Treatment of AIHA with BAFF or BAFF receptor inhibitory antibodies

Abstract

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

Description

Technical Field

[0001] The present invention relates to molecules that inhibit the BAFF pathway for use in the treatment of autoimmune hemolytic anemia (AIHA), particularly warm autoimmune hemolytic anemia (wAIHA). The present invention relates to a method for treating AIHA, particularly warm autoimmune hemolytic anemia (wAIHA), comprising administering to a subject in need thereof a molecule that inhibits the BAFF pathway, 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, particularly epratuzumab.

[0002] Sequence Listing This application includes a Sequence Listing that has been electronically submitted in ASCII format and is hereby incorporated by reference in its entirety.

Background Art

[0003] Hemolytic anemia is a form of anemia based on hemolysis, the irregular destruction of red blood cells (RBCs) by autoantibodies against red blood cells. The disease can be a primary or secondary disease (induced by drugs or associated with lymphoproliferation, autoimmunity, or infectious diseases, immunodeficiency, solid tumors, or transplantation). Autoimmune hemolytic anemia (AIHA) is a heterogeneous genotype group of diseases characterized by the destruction of RBCs caused by autoantibodies. AIHA can be classified based on the characteristics of the autoantibodies (see Berentsen S., Seminars in Hematology 55(2018), 141-149).

[0004] (AIHA) can be found in two basic variants: serologically, it is usually classified as warm antibody-mediated AIHA (wAIHA) or cold antibody-mediated AIHA (cAIHA). The first step of the autoimmune hemolysis process is an antigen-antibody reaction, as a result of which autoantibodies deposit on the surface of red blood cells, with or without complement binding.

[0005] In cold agglutinin disease (CAD), a variant of cAIHA, the etiology has been demonstrated to be completely dependent on the classical complement pathway (Berentsen 2018). Antigen-binding IgM (cold agglutinin) on the RBC surface binds to C1q and induces the classical complement pathway. Through a sequential reaction, C3b is formed. When warmed to 37°C, IgM dissociates from the cells and the aggregated RBCs are separated. However, C3b remains bound. C3b-coated RBCs are sequestered mainly in the liver by the mononuclear phagocyte system. On surviving RBCs, C3b is cleaved, leaving many C3d molecules. In some cases, complement activation proceeds beyond the C3b step with cleavage of C5, resulting in activation of the terminal pathway and intravascular hemolysis. In CAD, the autoantibody is a primary monoclonal antibody, with the IgMκ type exceeding 90%.

[0006] wAIHA accounts for 48 - 70% of patients with AIHA. wAIHA is characterized by the binding of primary polyclonal immunoglobulins (mainly IgG) to RBC antigens (Rh proteins or glycophorin A - D). This binding is maximal at 37°C but occurs at most temperatures, hence the term "warm type". The density of these RBC antigens is usually not high enough for complement to bind, but in some cases, complement also becomes bound to the RBCs. The opsonized RBCs are then modified (becoming spherocytes) and ultimately cleared by FcγRIII or C3b receptors on macrophages / activated lymphocytes in the lymphoid organs and spleen (extravascular hemolysis) (Jaeger et al 2020, Blood Rev).

[0007] Primary warm autoimmune hemolytic anemia (wAIHA) has been reported to be slightly less frequent compared to secondary wAIHA, with an estimated prevalence of 35 - 50% of all wAIHA being primary (Lechner and Jaeger 2010, Blood p.1831 - 8). Primary wAIHA is the most frequent type in children. For primary wAIHA, the main indicator for medical therapy is symptomatic anemia. In patients with milder and partially compensated hemolytic anemia (e.g., hemoglobin (Hb) level > 10 g / dL), patients are generally monitored with "watch and wait" therapy without treatment, that is, after comparing the potential burdens and benefits. Spontaneous remission is very rare, and since the disease is usually acute and severe, most patients require treatment, but many treated patients do not achieve or maintain complete remission.

[0008] wAIHA can also be secondary to underlying diseases or can be caused by various pharmaceuticals and organ transplants (Kalfa 2016). In adults, the most frequent underlying diseases associated with wAIHA are lymphoproliferative malignancies, such as chronic lymphocytic leukemia (CLL), and connective tissue disorders, especially SLE. In children, the most frequently reported causes of secondary wAIHA are Evans syndrome (ES), autoimmune diseases, and infections. The management of secondary wAIHA varies according to the underlying cause. Secondary wAIHA associated with autoimmune diseases such as SLE or ES is managed using a similar approach, that is, with the use of steroids and immunosuppressants, and secondary wAIHA associated with lymphoproliferative diseases, immunodeficiencies, and other conditions should be treated with targeted therapy according to current guidelines, depending on age and the underlying disease.

[0009] To date, there is no approved therapy for the treatment of AIHA and particularly wAIHA.

Brief Description of the Drawings

[0010]

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Mode for Carrying Out the Invention

[0011] In the absence of an approved therapy for AIHA, such as wAIHA, existing treatment options are limited. Available therapies are mostly symptomatic, with limited efficacy, and the response generally is not sustained / maintained after treatment discontinuation and can be associated with significant side effects and negative impacts on quality of life. This highlights the need for new therapies for AIHA, such as wAIHA, that can induce sustained or complete remission and allow treatment interruption, with the patient's hemoglobin level maintained within the normal range or at least above 10 g / dL (treatment-free remission [TFR]).

[0012] It has been found that inhibition of the BAFF pathway can lead to the treatment of AIHA, such as wAIHA. Accordingly, in one aspect, the present invention provides a molecule that inhibits the BAFF pathway for use in the treatment of autoimmune hemolytic anemia, such as wAIHA, in a human.

[0013] The molecule is a small chemical molecule or a large biomolecule, such as an antibody or a binding fragment thereof. The molecule can also be an RNA molecule that inhibits protein expression of the BAFF pathway. Further, the molecule can be a peptide, such as a BAFF antagonist, such as a BAFF analog that binds to but does not activate BAFF-R.

[0014] 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 promotes clearance of BAFF from the bloodstream.

[0015] 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. Instead, the BAFF-R inhibitor binds to BAFF-R and changes the conformation of BAFF-R without preventing BAFF-R from binding to BAFF, thereby blocking or reducing BAFF-R activation caused by BAFF binding (allosteric inhibition).

[0016] In one embodiment, the molecule is an antibody or a binding fragment thereof.

[0017] In one embodiment, the antibody or its binding fragment is a BAFF inhibitor and 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 tabalizumab or its binding fragment.

[0018] 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.

[0019] In one embodiment, the antibody or its binding fragment 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.

[0020] In one embodiment, the antibody or its binding fragment is a BAFF-R inhibitor also referred to as an anti-BAFF-R antibody or its binding fragment. In one embodiment, the anti-BAFF-R antibody or its binding fragment is atacicept or its binding fragment.

[0021] B cells play an important role in the etiology of autoimmune diseases. Depletion of B cells with the anti-CD20 monoclonal antibody rituximab is an established approach for treating autoimmune diseases such as wAIHA. However, the use of rituximab is associated with several limitations, such as insufficient depletion of B cells, particularly in tissues, and the survival of rituximab-resistant B cells, which play an important role in the refractoriness and chronicity of autoimmune diseases (Mahevas et al 2015, J Autoimmun p.22-30, Crickx et al 2021, Sci Transl Med.).

[0022] Recent studies have demonstrated 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 p.491-502). As a result of BAFF overexpression, B cell immune tolerance is disrupted, leading to autoimmune disorders (Mackay and Browning 2002, Nat Rev Immunol p.465-75). Increased concentrations of soluble BAFF (B cell activating factor) have been found in various autoimmune diseases such as Sjögren's syndrome (SS) and pemphigus vulgaris (PV). Increased serum BAFF levels have been detected in patients with wAIHA with low hemoglobin (<8g / dL) and high lactate dehydrogenase activity (Xu et al 2015, Int J Hematol p.394-400).

[0023] Targeting the BAFF pathway to improve clinical outcomes in autoimmune diseases such as systemic lupus erythematosus (SLE) and lupus nephritis (LN) has been successfully demonstrated with the monoclonal antibody belimumab (BENLYSTA® US Prescribing Information). In a recent clinical trial (Mahevas et al., Haematologica 2020 p.2449-2457), the anti-BAFF antibody belimumab (administered intravenously 5 times at 10 mg / kg for up to 12 weeks) was tested in 15 patients with persistent or refractory ITP, wAIHA and pathophysiologically related autoimmune diseases, in combination with rituximab (administered intravenously 2 times at 1000 mg for up to 2 weeks). 80% of the patients responded to this combination and maintained their response for 12 hours.

[0024] As a result of using defucosylated antibodies, enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) has also been shown to be able to improve clinical outcomes in autoimmune diseases such as lupus nephritis (LN) (Furie et al 2021, Ann Rheum Dis).

[0025] Ianalumab is a glycoengineered (defucosylated) fully human IgG1 monoclonal antibody against BAFF-R, see for example WHO Drug Information, Vol.34, No.2, page 426-7, 2020, “proposed INN: List 123, see under “p.280-281 ianalumabum”. This antibody is preferably expressed in host cells lacking fucosyl-transferase, for example in mammalian cells having an inactive FUT8 gene (e.g. FUT8 - / - ) to provide a functional defucosylated antibody.

[0026] Ianalumab is expressed on the surface of B cells, whereby B cells and their functions have two main modes of action: 1. Direct lysis and depletion of BAFF-R-expressing B cells due to enhanced antibody-dependent cell cytotoxicity (ADCC) caused by the Fc-deficient Fc region; 2. BAFF receptor blockade that disrupts BAFF-mediated signaling for B cell activation, maturation, proliferation, and survival; is targeted.

[0027] In preclinical studies, ianamab significantly enhanced ADCC against B cells and cytokine production by NK cells, and was more potent in depleting B cells compared to approved anti-CD20 antibodies such as rituximab, obinutuzumab, and ofatumumab (McWilliams et al 2019).

[0028] The antigen specificity of ianamab is directed against the BAFF receptor, BAFF-R (Syn: BR3), which is expressed on the surface of immature and mature B cells up to the lymphoblast stage. Therefore, pro-B and pre-B cells that express CD20 but not BAFF-R are expected to be unaffected by ianamab. Thus, compared to existing B cell-depleting anti-CD20 antibody therapies, ianamab targets a narrow range of more differentiated B cells.

[0029] To date, ianamab has been studied across multiple indications in autoimmune and hematological malignancies. Data from ongoing and completed studies indicate that treatment with ianamab is generally safe and well-tolerated. In particular, the efficacy of ianamab in primary Sjögren's syndrome (pSS) was demonstrated in a Phase II trial (Bowman SJ, et al(2021)).

[0030] Through this dual mechanism, Ianalumab can overcome the above limitations of currently available B-cell depletion therapies, such as rituximab, through potent B-cell depletion (ADCC) in combination with BAFF-R blockade, and as a result, it is expected to prevent BAFF-driven pathogenic rebound phenomena and resistance mechanisms, thus providing the basis for the treatment of AIHA, wAIHA. More generally, promising therapies in a dual-action approach targeting 1) the BAFF receptor pathway and 2) B-cell depletion can address unmet medical needs in AIHA, particularly in the case of CD20-negative B cells in wAIHA.

[0031] Therefore, the emergence of anti-BAFF and anti-BAFF-R antibodies (anti-BAFF receptor antibodies), particularly BAFF inhibitor molecules such as Ianalumab, in hematological autoimmune diseases such as AIHA and particularly wAIHA is supported by one, two, or all of the following: Therapeutic methods in which B-cell depletion has been established in the treatment of AIHA, such as wAIHA; In non-hematological autoimmune diseases, BAFF-R pathway inhibition has been demonstrated to be effective and safe (BENLYSTA® in SLE and LN); BAFF blockade in combination with B-cell depletion has been demonstrated to be effective and safe in ITP in conditions belonging to the same family as wAIHA (Mahevas et al 2021); From clinical trials with Ianalumab in other autoimmune diseases, its effectiveness has been demonstrated (e.g., RA, pSS); Ianalumab has demonstrated a favorable benefit-risk profile based on data from 480 patients exposed to Ianalumab in several autoimmune diseases; Supported by one, two, or all of them.

[0032] The use of anti-BAFF-R antibodies in AIHA and particularly in wAIHA results in a shorter treatment period, especially when compared to the treatment periods used in the treatment of diseases such as Sjögren's syndrome. Further, when other anti-B cell therapies known to date are used, such as rituximab, resistance occurs (which is thought to be at least partly related to the overcompensating biosynthesis of BAFF), and the dual-action mechanism of the anti-BAFF-R antibody should provide a barrier against such resistance development. Such resistance is unlikely to be found with the BAFF-R blocking antibodies used in the treatment of the present invention. Further, the advantage of inhibiting BAFF-R rather than BAFF ligand is that the interaction of BAFF with other possible binding sites of BAFF, except for BAFF-R such as TNFRSF13B / TACI, TNFRSF13, TNFRSF13C or TNFRSF17 / BCMA, is likely to be less affected or unaffected, and as a result, side effects based on the inhibition of other such binding sites are reduced or eliminated.

[0033] In one embodiment, the invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as epratuzumab, or a binding fragment thereof, each used in the treatment of primary or secondary wAIHA, particularly epratuzumab. In one embodiment, secondary wAIHA is not caused by a lymphoproliferative disorder (such as CLL), an immunodeficiency disorder or other immune disorder requiring targeted therapy, or immunosuppressive therapy.

[0034] The etiology and clinical symptoms of primary and some secondary wAIHA are similar and are associated with the disruption of B cell immune tolerance. Therefore, these patients are expected to benefit from the present invention.

[0035] In one embodiment, the present invention relates to an antibody or a binding fragment thereof used for the treatment of AIHA, such as 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.

[0036] In one embodiment, the present invention relates to an antibody or a binding fragment thereof used for the treatment of AIHA, such as wAIHA, wherein the antibody or the binding fragment thereof comprises VH having the amino acid sequence of SEQ ID NO: 17 and VL having the amino acid sequence of SEQ ID NO: 18, respectively.

[0037] In one embodiment, the present invention relates to an antibody or a binding fragment thereof used for the treatment of AIHA, such as wAIHA, wherein the antibody or the binding fragment thereof comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and a light chain variable region having the amino acid sequence of SEQ ID NO: 2.

[0038] The dosage, dosing schedule, route of administration, and treatment duration are selected with the goal of 1) achieving rapid, significant, and consistent depletion of B cells, 2) complete inhibition of the BAFF-R pathway in both blood and tissues, and 3) inducing a rapid and sustained therapeutic effect that is maintained after the end of the treatment period and allowing the patient to be withdrawn from treatment at an appropriate hemoglobin level.

[0039] Accordingly, in one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as atacicept, or a binding fragment thereof, particularly atacicept, wherein the antibody or the binding fragment thereof is administered at a dosage in the range of about 1 to 30 mg / kg, particularly in the range of about 1 to 27 mg / kg, and more particularly in the range of about 1 to 10 mg / kg.

[0040] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as epratuzumab, or a binding fragment thereof, particularly epratuzumab, which is administered once every 2, 3, 4, 6 or 8 weeks, particularly once every 4 weeks (+ / - 3 days), to a subject in need thereof.

[0041] In one embodiment, the administration is via an intravenous route or a subcutaneous route, particularly via an intravenous route.

[0042] In one embodiment, the present invention relates to an anti-BAFF-R antibody or a binding fragment thereof used in the treatment of AIHA, such as wAIHA. The anti-BAFF-R antibody or a binding fragment thereof, such as epratuzumab, is administered at a dose of about 1 to 10 mg / kg, about 3 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, such as epratuzumab, is administered once every 4 weeks (+ / - 3 days) to a subject in need thereof. In one embodiment, epratuzumab is administered once every 4 weeks (+ / - 3 days) at a dose of 3 mg / kg. In one embodiment, epratuzumab is administered once every 4 weeks (+ / - 3 days) at a dose of 9 mg / kg. In one embodiment, the administration is via an intravenous route or a subcutaneous route, particularly via an intravenous route.

[0043] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as epratuzumab, or a binding fragment thereof, particularly epratuzumab. The antibody or a binding fragment thereof is administered in 12 or fewer doses, 9 or fewer doses, 6 or fewer doses, 4 or fewer doses. In one embodiment, the antibody or a binding fragment thereof is administered in at least 3 doses or at least 4 doses. In one embodiment, the antibody or a binding fragment thereof is administered in 4 to 9 doses, 4 to 8 doses, or 4 to 6 doses.

[0044] In one embodiment, the anti-BAFF-R antibody or binding fragment thereof, such as epratuzumab, which is used in the treatment of AIHA, such as wAIHA, is administered in a total of 8 doses, 6 doses, or 4 doses, particularly a total of 4 doses. In one embodiment, the doses are administered consecutively, usually every 4 weeks (monthly).

[0045] In one embodiment, the present invention relates to an anti-BAFF-R antibody or binding fragment thereof, such as epratuzumab, which is used in AIHA, such as wAIHA. The anti-BAFF-R antibody or binding fragment thereof is administered for a period of up to about 12 months, up to about 9 months, up to about 6 months, or up to about 5 months, respectively, after administration of the first dose on day 1; or the anti-BAFF-R antibody or binding fragment thereof is administered for a period of up to about 4 months, preferably up to about 3 months, respectively, after administration of the first dose on day 1; or the anti-BAFF-R antibody or binding fragment thereof is administered for a period up to 20 weeks (+ / - 3 days) after administration of the first dose on day 1; the anti-BAFF-R antibody or binding fragment thereof is administered for a period up to 16 weeks (+ / - 3 days) after administration of the first dose on day 1; or the anti-BAFF-R antibody or binding fragment thereof is administered for a period up to 12 weeks (+ / - 3 days) after administration of the first dose on day 1.

[0046] In one embodiment, the present invention relates to epratuzumab used in the treatment of AIHA, such as wAIAH, or a method for treating AIHA, such as wAIAH, which includes administering epratuzumab to a subject in need thereof, usually in a therapeutically effective amount, wherein the subject is likely to achieve complete remission (CR) usually after the second dose, or after the third or fourth dose. CR is determined by any one, any two, or all of the following effects: (1) Normalization of hemoglobin (Hb level ≧ about 11 g / dL (female) or ≧ about 12 g / dL (male)); (2) Absence of evidence of hemolysis (normal levels of indirect bilirubin, LDH, haptoglobin, and / or reticulocytes); (3) Absence of red blood cell transfusion; and is determined by any one, any two, or all of the above.

[0047] In one embodiment, complete response is based on normalization of hemoglobin (Hb level ≥ about 11 g / dL (female) or ≥ about 12 g / dL (male)). In one embodiment, CR is determined by achievement of all of the above effects.

[0048] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering to a subject in need thereof eculizumab in a therapeutically effective amount, wherein the subject typically achieves sustained response at a dose in the range of preferably 3 - 9 mg / Kg, preferably after monthly administration, preferably after the second administration, or more likely after the third or fourth administration. As used herein, the term "sustained response" refers to the following effects: (1) The subject's hemoglobin blood concentration has reached 10 g / dL; (2) The subject's hemoglobin blood concentration has increased by about 2 g / dL or more from baseline; is determined by one or both of (binary effect), and the effect continues continuously for at least 3, 4, 5, 6, 7 weeks.

[0049] In a preferred embodiment, the effect continues continuously for at least 8 weeks. In a further preferred embodiment, the sustained response with binary effect continues continuously for at least 8 weeks.

[0050] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering to a subject in need thereof eculizumab in a therapeutically effective amount, during or after treatment, typically after the second administration, or more likely after the third or fourth administration, (1) The hemoglobin blood concentration of male subjects reaches about 10 g / dL or more, about 11 g / dL or more, and preferably about 12 g / dL or more; or (2) The hemoglobin blood concentration in female subjects is maintained at about 9 g / dL or more, about 10 g / dL or more, and preferably about 11 g / dL, and is maintained at about 10 g / dL or more, about 11 g / dL or more; Relates to a method.

[0051] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering eculizumab to a subject in need thereof in a therapeutically effective amount, wherein the subject does not require a blood transfusion during or after treatment, usually after the second dose, or more likely after the third or fourth dose. In one embodiment, the subject does not require a blood transfusion starting from the first day of treatment for at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 18 months, at least 2 years or at least 3 years.

[0052] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering eculizumab to a subject in need thereof in a therapeutically effective amount, wherein the subject does not have evidence of hemolysis during or after treatment, usually after the second dose, or more likely after the third or fourth dose. Evidence of hemolysis includes one, two, three or all abnormalities of biomarkers selected from the group consisting of bilirubin, LDH, haptoglobin, and reticulocytes. In one embodiment, the subject does not have evidence of hemolysis starting from the first day of treatment for at least 4 months, at least 6 months, at least 9 months, at least 1 year, at least 18 months, at least 2 years or at least 3 years.

[0053] In one embodiment, the present invention relates to anatumumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering anatumumab to a subject in need thereof, usually in a therapeutically effective amount, wherein the hemoglobin blood concentration of the subject in need thereof is, during or after treatment, usually after the second administration, or more likely after the third or fourth administration, increased 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, compared to the baseline.

[0054] In addition to any one of the foregoing embodiments, the hemoglobin blood concentration of the subject is measured at the time of the third dose administration, usually on the same day, either immediately before or after the third administration. In one embodiment, the hemoglobin blood concentration of the subject is measured between 9 weeks and 25 weeks after the first administration, particularly when the drug is administered once every 4 weeks.

[0055] In one embodiment, the subject hemoglobin blood concentration is measured weekly, bi-weekly, or monthly. In one embodiment, the hemoglobin blood concentration of the subject is measured bi-weekly until 25 weeks, and then monthly, and the first administration is interpreted as the first week, the first day.

[0056] In one embodiment, a use of the present invention according to any one of the foregoing embodiments, particularly using anatumumab, wherein the treatment is interrupted after 8 administrations, 6 administrations, or preferably 4 administrations. Usually, those doses are administered continuously. Usually, the drug is administered every 4 weeks.

[0057] In one embodiment, the present invention relates to anatumumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering anatumumab to a subject in need thereof, usually in a therapeutically effective amount, wherein when the subject reaches complete remission, usually and generally complete remission lasts for at least 3 weeks, usually 3 weeks or 1 month, during which at least 2 measurements are performed, and the treatment is interrupted.

[0058] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering eculizumab to a subject in need thereof, usually in a therapeutically effective amount, wherein the hemoglobin blood concentration of the subject reaches 10 g / dL or more for a period of usually and generally at least 3 weeks, usually 3 weeks or 1 month, with at least two measurements being performed during that period, and if continued, the treatment is interrupted.

[0059] In a further embodiment, the hemoglobin blood concentration of the subject (1) is maintained continuously at about 10 g / dL or more for 3 weeks; and (2) has an increase of ≧ 2 g / dL from baseline for 3 consecutive weeks; in which case the treatment is interrupted. Particularly when the drug is administered once every 4 weeks, the hemoglobin blood concentration of the subject is usually measured between 9 weeks and 25 weeks after the first administration.

[0060] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering eculizumab to a subject in need thereof, usually in a therapeutically effective amount, wherein the duration of efficacy is at least about 3 months, at least about 6 months, at least about 9 months, or at least about 12 months. In a further embodiment, the duration of efficacy is about 12 months, about 15 months, about 18 months, or about 24 months.

[0061] Particularly in the context of a clinical trial setting, such as Example 2, as used herein, the term "duration of efficacy" refers to subjects who have previously achieved sustained efficacy (at least 8 consecutive weeks of binary effect): from the first hemoglobin assessment indicating sustained efficacy, to the following events · Weekly assessments for at least 2 consecutive weeks * in which the hemoglobin level is less than 10 g / dL (the first date of the two relapse assessments is considered the date of relapse), · Initiation of any rescue therapy or prohibited therapy, · Death (regardless of cause), means the time until confirmation of loss of sustained response defined as the first of the above.

[0062] The following treatments are considered rescue drug therapies: · Treatment for any additional wAIHA not listed in the prohibited drug therapy · An increase in the dosage of supportive care by more than 20% compared to the pre-enrollment dosage, in accordance with the recommendations of expert opinion. Resuming the permitted supportive treatment at the pre-enrollment dosage or returning to the pre-enrollment dosage level after dosage reduction is not considered rescue drug therapy. · Transfusion is considered rescue treatment after 8 weeks and 1 day, as it can affect the Hb level and disrupt the effectiveness of eculizumab.

[0063] Prohibited drug therapies are live vaccines or attenuated live vaccines, intravenous or oral immunosuppressive drugs, rituximab, belimumab or other monoclonal antibodies, and other experimental therapies.

[0064] In one embodiment, the present invention relates to eculizumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, comprising administering eculizumab to a subject in need thereof, usually in a therapeutically effective amount, such that the subject enters a treatment-free remission (TFR) phase. As used herein, the term "treatment-free remission (TFR)" means a period during which a subject who has discontinued treatment has a temporary or permanent reduction or quiescence of the symptoms of the disease. In TFR, the subject typically and generally maintains a hemoglobin blood concentration of about 10 g / dL or more, generally preferably about 11 g / dL or more in females and about 12 g / dL or more in males. In TFR, the subject typically does not receive a transfusion. In TFR, the treating physician typically does not consider that the subject requires any treatment.

[0065] In one embodiment, the subject has a treatment-free remission (TFR) for 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.

[0066] As used herein, the term "relapse" means a decrease in hemoglobin below a normal level (e.g., above about 12 g / dL in males and above about 11 g / dL in females), and typically means remaining below the normal level for a period of time. In most cases of the condition, the term "relapse" means a decrease in hemoglobin below about 10 g / dL. The period is usually the period for at least two consecutive measurements, and usually the consecutive measurements are taken less than 2 months apart, less than 1 month apart, 3 weeks apart, 2 weeks apart, 1 week apart.

[0067] In one embodiment, the invention relates to epratuzumab for use in the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIAH, comprising administering epratuzumab to a subject in need thereof, usually in a therapeutically effective amount, wherein the subject has relapsed after TFR. TFR can be achieved by (1) an anti-BAFF antibody, such as belimumab; (2) an anti-BAFF-R antibody, such as epratuzumab, or a binding fragment thereof; or (3) another wAIAH treatment other than the above. In one embodiment, TFR is achieved by administration of epratuzumab.

[0068] In one embodiment, the present invention relates to anatumomab used for the treatment of AIHA, such as wAIAH, or a method of treating AIHA, such as wAIHA, which comprises administering anatumomab to a subject in need thereof, usually in a therapeutically effective amount, wherein the subject has relapsed after TFR and TFR is achieved by administration (retreatment) of anatumomab. In a further embodiment, the subject receives the same dosing schedule as that received prior to achieving TFR. The anatumomab treatment is for untreated subjects. In one embodiment, the subject is administered a lower dose than the dose administered prior to achieving TFR. In one embodiment, the subject is administered a higher dose than the dose administered prior to achieving TFR. The term "dose" as used in these retreatment embodiments means any one, two, or all of the amount in a single administration, the dosing interval, the total treatment period, or combinations thereof as described above.

[0069] In one embodiment, the present invention relates to an anti-BAFF-R antibody or a binding fragment thereof, such as anatumomab, used according to any one of the foregoing embodiments, wherein the anti-BAFF-R antibody or a binding fragment thereof is administered or to be administered as monotherapy for AIHA, such as wAIHA.

[0070] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF-R antibody, such as anatumomab, or a binding fragment thereof, each used for the treatment of warm autoimmune hemolytic anemia (wAIHA) in humans, particularly anatumomab, wherein the subject has failed at least one previous treatment line. The previous treatment can be the same or a different wAIHA treatment.

[0071] Different treatments for wAIHA include, but are not limited to, treatment with corticosteroids such as prednisone, prednisolone or their equivalents, and treatment with B cell depleting agents such as rituximab. In one embodiment, an anti-BAFF-R antibody or a binding fragment thereof, such as epratuzumab, is administered while tapering corticosteroids. In one embodiment, the subject has not been administered 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 has been administered a B cell depleting agent such as rituximab prior to treatment with the present invention, particularly prior to treatment with epratuzumab. Typically, the washout period is at least 12 weeks prior to administration according to the present invention.

[0072] In one embodiment, the present invention relates to an anti-BAFF-R antibody or a binding fragment thereof used according to any one of the foregoing embodiments, and the anti-BAFF-R antibody or a 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, at a low dosage (e.g., 15 mg / day or less, such as prednisone (lo) 2 - 5 mg / day, 1 - 10 mg / day), or while tapering corticosteroids; danazol (e.g., 200 mg three times a day); and erythropoietin (e.g., erythropoietin α, β or δ 1000 units / week).

[0073] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as epratuzumab, or a binding fragment thereof, particularly epratuzumab, wherein the antibody or a binding fragment thereof is administered to a subject having primary or secondary wAIHA, and the subject has had an inadequate response or recurrence after at least one treatment line, such as a patient having steroid resistance, dependence or intolerance. Generally, the subject has wAIHA previously demonstrated by a positive direct antiglobulin test (DAT) specific for anti-IgG or anti-IgA.

[0074] Steroid resistance: Failure to achieve a hematological response with prednisone (or prednisolone) at a dose of at least 1 mg / kg within 3 weeks. Steroid dependence: Requirement to continue prednisone (or prednisolone) at a dose exceeding 10 mg / day to maintain the response. Steroid intolerance: Side effects or anaphylaxis / anaphylaxis-like reactions that cause permanent discontinuation of steroids.

[0075] In one embodiment, the present invention relates to an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as ianalumab, or a binding fragment thereof, each for use in the treatment of wAIHA, particularly ianalumab, wherein the subject has a hemoglobin blood concentration of 10 g / mL or less, 9 g / dL or less, 8 g / dL or less, 7 g / dL or less, 6 g / dL or less, 5 g / dL or less. In one embodiment, the subject has a hemoglobin blood concentration of 10 g / mL or less. Generally, the subject is accompanied by the presence of symptoms associated with anemia.

[0076] In one embodiment, the subject's neutrophils are greater than 1000 / mm 3 .

[0077] In one embodiment, the serum creatinine in the subject is normal or less than 1.5 × the upper limit of the reference value (ULN).

[0078] In one embodiment, the subject is 12 - 17 years old in adolescence. Toxicology studies with ianalumab in cynomolgus monkeys were conducted in the following age ranges: 2.2 - 3.5 years (preliminary single / multiple dose studies); 5 - 6 years (4-week study); 4 - 5 years (13-week study); 4 - 6 years (26-week study). Safety issues regarding humans were not confirmed in these studies. Age conversion follows the general concept that 1 year in primates is considered equal to 4 years in humans (Baldrick 2010). This includes the human age range of 8.8 - 24 years, thereby including the age of adolescent patients planned to be included in the proposed Phase 3 trial.

[0079] In one aspect, the present invention relates to a method of treating a subject suffering from autoimmune hemolytic anemia (AIHA), such as warm autoimmune hemolytic anemia (wAIHA), comprising administering to the subject in need thereof an anti-BAFF antibody, such as belimumab, or an anti-BAFF antibody, such as atacicept, or a binding fragment thereof, particularly atacicept, in a therapeutically effective amount. The method particularly includes any one of the foregoing embodiments.

[0080] 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 atacicept, or a binding fragment thereof, particularly atacicept, in the manufacture of a medicament for treating a subject suffering from autoimmune hemolytic anemia (AIHA), such as warm autoimmune hemolytic anemia (wAIHA). The use particularly includes any one of the foregoing embodiments.

[0081] Definitions As used herein, the following terms are intended to have the following meanings.

[0082] A, An, The: As used herein, the terms "a", "an", "the" and similar terms used in connection with the present disclosure (particularly in connection with the claims) shall be construed to include both the singular and the plural unless otherwise indicated herein or clearly contradicted by the context. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein. They particularly represent "one or more", and an anti-BAFF-R antibody or a binding fragment thereof is referred to with respect to "one", meaning an anti-BAFF-R antibody or a binding fragment thereof having the same amino acid sequence.

[0083] "About" is particularly intended to include a deviation of ±20%, such as ±10%, such as ±5%, or ±2% from the specific numerical value following this word, and to include the recited numerical value itself.

[0084] And / or: "And / or" means that one or both or all of the components or features of a list are possible variants, in particular, two or more of them in an alternative or cumulative way that includes any sub-combinations of either of two alternatives. It can be replaced by "one or two or more or all of ~".

[0085] Additional agent: For convenience, an agent used in combination with an anti-BAFF-R antibody, an anti-BAFF-R antibody or a binding fragment thereof is referred to herein as an "additional" agent.

[0086] Antibody: The term "antibody" refers to a protein, such as an immunoglobulin chain or a fragment thereof, that includes at least one immunoglobulin variable domain sequence. The term "antibody" includes, for example, monoclonal antibodies (including full-length antibodies having an immunoglobulin Fc region). An antibody includes a full-length antibody, or a full-length immunoglobulin chain, or an antigen-binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. Also, an antibody can be a multi-selective antibody, for example, it includes a plurality of immunoglobulin variable domain sequences, and most of the first immunoglobulin variable domain sequences have binding specificity for a first epitope, and most of the second immunoglobulin variable domain sequences have binding specificity for a second epitope.

[0087] Anti-BAFF-R antibody and anti-BAFF antibody, or binding fragment thereof: As used herein, the term "anti-BAFF-R antibody" means an antibody that binds to BAFF-R. As used herein, the term "anti-BAFF antibody" means an antibody that binds to BAFF. As used herein, the term "binding fragment" means a part of an antibody that can bind to a BAFF-R epitope, is involved in the binding of BAFF to BAFF-R, and / or can bind to an epitope that negatively affects the activation of BAFF-R by BAFF. The binding of an antibody (or its binding fragment) to BAFF-R or to BAFF inhibits the binding of BAFF to BAFF-R, thereby reducing the formation of the BAFF / BAFF-R complex and / or reducing the activation of BAFF-R. Preferably, the antibody or its binding fragment reduces the formation of the BAFF / BAFF-R complex and / or reduces the 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 as compared to a suitable control (e.g., a sample without the presence of the antibody or its binding fragment, such as in an ELISA). Additionally or alternatively, the antibody or its binding fragment can dissociate a pre-formed BAFF / BAFF-R complex. In a preferred embodiment, the antibody or its binding fragment can dissociate at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more of the pre-formed BAFF-R complex. As described above, this property can be compared to a suitable control (e.g., a sample without the presence of the antibody or its binding fragment). Certain embodiments relate to an antibody or its binding fragment comprising the following complementarity determining regions (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).Certain embodiments of the invention include belimumab or a binding fragment thereof as an anti-BAFF-R antibody or a binding fragment thereof.

[0088] 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 under the accession number Q96RJ3 in UniProt / Swiss-Prot, and the nucleotide sequence encoding human BAFF-R can be found under the accession number NM_052945.4. It is mainly expressed in subsets of B lymphocytes and T cells.

[0089] Combination: The term "combination" or "in combination with" is not intended to mean that the therapies or therapeutic agents need to be administered simultaneously and / or formulated for co-delivery, although these delivery methods are included within the scope described herein. The combined therapeutic agents can be administered simultaneously with, before, or after one or more other additional therapies or therapeutic agents. The therapeutic agents or treatment protocols can be administered in any order. Generally, each agent will be administered at the dosage and / or time schedule determined for that agent. Furthermore, it will be understood that the additional therapeutic agents used in this combination can be administered together or separately in different compositions. Generally, it is envisioned that the additional therapeutic agents used in the combination will be utilized at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in the combination are lower than the levels used individually.

[0090] Effective amount: The term "effective amount" or "therapeutically effective amount" or "pharmaceutically effective amount" means the amount or content of an active agent that is sufficient to elicit a required or desired response, or in other words, an amount that is sufficient to elicit an apparent biological response when administered to a subject. Preferably, said amount relates to an amount that is therapeutically or, in a broader sense, even prophylactically effective against the progression of a disease or disorder as disclosed herein.

[0091] Patient / Subject: As used herein, the terms "patient" or "subject" are to be construed to mean a human. Except where otherwise noted, the terms "patient" or "subject" are used interchangeably herein.

[0092] in need of: As used herein, a subject is "in need of" such treatment if such subject would benefit biologically, medically or in terms of quality of life from such treatment.

[0093] Treat, treating, treatment: As used herein, the terms "treat," "treating," or "treatment" (which are interchangeable with each other) for any disease or disorder, in one embodiment, refer to alleviating a disease or disorder (e.g., slowing, or stopping, or reducing at least one manifestation of the disease or clinical symptoms or its pathological characteristics). In another embodiment, "treat," "treating," or "treatment" refer to reducing or alleviating at least one physical parameter or pathological characteristic of a disease, including, for example, cases that may not be distinguishable by the subject. In yet another embodiment, "treat," "treating," or "treatment" refer to modulating a disease or disorder physically (e.g., stabilizing at least one distinguishable or indistinguishable symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, "treat," "treating," or "treatment" refer to preventing or delaying the onset, manifestation, or progression of at least one symptom or pathological characteristic of a disease or disorder or related thereto. In yet another embodiment, "treat," "treating," or "treatment" refer to preventing the progression of a disease or delaying it to a more advanced stage or a more severe condition. The benefit to the patient to be treated is statistically significant or at least recognizable to the patient or the physician.

[0094] An anti-BAFF-R antibody (particularly, epratuzumab) or a binding fragment thereof and an additional agent can be administered simultaneously, in the same or separate compositions, or sequentially. For sequential administration, the anti-BAFF-R antibody or a binding fragment thereof can be administered first and the additional agent can be administered second, or the order of administration can be reversed.

[0095] In one aspect, the present invention provides a product for separate, sequential or simultaneous or combined use of the combination partners of the present invention, in particular a kit comprising two or more separate pharmaceutical compositions, at least one of the pharmaceutical compositions containing an anti-BAFF-R antibody, in particular belimumab, or a binding fragment thereof, respectively, and at least one other of them containing an additional agent. In one embodiment, the kit comprises means for separately accommodating the compositions, such as containers, divided bottles, divided foil packets. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules, etc.

Example

[0096] The present invention will be described by the following examples without limiting its scope.

[0097] Example 1 Pharmacokinetics-Pharmacodynamics Modeling To explain the belimumab concentration and CD19 + B cell count in patients with various autoimmune diseases, a population PK / PD (Zhang, J Pharmacokinet Pharmacodyn; 30(6):387-404. 2003) approach was used to construct a population PK / PD model.

[0098] Population PK / PD Model A two-compartment population PK model with linear clearance was fitted to intravenous and subcutaneous injection data derived from studies in RA patients and pSS patients. The PK / PD model was parameterized from the baseline B cell count (base), the B cell death rate (kout), the volume of the B cell peripheral compartment (Vb), the B cell inter-compartment transfer rate (Qb), the maximum stimulatory effect of belimumab on B cell (Emax) death rate, and the point of belimumab concentration at which the VAY736 effect is half-maximal (EC50).

[0099] PK Tissue Receptor Occupancy (RO) Structural Model The kinetics of circulating B cells explained by the population PK / PD model are not necessarily expected to predict clinical efficacy. Therefore, a hypothesis-driven tissue receptor occupancy (RO) model was also developed and used to consider the competitive binding of anatumomab and soluble BAFF (sBAFF) on BAFF-R under the pseudo-steady state assumption. The following equation relates pK (C anatumomab(t), nM) to BAFF-R engagement (ROVAY(t), %) by anatumomab:

Equation

[0100] To determine the BAFF-R occupancy in virtual (fictive) disease-related tissues, the following hypotheses were proposed based on in-hospital experiments: Tissue: Serum concentration ratio anatumomab: 1:5 · Tissue: Serum concentration ratio sBAFF: 4:1 Table 1 shows all the parameters used to predict tissue receptor occupancy.

[0101]

Table 1

[0102] Dose selection simulation for the proposed Phase 3 trial in wAIHA It was hypothesized that the PK of epratuzumab would be comparable in the target wAIHA patient population, as observed in other autoimmune diseases. Furthermore, based on available literature, baseline B cells in ITP patients are comparable to those previously measured in the epratuzumab study in pSS (Toffoletti et al 2008). Assuming a similarity in pathophysiology between ITP and wAIHA, a similar level of B cells in wAIHA was used as the baseline. Therefore, the final population PK / PD model was used to support the selection of dose and dosing schedule in the proposed Phase 3 study in wAIHA patients.

[0103] Furthermore, the same hypothesis-driven tissue RO model was also assumed to be appropriate for both autoimmune diseases and wAIHA, and therefore the PK-RO model described in Table 1 was used. Only the level of soluble BAFF concentration in serum was fixed at a lower level of 1.817 ng / mL for wAIHA patients instead of 2.7 ng / mL in the case of autoimmune diseases. Notably, the serum BAFF concentration reported in patients with AIHA was 1358.7 ± 141.0 pg / mL (Xu et al 2015), and the fixed level at 1.817 ng / mL was selected for conservative tissue RO prediction, approximately 3 standard deviations away from the mean value.

[0104] The following criteria: · B cell depletion (<10 cells / μL) within the dosing window; · Tissue RO (90% threshold) based on the hypothesized model shown in Table 1; · Epratuzumab PK evaluated by C trough > 1.8 μg / mL, which is the steady-state trough concentration with subcutaneous administration of 300 mg every 4 weeks, the dose that produced the highest clinical efficacy in the multiple-dose, dose-range finding study CVAY736A2201 in pSS patients (CSR A2201 at 52 weeks); were used to perform PKPD simulations to support the selection of a 4-week dosing interval.

[0105] From Figure 1 of the PKPD simulation, it is suggested that the dose and usage of ianalumab at 3 mg / kg and 9 mg / kg, administered intravenously every 4 weeks for a 16-week treatment period (total of 4 doses), could be considered for a Phase 3 study in wAIHA patients. With a low dose of 3 mg / kg intravenous administration every 4 weeks, only half of the simulated patients had a trough higher than 1.8 ug / mL, and more than 95% of the patients had a predicted tissue RO > 90% (Table 2). With a high dose of 9 mg / kg intravenous administration every 4 weeks, the coverage of PK and tissue RO in patients could increase.

[0106]

Table 2

[0107]

Table 3

[0108] After intravenous administration of 9 mg / kg of ianalumab, the simulated mean exposure after the final dose (Cmax 192 μg / mL and AUC0-28d 931 day * μg / mL) is within the previously confirmed values at the tested intravenous maximum dose in a study in pSS patients after a single intravenous dose of 10 mg / kg (mean Cmax 213 μg / mL and AUCinf 1140 day * μg / mL, n = 12), and in a study in CLL patients with intravenous administration of 9 mg / kg every 2 weeks (q2w) (mean Cmax 262 μg / mL and AUC0-28d,ss 3730 day * μg / mL, 2 doses over 4 weeks, q2w, n = 4).

[0109] From the comparison of the preclinical species with the simulated average exposure after monthly intravenous administration of 9 mg / kg of Ianalumab, a safety margin of 14 - 15 times and 4.3 - 5.6 times was demonstrated for Cmax and AUC respectively for monthly 9 mg / kg intravenous administration, indicating that the maximum dose of 9 mg / kg of intravenous Ianalumab administered every 4 weeks is safe.

[0110] Example 2: Ianalumab Treatment of wAIHA (Phase III Trial) Clinical trials determine the usefulness of Ianalumab (VAY736) in the treatment of wAIHA in patients who previously failed treatment. This is an open-label, crossover, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of Ianalumab compared to placebo in patients with warm autoimmune hemolytic anemia (wAIHA) who previously failed treatment.

[0111]

Table 4

[0112] The treatments under investigation are to administer Ianalumab or placebo intravenously (as a 2-hour infusion) every 4 weeks for 4 cycles of 4 doses, with or without the use of permitted supportive therapies. Two different dose levels of Ianalumab (3 and 9 mg / kg) are administered and compared to placebo in adult patients with wAIHA who previously failed treatment. The intravenous route of administration is preferred because the highest, standardized exposure established across disease backgrounds and with a favorable safety profile is achieved using this route. The intravenous route also has the advantage of having a low risk of local site reactions as observed with subcutaneous administration and with dose dependence confirmed for it.

[0113] The first evidence of promising clinical benefits of a short treatment course of epratuzumab was provided by the placebo-controlled, proof-of-concept study CVAY736X2201 conducted in 27 patients with primary Sjögren's syndrome (pSS). In this study, efficient depletion of circulating B cells and clear signs of efficacy that persisted until the end of the trial in a subset of clinical outcomes in the higher-dose group were confirmed after a single intravenous administration of epratuzumab (3 mg / kg or 10 mg / kg). Therefore, a 16-week epratuzumab treatment period (4 infusions every 4 weeks) was selected for the phase 3 trial.

[0114] Ninety participants will be randomized in a 1:1:1 ratio to either epratuzumab, placebo 3 mg / kg, or 9 mg / kg. The randomization stratification factor is previous exposure to rituximab (yes vs no) before randomization.

[0115] Supportive therapy (which should have been stable for at least 4 weeks before randomization to the trial) may consist of steroids (prednisone (oral) up to 15 mg / day), erythropoietin α, β, or δ 10,000 units / week, or danazol 200 mg three times a day. If the above supportive therapy is insufficient and the participant requires additional support to maintain a safe level of hemoglobin before epratuzumab exerts its therapeutic effect, red blood cell transfusions and intravenous immunoglobulin (IVIG) are permitted.

[0116] To prevent potential confounding of efficacy due to the effects of transfusions and IVIG (intravenous immunoglobulin), a 4-week washout is performed; only hemoglobin values measured after this washout period are used for the assessment of efficacy endpoints (sustained response, response, complete response).

[0117] Prohibited drug therapies are live vaccines or attenuated live vaccines, intravenous or oral immunosuppressive drugs, rituximab, belimumab or other monoclonal antibodies, and other experimental therapies.

[0118] If clinically indicated (e.g., to ensure patient safety), the treating physician may also administer rescue medications. The study implementer should define rescue treatment in accordance with local practice, except for the drug therapies listed in the above paragraph. The following treatments are considered rescue drug therapies: - Treatment for any additional warm AIHA not listed among the prohibited drug therapies. - An increase in the dosage of supportive therapy exceeding 20% compared to the pre-registration dosage, following the recommendations of expert opinion. Resuming the permitted supportive treatment at the pre-registration dosage or returning to the pre-registration dosage level after a dosage reduction is not considered rescue drug therapy. - Transfusion is considered rescue treatment after the first day of week 8, as it may affect Hb levels and confound the effectiveness of eculizumab.

[0119] Eligible participants for inclusion in this study are male or female patients aged 18 years or older. Patients with primary or secondary warm AIHA (previously demonstrated by a positive direct antiglobulin test (DAT) specific for anti-IgG or anti-IgA), who have had inadequate response or recurrence after at least one treatment line, such as patients with steroid resistance, dependence, or intolerance.

[0120] Patients with a hemoglobin concentration < 10 g / dL at screening, accompanied by the presence of symptoms related to anemia (reasonable: patients with a hemoglobin level < 10 g / dL have decompensated hemolytic anemia and thus require treatment to increase the hemoglobin level), and The dosage of supportive therapy must have been stable for at least 4 weeks before randomization.

[0121] Participants who meet any of the following criteria are not eligible for inclusion in this study. · Patients with secondary warm AIHA associated with a hematological disorder requiring immunosuppressive drugs and accompanied by bone marrow or other immune diseases, or patients with other forms of AIHA (cold or intermediate), Evans syndrome, or the presence of other cytopenias ·Previous use of B-cell depletion therapy within 12 weeks prior to randomization ·Active virus, bacteria, or other infections (tuberculosis or SARS-CoV-2) ·Primary or secondary immunodeficiency, or known history of being positive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) ·Live vaccine or attenuated live vaccine within 4 weeks prior to randomization ·Or, the following conditions: - Neutrophils: < 1000 / mm 3 - Serum creatinine > 1.5 × upper limit of normal (ULN) Patients having The following conditions: - Neutrophils: < 1000 / mm 3 - Serum creatinine > 1.5 × upper limit of normal (ULN) Patients having

[0122] Randomized treatment period (16 weeks): On the first day of the first week, the patient is randomly assigned in a 1:1:1 ratio to one of the following three arms: Arm A (intravenous infusion of 3 mg / kg of Ianalumab every 4 weeks), Arm B (intravenous infusion of 9 mg / kg of Ianalumab every 4 weeks), or Arm C (intravenous infusion of Rasivo every 4 weeks). During this 16-week randomized treatment period, the participants are administered a total of 4 doses of the study treatment, which are administered once every 4 weeks at the following visits: on the first day of week 1, the first day of week 5, the first day of week 9, and the first day of week 13. The study treatment is administered by intravenous infusion over a period of 2 hours (+ / - 15 minutes). In addition to the study treatment, the patient receives premedication (corticosteroids, paracetamol / acetaminophen or NSAIDs and antihistamines according to the local facility guidelines) to reduce the risk of possible infusion-related systemic reactions, and supportive therapy is also provided in all treatment arms (see the above paragraph). The randomized treatment period is the period for evaluating the primary endpoint (see above). After the end of the 16-week randomized treatment period, all participants enter a follow-up period and are monitored for efficacy and safety, or the open-label extension period for placebo-treated participants, depending on how the participants respond to the study treatment. · The visit frequency is bi-weekly (q2w) during the treatment period (day 1 to week 16). For the follow-up period of the primary endpoint, for safety, it is monthly for the first 20 weeks after the last dose, and then 4 times a year until 2 years after the last dose; for efficacy, it is monthly for the first 2 years after the last dose, and then 4 times a year until the loss of sustained efficacy is confirmed or until the end of the study.

[0123] The primary endpoint is a binary variable indicating whether the patient achieves sustained efficacy (an increase in Hb of ≥ 10 g / dL and ≥ 2 g / dL from baseline during at least 8 consecutive weekly evaluations) from the first day of week 9 to the first day of week 25 in the absence of rescue drug therapy or prohibited treatment before achieving sustained efficacy.

[0124] An important secondary efficacy endpoint / variable is: duration of response, · For participants who had previously achieved sustained response: From the first hemoglobin assessment showing sustained response (as defined by the primary endpoint), the following events: At least two consecutive weekly assessments * With hemoglobin levels < 10 g / dL (the first date of the two relapse assessments is considered the relapse date), Initiation of any rescue medication or prohibited treatment, Death (regardless of cause); Is defined as the time until confirmation of loss of sustained response, defined as the first of the following: · For participants who did not achieve sustained response according to the definition of the primary endpoint: The response duration is 0 days.

[0125] Example 3 Decrease in autoantibodies in patients participating in a primary Sjögren's syndrome (pSS) trial In a primary Sjögren's syndrome (pSS) trial, 190 patients with pSS were treated with subcutaneous ianalumab (24 weeks, 5, 50, 150, or 300 mg every 4 weeks) or placebo (Bowman SJ, Fox R, Doerner 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). From this study, a significant dose-response effect of ianalumab on ESSDAI and an increase in simulated salivary volume were shown, with the highest effect confirmed at the highest dose.

[0126] For the interpretation of quantitative data on the effect of VAY736 on autoantibodies in this trial, SSA Ro52kd / TRIM21, SSA Ro60kd, and SSB autoantibodies were analyzed at the same dilution for baseline and post-treatment samples using the kit FIDIS™ Connective Profile.

[0127] The following data represent data obtained in the VAY736 treatment arm for SSAro52 (Figure 2A), SSAro60 (Figure 2B), and SSB autoantibodies (Figure 2C) using the optimal dilution at baseline, week 12, and week 24. The data are represented as percent change from baseline. From the results, the decrease in the three autoantibodies with VAY736 was dose-dependent between 5 mg, 50 mg, and 300 mg, and this phenomenon of autoantibodies in the placebo reached a maximum decrease of 4% at week 24 compared to 12 - 16% in the 50 and 300 mg VAY736 treatment arms.

[0128] Example 4: Decrease in autoantibodies in patients participating in a systemic lupus erythematosus (SLE) trial This is a double-blind, randomized, placebo-controlled, multi-site two-arm study evaluating a dose of 300 mg of ianalumab administered subcutaneously once monthly versus placebo in patients with SLE receiving standard therapy. The study regimen is 300 mg of ianalumab administered subcutaneously once monthly for an 18-month treatment period.

[0129] Important inclusion criteria Meeting four or more of the 11 American College of Rheumatology 1997 classification criteria for SLE at screening, Patients diagnosed with SLE for at least 6 months prior to screening, Serum titers evaluated at screening of ANS (≧1:80) in a pattern consistent with the diagnosis of SLE, such as minimal anti-double-stranded DNA (anti-dsDNA) or anti-Ro (SSA) or anti-La (SSB) or anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm), The following: When corticosteroids are the single standard therapy drug: oral administration of 30 mg / day or less for at least 8 weeks before randomization and stable administration for more than 2 weeks before randomization, When oral corticosteroid is not the single standard treatment drug: Stable oral administration of prednisone or equivalent at 30 mg / day or less for at least 8 weeks before randomization, and stable administration for more than 2 weeks before randomization. According to, being currently receiving corticosteroid and / or anti-malaria and / or thalidomide treatment and / or another DMARD. Receiving anti-malaria and / or thalidomide treatment and / or one of the following DMARDs: methotrexate or imidazole derivative (e.g., azathioprine, mizoribine) or mycophenolic acid derivative (e.g., mycophenolate mofetil) for at least 12 weeks before screening, and stable administration for more than 8 weeks before randomization. Being currently receiving.

[0130] Combinations of other DMARDs are 6 or more SLEDAI-2K scores not permitted in screening. In screening, - At least one "A" in either the mucocutaneous domain or the musculoskeletal domain. Or - At least one "B" in either the mucocutaneous or musculoskeletal domain, and at least one "A" or "B" in the second domain. The BILAG-2004 score of. Body weight is at least 40 kg at screening.

[0131] Important exclusion criteria Treatment history received before screening: - Within 12 weeks: Intravenous high-dose corticosteroid, calcineurin inhibitor, or other oral DMARDs other than those listed in inclusion criterion 6. - Within 24 weeks: Cyclophosphamide, or biologic agents, such as intravenous Ig, plasmapheresis, anti-TNF-α mAb, CTLA4-Fc Ig (abatacept) or BAFF-targeting agent (e.g., belimumab). - Any B-cell depletion therapy (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening and B cell count < 50 cells / μL at the screening time point The presence of severe lupus nephritis defined by proteinuria > 6 g / day or equivalent, using spot urine protein / creatinine ratio, or serum creatinine > 2.5 mg / dL (221.05 μmol / L), or requiring immunosuppressive induction or maintenance therapy beyond protocol-defined limits

[0132] Assessment of efficacy: · SRI-4 (SLE responder index) · Physician Global Assessment Visual Analog Scale (PhGA-VAS) · Patient Global Assessment (VAS) · Flare rate according to the BILAG-2004 score · Lupus Low Disease Activity State (LLDAS)

[0133] Results: The percentage of study patients who achieved the composite primary endpoint of SRI-4 at week 28 with a reduction in sustained prednisone of 5 mg / day or less was 42% higher with ianalumab compared to placebo. Ianalumab was also superior to placebo with respect to the incidence of moderate or severe flares (45% vs 73%, respectively) and time to first flare (median not reached vs 11.9 weeks, respectively). The differences between ianalumab and placebo at week 28 were 50% for the percentage of patients achieving an SRI-4 response, 34% for reduced corticosteroid use, 43% for the combined primary endpoint of these two outcomes, 20% for low disease activity state (LLDAS) lupus, and 31% for the lupus composite assessment based on BILAG (BICLA). Ianalumab had good tolerability, and no new safety signals were detected during the double-blind 28-week treatment period, the open-label treatment period (weeks 28 - 52), and the subsequent safety follow-up period. The effect of VAY736 on C1q autoantibodies was determined using an enzyme immunoassay (EIA) provided by BUEHLMANN LABORATORIES, product reference number EK-AC1QA-U.

[0134] The following data represent data obtained at baseline, week 12, and week 24. The data are presented as geometric mean ratios relative to baseline. The results clearly show that the reduction in anti-C1q autoantibodies with VAY736 reaches approximately 40% compared to 18% for the placebo ratio at week 29 relative to baseline (Figure 3A).

[0135] The VAY736 effect on anti-dsDNA autoantibodies was determined by INOVA QUANTA Lite SC ELISA.

[0136] Data obtained at baseline, week 12, and week 24 are presented as geometric mean ratios relative to baseline (Figure 3B). The results clearly show that the reduction in anti-dsDNA autoantibodies with VAY736 reaches approximately 40% compared to 10% for the placebo ratio at week 29 relative to baseline.

[0137] Conclusion: From all these data, it can be seen that VAY736 reduces autoantibodies in pSS or SLE patients. This effect is dose- and time-dependent for VAY736. Elevated autoantibodies play an important role in the onset and progression of AIHA, such as wAIHA, and are reduced by treatment with VAY736.

[0138] Example 5 Preclinical study of the effect of eculizumab The most widely used mouse model of immune thrombocytopenia is a short-term passive model in which platelet levels are measured following injection of antiplatelet antibodies that induce platelet removal by phagocytes (Crow A.R 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 disease establishment. A recently developed active model of ITP (Chow L.et al. Blood (2010) 115(6):1247 - 1253) shows similarities to the clinical features of human severe ITP and more accurately represents the immune deficiency of chronic ITP. It has actually been described to induce a sustained reduction in platelet levels that depends on the presence of both B and T cells. In this model, wild-type platelets are injected into CD61-deficient mice to elicit an immune response against mouse splenocytes, which are then transplanted into severe combined immunodeficiency (SCID) mice, and a sharp decrease in platelet levels is induced within one week. Both the CD19 and CD8 positive progenitor populations are required to induce persistently reduced levels of circulating platelets.

[0139] Since epratuzumab depletes mouse B cells, the inventors therefore expect that the effect of epratuzumab on chronic ITP in this mouse model will be understood. Splenocytes from mouse immunization against platelet CD61 are transplanted into SCID mice. Mice are treated with 2 - 4 injections of 1) PBS, 2) 10 mg / kg epratuzumab or 3) 100 mg / kg epratuzumab. Mice are bled weekly for 4 weeks to evaluate platelet count determination. An increase in platelet count determination is expected to be seen over time, confirming the efficacy of epratuzumab in chronic ITP. The efficacy of epratuzumab in this model will confirm its potential in the treatment of ITP and potentially B cell - mediated cytopenias such as wAIHA.

[0140] Although various specific embodiments have been illustrated and described, it will be understood that various changes may be made without departing from the spirit and scope of the present disclosure.

[0141] All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, and other document were specifically and individually indicated to be incorporated by reference for every purpose. If there is any conflict between one or more teachings of the references incorporated herein and the present disclosure, the teachings of this specification are intended.

Claims

**Claim 1** An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use in the treatment of warm autoimmune hemolytic anemia (wAIHA) in a subject. **Claim 2** The antibody or binding fragment thereof according to claim 1, which is an anti-BAFF antibody or a binding fragment thereof. **Claim 3** The antibody or binding fragment thereof according to claim 1 or 2, which is an anti-BAFF-R antibody or a binding fragment thereof. **Claim 4** The antibody or binding fragment thereof for use according to any one of claims 1 to 3, wherein the wAIHA is primary wAIHA. **Claim 5** The antibody or binding fragment thereof for use according to any one of claims 1 to 3, wherein the wAIHA is secondary wAIHA. **Claim 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 had insufficient efficacy or had relapsed after at least one treatment line, including patients having steroid resistance, dependence or intolerance. **Claim 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. **Claim 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. **Claim 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 an inalumab or a binding fragment thereof. **Claim 10** The antibody or binding fragment thereof for use according to any one of claims 1 to 9, wherein the antibody or binding fragment thereof is a defucosylated antibody or a binding fragment thereof. **Claim 11** The antibody or binding fragment thereof for use according to any one of claims 1 to 10, which is belimumab. **Claim 12** The antibody or binding fragment thereof for use according to any one of claims 1 to 11, 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. **Claim 13** An antibody or binding fragment thereof for use according to any one of claims 1 to 12, which is administered to a subject in need thereof at a dose of about 1 to about 10 mg / kg.

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

15. An antibody or binding fragment thereof for use according to any one of claims 12 to 14, which is belimumab.

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

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

18. An antibody or binding fragment thereof for use according to any one of claims 1 to 17, which is administered intravenously (i.v.) to a subject in need thereof.

19. An antibody or binding fragment thereof for use according to any one of claims 1 to 18, which is administered to a subject in need thereof once every 4 weeks (monthly, + / - 3 days).

20. The antibody is belimumab, and belimumab is administered intravenously to a subject in need thereof once every 4 weeks (monthly, + / - 3 days) at a dose of 3 mg / kg, for use according to any one of claims 1 to 19.

21. The antibody is belimumab, and belimumab is administered intravenously to a subject in need thereof once every 4 weeks (monthly, + / - 3 days) at a dose of 9 mg / kg, for use according to any one of claims 1 to 20.

22. An antibody or binding fragment thereof for use according to any one of claims 1 to 21, wherein the subject achieves complete response.

23. An antibody or binding fragment thereof for use according to any one of claims 1 to 22, wherein the subject achieves sustained response.

24. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 23, which is administered in 6 or fewer administrations or 4 or fewer administrations.

25. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 24, which is administered in at least 4 administrations.

26. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 25, administered in a total of about 8 administrations, about 6 administrations, or about 4 administrations.

27. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 26, wherein the antibody is epratuzumab and epratuzumab is administered in a total of 4 administrations.

28. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 27, administered for 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 after administration of the first dose on day 1.

29. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 28, wherein the hemoglobin blood concentration of the subject reaches about 10 g / dL or more after administration of the antibody or binding fragment thereof, preferably epratuzumab.

30. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 29, wherein the hemoglobin blood concentration of the subject increases by about 2 g / dL or more after administration of the anti-BAFF-R antibody or binding fragment thereof, preferably epratuzumab.

31. An antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 30, wherein the hemoglobin blood concentration of the subject reaches about 10 g / dL or more and increases by about 2 g / dL or more after administration of the anti-BAFF-R antibody or binding fragment thereof, preferably epratuzumab.

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 the hemoglobin blood concentration occurs after administration of the third dose.

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

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

35. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 34, which is administered as a monotherapy.

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

37. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to claim 36, wherein one or more of the additional agents are supportive therapies, preferably the supportive therapies are selected from the group consisting of corticosteroids, particularly prednisone or prednisolone or equivalents, danazol, and erythropoietin (e.g., erythropoietin α, β or δ).

38. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to claim 36 or 37, wherein one or more of the additional agents are corticosteroids, particularly the antibody or binding fragment thereof that inhibits the BAFF pathway is administered when the corticosteroid is tapered.

39. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 38, wherein the subject has failed in at least one previous treatment line.

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

41. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to claim 40, wherein the different treatment includes treatment with corticosteroids, such as prednisolone, prednisone or its equivalents, or B cell depleting agents, such as rituximab.

42. The antibody or binding fragment thereof that inhibits the BAFF pathway for use according to any one of claims 1 to 41, 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 a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 42, wherein the treatment is interrupted after 4 administrations, 6 administrations, 8 administrations, 9 administrations or 12 administrations.

44. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 43, wherein the treatment is interrupted after complete remission is achieved.

45. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 44, wherein the treatment is interrupted after sustained remission is achieved.

46. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 45, wherein the subject achieves treatment-free remission (TFR).

47. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to claim 46, wherein the TFR is remission 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.

48. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 47, wherein the subject relapses after TFR, preferably the antibody or the binding fragment thereof that inhibits the BAFF pathway is epratuzumab; preferably the subject was administered epratuzumab before TFR.

49. An antibody or a binding fragment thereof that inhibits the BAFF pathway, for use according to any one of claims 1 to 48, wherein the subject is 12 to 17 years old in adolescence.

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

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

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

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

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

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

56. The method according to any one of claims 51 to 55, wherein the wAIHA is primary or secondary wAIHA, and the subject had an insufficient response or had a recurrence after at least one line of treatment, including patients having steroid resistance, dependence, or intolerance.

57. The method according to any one of claims 53 to 56, wherein the antibody or its binding fragment comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively, and CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, respectively.

58. The method according to any one of claims 53 to 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 according to any one of claims 53 to 58, wherein the anti-BAFF-R antibody or its binding fragment is anatumumab or its binding fragment.

60. The method according to any one of claims 53 to 59, wherein the antibody or its fragment is a defucosylated antibody.

61. The method according to any one of claims 52, 54 to 58, or 60, wherein the antibody or its fragment is belimumab.

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

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

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

65. The method according to any one of claims 62 to 64, wherein the antibody is anatumumab or its binding fragment.

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

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

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

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

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

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

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

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

74. The method according to any one of claims 51 to 73, wherein the antibody or its binding fragment is administered in 6 or fewer administrations or 4 or fewer administrations.

75. The method according to any one of claims 51 to 74, wherein the antibody or its binding fragment is administered in at least 4 administrations.

76. The method according to any one of claims 51 to 75, wherein the antibody or its binding fragment is administered in a total of about 8 administrations, about 6 administrations, or about 4 administrations.

77. The method according to any one of claims 51 to 76, wherein the antibody is epratuzumab, and epratuzumab is administered in a total of 4 administrations.

78. The method according to any one of claims 51 to 77, wherein after administration of the first dose on day 1, the antibody or its binding fragment is administered for 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.

79. The method according to any one of claims 51 to 78, wherein the hemoglobin blood concentration of the subject reaches about 10 g / dL or more after administration of the antibody or its binding fragment.

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

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

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

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

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

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

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

87. The method according to claim 86, wherein the one or more additional agents are supportive therapies, preferably the supportive therapies are selected from the group consisting of corticosteroids, particularly prednisone or prednisolone or equivalents, danazol, and erythropoietin (e.g., erythropoietin α, β or δ).

88. The method according to claim 86 or 87, wherein the one or more additional agents are corticosteroids, and in particular the antibody or a binding fragment thereof that inhibits the BAFF pathway is administered when the corticosteroid is tapered.

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

90. The method according to claim 89, wherein the previous treatment line is the same or different wAIHA treatment.

91. The method according to claim 90, wherein the different treatment includes treatment with corticosteroids, such as prednisolone, prednisone or equivalents, or B cell depletion agents, such as rituximab.

92. The method according to 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 according to any one of claims 51 to 92, wherein the treatment is interrupted after 4 administrations, 6 administrations, 8 administrations, 9 administrations or 12 administrations.

94. The method according to any one of claims 51 to 93, wherein the treatment is interrupted after complete efficacy is achieved.

95. The method according to any one of claims 51 to 94, wherein the treatment is interrupted after sustained efficacy is achieved.

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

97. The method according to claim 96, wherein the TFR lasts 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 according to any one of claims 51 to 97, wherein the subject relapses after TFR.

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