BAFF inhibitor, which is also referred to as an anti-BAFF antibody or its binding fragment. In one embodiment, the anti-BAFF antibody or its binding fragment is belimumab or its binding fragment. In one embodiment, the anti-BAFF antibody or its binding fragment is tembrolizumab or its binding fragment.

[0022] In one embodiment, the antibody or its binding fragment comprises CDR-H1, CDR-H2 and CDR-H3 having the amino acid sequences of SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, respectively, and CDR-L1, CDR-L2 and CDR-L3 having the amino acid sequences of SEQ ID NO: 14, SEQ ID NO: 15 and SEQ ID NO: 16, respectively.

[0023] In one embodiment, the antibody or binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10, respectively.

[0024] In one embodiment, the antibody or binding fragment thereof is a BAFF-R inhibitor, which is also referred to as an anti-BAFF-R antibody or binding fragment thereof. In one embodiment, the anti-BAFF-R antibody or binding fragment thereof is ibrutinib or a binding fragment thereof.

[0025] B cells play an important role in the pathogenesis of autoimmune diseases. Depletion of B cells using the anti-CD20 monoclonal antibody rituximab is an established approach for the treatment of autoimmune diseases, including wAIHA. However, the use of rituximab is associated with several limitations, including insufficient B cell depletion, especially in tissues, and the persistence of rituximab-resistant B cells, which play a key role in the refractory and chronic nature of autoimmune diseases (Mahévas et al. 2015, J Autoimmun [Journal of Autoimmunity] pp. 22-30, Crickx et al. 2021, Sci Transl Med. [Science Translational Medicine]).

[0026] Recent studies have shown that the BAFF-R signaling pathway is involved in the activation of B cell effector functions, such as antibody production, isotype class switching, B cell proliferation, maturation and survival (Mackay and Schneider 2009, Nat Rev Immunol [Natural Immunology Reviews] pp. 491-502). BAFF overexpression leads to the breakdown of B cell immune tolerance, thereby causing autoimmune diseases (Mackay and Browning 2002, Nat Rev Immunol [Natural Immunology Reviews] pp. 465-75). Increased concentrations of soluble BAFF (B cell activating factor) are found in various autoimmune diseases, including Sjögren's syndrome (SS) and pemphigus vulgaris (PV). Elevated serum BAFF levels have been detected in wAIHA patients with low hemoglobin (<8 g / dL) and high lactate dehydrogenase activity (Xu et al. 2015, Int J Hematol [International Journal of Hematology] pp. 394-400).

[0027] Belimumab (a monoclonal antibody U.S. Prescribing Information) has successfully demonstrated that targeting the BAFF pathway in autoimmune diseases such as systemic lupus erythematosus (SLE) and lupus nephritis (LN) improves clinical outcomes. A recent clinical study (Mahevas et al., Haematologica [Hematology] 2020 pp. 2449-2457) tested the anti-BAFF antibody belimumab (5 doses of 10 mg / kg i.v. for up to 12 weeks) with rituximab (2 doses of 1000 mg i.v. for up to 2 weeks) in 15 patients with persistent or refractory ITP, an autoimmune disease associated with the pathophysiology of wAIHA. 80% of patients responded to this combination and maintained their response for 12 months.

[0028] It has also been shown that enhanced antibody-dependent cellular cytotoxicity (ADCC) due to the use of afucosylated antibodies can improve clinical outcomes in autoimmune diseases such as lupus nephritis (LN) (Furie et al. 2021, Ann Rheum Dis [Annals of Rheumatic Diseases]).

[0029] Ilimumab is a glycoengineered (fucosylated) fully human IgG1 monoclonal antibody against BAFF-R, see, e.g., WHO Drug Information, Vol. 34, No. 2, pp. 426-7, 2020, "Recommendation INN: List 123, according to ianalumabum, pp. 280-281". The antibody may preferably be expressed in a host cell lacking a fucosyltransferase, e.g., in a host cell with an inactivated FUT8 gene (e.g., FUT8 - / - ) to provide functional non-fucosylated antibodies.

[0030] Ilimumab is expressed on the surface of B cells, thereby targeting B cells and their functions. It has two main modes of action:

[0031] 1. Direct lysis and depletion of BAFF-R expressing B cells through enhanced antibody-dependent cellular cytotoxicity (ADCC) due to its fucose-deficient Fc region; and

[0032] 2. BAFF receptor blockade interrupts BAFF-mediated signal transduction of B cell activation, maturation, proliferation and survival.

[0033] In preclinical studies, ibrutinib significantly enhanced ADCC against B cells and cytokine production by NK cells and was more effective in depleting B cells than approved anti-CD20 antibodies, including rituximab, obinutuzumab, and ofatumumab (McWilliams et al. 2019).

[0034] The antigenic specificity of inlilumab is for the BAFF receptor BAFF-R (Syn: BR3), which is expressed on the surface of immature and mature B cells until the lymphoblast stage. Therefore, progenitor B cells and pre-B cells that express CD20 but not BAFF-R are not expected to be affected by inlilumab. Therefore, inlilumab targets a narrower spectrum of more differentiated B cells compared to existing anti-CD20 antibody therapies that deplete B cells.

[0035] To date, ibrutinib has been studied in multiple indications in autoimmune diseases and hematological malignancies. Data from ongoing and completed studies show that treatment with ibrutinib is generally safe and well tolerated. Among them, ibrutinib demonstrated efficacy against primary Sjögren's syndrome (pSS) in a Phase II study (Bowman SJ, et al. (2021)).

[0036] Through its dual mechanism of action, ipilimumab is expected to overcome the above limitations of currently available B cell depleting therapies (such as rituximab) by combining effective B cell depletion (ADCC) with BAFF-R blockade, thereby preventing BAFF-driven pathogenic rebound and resistance mechanisms and thus providing a basis for the treatment of AIHA, especially wAIHA. More generally, promising treatments with dual-action approaches targeting 1) the BAFF receptor pathway as well as 2) B cell depletion could address unmet medical needs in AIHA, especially wAIHA, but also in the case of CD20-negative B cells.

[0037] Therefore, the development of molecules that inhibit BAFF, such as anti-BAFF and anti-BAFF-R antibodies (anti-BAFF receptor antibodies), particularly ibrutinib, in hematologic autoimmune diseases, including AIHA and particularly wAIHA, is supported by one, more than one, or all of the following:

[0038] B cell depletion is an established therapeutic measure for the treatment of AIHA (e.g., wAIHA);

[0039] BAFF-R pathway inhibition has been shown to be effective and safe in non-hematologic autoimmune diseases (SLE and LN). );

[0040] BAFF blockade combined with B cell depletion has been shown to be effective and safe in ITP, a condition that belongs to the same family of hematologic autoimmune diseases as wAIHA (Mahévas et al. 2021);

[0041] Clinical studies of ipilimumab have demonstrated its efficacy in other autoimmune diseases (e.g., RA, pSS);

[0042] Based on data from 480 patients exposed to ibrutinib in several autoimmune diseases, ibrutinib showed a favorable benefit-risk profile.

[0043] The use of anti-BAFF-R antibodies in the setting of AIHA, and in particular wAIHA, would allow for short-term treatment, especially compared to the duration of treatment used for the treatment of, for example, Sjögren's disease. Furthermore, while resistance develops with other anti-B cell therapies known to date, such as rituximab, which appears to be at least partly related to an overcompensatory biosynthesis of BAFF, the dual mechanism of action of anti-BAFF-R antibodies should provide a barrier to the development of such resistance. Such resistance may not be found with the BAFF-R blocking antibodies currently used in therapy. Furthermore, an advantage of inhibiting BAFF-R rather than BAFF ligands may be that the interaction of BAFF with other possible BAFF binding sites other than BAFF-R, such as TNFRSF13B / TACI, TNFRSF13, TNFRSF13C or TNFRSF17 / BCMA, may be less or not affected, so that side effects based on the inhibition of such other binding sites are reduced or eliminated.

[0044] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as inulimumab, or a binding fragment thereof, in particular inulimumab, for treating primary wAIHA or secondary wAIHA, respectively. In one embodiment, secondary wAIHA is not due to a lymphoproliferative disease (e.g., CLL), an immunodeficiency, or other immune disease requiring targeted therapy or immunosuppressive therapy.

[0045] The pathogenesis and clinical manifestations of primary and several secondary wAIHA are similar and are associated with the breakdown of B cell immune tolerance. Therefore, it is expected that these patients will benefit from the present invention.

[0046] In one embodiment, the present invention relates to an antibody or a binding fragment thereof for treating AIHA (e.g., wAIHA), wherein the antibody or the binding fragment thereof 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.

[0047] In one embodiment, the present invention relates to an antibody or a binding fragment thereof for treating AIHA (eg, wAIHA), wherein the antibody or binding fragment thereof comprises a VH having an amino acid sequence of SEQ ID NO: 17 and a VL having an amino acid sequence of SEQ ID NO: 18, respectively.

[0048] In one embodiment, the present invention relates to an antibody or a binding fragment thereof for treating AIHA (eg, wAIHA), wherein the antibody or binding fragment thereof comprises a heavy chain having an amino acid sequence of SEQ ID NO: 1 and a light chain variable region having an amino acid sequence of SEQ ID NO: 2.

[0049] The dose, schedule, route of administration, and duration of treatment are selected with the goals of: 1) achieving rapid, profound, and consistent depletion of B cells, 2) complete inhibition of the BAFF-R pathway in blood and tissues, and 3) inducing a rapid and durable response that is maintained beyond the end of the treatment period, allowing patients to discontinue treatment at adequate hemoglobin levels, within a limited treatment duration.

[0050] Therefore, in one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as irumumab, or a binding fragment thereof, in particular irumumab, respectively, wherein the antibody or binding fragment thereof is to be administered at a dose in the range of about 1 to 30 mg / kg, in particular about 1 to 27 mg / kg, more particularly about 1 to 10 mg / kg.

[0051] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as ipilimumab, or a binding fragment thereof, in particular ipilimumab, respectively, administered to a subject in need thereof once every 2, 3, 4, 6 or 8 weeks, in particular once every 4 weeks (+ / - 3 days).

[0052] In one embodiment, administration is by intravenous route or subcutaneous route, particularly by intravenous route.

[0053] In one embodiment, the present invention relates to an anti-BAFF-R antibody or a binding fragment thereof for treating AIHA (e.g., wAIHA), wherein the anti-BAFF-R antibody or a binding fragment thereof (e.g., ilimumab) will be administered at a dose of about 1 to 10 mg / kg, about 3 mg / kg to 9 mg / kg, about 3 mg / kg, or about 9 mg / kg. In one embodiment, the anti-BAFF-R antibody or a binding fragment thereof (e.g., ilimumab) will be administered to a subject in need once every 4 weeks (+ / - 3 days). In one embodiment, ilimumab will be administered once every four weeks (+ / - 3 days) at a dose of 3 mg / kg. In one embodiment, ilimumab will be administered once every four weeks (+ / - 3 days) at a dose of 9 mg / kg. In one embodiment, administration is by intravenous or subcutaneous route, in particular by intravenous route.

[0054] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as irumumab, or a binding fragment thereof, in particular irumumab, respectively, wherein the antibody or its binding fragment will be administered for no more than 12 doses, no more than 9 doses, no more than 6 doses, no more than 4 doses. In one embodiment, the antibody or its binding fragment will be administered for at least 3 doses or at least 4 doses. In one embodiment, the antibody or its binding fragment will be administered for 4 to 9 doses, 4 to 8 doses, or 4 to 6 doses.

[0055] In one embodiment, an anti-BAFF-R antibody or binding fragment thereof, such as ibrutinib, is used to treat AIHA, such as wAIHA, wherein the antibody or binding fragment thereof is administered for a total of 8, 6 or 4 doses, in particular a total of 4 doses. In one embodiment, the doses are administered continuously, typically every four weeks (monthly).

[0056] In one embodiment, the present invention relates to an anti-BAFF-R antibody or a binding fragment thereof, such as ilimumab, for use in treating AIHA (e.g., wAIHA), wherein the anti-BAFF-R antibody or its binding fragment is to be administered within a period of up to about 12 months, about 9 months, about 6 months, or about 5 months after the first dose is administered on Day 1, respectively; or wherein the anti-BAFF-R antibody or its binding fragment is to be administered within a period of up to about 4 months, preferably about 3 months, after the first dose is administered on Day 1, respectively; or wherein the anti-BAFF-R antibody or its binding fragment is to be administered within a period of up to 20 weeks (+ / - 3 days) after the first dose is administered on Day 1, respectively; or wherein the anti-BAFF-R antibody or its binding fragment is to be administered within a period of up to 16 weeks (+ / - 3 days) after the first dose is administered on Day 1; or wherein the anti-BAFF-R antibody or its binding fragment is to be administered within a period of up to 12 weeks (+ / - 3 days) after the first dose is administered on Day 1.

[0057] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering, generally a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject achieves a complete response (CR), generally after the 2nd dose or more likely after the 3rd dose or after the 4th dose. CR is judged by any one, any two or all of the following effects:

[0058] (1) normalization of hemoglobin (Hb level ≥ approximately 11 g / dL (female) or ≥ approximately 12 g / dL (male));

[0059] (2) no evidence of hemolysis (normal levels of indirect bilirubin, LDH, haptoglobin, and / or reticulocytes);

[0060] (3) No red blood cell transfusion.

[0061] In one embodiment, a complete response refers to normalization of hemoglobin (Hb level ≥ 11 g / dL (female) or ≥ 12 g / dL (male)). In one embodiment, CR is judged by achieving all of the above effects.

[0062] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method for treating AIHA (e.g., wAIHA), comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject achieves a durable response, typically after the 2nd dose or more likely after the 3rd dose or more likely after the 4th dose, preferably monthly doses, preferably in a dose range of 3 mg / Kg to 9 mg / Kg. The term "durable response" as used herein is judged by one or both of the following effects (binary effects), and the effect lasts for at least 3, 4, 5, 6, 7 weeks:

[0063] (1) The subject's hemoglobin blood concentration has reached 10 g / dL;

[0064] (2) The subject's hemoglobin blood concentration increased by approximately 2 g / dL or more from baseline

[0065] In a preferred embodiment, the effect lasts for at least 8 consecutive weeks. In another preferred embodiment, the durable response with dual effect lasts for at least 8 consecutive weeks.

[0066] In one embodiment, the present invention relates to ibrutinib for use in treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering to a subject in need thereof a therapeutically effective amount of ibrutinib, wherein the hemoglobin blood concentration is

[0067] (1) male subjects have reached about 10 g / dL or higher, about 11 g / dL or higher, preferably about 12 g / dL or higher; or

[0068] (2) Female subjects maintain about 9 g / dL or higher, about 10 g / dL or higher, preferably about 11 g / dL, maintain about 10 g / dL or higher, about 11 g / dL or higher,

[0069] During or after treatment, usually after the 2nd dose or more likely after the 3rd dose or after the 4th dose.

[0070] In one embodiment, the invention relates to ibrutinib for use in treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering, typically a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject does require a blood transfusion during and after treatment, typically after the 2nd dose or more likely after the 3rd or 4th dose. In one embodiment, the subject does not require a blood transfusion for at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 18 months, at least two years, or at least three years from day 1 of treatment.

[0071] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject has no evidence of hemolysis during and after treatment, typically after the second dose or more likely after the third or fourth dose. Evidence of hemolysis includes abnormalities in one, two, three, or all biomarkers selected from the group consisting of bilirubin, LDH, haptoglobin, and reticulocytes. In one embodiment, the subject has no evidence of hemolysis for at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 18 months, at least two years, or at least three years from day 1 of treatment.

[0072] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein after administration of ibrutinib, the hemoglobin blood concentration of the subject in need thereof increases by about 1 g / dL or more, particularly about 2 g / dL or more, particularly about 3 g / dL or more, particularly about 4 g / dL or more during or after treatment compared to baseline, typically after the second dose or more likely after the third or fourth dose.

[0073] According to any of the foregoing embodiments, the subject's hemoglobin blood concentration is measured at, before or after the third dose, typically on the same day. In one embodiment, the subject's hemoglobin blood concentration is measured between weeks 9 and 25 after the first dose, particularly when the drug is administered every four weeks.

[0074] In one embodiment, the subject's hemoglobin blood concentration is measured weekly, biweekly or monthly. In one embodiment, the subject's hemoglobin blood concentration is measured biweekly until week 25, and once a month thereafter, with the first administration being day 1 of week 1.

[0075] In one embodiment, according to the use of the invention as described in any of the preceding embodiments, in particular with ibrutinib, treatment is stopped after 8 doses, after 6 doses or preferably after 4 doses. Usually these doses are administered continuously. Usually the drug is administered every four weeks.

[0076] In one embodiment, the invention relates to ibrutinib for use in treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering to a subject in need thereof, generally a therapeutically effective amount of ibrutinib, wherein treatment is stopped when the subject achieves a complete response, usually and typically, when the complete response lasts for at least three weeks, generally three weeks or one month, during which at least 2 measurements are taken.

[0077] In one embodiment, the invention relates to ibrutinib for use in treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering to a subject in need thereof, generally a therapeutically effective amount of ibrutinib, wherein treatment is discontinued when the subject's hemoglobin blood concentration reaches 10 g / dL or higher and is sustained, usually and typically, for at least three weeks, usually three weeks or one month, during which at least 2 measurements are taken.

[0078] In another embodiment, treatment is stopped when the subject's hemoglobin blood concentration is

[0079] (1) Maintained at approximately 10 g / dL or higher for 3 consecutive weeks; and

[0080] (2) An increase of ≥2 g / dL from baseline for 3 consecutive weeks.

[0081] The subject's hemoglobin blood concentration is usually measured between weeks 9 and 25 after the first administration, especially when the drug is given every four weeks.

[0082] In one embodiment, the invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering to a subject in need thereof, generally a therapeutically effective amount of ibrutinib, wherein the duration of response is at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months. In another embodiment, the duration of response is about 12 months, about 15 months, about 18 months, or about 24 months.

[0083] The term "duration of response", as used herein, particularly in a clinical trial setting, such as Example 2, refers to a subject who previously achieved a durable response (binary response for at least 8 consecutive weeks): the time from the first hemoglobin assessment indicating a durable response to the time of confirmation of loss of durable response, defined as the first of the following events:

[0084] · Hemoglobin level less than 10 g / dL* on at least two consecutive weekly assessments (the date of the first of the two relapse assessments will be considered the date of relapse),

[0085] · start any resuscitative or withholding treatment,

[0086] Death (regardless of cause).

[0087] The following treatments are considered rescue medicine:

[0088] Any other wAIHA-guided treatment not listed as prohibited medications

[0089] Dose increases of >20% in supportive care compared to pre-enrollment doses are consistent with expert advice and opinion. Restarting allowed supportive care at pre-enrollment doses or returning to pre-enrollment dose levels after dose reductions are not considered rescue medication.

[0090] Starting from week 8 day 1, blood transfusion is considered rescue therapy because it may affect Hb levels and confound the efficacy of ibrutinib.

[0091] Contraindicated drugs are live or live attenuated vaccines, IV or oral immunosuppressive drugs, rituximab, belimumab or other monoclonal antibodies, and other experimental therapies.

[0092] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method for treating AIHA (e.g., wAIHA), the method comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject enters a treatment-free remission (TFR) phase. The term "treatment-free remission (TFR)" as used herein refers to a period of time during which a subject stops treatment due to a temporary or permanent reduction or regression of disease manifestations. In TFR, the subject usually and typically maintains a hemoglobin blood concentration of about 10 g / dL or higher, typically and preferably about 11 g / dL or higher for women and about 12 g / dL or higher for men. In TFR, the subject does not usually receive a blood transfusion. In TFR, the treating physician does not usually consider the subject to require any treatment.

[0093] In one embodiment, the subject's treatment-free remission (TFR) lasts at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, or up to about 2 years, up to about 3 years, up to about 4 years.

[0094] The term "relapse", as used herein, refers to a drop in hemoglobin below normal levels (e.g., about 12 g / dL and above for males, about 11 g / dL and above for females) and generally remains below normal levels for a period of time. In most cases, the term "relapse" refers to a drop in hemoglobin below about 10 g / dL. The time period is generally for at least 2 consecutive measurements, typically less than 2 months apart, less than one month apart, less than 3 weeks apart, less than 2 weeks apart, one week apart.

[0095] In one embodiment, the invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method of treating AIHA (e.g., wAIHA), comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject relapses after TFR. TFR can be achieved by administering (1) an anti-BAFF antibody, such as belimumab; (2) an anti-BAFF-R antibody, such as ibrutinib, or a binding fragment thereof; or (3) neither of the above, but another wAIHA treatment. In one embodiment, TFR is achieved by administering ibrutinib.

[0096] In one embodiment, the present invention relates to ibrutinib for treating AIHA (e.g., wAIAH), or to a method for treating AIHA (e.g., wAIHA), comprising administering a therapeutically effective amount of ibrutinib to a subject in need thereof, wherein the subject relapses after TFR, and TFR is achieved by administering ibrutinib (re-treatment). In another embodiment, the subject receives the same dosing regimen as received before achieving TFR. The subject does not receive ibrutinib treatment. In one embodiment, the subject receives a dose that is less than the dose he received before achieving TFR. In one embodiment, the subject receives a dose that is more than the dose he received before achieving TFR. The term "dose" used in these re-treatment embodiments refers to a single administered amount, a dosing interval, a total treatment duration, or any one, two, or all combinations of the above.

[0097] In one embodiment, the invention relates to an anti-BAFF-R antibody or a binding fragment thereof, e.g., ipilimumab, for use according to any of the preceding embodiments, wherein the anti-BAFF-R antibody or a binding fragment thereof is or is to be administered as a monotherapy for AIHA (e.g., wAIHA).

[0098] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as inulimumab, or a binding fragment thereof, in particular inulimumab, for use in treating human warm autoimmune hemolytic anemia (wAIHA), wherein the subject has failed at least one prior line of treatment. The prior treatment can be the same or a different wAIHA treatment.

[0099] Different wAIHA treatments include, but are not limited to, treatment with corticosteroids, such as prednisolone, prednisone or their equivalents, treatment with B cell depleting agents, such as rituximab. In one embodiment, an anti-BAFF-R antibody or a binding fragment thereof, such as iliumab, is administered while gradually reducing corticosteroids. In one embodiment, the subject has not received a B cell depleting agent, such as rituximab, for at least 12 weeks prior to administration according to the present invention. In an alternative embodiment, the subject receives a B cell depleting agent, such as rituximab, prior to treatment with the present invention, particularly prior to treatment with iliumab. Typically, the washout period is at least 12 weeks prior to administration according to the present invention.

[0100] In one embodiment, the invention relates to an anti-BAFF-R antibody or binding fragment thereof for use according to any of the preceding embodiments, wherein the anti-BAFF-R antibody or binding fragment thereof is administered in combination with one or more additional agents. The one or more agents include, but are not limited to, corticosteroids, particularly prednisone or prednisolone or their equivalents, particularly in a low-dose regimen (e.g., 15 mg / day or less, such as 1 to 10, such as 2 to 5 mg / day prednisolone) or while gradually reducing corticosteroids; danazol (e.g., 200 mg, 3 times a day); and erythropoietin (e.g., erythropoietin alpha, beta or delta 10 00 units / week).

[0101] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as ipilimumab, or a binding fragment thereof, particularly ipilimumab, respectively, wherein the antibody or its binding fragment is to be administered to a subject, wherein the subject suffers from primary or secondary wAIHA and the subject has an inadequate response to at least one line of treatment or has relapsed after at least one line of treatment, including patients who are steroid-resistant, dependent or intolerant. Typically, the subject suffers from wAIHA, which has been previously demonstrated by a positive direct antiglobulin test (DAT) specific for anti-IgG or anti-IgA.

[0102] Steroid resistance: Failure to achieve a hematologic response within 3 weeks of taking at least 1 mg / kg of prednisone(lone). Steroid dependence: Requires continued doses of >10 mg / day of prednisone(lone) to maintain response. Steroid intolerance: Side effects or allergic / anaphylactoid reactions leading to permanent discontinuation of steroids.

[0103] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as ipilimumab, or a binding fragment thereof, particularly ipilimumab, for use in treating wAIHA, wherein the subject has a hemoglobin blood concentration of 10 g / mL or less, 9 g / dL or less than 9 g / dL, 8 g / dL or less than 8 g / dL, 7 g / dL or less than 7 g / dL, 6 g / dL or less than 6 g / dL, 5 g / dL or less than 5 g / dL. In one embodiment, the subject has a hemoglobin blood concentration of 10 g / mL or less. Typically, the subject is associated with the onset of symptoms associated with anemia.

[0104] In one embodiment, the subject has more than 1000 neutrophils / mm 3

[0105] In one embodiment, the subject's serum creatinine is normal or less than 1.5 x upper limit of normal (ULN).

[0106] In one embodiment, the subjects are adolescents aged 12 to 17 years. Toxicology studies using ibrutinib in cynomolgus monkeys were conducted in the following age ranges: 2.2 to 3.5 years (preliminary single / multiple dose studies); 5 to 6 years (4-week studies); 4 to 5 years (13-week studies); 4 to 6 years (26-week studies). No human-related safety issues were found in these studies. The age conversion follows the general concept that 1 year in primates is considered equivalent to 4 years in humans (Baldrick 2010). This covers the human age range of 8.8-24 years, thereby covering the ages of adolescent patients planned to be included in the proposed Phase 3 trial.

[0107] In one aspect, the invention relates to a method for treating a subject with autoimmune hemolytic anemia (AIHA), such as warm autoimmune hemolytic anemia (wAIHA), wherein the method comprises administering to a subject in need thereof, respectively, a therapeutically effective amount of an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as inulimumab, or a binding fragment thereof, in particular inulimumab. The method particularly comprises any one of the preceding embodiments.

[0108] In one aspect, the present invention relates to the use of an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as ipilimumab, or a binding fragment thereof, in particular ipilimumab, in the preparation of a medicament for treating a subject with autoimmune hemolytic anemia (AIHA), such as warm autoimmune hemolytic anemia (wAIHA), respectively. The use particularly includes any one of the aforementioned embodiments.

[0109] definition

[0110] As used herein, the following terms are intended to have the following meanings:

[0111] one / kind, said / the As used herein, the terms "a / an", "the", and similar terms used in the context of this disclosure (especially in the context of the claims) should be interpreted as covering both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context. Therefore, the terms "a" (or "a kind"), "one or more", and "at least one" can be used interchangeably herein. They can represent "one or more", especially when an anti-BAFF-R antibody or a binding fragment thereof is mentioned, they represent "one", referring to an anti-BAFF-R antibody or a binding fragment thereof of the same amino acid sequence.

[0112] “ about " is specifically intended to include deviations of ±20%, such as ±10%, such as ±5%, or ±2% of the specific numerical value following the word, and to include the stated numerical value itself.

[0113] and / or : The term "and / or" means each or both or all of the listed components or features, especially possible variations in which two or more are alternative or cumulative, including any subcombination of two alternatives. It can be replaced by "one or more or all".

[0114] Other medicines For convenience, agents used in combination with an anti-BAFF-R antibody, or an anti-BAFF antibody or binding fragment thereof are referred to herein as "additional" agents.

[0115] Antibody : The term "antibody" refers to a protein comprising at least one immunoglobulin variable domain sequence, for example, an immunoglobulin chain or a fragment thereof. The term "antibody" includes, for example, a monoclonal antibody (including a full-length antibody having an immunoglobulin Fc region). Antibodies include full-length antibodies, or full-length immunoglobulin chains, or antigen-binding fragments or functional fragments of full-length antibodies or full-length immunoglobulin chains. Antibodies can also be multispecific antibodies, for example, they include multiple immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence in the multiple has binding specificity to a first epitope, and a second immunoglobulin variable domain sequence in the multiple has binding specificity to a second epitope.

[0116] Anti-BAFF-R antibodies and anti-BAFF antibodies or binding fragments thereof: As used herein, the term "anti-BAFF-R antibody" refers to an antibody that binds to BAFF-R. As used herein, the term "anti-BAFF antibody" refers to an antibody that binds to BAFF. As used herein, the term "binding fragment" refers to a portion of an antibody that is capable of binding to an epitope of BAFF-R, particularly an epitope that is involved in the binding of BAFF to BAFF-R and / or negatively affects the activation of BAFF by BAFF-R. The binding of the antibody (or its binding fragment) to BAFF-R or BAFF inhibits the binding of BAFF-R to BAFF, thereby reducing the formation of the BAFF / BAFF-R complex, and / or reducing the activation of BAFF-R. Suitably, the antibody or binding fragment thereof may reduce the formation of BAFF / BAFF-R complexes and / or reduce activation of BAFF-R 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 in which the antibody or binding fragment thereof is not present, e.g., in an ELISA). Additionally or alternatively, the antibody or binding fragment thereof may dissociate preformed BAFF / BAFF-R complexes. In a suitable embodiment, the antibody or binding fragment thereof may 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 preformed BAFF / BAFF-R complexes. As previously described, this property may be compared to a suitable control (e.g., a sample in which the antibody or binding fragment thereof is not present). Specific embodiments relate to antibodies or binding fragments thereof comprising the following complementarity determining sequences (CDRs): CDR-H1 (SEQ ID NO: 3), CDR-H2 (SEQ ID NO: 4), CDR-H3 (SEQ ID NO: 5), CDR-L1 (SEQ ID NO: 6), CDR-L2 (SEQ ID NO: 7) and CDR-L3 (SEQ ID NO: 8). Specific embodiments of the present invention include ibrutinib or a binding fragment thereof as an anti-BAFF-R antibody or a binding fragment thereof.

[0117] BAFF-R: The term "BAFF-R" refers to the B cell activating factor receptor protein. BAFF-R is also known as TNF receptor superfamily member 13C (TNFRSF13C). Human and mouse amino acid and nucleic acid sequences can be found in public databases, such as GenBank, UniProt and Swiss-Prot. For example, the amino acid sequence of human BAFF-R can be found as UniProt / Swiss-Prot accession number Q96RJ3, and the nucleotide sequence encoding human BAFF-R can be found as accession number NM_052945.4. It is mainly expressed on B lymphocytes and T cell subsets.

[0118] combination : The term "combination" or "in combination with..." is not intended to imply that therapies or therapeutic agents must be administered simultaneously and / or that these therapies or therapeutic agents are formulated for delivery together, although these delivery methods are also within the scope described herein. The therapeutic agent in the combination can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. These therapeutic agents or treatment regimens can be administered in any order. Typically, each medicament will be administered with a dose and / or schedule determined for the medicament. It will also be further understood that the additional therapeutic agents used in the combination can be administered together or separately with different compositions. Typically, it is expected that the additional therapeutic agents used in the combination are used at a level that does not exceed the level when they are used alone. In some embodiments, the level used in the combination will be lower than the level used alone.

[0119] Effective amount : The term "effective amount" or "therapeutically effective amount" or "pharmaceutically effective amount" means the amount or quantity of an active agent that is sufficient to cause a desired or desired response when administered to a subject, or in other words, an amount sufficient to cause a perceptible biological response. The amount preferably relates to an amount that is effective in therapeutically or in a broader sense also in prophylaxis against the progression of a disease or disorder as disclosed herein.

[0120] Patients / Subjects : As used herein, the term "patient" or "subject" is understood to mean a human. Unless otherwise indicated, the term "patient" or "subject" is used interchangeably herein.

[0121] need : As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0122] Treatment:As used herein, the term "treat, treating or treatment" (interchangeably) any disease or disorder refers to improving the disease or disorder (e.g., slowing down or preventing or reducing the development of the disease or at least one clinical symptom or pathological feature thereof) in one embodiment. In another embodiment, "treatment" refers to alleviating or improving at least one physical parameter or pathological feature of the disease, for example, including those that cannot be discerned by the subject. In yet another embodiment, "treatment" refers to regulating the disease or disorder physically (e.g., stabilizing at least one discernible or indiscernible symptom) or physiologically (e.g., stabilizing physical parameters) or in both aspects. In yet another embodiment, "treatment" refers to preventing or delaying the onset or development or progression of a disease or disorder, or at least one symptom or pathological feature associated therewith. In yet another embodiment, "treatment" refers to preventing or delaying the progression of a disease to a more advanced or more serious condition. The benefit to the patient to be treated is statistically significant, or at least perceptible to the patient or physician.

[0123] The anti-BAFF-R antibody (particularly ipilimumab) or its binding fragment and the additional agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the anti-BAFF-R antibody or its binding fragment can be administered first, and the additional agent can be administered second, or the order of administration can be reversed.

[0124] In one aspect, the invention provides a product for separate, sequential or simultaneous or parallel use of a combination partner of the invention, in particular a kit comprising two or more separate pharmaceutical compositions, at least one of which contains an anti-BAFF-R antibody, in particular ibrutinib or a binding fragment thereof, and at least one of which contains an additional pharmaceutical agent. In one embodiment, the kit comprises a device for separately retaining the compositions, such as a container, a separate bottle, or a separate foil bag. An example of such a kit is a blister pack, such as is typically used for packaging tablets, capsules, etc.

[0125] Examples

[0126] The following examples illustrate the invention without limiting its scope.

[0127] Example 1 Pharmacokinetic-pharmacodynamic modeling

[0128] A population PK / PD model was established using a sequential PK / PD (Zhang, J Pharmacokinet Pharmacodyn; 30(6): 387-404. 2003) approach to describe ibrutinib concentrations and CD19+ B cell counts in patients with various autoimmune diseases.

[0129] Population PK / PD Model

[0130] A two-compartment population PK model with linear clearance was fitted to the iv and sc data from the RA and pSS patient studies. The PK / PD model was parameterized based on B cell count at baseline (basal), B cell death rate (kout), peripheral compartment volume of B cells (Vb), intercompartmental turnover rate of B cells (Qb), maximal stimulation of B cell death rate by ibrutinib (Emax), and the ibrutinib concentration at which the VAY736 effect was half-maximal (EC50).

[0131] PK tissue receptor occupancy (RO) structural model

[0132] Since circulating B cell dynamics described by population PK / PD models do not necessarily predict clinical efficacy, a hypothesis-driven tissue receptor occupancy (RO) model was also developed and used to consider the competitive binding of inlilumab and soluble BAFF (sBAFF) to BAFF-R under a quasi-steady-state assumption. The following equation converts PK(C 伊利尤单抗 (t), nM) and BAFF-R binding of ibrutinib (ROVAY (t), %):

[0133]

[0134] Among them C sBAFF is the concentration of soluble BAFF in tissue (nM), Kd 伊利尤单抗 and Kd sBAFF are the dissociation constants of involumab to BAFF-R and sBAFF to BAFF-R, respectively. The above equations assume that the ligand is in reasonable excess compared to the receptor. It is further assumed that the sBAFF concentration is approximately constant, while the involumab concentration varies with time.

[0135] To determine the occupancy of BAFF-R in tissues relevant to the fictitious disease, the following hypotheses were made, supported by in-house experiments:

[0136] Tissue:serum concentration ratio of Ilimumab: 1:5

[0137] · sBAFF tissue: serum concentration ratio: 4:1

[0138] Table 1 lists all parameters used for tissue receptor occupancy prediction.

[0139] Table 1 Tissue receptor occupancy model parameters

[0140]

[0141]

[0142] Simulation of Dose Selection for the Proposed Phase 3 Study in wAIHA

[0143] It was hypothesized that the PK of ipilimumab in the target wAIHA patient population would be comparable to that observed in other autoimmune diseases. Furthermore, based on the available literature, baseline B cells in ITP patients were comparable to those measured in a previous study of ipilimumab in pSS (Toffoletti et al. 2008). Given the pathophysiological similarities between ITP and wAIHA, similar levels of B cells in wAIHA were used as a baseline. Therefore, a final population PK / PD model was used to support dose and regimen selection in the proposed phase 3 study in wAIHA patients.

[0144] In addition, the same hypothesis-driven tissue RO model was assumed to apply to autoimmune diseases and wAIHA, so the PK-RO model described in Table 1 was used. For wAIHA patients, only the serum soluble BAFF concentration level was fixed at a lower level of 1.817 ng / mL instead of 2.7 ng / mL in autoimmune diseases. Of note, the serum BAFF concentration reported in AIHA patients is 1358.7 ± 141.0 pg / mL (Xu et al. 2015), and the fixed level of 1.817 ng / mL was chosen for conservative tissue RO prediction, which is approximately 3 standard deviations from the mean.

[0145] PKPD simulations were performed to support the selection of a 4-week dosing interval using the following criteria:

[0146] B cell depletion within the dosing window (<10 cells / μL);

[0147] Tissue RO (90% threshold) based on the hypothetical model described in Table 1;

[0148] Ilimumab PK was assessed by Ctrough >1.8 μg / mL, which is the steady-state trough concentration for 300 mg q4ws.c., the dose that resulted in the highest clinical response in the multiple-dose, dose-ranging finding study CVAY736A2201 in pSS patients (CSR A2201 at Week 52).

[0149] PKPD simulation Figure 1The results showed that for a phase 3 study in patients with wAIHA, 3 mg / kg and 9 mg / kg i.v. i.p. i.p. i.p. q4w could be considered for i.v. i.p. i.p. 3 mg / kg for a treatment period of 16 weeks (4 doses). The lower dose of 3 mg / kg iv q4w resulted in trough values ​​above 1.8 ug / mL in half of the simulated patients and predicted tissue RO > 90% in > 95% of patients (Table 2). The higher dose of 9 mg / kg i.v. i.p. i.p. q4w could increase patient coverage for PK and tissue RO.

[0150] Table 2 PK, B cell and tissue RO characteristics of the proposed dosing regimen

[0151]

[0152]

[0153] LLOQ = 0.025 μg / mL

[0154] *B-cell recovery was defined as ≥80% of baseline or ≥50 cells / μL.

[0155] **The end of follow-up was defined as 1 year after discontinuation of ibrutinib treatment.

[0156] ***Predicted tissue RO is based on trough concentrations prior to the last dose of ibrutinib.

[0157] In studies following a single iv dose of 10 mg / kg in pSS patients (mean Cmax 213 μg / mL and AUCinf 1140day*μg / mL, n=12) and in studies following iv doses of 9 mg / kg q2w in CLL patients (cycle 3 mean Cmax 262 μg / mL and AUC0-28d 2630day*μg / mL, 2 doses in 4 weeks, q2w, n=4), mean simulated exposures after the last dose of ibrutinib 9 mg / kg i.v. doses (Cmax 192 μg / mL and AUC0-28d 1931day*μg / mL) were within the range previously observed at the highest iv dose tested.

[0158] Comparative exposures between preclinical species and mean simulated exposures following monthly iv dosing of 9 mg / kg of ibrutinib indicated that 14- to 15-fold and 4.3- to 5.6-fold safety margins were observed for Cmax and AUC, respectively, for monthly 9 mg / kg iv dosing, suggesting that the highest ibrutinib dose of 9 mg / kg ivq4w 9 is safe.

[0159] Example 2: Ilimumab for wAIHA (Phase III study)

[0160] A clinical study established the usefulness of ibrutinib (VAY736) for the treatment of wAIHA in patients who had failed prior treatment.

[0161] This is a randomized, double-blind, placebo-controlled trial with an open-label crossover period to evaluate the efficacy and safety of ibrutinib versus placebo in patients with warm autoimmune hemolytic anemia (wAIHA) who have failed prior treatment.

[0162]

[0163]

[0164] Treatments of interest consisted of either ibrutinib or placebo administered iv (as a 2-hour infusion) every 4 weeks for 4 divided doses for 4 cycles, with or without permitted supportive care. Two different dose levels of ibrutinib (3 and 9 mg / kg) were administered compared with placebo in adult patients with wAIHA who had failed prior therapy. The iv route of administration was preferred because the highest and targeted exposure to the disease with an established and favorable safety profile in the clinical setting has been achieved using this route. The iv route also has the advantage of a lower risk of causing local site reactions, as observed with sc dosing, and for which a dose dependency was observed.

[0165] The potential clinical benefit of a shorter course of ibrutinib was first demonstrated in a placebo-controlled, proof-of-concept study, CVAY736X2201, in 27 patients with primary Sjögren's syndrome (pSS). In this study, effective depletion of circulating B cells and clear signs of efficacy were observed after a single iv dose of ibrutinib (3 mg / kg or 10 mg / kg), which persisted in the higher dose group until the end of the study in a subset of clinical outcomes. Therefore, a 16-week ibrutinib treatment duration (4 infusions q4w) was selected for the Phase 3 study.

[0166] Ninety participants were randomized in a 1:1:1 ratio to 3 mg / kg or 9 mg / kg of ipilimumab or placebo. The randomization stratification factor was prior exposure to rituximab (yes vs no) before randomization.

[0167] Supportive care (should be stable for at least 4 weeks prior to randomization into the study) may include steroids (prednisolone up to 15 mg / day), erythropoietin alpha, beta, or delta 10,000 units / week, or danazol 200 mg three times / day. Red blood cell transfusions and intravenous immunoglobulin (IVIG) are permitted if the above supportive care is insufficient and the subject requires additional support to maintain a safe level of hemoglobin before ibrutinib develops its therapeutic effect.

[0168] To avoid potential confounding of efficacy due to the effects of transfusions and IVIG (i.v. immunoglobulin), a 4-week washout was implemented; only hemoglobin values measured after this washout period were used to assess efficacy endpoints (durable response, response, complete response).

[0169] Prohibited medications are live or live-attenuated vaccines, i.v. or oral immunosuppressive medications, rituximab, belimumab or other monoclonal antibodies, and other experimental therapies.

[0170] If clinically indicated (e.g., to ensure patient safety), the treating physician may also administer rescue medications. The investigator should prescribe rescue treatment according to local practice, except for the medications listed in the previous paragraph. The following treatments are considered rescue medications:

[0171] Any other wAIHA-directed treatment not listed among the prohibited medications

[0172] A >20% increase in the dose of supportive care compared to the pre-enrollment dose, which is in line with expert recommendations and opinions. Restarting permitted supportive treatment at the pre-enrollment dose or resuming to the pre-enrollment dose level after dose reduction is not considered a rescue medication.

[0173] Starting from Day 1 of Week 8, transfusions are considered rescue treatment as they may affect Hb levels and confound the efficacy of eculizumab.

[0174] Participants eligible for inclusion in this study are male or female patients 18 years of age and older. Patients with primary or secondary wAIHA (previously demonstrated by anti-IgG or anti-IgA specific positive direct antiglobulin test (DAT)) who have an inadequate response to at least one line of treatment or who relapse after at least one line of treatment, including patients who are steroid-resistant, -dependent, or -intolerant.

[0175] The hemoglobin concentration in the patient at screening <10 g / dL, associated with the presence of anemia-related symptoms (rationale: patients with a hemoglobin level below 10 g / dL have decompensated hemolytic anemia and thus require treatment to increase the hemoglobin level), and

[0176] Before randomization, the dose of supportive care must be stable for at least 4 weeks

[0177] Participants meeting any of the following criteria are not eligible for inclusion in this study.

[0178] · Patients with wAIHA secondary to a hematological disease involving the bone marrow or other immune diseases requiring immunosuppressants, or the presence of other forms of AIHA (cold or moderate), Evan syndrome, or other cytopenias

[0179] Previous use of B-cell depleting therapy within 12 weeks before randomization

[0180] Active viral, bacterial, or other infection (including tuberculosis or SARS-CoV-2)

[0181] Known history of primary or secondary immunodeficiency, or positive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B virus (HBV)

[0182] · Live or live attenuated vaccine administered within 4 weeks prior to randomization

[0183] Or patients with the following conditions:

[0184] Oral neutrophils: <1000 / mm 3

[0185] Serum creatinine >1.5× upper limit of normal (ULN)

[0186] Patients with:

[0187] Oral neutrophils: <1000 / mm 3

[0188] Serum creatinine >1.5× upper limit of normal (ULN)

[0189] Randomized treatment period (16 weeks):

[0190] On week 1, day 1, patients were randomized in a 1:1:1 ratio to one of three groups: Group A (iliumab 3 mg / kg, intravenous injection, every 4 weeks), Group B (iliumab 9 mg / kg, intravenous injection, every 4 weeks), or Group C (placebo, intravenous injection, every 4 weeks). During this 16-week randomized treatment period, participants received a total of 4 doses of study treatment, one dose every 4 weeks at the following visits: week 1, day 1, week 5, day 1, week 9, day 1, and week 13, day 1. Study treatment was administered by iv infusion over 2 hours (+ / -15 min). In addition to study treatment, patients received premedication (corticosteroids, paracetamol / acetaminophen, or NSAIDs and antihistamines, according to local institutional guidelines) to mitigate the risk of potential systemic infusion-related reactions, and supportive care was also allowed in all treatment groups (see previous paragraph). The randomized treatment period was the primary endpoint assessment period (see above). After completing the 16-week randomized treatment period, all participants entered a follow-up period to monitor efficacy and safety, or placebo-treated participants entered an open-label extension period, depending on the participant's response to study treatment.

[0191] Visits will be every other week (q2w) during the treatment period (week 1 to week 16) and for the primary endpoint follow-up; monthly safety checks for the first 20 weeks after the last dose, then quarterly for up to 2 years after the last dose; monthly efficacy checks for the first 2 years after the last dose, then quarterly until loss of durable response is confirmed or the study is ended

[0192] The primary endpoint was a binary variable indicating whether the patient achieved a durable response (Hb ≥10 g / dL and an increase of ≥2 g / dL from baseline for at least 8 consecutive weekly assessments) between Week 9 Day 1 and Week 25 Day 1, without rescue medication or withholding treatment until a durable response was achieved.

[0193] Key secondary efficacy endpoints / variables were: Duration of response, defined as

[0194] For participants who previously achieved a durable response: time from the first hemoglobin assessment showing a durable response (as defined in the primary endpoint) to confirmation of loss of durable response, defined as the first of the following events:

[0195] · Hemoglobin level less than 10 g / dL* on at least two consecutive weekly assessments (the date of the first of the two relapse assessments will be considered the date of relapse),

[0196] · start any resuscitative or withholding treatment,

[0197] Death (regardless of the cause);

[0198] For participants who did not achieve a durable response as defined by the primary endpoint: Duration of response was zero days.

[0199] Example 3 Reduction of autoantibodies in patients participating in a primary Sjögren's syndrome (pSS) trial.

[0200] In the primary Sjögren's syndrome (pSS) trial, 190 patients with pSS were treated with subcutaneous ibrutinib (5, 50, 150, or 300 mg q4w for 24 weeks) or placebo (Bowman SJ, Fox R, T et al. (2021) Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet; 399(10320): 161-171). The study showed a significant dose-response effect of ianalumab on ESSDAI, with an increase in stimulated salivary flow, with the greatest effect observed at the highest dose.

[0201] For the quantitative data interpretation of the effect of VAY736 on autoantibodies in this trial, the kit FIDIS TM Connective Profile analyzed SSA Ro52kd / TRIM21, SSRo60kd, and SSB autoantibodies at the same dilutions in baseline and post-treatment samples.

[0202] The following data represent SSAro52 ( Figure 2A )、SSAro60( Figure 2B ) and SSB autoantibodies ( Figure 2C The data are presented as % change from baseline. The results clearly showed that the reduction of the three autoantibodies in VAY736 was dose-dependent between the 5 mg, 50 and 300 mg doses, with this reduction in autoantibodies in placebo reaching a maximum at week 24 with a decrease of 4%, compared to 12% to 16% in the 50 and 300 mg VAY736 treatment groups.

[0203] Example 4: Reduction of Autoantibodies in Patients Participating in a Systemic Lupus Erythematosus (SLE) Trial

[0204] This study is a double-blind, randomized, placebo-controlled, multicenter, two-arm study in SLE patients receiving standard of care therapy to evaluate 300 mg of ipilimumab administered sc once monthly (vs. placebo). The dose regimen of this study is 300 mg sc ipilimumab once monthly for 18 months.

[0205] Key inclusion criteria

[0206] Meet ≥ 4 of the 11 American College of Rheumatology 1997 classification criteria for SLE at screening

[0207] Patients were diagnosed with SLE for at least 6 months before screening

[0208] Elevated serum titers on ANA screening (≥1:80) including at least anti-double-stranded DNA (anti-ds DNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm) in a pattern consistent with a diagnosis of SLE

[0209] Currently receiving corticosteroid and / or antimalarial and / or thalidomide therapy and / or other DMARDs according to the following:

[0210] In cases where corticosteroids are the sole standard of care medication: oral dose ≤30 mg / d for at least 8 weeks prior to randomization and at a stable dose for ≥2 weeks prior to randomization

[0211] In cases where oral corticosteroids are not used as a single standard of care medication: stable oral dose of prednisone or equivalent ≤ 30 mg / d for at least 8 weeks prior to randomization and on a stable dose for ≥ 2 weeks prior to randomization

[0212] Antimalarial treatment and / or thalidomide treatment and / or one of the following DMARDs: methotrexate or imidazole derivatives (e.g. azathioprine, mizoribine) or mycophenolic acid derivatives (e.g. mycophenolate mofetil) for at least 12 weeks prior to screening and at a stable dose for ≥8 weeks prior to randomization.

[0213] SLEDAI-2K score ≥6 at screening, combination with other DMARDs is not permitted At screening, BILAG-2004 scores were as follows:

[0214] - At least one "A" in either the mucocutaneous or musculoskeletal regions, or

[0215] - One "B" in either the mucocutaneous or musculoskeletal regions and at least one "A" or "B" in the second region

[0216] At screening, weigh at least 40 kg

[0217] Key exclusion criteria

[0218] Prior to screening, there was a history of receiving the following medications:

[0219] - Within 12 weeks: iv high-dose corticosteroids, calcineurin inhibitors, or other oral DMARDs, except as listed in inclusion criteria 6

[0220] - Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, plasmapheresis, anti-TNF-mAb, CTLA4-Fc Ig (abatacept), or BAFF-targeted agents (eg, belimumab)

[0221] - Administration of any B cell depleting therapy (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (abatacept) within 52 weeks prior to screening and B cell count <50 cells / μL at screening

[0222] Severe lupus nephropathy as defined by proteinuria greater than 6 g / day or equivalent using a spot urine protein to creatinine ratio, or serum creatinine greater than 2.5 mg / dL (221.05 μmol / L), or requiring immunosuppressive induction or maintenance therapy beyond protocol-defined limits

[0223] Efficacy evaluation:

[0224] SRI-4 (SLE Responder Index)

[0225] Physician Global Assessment Visual Analogue Scale (PhGA-VAS)

[0226] Patient Global Assessment (VAS)

[0227] Sudden exacerbation rate scored by BILAG-2004

[0228] Lupus Low Disease Activity State (LLDAS)

[0229] result:

[0230] With sustained prednisolone taper of ≤5 mg / d, a 42% higher proportion of study patients in the ibrutinib group than in the placebo group achieved the composite primary endpoint of SRI-4 at week 28. Ibrutinib was also superior to placebo for the incidence of moderate or severe flares (45% vs. 73%, respectively) and time to first flare (median not reached vs. 11.9 weeks, respectively). At week 28, the differences between ibrutinib and placebo were: 50% for the proportion of patients achieving an SRI-4 response, 34% for reduced corticosteroid use, 43% for the primary combined endpoint of these two outcomes, 20% for lupus low disease activity state (LLDAS), and 31% for the BILAG-based combined lupus assessment (BICLA). Ibrutinib was well tolerated, with no new safety signals detected during the 28-week blinded treatment period as well as during the open-label treatment period (weeks 28 to 52) and subsequent safety follow-up.

[0231] The effect of VAY736 on C1q autoantibodies was determined using an enzyme immunoassay (EIA) provided by BUHLMANN Laboratories, product reference number EK-AC1 QA-U.

[0232] The following data represent data obtained at baseline, week 12, and week 24. Data are presented as geometric mean ratios relative to baseline. The results clearly show that at week 29, the rate of anti-C1q autoantibodies was reduced by nearly 40% with VAY736 compared to 18% with placebo ( Figure 3A ).

[0233] The effect of VAY736 on anti-dsDNA autoantibodies was determined by INOVA QUANTA Lite SC ELISA.

[0234] Data obtained at baseline, week 12, and week 24 are expressed as geometric mean ratios relative to baseline ( Figure 3B ). The results clearly showed that at week 29, the rate of anti-dsDNA autoantibodies was reduced by nearly 40% with VAY736 compared to 10% with placebo.

[0235] Conclusion: All these data suggest that VAY736 reduces autoantibodies in patients with pSS or SLE. This effect is VAY736 dose- and time-dependent. Elevated autoantibodies play an important role in the development and progression of AIHA (e.g., wAIHA), and autoantibodies are reduced by treatment with VAY736.

[0236] Example 5 Preclinical study of the effect of Ilimumab

[0237] The most commonly used mouse model of immune thrombocytopenia is a short-term passive model that measures platelet levels after injection of antiplatelet antibodies that induce platelet elimination by phagocytes (Crow AR et al., Br J Haematology, 2001, 115(3), 679-86). However, this model is not suitable for studying chronic ITP, particularly the role of immune cells in the establishment of the disease. A recently developed active model of ITP (Chow L et al. Blood (2010) 115(6): 1247-1253) resembles the clinical features of severe ITP in humans and more accurately represents the immune deficiency of chronic ITP. In fact, a dependence on the presence of B cells and T cells has been described for inducing a sustained decrease in platelet levels. In this model, CD61-deficient mice are injected with wild-type platelets to generate an immune response, and then spleen cells from the mice are transferred into severe combined immunodeficient (SCID) mice, which induces a strong decrease in platelet levels within a week. Both CD19 and CD8 positive populations are required to induce a sustained decrease in circulating platelet levels.

[0238] Because ibrutinib depletes mouse B cells, we expected to see an effect on chronic ITP in this mouse model. Splenocytes from mice immunized against platelet CD61 were transferred into SCID mice. Mice were treated with 2 to 4 injections of 1) PBS, 2) 10 mg / kg ibrutinib, or 3) 100 mg / kg ibrutinib. Mice were bled weekly for 4 weeks to assess their platelet counts. Platelet counts are expected to increase over time, confirming the efficacy of ibrutinib in chronic ITP. The efficacy of ibrutinib in this model will confirm its potential in the treatment of B cell-mediated cytopenias such as ITP and potentially wAIHA.

[0239] While various specific embodiments have been illustrated and described, it should be appreciated that various changes can be made without departing from the spirit and scope of one or more of the present disclosures.

[0240] All publications, patents, patent applications, and other documents cited in this application are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes. In the event of any inconsistency between one or more references incorporated herein and the teachings of the present disclosure, the teachings of the present specification are contemplated.

Claims

1. An antibody or binding fragment thereof that inhibits the BAFF pathway for use in treating warm autoimmune hemolytic anemia (wAIHA) in a subject.

2. The antibody or binding fragment thereof according to claim 1, wherein the antibody or binding fragment thereof is an anti-BAFF antibody or binding fragment thereof.

3. The antibody or binding fragment thereof according to claim 1 or 2, wherein the antibody or binding fragment thereof is an anti-BAFF-R antibody or binding fragment thereof.

4. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the wAIHA is primary wAIHA.

5. The antibody or binding fragment thereof for use according to any one of claims 1 to 3, wherein the wAIHA is secondary wAIHA.

6. The antibody or binding fragment thereof for use according to any one of claims 1 to 5, wherein the wAIHA is primary or secondary wAIHA and the subject has an inadequate response to or has relapsed after at least one line of treatment, including steroid-resistant, dependent or intolerant patients.

7. The antibody or binding fragment thereof for use according to any one of claims 3 to 6, wherein the antibody or binding fragment thereof 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.

8. The antibody or binding fragment thereof for use according to any one of claims 3 to 7, wherein the antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2, respectively.

9. The antibody or binding fragment thereof for use according to any one of claims 3 to 8, wherein the antibody or binding fragment thereof is ibrutinib or a binding fragment thereof.

10. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is afucosylated.

11. The antibody or binding fragment thereof for use according to any one of the preceding claims, which is belimumab.

12. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered to a subject in need thereof at a dose of about 1 to about 27 mg / kg.

13. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered to a subject in need thereof at a dose of about 1 mg / kg to about 10 mg / kg.

14. The antibody or binding fragment thereof for use according to claim 12 or 13, wherein the antibody is an anti-BAFF-R antibody.

15. The antibody or binding fragment thereof for use according to any one of claims 12 to 14, wherein the antibody is ibrutinib.

16. The antibody or binding fragment thereof for use according to claim 14 or 15, wherein the antibody or binding fragment thereof is to be administered to a subject in need thereof at a dose of about 3 mg / kg.

17. The antibody or binding fragment thereof for use according to claim 14 or 15, wherein the antibody or binding fragment thereof is to be administered to a subject in need thereof at a dose of about 9 mg / kg.

18. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is administered intravenously (iv) to a subject in need thereof.

19. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered to a subject in need thereof once every 4 weeks (monthly, + / - 3 days).

20. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is ibrutinib, wherein ibrutinib is administered intravenously once every 4 weeks (monthly, + / - 3 days) at a dose of 3 mg / kg to a subject in need thereof.

21. The antibody or binding fragment thereof for use according to any one of the preceding claims, wherein the antibody is ibrutinib, wherein ibrutinib is administered intravenously once every 4 weeks (monthly, + / - 3 days) at a dose of 9 mg / kg to a subject in need thereof.

22. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the subject achieves a complete response.

23. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the subject achieves a durable response.

24. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered in no more than 6 doses or in no more than 4 doses.

25. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered in at least 4 doses.

26. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is to be administered for a total of about 8 doses, about 6 doses, or about 4 doses.

27. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the antibody is inulimumab, wherein inulimumab is to be administered for a total of 4 doses.

28. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any of the preceding claims, wherein the antibody or binding fragment thereof is to be administered within a period of up to about 12 months, up to about 9 months, up to about 6 months, up to about 4 months, up to about 3 months, respectively, after administration of the first dose on day 1.

29. An antibody or binding fragment thereof for use that inhibits the BAFF pathway according to any one of the preceding claims, wherein the subject's hemoglobin blood concentration reaches about 10 g / dL or higher after administration of the antibody or binding fragment thereof, wherein preferably the antibody or binding fragment thereof is irumumab.

30. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any of the preceding claims, wherein the subject's hemoglobin blood concentration increases by about 2 g / dL or more from baseline after administration of the anti-BAFF-R antibody or binding fragment thereof, wherein preferably the antibody or binding fragment thereof is irumumab.

31. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any of the preceding claims, wherein the subject's hemoglobin blood concentration reaches about 10 g / dL or more and increases by 2 g / dL or more from baseline after administration of the anti-BAFF-R antibody or binding fragment thereof, wherein preferably the antibody or binding fragment thereof is irumumab.

32. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 29 to 31, wherein the increase in hemoglobin blood concentration occurs after administration of a third dose.

33. The antibody or binding fragment thereof for use that inhibits the BAFF pathway according to any one of claims 29 to 32, wherein the increase in hemoglobin blood concentration is maintained for at least 3 consecutive weeks, preferably for at least 8 consecutive weeks.

34. An antibody or binding fragment thereof for use that inhibits the BAFF pathway as claimed in any one of claims 29 to 33, wherein the increase in hemoglobin blood concentration is maintained for at least 3 consecutive weeks, preferably for at least 8 consecutive weeks, between about week 9 and about week 25.

35. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the antibody or binding fragment thereof is administered as a monotherapy.

36. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 34, wherein the antibody or binding fragment thereof is to be administered in combination with one or more additional agents.

37. An antibody or binding fragment thereof for use that inhibits the BAFF pathway as described in claim 36, wherein the one or more additional agents are supportive care, wherein preferably the supportive care is selected from the group consisting of corticosteroids, in particular prednisone or prednisolone or equivalents, danazol and erythropoietin (e.g. erythropoietin α, β or δ).

38. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in claim 36 or 37, wherein the one or more additional agents are corticosteroids, in particular the antibody or binding fragment thereof that inhibits the BAFF pathway is administered while gradually reducing the corticosteroid.

39. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the subject has failed at least one prior line of treatment.

40. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to claim 39, wherein the previous line of treatment is the same or a different wAIHA treatment.

41. An antibody or binding fragment thereof for use that inhibits the BAFF pathway as claimed in claim 40, wherein the different treatment comprises treatment with a corticosteroid, such as prednisolone, prednisone or an equivalent thereof, or treatment with a B cell depleting agent, such as rituximab.

42. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as described in any of the preceding claims, wherein the subject has a hemoglobin blood concentration of about 10 g / dL or less, about 9 g / dL or less, about 8 g / dL or less, about 7 g / dL or less, about 6 g / dL or less, or about 5 g / dL or less.

43. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of the preceding claims, wherein the treatment is stopped after 4, 6, 8, 9 or 12 doses.

44. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the treatment is stopped after a complete response is achieved.

45. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the treatment is stopped after a durable response is achieved.

46. ​​An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any one of the preceding claims, wherein the subject achieves treatment free remission (TFR).

47. An antibody or binding fragment thereof for use that inhibits the BAFF pathway as described in claim 46, wherein the time period of TFR is about 5 years, 4 years, 3 years, 2 years, 18 months, 16 months, 14 months, 12 months, 9 months, 6 months or 3 months.

48. An antibody or binding fragment thereof that inhibits the BAFF pathway for use as claimed in any of the preceding claims, wherein the subject relapses after TFR, wherein preferably the antibody or binding fragment thereof that inhibits the BAFF pathway is ibrutinib; and wherein preferably the subject is administered ibrutinib prior to TFR.

49. An antibody or binding fragment thereof for use that inhibits the BAFF pathway as claimed in any one of the preceding claims, wherein the subject is a teenager between 12 and 17 years old.

50. Use of an antibody or a binding fragment thereof that inhibits the BAFF pathway in the preparation of a medicament for treating warm autoimmune hemolytic anemia (wAIHA).

51. A method of treating warm autoimmune hemolytic anemia (wAIHA) in a subject, particularly a subject in need thereof, comprising administering a typically therapeutically effective amount of an antibody or binding fragment thereof that inhibits the BAFF pathway.

52. The method of claim 51, wherein the antibody or binding fragment thereof is an anti-BAFF antibody or binding fragment thereof.

53. The method of claim 51, wherein the antibody or binding fragment thereof is an anti-BAFF-R antibody or binding fragment thereof.

54. The method of any one of claims 51-53, wherein the wAIHA is primary wAIHA.

55. The method of any one of claims 51-53, wherein the wAIHA is secondary wAIHA.

56. The method of any one of claims 51-55, wherein the wAIHA is primary or secondary wAIHA, and wherein the subject has an inadequate response to or has relapsed after at least one line of treatment, including steroid-resistant, dependent, or intolerant patients.

57. The method of any one of claims 53-56, wherein the antibody or binding fragment thereof 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.

58. The method of any one of claims 53-57, wherein the anti-BAFF-R antibody comprises a heavy chain having the amino acid sequence of SEQ ID NO: 1 and a light chain having the amino acid sequence of SEQ ID NO: 2, respectively.

59. The method of any one of claims 53-58, wherein the anti-BAFF-R antibody or binding fragment thereof is ibrutinib or a binding fragment thereof.

60. The method of any one of claims 53-59, wherein the antibody or fragment thereof is an afucosylated antibody.

61. The method of any one of claims 52, 54-58 or claim 60, wherein the antibody or fragment thereof is belimumab.

62. The method of any one of claims 51 to 61, wherein the antibody or binding fragment thereof is administered to a subject in need thereof at a dose of about 1 to about 27 mg / kg.

63. The method of any one of claims 51 to 62, wherein the antibody or binding fragment thereof is administered to a subject in need thereof at a dose of about 1 mg / kg to about 10 mg / kg.

64. The method of claim 62 or 63, wherein the antibody or binding fragment thereof is an anti-BAFF-R antibody.

65. The method of any one of claims 62 to 64, wherein the antibody is ibrutinib or a binding fragment thereof.

66. The method of claim 64 or 65, wherein the antibody or binding fragment thereof is administered to a subject in need thereof at a dose of about 3 mg / kg.

67. The method of claim 64 or 65, wherein the antibody or binding fragment thereof is administered to a subject in need thereof at a dose of about 9 mg / kg.

68. The method of any one of claims 51 to 67, wherein the antibody or binding fragment thereof is administered intravenously (iv) to a subject in need thereof.

69. The method of any one of claims 51 to 68, wherein the antibody or binding fragment thereof is administered to a subject in need thereof once every 4 weeks (monthly, + / - 3 days).

70. The method of any one of claims 51 to 69, wherein the antibody is ibrutinib, wherein ibrutinib is administered intravenously to a subject in need thereof once every 4 weeks (monthly, + / - 3 days) at a dose of 3 mg / kg.

71. The method of any one of claims 51 to 69, wherein the antibody is ibrutinib, wherein ibrutinib is administered intravenously to a subject in need thereof once every 4 weeks (monthly, + / - 3 days) at a dose of 9 mg / kg.

72. The method of any one of claims 51 to 71, wherein the subject achieves a complete response.

73. The method of any one of claims 51 to 72, wherein the subject achieves a durable response.

74. The method of any one of claims 51 to 73, wherein the antibody or binding fragment thereof is administered in no more than 6 doses or no more than 4 doses.

75. The method of any one of claims 51 to 74, wherein the antibody or binding fragment thereof is administered for at least 4 doses.

76. The method of any one of claims 51 to 75, wherein the antibody or binding fragment thereof is administered for a total of about 8 doses, about 6 doses, or about 4 doses.

77. The method of any one of claims 51 to 76, wherein the antibody is ibrutinib, wherein ibrutinib is administered for a total of 4 doses.

78. The method of any one of claims 51 to 77, wherein the antibody or binding fragment thereof is administered within a period of up to about 12 months, up to about 9 months, up to about 6 months, up to about 4 months, up to about 3 months, respectively, after administration of the first dose on Day 1.

79. The method of any one of claims 51 to 78, wherein the subject's hemoglobin blood concentration reaches about 10 g / dL or greater following administration of the antibody or binding fragment thereof.

80. The method of any one of claims 51 to 79, wherein the subject's hemoglobin blood concentration increases by about 2 g / dL or more from baseline following administration of the anti-BAFF-R antibody or binding fragment thereof.

81. The method of any one of claims 51 to 80, wherein the subject's hemoglobin blood concentration reaches about 10 g / dL or more and increases by 2 g / dL or more from baseline following administration of the anti-BAFF-R antibody or binding fragment thereof.

82. The method of any one of claims 79 to 81, wherein the increase in hemoglobin blood concentration occurs after administration of a third dose.

83. The method of any one of claims 79 to 82, wherein the increase in hemoglobin blood concentration is maintained for at least 3 weeks, preferably for at least 8 consecutive weeks.

84. The method of any one of claims 79 to 83, wherein the increase in hemoglobin blood concentration is maintained between about week 9 to about week 25 for at least 3 consecutive weeks, preferably for at least 8 consecutive weeks.

85. The method of any one of claims 51 to 84, wherein the antibody or binding fragment thereof is administered as a monotherapy.

86. The method of any one of claims 51-84, wherein the antibody or binding fragment thereof is administered in combination with one or more additional agents.

87. The method of claim 86, wherein the one or more additional agents is supportive care, wherein preferably the supportive care is selected from the group consisting of corticosteroids, in particular prednisone or prednisolone or equivalent, danazol and erythropoietin (e.g. erythropoietin alpha, beta or delta).

88. The method of claim 86 or 87, wherein the one or more additional agents are corticosteroids, particularly the antibody or binding fragment thereof that inhibits the BAFF pathway is administered while the corticosteroid is tapered.

89. The method of any one of claims 51 to 88, wherein the subject has failed at least one prior line of treatment.

90. The method of claim 89, wherein the prior line of treatment is the same or a different wAIHA treatment.

91. The method of claim 90, wherein the different treatment comprises treatment with a corticosteroid, such as prednisolone, prednisone, or an equivalent thereof, or treatment with a B cell depleting agent, such as rituximab.

92. The method of any one of claims 51 to 91, wherein the subject has a hemoglobin blood concentration of about 10 g / dL or less, about 9 g / dL or less, about 8 g / dL or less, about 7 g / dL or less, about 6 g / dL or less, or about 5 g / dL or less.

93. The method of any one of claims 51 to 92, wherein the treatment is stopped after 4, 6, 8, 9, or 12 doses.

94. The method of any one of claims 51 to 93, wherein the treatment is stopped after a complete response is achieved.

95. The method of any one of claims 51 to 94, wherein the treatment is stopped after a durable response is achieved.

96. The method of any one of claims 51 to 95, wherein the subject achieves treatment-free remission (TFR).

97. The method of claim 96, wherein the TFR is continued for a period of about 5 years, 4 years, 3 years, 2 years, 18 months, 16 months, 14 months, 12 months, 9 months, 6 months, or 3 months.

98. The method of any one of claims 51 to 97, wherein the subject relapses after TFR.

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