Methods and compositions for treating IgG4-related diseases

Abstract

The present invention provides compositions and methods for treating and ameliorating the symptoms of IgG4-RD using an antibody or antigen-binding fragment thereof that specifically binds to human CD19. The present disclosure provides both improving the treatment of human patients having active (continuous relapse) IgG4-RD using a CD19 antibody (e.g., obexelimab), and preventing recurrence (relapse of relapse) of IgG4-RD. The present disclosure is directed to improved treatment of human patients having active IgG-RD using a CD19 antibody (e.g., obexelimab), and prevention of recurrence of IgG4-RD.

Description

Background Art

[0001] IgG4-related disease (IgG4-RD) is a severe, rare, chronic fibroinflammatory condition that typically affects multiple organs and can result in significant organ dysfunction and failure, and even death if the condition is not recognized and treated in a timely manner. This disease commonly affects major organs such as the pancreas, liver, kidney, lung, and eye, and pancreato-biliary tract disease is present in approximately half of cases (Wallace et al, 2019). Patients may present with involvement of a single organ, but more frequently present with involvement of multiple organs. As the disease progresses and the patient experiences new or worsening signs / symptoms (flares), additional organs develop lesions, and the cellular inflammation that characterizes early disease moves towards a more fibrotic stage, causing major tissue damage and ultimately organ failure (Perugino 2016). For example, cholangitis due to IgG4-RD can lead to liver failure, IgG4-related (type 1) autoimmune pancreatitis can lead to failure of either or both the endocrine and exocrine pancreas, and IgG4-related aortitis can lead to aneurysm and / or aortic dissection. Current therapies used for the long-term treatment of IgG4-RD often cause significant toxicity and must be discontinued. There is an unmet need for patients with active IgG4-RD.

Summary of the Invention

[0002] The present disclosure provides for both improving the treatment of human patients with active (relapsing) IgG4-RD and preventing recurrence (relapse of relapse) of IgG4-RD using a CD19 antibody (e.g., obexelimab). The present disclosure is directed to improved treatment of human patients with active IgG-RD and prevention of recurrence of IgG4-RD using a CD19 antibody (e.g., obexelimab). The present disclosure is also directed to methods of preventing recurrence of IgG4-RD using a CD19 antibody (e.g., obexelimab). In particular, the present disclosure provides methods, compositions, and uses of a CD19 antibody (e.g., obexelimab) in adult human patients (i.e., 18 years of age or older) with IgG4-RD, including those with novel, relapsing, or refractory IgG4-RD, for treating, improving, stabilizing, or reducing one or more symptoms of IgG4-RD, such as reducing the incidence of disease relapse.

[0003] In some embodiments, the present disclosure provides methods, compositions, and uses of a CD19 antibody (e.g., obexelimab) in adult human patients (i.e., 18 years of age or older) with IgG4-RD, including those with novel, relapsing, or refractory IgG4-RD, for treating, improving, stabilizing, or reducing one or more symptoms of IgG4-RD, such as reducing the occurrence or severity of disease relapse.

[0004] In one aspect, the present invention provides a method of treating or preventing an IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient 18 years of age or older at a dose of 250 mg per week. In one aspect, the present invention provides a method of treating an IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient 18 years of age or older at a dose of 250 mg once a week.

[0005] In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg twice a week. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg twice a week. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg every three days. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 250 mg every seven days.

[0006] In some embodiments, obexelimab can be subcutaneously administered to human patients 18 years of age or older at a dose of 200 mg once a week. In some embodiments, obexelimab can be subcutaneously administered to human patients 18 years of age or older at a dose of 125 mg twice a week. In some embodiments, obexelimab is subcutaneously administered to human patients 18 years of age or older at a dose of 100 mg twice a week. In some embodiments, obexelimab is subcutaneously administered to human patients 18 years of age or older at a dose of 300 mg once a week. In some embodiments, obexelimab is subcutaneously administered to human patients 18 years of age or older at a dose of 150 mg twice a week.

[0007] In some embodiments, obexelimab is administered as a liquid formulation containing 125 mg / mL of obexelimab. In some embodiments, obexelimab is administered as 2 × 1 mL injections or 1 × 2 mL injection. In some embodiments, obexelimab is administered as 2 × 1 mL injections or 1 × 2 mL injection for a total dose of 250 mg. In some embodiments, obexelimab injections are administered simultaneously. In some embodiments, obexelimab injection solutions are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or 20 minutes of each other. In some embodiments, obexelimab injection solutions are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours of each other.

[0008] In some embodiments, obexelimab is administered as a liquid formulation containing 125 mg / mL obexelimab as 4 × 0.25 mL injections. In some embodiments, obexelimab is administered at a total dose of 250 mg in a liquid formulation containing 125 mg / mL obexelimab as 4 × 0.25 mL injections. In some embodiments, the obexelimab injections are administered simultaneously. In some embodiments, the obexelimab injection solutions are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or within 20 minutes of each other. In some embodiments, the obexelimab injection solutions are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or within 12 hours of each other.

[0009] In some embodiments, obexelimab is administered as a single injection in a liquid formulation. In some embodiments, obexelimab is administered as a single injection in a liquid formulation at a total dose of 250 mg.

[0010] In some embodiments, obexelimab is self-injected by the patient. In some embodiments, obexelimab is injected by someone other than the patient (e.g., a caregiver). In some embodiments, obexelimab is administered under the supervision of a clinician.

[0011] In some embodiments, obexelimab is administered as a liquid formulation containing 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, and 0.1 mg / mL polysorbate 80 at pH 5.5. In some embodiments, obexelimab is administered as a liquid formulation containing 100 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, and 0.1 mg / mL polysorbate 80 at pH 5.5. In some embodiments, an anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 80 - 200 mg / mL obexelimab, 1.5 - 3 mg / mL sodium acetate trihydrate, 0.10 - 0.20 mg / mL acetic acid (density 1.053 g / mL), 10 - 50 mg / mL L-proline, 0.05 - 0.2 mg / mL polysorbate 80, and pH 5.0 - 6.0.

[0012] In some embodiments, the method comprises administering an anti-CD19 antibody (e.g., obexelimab) to a human patient who is receiving glucocorticoid (GC) therapy. In some embodiments, the method comprises administering an anti-CD19 antibody (e.g., obexelimab) to a human patient who is not receiving glucocorticoid (GC) therapy.

[0013] In some embodiments, the GC therapy is administered at a dose of 20 - 60 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of 10 - 100 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of about 1 - 70 mg / day, about 5 - 70 mg / day, about 10 - 70 mg / day, about 15 - 70 mg / day, about 20 - 70 mg / day, about 25 - 70 mg / day, about 30 - 70 mg / day, about 35 - 70 mg / day, about 40 - 70 mg / day of prednisone or a corresponding dose. In some embodiments, the GC therapy is administered at a dose of about 1 - 60 mg / day, about 5 - 60 mg / day, about 10 - 60 mg / day, about 15 - 60 mg / day, about 20 - 60 mg / day, about 25 - 60 mg / day, about 30 - 60 mg / day, about 35 - 60 mg / day, about 40 - 60 mg / day of prednisone or an equivalent dose.

[0014] In some embodiments, the GC therapy is administered at a dose of about 1 - 150 mg / day, about 5 - 150 mg / day, about 10 - 150 mg / day, about 15 - 150 mg / day, about 20 - 150 mg / day, about 25 - 150 mg / day, about 30 - 150 mg / day, about 35 - 150 mg / day, about 40 - 150 mg / day, about 45 - 150 mg / day, about 50 - 150 mg / day, about 55 - 150 mg / day, about 60 - 150 mg / day, about 65 - 150 mg / day, about 70 - 150 mg / day, about 75 - 150 mg / day, about 80 - 150 mg / day, about 90 - 150 mg / day, or about 100 - 150 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of about 5 - 120 mg / day, about 5 - 110 mg / day, about 10 - 90 mg / day, about 15 - 100 mg / day, about 20 - 100 mg / day, about 25 - 100 mg / day, about 30 - 100 mg / day, about 35 - 100 mg / day, about 40 - 100 mg / day, about 45 - 100 mg / day, about 50 - 100 mg / day, about 55 - 100 mg / day, about 60 - 100 mg / day, about 65 - 100 mg / day, about 70 - 100 mg / day, about 75 - 100 mg / day, about 80 - 100 mg / day, or about 90 - 100 mg / day of prednisone or an equivalent dose.

[0015] In some embodiments, the GC therapy is administered at a prednisone equivalent dose of up to about 150 mg / day, up to about 120 mg / day, up to about 110 mg / day, up to about 100 mg / day, up to about 90 mg / day, up to about 80 mg / day, up to about 70 mg / day, up to about 60 mg / day, up to about 50 mg / day, up to about 40 mg / day, up to about 30 mg / day, up to about 20 mg / day, up to about 15 mg / day, up to about 10 mg / day, up to about 5 mg / day, or up to about 1 mg / day.

[0016] In some embodiments, the GC therapy is administered at a prednisone equivalent dose of 0.1 - 1 mg / kg / day, 0.1 - 0.8 mg / kg / day, 0.1 - 0.7 mg / kg / day, 0.1 - 0.6 mg / kg / day, 0.1 - 0.5 mg / kg / day, 0.1 - 0.4 mg / kg / day, 0.1 - 0.3 mg / kg / day, 0.1 - 0.2 mg / kg / day, or 0.05 - 0.1 mg / kg / day.

[0017] In some embodiments, the GC therapy is administered at a prednisone equivalent dose of up to 1 mg / kg / day. In some embodiments, the GC therapy is administered at a dose of up to 0.9 mg / kg / day, up to 0.8 mg / kg / day, up to 0.7 mg / kg / day, up to 0.6 mg / kg / day, up to 0.5 mg / kg / day, up to 0.4 mg / kg / day, up to 0.3 mg / kg / day, up to 0.2 mg / kg / day, or up to 0.1 mg / kg / day of prednisone or an equivalent.

[0018] In some embodiments, the prednisone equivalent dose is determined as shown in Table 3.

[0019] In some embodiments, the GC therapy is administered with a high dose of prednisone or an equivalent. In some embodiments, the patient has been administered a high dose of GC therapy and is less likely to respond to any treatment therapy. In some embodiments, the patient did not respond to previous therapies prior to administration of the anti - CD19 antibody (e.g., obexelimab).

[0020] In some embodiments, GC therapy is continued during treatment with obexelimab. In some embodiments, GC therapy is tapered during treatment with obexelimab. In some embodiments, GC therapy is tapered prior to treatment with obexelimab. In some embodiments, GC therapy is tapered to completion. In some embodiments, obexelimab is administered in combination with GC therapy. In some embodiments, obexelimab is administered without the use of GC therapy.

[0021] In some embodiments, obexelimab is administered for a period sufficient to treat, ameliorate, stabilize, or reduce one or more symptoms of IgG4-RD compared to a control. In some embodiments, at least one symptom is found in an organ selected from lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, heart, pericardium, orbits, nasal cavity, lungs, bile ducts, salivary glands, and pancreas.

[0022] In some embodiments, obexelimab is administered to the patient until complete remission. In some embodiments, obexelimab is administered to a human patient during a disease-free period.

[0023] In some embodiments, obexelimab is administered to the patient until complete remission or until the physician determines that the patient has no clinical evidence of disease relapse. In some embodiments, obexelimab is administered until the physician determines that the patient has no clinical evidence of disease relapse. In some embodiments, obexelimab is administered to the patient until the patient no longer has clinical evidence of disease relapse.

[0024] In some embodiments, the disease-free period is referred to as the time to disease flare (TDF). In some embodiments, TDF is measured in days. In some embodiments, TDF is measured in weeks. In some embodiments, TDF is measured in months. In some embodiments, TDF is measured in years.

[0025] In some embodiments, the relapse-free period is determined by the number of days until disease relapse. In some embodiments, the relapse-free period is at least 10 days, 20 days, 30 days, 40 days, 50 days, 60 days, 70 days, 80 days, or 90 days from the first administration of obexelimab. In some embodiments, the relapse-free period is at least 28 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 63 days, at least 70 days, at least 77 days, at least 84 days, at least 91 days, at least 98 days, at least 105 days, at least 112 days, at least 119 days, at least 126 days, at least 133 days, at least 140 days, at least 147 days, at least 154 days, at least 161 days, at least 168 days, at least 175 days, at least 182 days, at least 189 days, at least 196 days, at least 203 days, at least 210 days, at least 217 days, at least 224 days, at least 231 days, at least 238 days, at least 245 days, at least 252 days, at least 259 days, at least 266 days, at least 273 days, at least 280 days, 287 days, at least 294 days, at least 301 days, at least 308 days, at least 315 days, at least 322 days, at least 329 days, at least 336 days, at least 343 days, at least 350 days, at least 357 days, or at least 364 days from the first administration of obexelimab.

[0026] In some embodiments, the relapse-free period is at least 60 days, at least 70 days, at least 80 days, at least 90 days, at least 100 days, at least 120 days, at least 150 days, at least 160 days, at least 190 days, at least 220 days, at least 250 days, at least 280 days, at least 310 days, at least 340 days, or at least 365 days from the first administration of obexelimab. In some embodiments, the relapse-free period is at least 160 days. In some embodiments, the relapse-free period is at least 160 days, at least 161 days, at least 162 days, at least 163 days, at least 164 days, at least 165 days, at least 166 days, at least 167 days, at least 168 days, at least 169 days, at least 170 days, at least 171 days, at least 172 days, at least 173 days, at least 174 days, at least 175 days, at least 176 days, at least 177 days, at least 178 days, at least 179 days, or at least 180 days. In some embodiments, the relapse-free period is at least 169 days from the first administration of obexelimab.

[0027] In some embodiments, the recurrence-free period is at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, at least 12 weeks, at least 13 weeks, at least 14 weeks, at least 15 weeks, at least 16 weeks, at least 17 weeks, at least 18 weeks, at least 19 weeks, at least 20 weeks, at least 21 weeks, at least 22 weeks, at least 23 weeks, at least 24 weeks, at least 25 weeks, at least 26 weeks, at least 27 weeks, at least 28 weeks, at least 29 weeks, at least 30 weeks, at least 31 weeks, at least 32 weeks, at least 33 weeks, at least 34 weeks, at least 35 weeks, at least 36 weeks, at least 37 weeks, at least 38 weeks, at least 39 weeks, at least 40 weeks, at least 41 weeks, at least 42 weeks, at least 43 weeks, at least 44 weeks, at least 45 weeks, at least 46 weeks, at least 47 weeks, at least 48 weeks, at least 49 weeks, at least 50 weeks, at least 51 weeks, or at least 43 weeks from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 52 weeks from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 40 weeks, at least 45 weeks, at least 50 weeks, at least 52 weeks, at least 55 weeks, at least 60 weeks from the administration of obexelimab. In some embodiments, the recurrence-free period is at least 52 weeks from the administration of obexelimab.

[0028] In some embodiments, the recurrence-free period is at most 40 weeks, at most 45 weeks, at most 50 weeks, at most 52 weeks, at most 55 weeks, at most 60 weeks from the first administration of obexelimab. In some embodiments, the recurrence-free period is at most 52 weeks from the first administration of obexelimab.

[0029] In some embodiments, the recurrence-free period is at least 2 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 6 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 9 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 12 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 18 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 24 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 30 months from the first administration of obexelimab.

[0030] In some embodiments, the recurrence-free period is at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, at least 24 months, at least 25 months, at least 26 months, at least 27 months, at least 28 months, at least 29 months, or at least 30 months from the first administration of obexelimab.

[0031] In some embodiments, the recurrence-free period is at least 2 to 12 months, at least 2 to 10 months, at least 2 to 8 months, at least 2 to 6 months, or at least 2 to 4 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 3 to 12 months, at least 3 to 10 months, at least 3 to 8 months, at least 3 to 6 months, at least 3 to 5 months, or at least 3 to 4 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 4 to 12 months, at least 4 to 10 months, at least 4 to 8 months, at least 4 to 6 months, or at least 4 to 5 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 5 to 12 months, at least 5 to 10 months, at least 5 to 8 months, or at least 5 to 6 months from the first administration of obexelimab. In some embodiments, the recurrence-free period is at least 6 to 12 months, at least 6 to 10 months, at least 6 to 8 months, or at least 6 to 7 months from the first administration of obexelimab.

[0032] In some embodiments, the recurrence-free period is at least 1 year, at least 1.5 years, at least 2 years, at least 2.5 years, at least 3 years, at least 4 years, or at least 5 years from the first administration of obexelimab.

[0033] In some embodiments, obexelimab is administered as maintenance therapy. In some embodiments, the patient is recurrence-free while taking obexelimab. In some embodiments, the patient is recurrence-free while taking obexelimab at a dose of 250 mg once a week. In some embodiments, the recurrence-free period is until obexelimab is discontinued. In some embodiments, the recurrence-free period is at least 7 days after obexelimab is discontinued. In some embodiments, the recurrence-free period is at least 14 days after obexelimab is discontinued. In some embodiments, the recurrence-free period is at least 21 days after obexelimab is discontinued. In some embodiments, the recurrence-free period is at least 28 days after obexelimab is discontinued.

[0034] In some embodiments, obexelimab is administered to a patient until the patient has an active IgG4-RD disease relapse. In some embodiments, obexelimab is administered to a patient until the patient has a relapse of active IgG4-RD that requires initiation of rescue therapy. In some embodiments, obexelimab is administered while the patient has an active IgG4-RD disease relapse.

[0035] In some embodiments, rescue therapy includes administration of GC therapy. In some embodiments, rescue therapy involves initiation of non-GC therapy to control the symptoms of relapse.

[0036] In some embodiments, the human patient is refractory or relapsing to previous treatment for IgG4-RD. In some embodiments, the human patient is refractory or relapsing to rituximab. In some embodiments, the human patient is refractory or relapsing to another CD19 therapy.

[0037] In some embodiments, the human patient is evaluated for disease activity using the IgG4-RD responder index (RI). In some embodiments, the human patient achieves a decrease of two or more points in the IgG4-RD RI from day 1 of obexelimab administration. In some embodiments, the human patient meets the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria with an IgG4-RD score greater than 20 prior to obexelimab administration.

[0038] In some embodiments, obexelimab is administered for a period sufficient to improve, stabilize, or reduce one or more symptoms of IgG4-RD as compared to a control. In some embodiments, at least one symptom is seen in an organ selected from lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, heart, pericardium, orbits, nasal cavity, lungs, bile ducts, salivary glands, and pancreas. In some embodiments, obexelimab is administered to a patient until complete remission. In some embodiments, obexelimab is administered to a patient at dosing intervals during a relapse-free period. In some embodiments, the relapse-free period is determined by the number of days until disease relapse. In some embodiments, the relapse-free period is at least 30, 40, 50, 60, 70, 80, or 90 days from the first administration of obexelimab. In some embodiments, the relapse-free period is greater than 90 days. In some embodiments, the relapse-free period is up to 40, 45, 50, or 52 weeks from the first administration of obexelimab.

[0039] In some embodiments, obexelimab is administered to a patient until the patient has a relapse of active IgG4-RD that requires initiation of rescue therapy. In some embodiments, rescue therapy includes administration of GC therapy. In some embodiments, rescue therapy includes administration of GC therapy in combination with obexelimab. In some embodiments, the patient is relapsing or refractory to previous therapy for IgG4-RD. In some embodiments, the patient is relapsing or refractory to rituximab.

[0040] In some embodiments, the patient has IgG4-related sialadenitis (chronic sclerosing sialadenitis, Kuttner tumor, Mikulicz's disease), IgG4-related dacryoadenitis (Mikulicz's disease), IgG4-related ophthalmic diseases (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic rhinosinusitis IgG4-related hypophysitis (IgG4-related panhypophysitis, IgG4-related hypopituitarism, IgG4-related inhibitory neuron uremia, autoimmune hypothesis), IgG4-related folliculitis, IgG4-related leptomeningitis (idiopathic hypertrophic pachymeningitis), IgG4-related pancreatitis (type 1 autoimmune pancreatitis, IgG4-related AIP, lymphoplasmacytic sclerosing pancreatitis, chronic pancreatitis with diffuse irregular stenosis of the main pancreatic duct), IgG4-related lung diseases (pulmonary inflammatory pseudotumor), IgG4-related pleurisy, IgG4-related liver disorders, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortitis), IgG4-related peritonitis (chronic peritonitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrosing mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis, Albarran-Ormond syndrome, Ormond disease (retroperitoneal fibrosis), peripheral fasciitis, Gerota fasciitis / syndrome, fibrous perianeuritis, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, nonspecific retroperitonitis, sclerosing retroperitonitis, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related enteritis (subtype:Present IgG4-RD symptoms selected from the group consisting of mesenteric pancreatitis, mesenteric lipodystrophy, and retroperitoneal panniculitis (sclerosing mesenteritis, systemic nodular pancreatitis, enteric inflammatory fat sclerosis, enteric Weber-Christian disease, mesenteric fat granuloma, heterologous granulomatous enteritis), IgG4-related mastitis (sclerosing mastitis), IgG4-related kidney disease (IgG4-RKD), IgG4-related tubulointerstitial nephritis (IgG4-TIN), IgG4-related membranous glomerulonephritis (idiopathic tubulointerstitial nephritis), IgG4-related prostatitis, IgG4-related perienteritis (chronic glossodynia), IgG4-related cystic pseudotumor, IgG4-related epididymitis (intestinal fibrosing pseudotumor, inflammatory pseudotumor of the spermatic cord, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, proliferative balanitis, chronic proliferative perioral dermatitis, fibrosing perioral dermatitis, nodular perioral dermatitis, reactive perioral dermatitis, fibrous mesothelioma), IgG4-related lymphadenopathy, IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineural diseases, and IgG4-related thyroid diseases (Riedel thyroiditis), inflammatory pseudotumor, and multiple sclerosis.

[0041] In some embodiments, the patient presents IgG4-RD symptoms selected from the group consisting of autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), eosinophilic granulomatosis with polyangiitis (affecting the orbit and upper airway), fibrosing mediastinitis, idiopathic hypertrophic pachymeningitis, idiopathic tubulointerstitial nephritis, inflammatory pseudotumor, Kuttner tumor, Mikulicz disease, fibrotic atherosclerosis, periodontitis, periarteritis, inflammatory aortic multifocal surgery, Ormond disease (retroperitoneal fibrosis), Riedel thyroiditis, and sclerosing enteritis.

Brief Description of the Drawings

[0042]

Figure 1

Figure 2

Figure 3

[0043] The present invention provides a method for treating IgG4-related diseases in human patients in need of treatment by administering an anti-CD19 antibody >18 years of age at a therapeutically effective dose and dosing interval for a treatment period sufficient to improve, stabilize, or reduce one or more symptoms of IgG4-related diseases as compared to a control (e.g., start of treatment).

[0044] In one aspect, the present invention provides a method for reducing the risk of recurrence in adult patients. In one aspect, the present invention provides a method for reducing the risk of recurrence in adult patients having IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obexelimab to the patient. In one aspect, the present invention provides a method for treating active IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obexelimab to the patient.

[0045] In one aspect, the present invention provides a method for preventing flare recurrence in adult patients. In one aspect, the present invention provides a method for preventing relapse in adult patients having IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obexelimab to the patient. In one aspect, the present invention provides a method for preventing signs or symptoms of active IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obexelimab to the patient.

[0046] In some embodiments, the method comprises administering obexelimab at a dose of 250 mg. In some embodiments, the method comprises administering obexelimab at a dose of 250 mg every 7 days. In some embodiments, the method comprises administering obexelimab at a dose of 250 mg every 7 days to an adult patient (e.g., a patient at least 18 years of age). In some embodiments, the method comprises administering obexelimab subcutaneously.

[0047] In one aspect, the present invention provides a method for reducing the risk of relapse in adult patients, the method comprising subcutaneously administering obexelimab to an adult patient at a dose of 250 mg every 7 days.

[0048] Various aspects of the present invention are described in detail in the following sections. The use of the sections is not intended to limit the present invention. Each section can be applied to any aspect of the present invention. In this application, unless otherwise stated, the use of "or" means "and / or". Definitions

[0049] Several definitions are set forth herein. Such definitions are meant to include grammatical equivalents.

[0050] Antibody: As used herein, the term "antibody" means a protein comprising one or more polypeptides substantially encoded by all or part of a recognized immunoglobulin gene. Recognized immunoglobulin genes include, for example in humans, kappa (K), lambda (l), and heavy chain loci, which together include numerous variable region genes, and constant region genes mu (u), delta (d), gamma (y), sigma (s), and alpha (a) encoding IgM, IgD, IgG (IgG1, IgG2, IgG3, and IgG4), IgE, and IgA (IgA1 and IgA2) isotypes, respectively. Antibodies herein are intended to include full-length antibodies and antibody fragments, and can refer to natural antibodies from any organism, engineered antibodies, or antibodies recombinantly produced for experimental, therapeutic, or other purposes.

[0051] CD32b + Cell or FcγRIIb + Cell: As used herein, "CD32b + Cell" or "FcγRIIb +The term "cell" means any cell or cell type that expresses CD32b (FcγRIIb). Examples of CD32b+ cells include, but are not limited to, B cells, plasma cells, dendritic cells, macrophages, neutrophils, mast cells, basophils, or eosinophils.

[0052] CDC or complement-dependent cytotoxicity: As used herein, the term "CDC" or "complement-dependent cytotoxicity" means a reaction in which one or more complement protein components recognize a bound antibody on a target cell and subsequently cause lysis of the target cell.

[0053] Effector function: As used herein, the term "effector function" means a biochemical event resulting from the interaction of the Fc region of an antibody with an Fc receptor or ligand. Effector functions include FcγR-mediated effector functions such as ADCC and ADCP, as well as complement-mediated effector functions such as CDC. Additionally, effector functions include FcγRIIb-mediated effector functions such as inhibitory functions (e.g., downregulation, reduction, inhibition, etc. of B cell responses, e.g., humoral immune responses).

[0054] Effector cell: As used herein, the term "effector cell" means an immune system cell that expresses one or more Fc receptors and / or complement receptors and mediates one or more effector functions. Examples of effector cells include, but are not limited to, monocytes, macrophages, neutrophils, dendritic cells, eosinophils, mast cells, platelets, B cells, large granular lymphocytes, Langerhans cells, natural killer (NK) cells, and γδ T cells. It may be derived from any organism including, but not limited to, humans, mice, rats, rabbits, and monkeys.

[0055] Fc or Fc region: As used herein, the terms "Fc" or "Fc region" mean a polypeptide that includes the first constant region immunoglobulin domain and, optionally, the constant region of an antibody excluding a portion of the hinge. Thus, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, as well as the flexible hinge N-terminus to these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc includes the immunoglobulin domains Cgamma2 and Cgamma3 (Cg2 and C3), as well as the hinge between Cgamma1 (Cg1) and Cgamma2 (Cg2). The boundaries of the Fc region can vary, but the human IgG heavy chain Fc region is typically defined to include residue C226 or P230 at its carboxyl terminus, and the numbering follows the EU index as in Kabat. Fc can refer to this region alone or in the context of an Fc polypeptide, as described below.

[0056] Fc gamma receptor, or FcγR: As used herein, the term "Fc gamma receptor" or "FcγR" means any member of the protein family that binds to the Fc region of an IgG antibody and is substantially encoded by the FcγR gene. In humans, this family includes, but is not limited to, FcγRI (CD64), including the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including the isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including the isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIIb-NA1 and FcγRIIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65, incorporated herein by reference in its entirety), as well as any undiscovered human FcγR or FcγR isoform or allotype. FcγR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcγR includes, but is not limited to, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγR or FcγR isoform or allotype.

[0057] Flare: The term "flare" in the context of IgG4-RD is defined as the reappearance of previous signs / symptoms, or the appearance of new signs / symptoms of IgG4-RD. In certain embodiments, in the context of IgG4-RD, a "flare" is the reappearance of previous signs / symptoms, or the appearance of new signs / symptoms of IgG4-RD, which in the opinion of the treating physician and adjudication committee requires the initiation of rescue therapy. In some embodiments, an IgG4-RD flare is the reappearance of previous signs / symptoms of IgG4-RD, or the appearance of new signs / symptoms, that meet the IgG4-RD flare criteria.

[0058] Modification: As used herein, the term "modification" means a change in the physical, chemical, or sequence properties of a protein, polypeptide, antibody, or immunoglobulin. Modifications described herein include amino acid modifications and glycoform modifications.

[0059] Target antigen: As used herein, the term "target antigen" means the molecule bound by the variable region of a given antibody or the fusion partner of an Fc fusion. The target antigen may be a protein, carbohydrate, lipid, or other compound. An antibody or Fc fusion is said to be "specific" for a given target antigen based on having an affinity for the target antigen. In some embodiments, the target antigen of obexelimab is CD19.

[0060] Target cell: As used herein, the term "target cell" means a cell that expresses a target antigen.

[0061] Obexelimab: As used herein, the term "obexelimab" is an Fc-engineered humanized monoclonal antibody (mAb) that binds to the human B cell-restricted surface antigen CD19 and has enhanced Fc binding to Fcγ receptor IIb (FcγRIIb). The molecule is an IgG1 immunoglobulin having two amino acid substitutions in the constant portions of the kappa light chain and the heavy chain. Obexelimab is a monoclonal antibody having a predicted mass of approximately 147,426 Da based on its amino acid sequence. The heavy and light chains of obexelimab are given by SEQ ID NO: 10 and SEQ ID NO: 9, respectively.

[0062] Disease-free period: As used herein, the term "disease-free period" is defined as the time interval between the start of administration of an anti-CD19 antibody (e.g., obexelimab) and the recurrence of disease relapse.

[0063] Rescue therapy: As used herein, the term "rescue therapy" refers to the use of a therapy to treat suspected recurrence or worsening of disease symptoms. In some embodiments, the rescue therapy is a different approved therapy. In some embodiments, the rescue therapy can be any therapy used to reduce symptoms associated with IgG4-RD disease relapse. A common rescue therapy for IgG4-RD is glucocorticoid (GC) rescue therapy. Other rescue therapies include rituximab, and other anti-CD19 antibody therapies, but are only a few examples. Obexelimab and variants thereof

[0064] According to the present invention, obexelimab and variants thereof are used to treat human patients suffering from IgG4-RD. Obexelimab is a CD-19 directed antibody for the treatment of non-cytolytic active IgG4-RD (immunoglobulin G4-related disease) and for reducing the risk of relapse in adult patients. In one aspect, the present invention provides a method of administering obexelimab to reduce the risk of relapse in adult patients. In one aspect, the present invention provides a method of administering obexelimab to reduce the risk of relapse in adult patients having IgG4-RD (immunoglobulin G4-related disease). In one aspect, the present invention provides a method of administering obexelimab for the treatment of active IgG4-RD (immunoglobulin G4-related disease) and for reducing the risk of recurrence in adult patients.

[0065] Obexelimab is a monoclonal antibody specific for CD19 and comprises a light chain having a variable region comprising: CDR1 comprising RSSKSLQNVNGNTYLY (SEQ ID NO: 2), CDR2 comprising RMSNLNS (SEQ ID NO: 3), and CDR3 comprising MQHLEYPIT (SEQ ID NO: 4), and a heavy chain having a variable region comprising CDR1 comprising SYVMH (SEQ ID NO: 5), CDR2 containing WIGYINPYNDGTKY (SEQ ID NO: 6), and CDR3 containing GTYYYGTRVFDY (SEQ ID NO: 7), and the heavy chain contains amino acid substitutions at Fc region S267E and L328F as compared to SEQ ID NO: 8 below, ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 8), The numbering follows the EU index as in Kabat.

[0066] In one embodiment, as shown in Table 1, obexelimab comprises a light chain containing the amino acid sequence of (SEQ ID NO: 9) and a heavy chain containing the amino acid sequence of (SEQ ID NO: 10).

Table 1

[0067] In one embodiment, obexelimab comprises a light chain variable region containing SEQ ID NO: 11 and a heavy chain variable region containing SEQ ID NO: 12.

[0068] Obexelimab acts by utilizing the regulation of B cell receptor (BCR) signaling by FcγRIIB1. Obexelimab binds to CD19 of the BCR complex, and its Fc is engineered to increase its affinity for the inhibitory FcγRIIB. Since CD19 is associated with the BCR, tethering of obexelimab to FcγRIIB of CD19 on the same cell equilibrates the BCR complex for inhibition of antigen-induced BCR aggregation. Obexelimab utilizes the natural inhibitory mechanism of FcγRIIb, the only Fc receptor expressed by B cells, which acts as a negative regulator under conditions of antigen excess and immune complex formation (Chu et al., 2014). Obexelimab may also not mediate B cell killing and thus may have an improved safety profile compared to B cell-depleting antibodies. Variant

[0069] In one embodiment, a variant of obexelimab is an immunoglobulin specific for CD19 and comprises a light chain comprising a variable region having CDR1 comprising SEQ ID NO: 2, CDR2 comprising SEQ ID NO: 3, and CDR3 comprising SEQ ID NO: 4, and a heavy chain comprising a variable region having CDR1 comprising SEQ ID NO: 5, CDR2 comprising SEQ ID NO: 6, and CDR3 comprising SEQ ID NO: 7, wherein the heavy chain comprises amino acid substitutions at Fc region S267E and L328F compared to SEQ ID NO: 8, and the numbering follows the EU index as in Kabat.

[0070] In some embodiments, a variant of obexelimab comprises a heavy chain variable region (VH) and / or a light chain variable region (VL) comprising CDR1, CDR2, and CDR3, each of which differs from each of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, and / or SEQ ID NO: 7 by 1, 2, 3, 4, or 5 or fewer amino acid residues.

[0071] In one embodiment, a variant of obexelimab comprises a light chain having an amino acid sequence that is 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 9 and / or comprising amino acid substitutions at Fc region S267E and L328F as compared to SEQ ID NO: 10, with numbering according to the EU index as in Kabat.

[0072] In some embodiments, a preferred variant of obexelimab binds to the same epitope on human CD19 as an antibody comprising the light chain of SEQ ID NO: 9 and the heavy chain of SEQ ID NO: 10. Epitope binding may be determined by methods known in the art.

[0073] In some embodiments, a suitable variant of obexelimab competes for binding to human CD19 as an antibody comprising the light chain of SEQ ID NO: 9 and the heavy chain of SEQ ID NO: 10 under a binning assay known in the art. As used herein, a binning assay refers to any method for locally mapping the epitope to which an antibody binds. Standard methods for such characterization of antibodies, also known as epitope binning, typically involve surface plasmon resonance (SPR) technology. Using SPR, monoclonal antibody candidates are screened in pairs for binding to the target protein. Other standard methods include ELISA-based screens, which may require the synthesis of a set of overlapping peptides corresponding to the protein of interest.

[0074] In some embodiments, human CD19 comprises the amino acid sequence of SEQ ID NO: 1. MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRE SPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPG WTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPE IWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPK GPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEIT ARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPT RRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDV QADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYE NPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSL GSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRM GTWSTR (SEQ ID NO: 1) Fc receptor binding property

[0075] The anti-CD19 antibodies disclosed herein (e.g., obexelimab) include Fc variants having enhanced Fc binding to the inhibitory Fcγ receptor IIb (FcγRIIb). FcγRIIb, the only FcR on B cells, functions as an antibody-sensing downregulator of humoral immunity that is naturally associated by immune complexes. When sufficient antibody is produced against a given antigen, specific immune complexes are formed, co-engaging FcγRIIb and the B cell receptor (BCR) with high avidity and selectively suppressing only B cells that recognize cognate antigen. In addition, FcγRIIb modulates the activity of other B cell stimulants, including interleukin (IL)-4, LPS, and BAFF, which amplify BCR-driven proliferation and differentiation. By simultaneously binding to CD19 and FcγRIIb, obexelimab (and the variants described herein) mimics the action of antigen-antibody complexes and downregulates B cell activity.

[0076] The Fc variants disclosed herein can be optimized for various Fc receptor binding properties. Fc variants that are engineered or predicted to exhibit one or more optimized properties are referred to herein as "optimized Fc variants". Properties that can be optimized include, but are not limited to, enhancing or reducing affinity for FcγR. In one embodiment, the Fc variants disclosed herein are optimized to have enhanced affinity for the inhibitory receptor FcγRIIb. In other embodiments, the immunoglobulins disclosed herein provide enhanced affinity for FcγRIIb, but reduced affinity for one or more activating FcγRs, including, for example, FcγRI, FcγRIIa, FcγRIIIa, and / or FcγRIIIb. FcγR receptors can be expressed on cells from any organism, including but not limited to humans, cynomolgus monkeys, and mice. The Fc variants disclosed herein can be optimized to have enhanced affinity for human FcγRIIb.

[0077] Fc variants contain one or more amino acid modifications relative to the parental Fc polypeptide, and the amino acid modification(s) provide one or more optimized properties. The Fc variants disclosed herein differ in amino acid sequence from their parent by at least one amino acid modification. Thus, the Fc variants disclosed herein have at least one amino acid modification compared to the parent. Alternatively, the Fc variants disclosed herein can have two or more amino acid modifications compared to the parent, e.g., about 2 to 50 amino acid modifications, e.g., about 2 to 10 amino acid modifications, about 2 to about 5 amino acid modifications, etc., compared to the parent. Thus, the sequence of the Fc variant and the sequence of the parental Fc polypeptide are substantially homologous. For example, the variant Fc variant sequences herein have about 80% homology, e.g., at least about 90% homology, at least about 95% homology, at least about 98% homology, at least about 99% homology, etc., with the parental Fc variant sequences. The modifications disclosed herein include amino acid modifications including insertions, deletions, and substitutions. The modifications disclosed herein also include glycoform modifications.

[0078] The modifications may be made genetically using molecular biology or may be made enzymatically or chemically.

[0079] The Fc variants disclosed herein are defined according to the amino acid modifications that compose them. Thus, for example, S267E is an Fc variant having substitution S267E relative to the parental Fc polypeptide. Similarly, S267E / L328F defines an Fc variant having substitutions S267E and L328F relative to the parental Fc polypeptide. The identity of the WT amino acids need not be specified, in which case the aforementioned variants are referred to as 267E / 328F. It should be noted that the order in which the substitutions are provided is arbitrary, i.e., for example, 267E / 328F is the same Fc variant as 328F / 267E, etc. Unless otherwise indicated, the positions discussed herein are numbered according to the EU index described in Kabat (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, which is hereby incorporated by reference in its entirety). Briefly, EU is the name of the first antibody molecule whose entire amino acid sequence was determined (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, which is hereby incorporated by reference in its entirety), and its amino acid sequence serves as the standard numbering scheme for the heavy chain constant region. The EU protein serves as the standard reference for defining the numbering. Kabat et al. list the EU sequence in a set of indicators that align the EU sequence with other antibody sequences as a tool necessary to align antibodies to the EU numbering scheme. Thus, as will be understood by those skilled in the art, the standard way to refer to EU numbering is to refer to the sequence alignment of Kabat et al. in order to place EU in relation to other antibodies of variable domain length. Thus, as used herein, "EU index as in Kabat" or "numbering follows the EU index as in Kabat" refers to the numbering of EU antibodies as described in Kabat.

[0080] In certain embodiments, the Fc variants disclosed herein are based on human IgG sequences, and thus the human IgG sequences are used as the "base" sequences to which other sequences, including but not limited to sequences from other organisms such as rodent and primate sequences, are compared. Immunoglobulins may also include sequences from other immunoglobulin classes such as IgA, IgE, IgGD, IgGM. The Fc variants disclosed herein are engineered in the context of one parental IgG, but it is contemplated that the variants can be engineered in the context of, or "transferred" to, another second parental IgG. This is typically done by determining the "equivalent" or "corresponding" residues and substitutions between the first and second IgGs based on sequence or structural homology between the sequences of the first and second IgGs. To establish homology, the amino acid sequence of the first IgG outlined herein is directly compared to the sequence of the second IgG. After the sequences are aligned, one or more of the homology alignment programs known in the art (e.g., using residues conserved across species) are used to allow for insertions and deletions necessary to maintain the alignment (i.e., avoiding removal of residues conserved by any deletions and insertions), and residues corresponding to specific amino acids in the primary sequence of the first immunoglobulin are defined. Alignment of conserved residues can conserve 100% of such residues. However, alignments of conserved residues greater than 75% or even as little as 50% are also suitable for defining equivalent residues. Equivalent residues may also be defined by determining the structural homology between the first and second IgGs at the level of the tertiary structure of the IgG whose structure has been determined. In this case, equivalent residues are defined as those for which the atomic coordinates of two or more backbone atoms of a particular amino acid residue of the parent or precursor (N on N, CA on CA, C on C, and O on O) are within about 0.13 nm after alignment. In another embodiment, equivalent residues are within about 0.1 nm after alignment. The alignment is achieved after the best model is oriented and positioned such that it results in the maximum overlap of the atomic coordinates of the non-hydrogen protein atoms of the protein.Regardless of how equivalent or corresponding residues are determined, and regardless of the identity of the parent IgG from which the IgG is made, it is intended to be conveyed that the Fc variants discovered as disclosed herein can be engineered into any second parent IgG having significant sequence or structural homology to the Fc variant. Thus, for example, where a variant antibody is generated where the parent antibody is human IgG1, by using the methods described above or other methods for determining equivalent residues, the variant antibody may be engineered into another IgG1 parent antibody that binds a different antigen, a human IgG2 parent antibody, a human IgA parent antibody, a mouse IgG2a or IgG2b parent antibody, etc. Again, as noted above, the context of the parent Fc variant does not affect the ability to transfer the disclosed Fc variants to other parent IgGs.

[0081] As used herein, the terms "greater affinity", "improved affinity", "enhanced affinity", or "better affinity" than a parental Fc polypeptide mean that the Fc variant binds to an Fc receptor with a significantly higher equilibrium association constant (KA or Ka) or lower equilibrium dissociation constant (KD or Kd) than the parental Fc polypeptide when the amounts of the variant and the parental polypeptide in the binding assay are essentially the same. For example, an Fc variant having improved Fc receptor binding affinity may exhibit an improvement in Fc receptor binding affinity of about 5-fold to about 1000-fold, such as about 10-fold to about 500-fold, compared to the parental Fc polypeptide, and the Fc receptor binding affinity is determined by, for example, but not limited to, the binding methods disclosed herein including Biacore, by one of ordinary skill in the art. Thus, "a reduction in affinity" as compared to the parental Fc polypeptide used herein means that the Fc variant binds to the Fc receptor with a significantly lower KA or higher KD than the parental Fc polypeptide. A greater or reduced affinity can also be defined in comparison to the absolute level of affinity. For example, according to the data herein, WT (native) IgG1 binds to FcγRIlb with an affinity of about 1.5 mM, or about 1500 nM. Further, some of the Fc variants described herein bind to FcγRIIb with an affinity about 10-fold higher than WT IgG1. As disclosed herein, greater or enhanced affinity means having a KD of less than about 100 nM, such as about 10 nM to about 100 nM, about 1 to about 100 nM, or less than about 1 nM.

[0082] In one embodiment, the Fc variant provides a selectively enhanced affinity for FcγRIIb as compared to one or more activating receptors. Selectively enhanced affinity means that the Fc variant has an improved affinity for FcγRIIB relative to the activating receptor(s) as compared to the parental Fc polypeptide, but has a reduced affinity for the activating receptor(s) as compared to the parental Fc polypeptide, or that the Fc variant has an improved affinity for both FcγRIIb and the activating receptor(s) as compared to the parental Fc polypeptide, but the improvement in affinity is greater for FcγRIIb than for the activating receptor(s). In alternative embodiments, the Fc variant reduces or ablates binding to one or more activating FcγRs, reduces or ablates binding to one or more complement proteins, reduces or ablates one or more FcγR-mediated effector functions, and / or reduces or ablates one or more complement-mediated effector functions.

[0083] The presence of different polymorphic forms of FcγR provides yet another parameter that affects the therapeutic utility of the Fc variants disclosed herein. The specificity and selectivity of a given Fc variant for different classes of FcγR significantly affects the ability of the Fc variant to target a given antigen for the treatment of a given disease, but the specificity or selectivity of the Fc variant for different polymorphic forms of these receptors can partially determine which studies or preclinical experiments are appropriate for testing, and ultimately which patient populations may or may not respond to treatment. Thus, the specificity or selectivity of the Fc variants disclosed herein for Fc receptor polymorphisms, including but not limited to FcγRIIa, FcγRIIIa, etc., can be used to guide effective studies and preclinical experiments, clinical trial design, patient selection, dosing dependence, and / or the selection of other aspects of clinical trials.

[0084] The Fc variants disclosed herein may include modifications that modulate interactions with Fc receptors other than FcγRs, including but not limited to complement proteins, FcRn, and Fc receptor homologs (FcRH). Examples of FcRH include, but are not limited to, FcRFH, FcRH2, FcRH3, FcRH4, FcRH5, and FcRH6 (Davis et al., 2002, Immunol. Reviews 190:123-136).

[0085] An important parameter for determining the most beneficial selectivity of a given Fc variant for treating a given disease is the context of the Fc variant. Thus, the selectivity or specificity of the Fc receptor of a given Fc variant will provide different properties depending on whether the antibody, Fc fusion, or Fc variant is constructed with a binding fusion partner. In one embodiment, the Fc receptor specificity of the Fc variants disclosed herein determines their therapeutic utility. The utility of a given Fc variant for therapeutic purposes will depend on the epitope or conformation of the target antigen and the disease or indication being treated. For some targets and indications, it may be beneficial to have greater FcγRIIb affinity and reduced activated FcγR-mediated effector function. For other target antigens and therapeutic uses, it may be beneficial to increase the affinity for FcγRIIb or to increase the affinity for both FcγRIIb and activating receptors. Formulations and Pharmaceutical Compositions

[0086] The present invention provides pharmaceutical compositions and formulations of anti-CD19 antibodies (e.g., obexelimab). The formulations of the anti-CD19 antibodies disclosed herein are prepared for storage by mixing the antibody having the desired purity in the form of a lyophilized formulation or an aqueous solution with any pharmaceutically acceptable carrier, excipient, or stabilizer (see Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980, which is hereby incorporated by reference in its entirety).

[0087] In some embodiments, the subject pharmaceutical composition comprises anti-CD19 antibodies (e.g., obexelimab) at various concentrations. In some embodiments, suitable formulations may contain the subject antibody at a concentration of up to about 250 mg / ml (e.g., up to about 225 mg / ml, up to 200 mg / ml, up to 150 mg / ml, up to 140 mg / ml, up to 130 mg / ml, up to 125 mg / ml, up to 120 mg / ml, up to 115 mg / ml, up to 110 mg / ml, up to 105 mg / ml, up to 100 mg / ml, up to 90 mg / ml, up to 80 mg / ml, up to 70 mg / ml, up to 60 mg / ml, up to 50 mg / ml, up to 40 mg / ml, up to 30 mg / ml, up to 25 mg / ml, up to 20 mg / ml, up to 10 mg / ml).

[0088] In some embodiments, suitable formulations may contain an anti-CD19 antibody at a concentration in the range of about 10 - 300 mg / ml (e.g., about 10 - 250 mg / ml, about 10 - 200 mg / ml, about 10 - 180 mg / ml, about 10 - 160 mg / ml, about 10 - 150 mg / ml, about 10 - 140 mg / ml, about 10 - 130 mg / ml, about 10 - 125 mg / ml, about 100 - 125 mg / ml, about 100 - 180 mg / ml, about 100 - 150 mg / ml, about 100 - 130 mg / ml, about 100 - 125 mg / ml, about 100 - 170 mg / ml, about 100 - 160 mg / ml, about 100 - 150 mg / ml, about 100 - 200 mg / ml, about 120 - 130 mg / ml).

[0089] In some embodiments, formulations suitable for subcutaneous administration may contain the subject protein at a concentration of approximately 100 mg / ml, 115 mg / ml, 120 mg / ml, 125 mg / ml, 130 mg / ml, 135 mg / ml, 140 mg / ml, 145 mg / ml, 150 mg / ml, 200 mg / ml, or 300 mg / ml.

[0090] In some embodiments, isotonic solutions are used. In some embodiments, slightly hypertonic solutions (e.g., up to 300 mM (e.g., up to 250 mM, 200 mM, 175 mM, 150 mM, 125 mM) of sodium chloride in 5 mM sodium phosphate at pH 7.0) and sugar-containing solutions (e.g., up to 3% (e.g., up to 2.4%, 2.0%, 1.5%, 1.0%) of sucrose in 5 mM sodium phosphate at pH 7.0). In some embodiments, a suitable formulation composition is physiological saline (e.g., 150 mM NaCl in water).

[0091] Many therapeutic agents, particularly the antibodies of the present invention, require controlled pH and specific excipients to maintain their solubility and stability in the pharmaceutical compositions of the present invention.

[0092] The pH of the pharmaceutical composition is an additional factor that can change the solubility of the anti-CD19 antibody (e.g., obexelimab) in the aqueous pharmaceutical composition. In some embodiments, the pharmaceutical compositions of the present invention contain one or more buffers. In some embodiments, the compositions according to the present invention contain an amount of buffer sufficient to maintain the optimal pH of the composition at about 4.0 - 8.0, about 5.0 - 7.5, about 5.5 - 7.0, about 6.0 - 7.0, and about 6.0 - 7.5. In other embodiments, the buffer contains up to about 50 mM (e.g., up to about 45 mM, 40 mM, 35 mM, 30 mM, 25 mM, 20 mM, 15 mM, 10 mM, 5 mM) of sodium phosphate. Suitable buffers include, for example, acetate, succinate, citrate, phosphate, other organic acids, and tris(hydroxymethyl)aminomethane ("tris").

[0093] Suitable buffer concentrations can be, for example, from about 1 mM to about 100 mM, or from about 3 mM to about 20 mM, depending on the desired isotonicity of the buffer and the formulation. In some embodiments, suitable buffers are present at a concentration of about 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, or 100 mM.

[0094] In some embodiments, the formulation contains an isotonic agent to maintain the isotonicity of the formulation. Exemplary isotonic agents include, but are not limited to, glycine, sorbitol, mannitol, sodium chloride, and arginine. In some embodiments, suitable isotonic agents can be present in the formulation at a concentration of about 0.01 - 5 wt% (e.g., 0.05, 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, or 5.0 wt%).

[0095] In some embodiments, the formulation may contain a stabilizer to protect the antibody. Typically, suitable stabilizers are non-reducing sugars such as sucrose, raffinose, trehalose, or amino acids such as glycine, arginine, and methionine. The amount of stabilizer in the formulation is generally an amount such that the formulation is isotonic. However, hypertonic formulations may also be suitable. Further, the amount of stabilizer should not be too low such that unacceptable amounts of antibody degradation / aggregation occur. Exemplary stabilizer concentrations in the formulation can range from about 1 mM to about 400 mM (e.g., about 30 mM to about 300 mM, and about 50 mM to about 100 mM), or alternatively from 0.1 wt% to 15 wt% (e.g., 1 wt% to 10 wt%, 5 wt% to 15 wt%, 5 wt% to 10 wt%). In some embodiments, the mass ratio of stabilizer to therapeutic agent is about 1:1. In other embodiments, the mass ratio of stabilizer to therapeutic agent can be about 0.1:1, 0.2:1, 0.25:1, 0.4:1, 0.5:1, 1:1, 2:1, 2.6:1, 3:1, 4:1, 5:1, 10:1, or 20:1. In some embodiments suitable for lyophilization, the stabilizer is also a cryoprotectant.

[0096] The pharmaceutical compositions, formulations, and related methods of the invention deliver an anti-CD19 antibody (e.g., subcutaneously) and are useful for the treatment of related diseases. The pharmaceutical compositions of the invention are particularly useful for delivering an anti-CD19 antibody (e.g., obexelimab) to patients suffering from IgG4-RD.

[0097] In some embodiments, it is desirable to add a surfactant to the formulation. Exemplary surfactants include nonionic surfactants such as polysorbates (e.g., polysorbate 20 or 80); poloxamers (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glucoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocoamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl); myristarnidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; methyl sodium cocoyl taurate, or methyl disodium oleoyl taurate; and the MONAQUAT™ series (Mona Industry, Inc. Patterson N.J.), polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics® PF68, etc.). Typically, the amount of surfactant added is an amount that reduces protein aggregation and minimizes particle or foam formation. For example, the surfactant may be present in the formulation at a concentration of about 0.001 - 0.5% (e.g., about 0.005 - 0.05%, or 0.005 - 0.01%). In particular, the surfactant may be present in the formulation at a concentration of approximately 0.005%, 0.01%, 0.02%, 0.1%, 0.2%, 0.3%, 0.4%, or 0.5%, etc.

[0098] In some embodiments, suitable formulations may further include one or more bulking agents, particularly for lyophilization. A "bulking agent" is a compound that adds mass to the lyophilization mixture and contributes to the physical structure of the lyophilized cake. For example, a bulking agent can improve the appearance of the lyophilized cake (e.g., an essentially uniform lyophilized cake). Suitable bulking agents include, but are not limited to, sodium chloride, lactose, mannitol, glycine, sucrose, trehalose, hydroxyethyl starch. Exemplary concentrations of the bulking agent are from about 1% to about 10% (e.g., 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, and 10.0%).

[0099] The formulations according to the present invention can be evaluated based on product quality analysis, reconstitution time (when lyophilized), quality of reconstitution (when lyophilized), high molecular weight, moisture, and glass transition temperature. Typically, protein quality and product analysis include product degradation rate analysis using methods including, but not limited to, size exclusion HPLC (SE-HPLC), cation exchange HPLC (CEX-HPLC), X-ray diffraction (XRD), modulated differential scanning calorimetry (mDSC), reverse phase HPLC (RP-HPLC), multi-angle light scattering (MALS), fluorescence, ultraviolet absorption, nephelometry, capillary electrophoresis (CE), SDS-PAGE, and combinations thereof. In some embodiments, the evaluation of the product according to the present invention may include the step of evaluating the appearance (either the appearance of the liquid or the cake).

[0100] Generally, the formulations (lyophilized or aqueous) can be stored at room temperature for an extended period. The storage temperature can typically be in the range of 0°C to 45°C (e.g., 4°C, 20°C, 25°C, 45°C, etc.). The formulations may be stored for periods ranging from several months to several years. The storage time is generally 24 months, 12 months, 6 months, 4.5 months, 3 months, 2 months, or 1 month. The formulations can be stored directly in the container used for administration, eliminating the need for a transfer step.

[0101] The formulation can be stored directly in the lyophilization container (when lyophilized), which can also function as a reconstitution container and eliminate the transfer step. Alternatively, the lyophilized product formulation may be measured into smaller increments for storage. Storage should generally avoid situations that lead to protein degradation, including but not limited to exposure to sunlight, UV radiation, other forms of electromagnetic radiation, excessive heat or cold, rapid thermal shock, and mechanical shock.

[0102] In some embodiments, the formulations according to the invention are in liquid or aqueous form. In some embodiments, the formulations of the invention are lyophilized. Such lyophilized formulations may be reconstituted by adding one or more diluents thereto prior to administration to the patient. Suitable diluents include, but are not limited to, sterile water, bacteriostatic water for injection, and sterile saline. Preferably, upon reconstitution, the antibodies contained therein are stable, soluble, and well-tolerated upon administration to the patient.

[0103] The pharmaceutical compositions of the invention are characterized by their tolerability. As used herein, the terms "tolerable" and "tolerability" refer to the ability of the pharmaceutical compositions of the invention not to cause an adverse reaction in the patient to whom such a composition is administered, or alternatively, not to cause a severe adverse reaction in the patient to whom such a composition is administered. In some embodiments, the pharmaceutical compositions of the invention are well tolerated by the patients to whom such compositions are administered.

[0104] Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as phosphoric acid, citrate, acetate, and other organic acids, antioxidants including ascorbic acid and methionine, preservatives (such as octadecyl dimethyl benzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol, etc.), low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine, monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin, chelating agents such as EDTA, sugars such as sucrose, mannitol, trehalose or sorbitol, sweeteners and other flavoring agents, fillers such as microcrystalline cellulose, lactose, corn and other starches, binders, additives, coloring agents, salt-forming counterions such as sodium, metal complexes (e.g., Zn-protein complexes), and / or nonionic surfactants such as TWEEN(trademark), PLURONICS(trademark) or polyethylene glycol (PEG).

[0105] In some embodiments, the pharmaceutical compositions containing the antibodies disclosed herein may be in a water-soluble form, such as existing as pharmaceutically acceptable salts, which means including both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable, and are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0106] Examples of "pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Some embodiments include at least one of ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary amines, secondary amines, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0107] Formulations used for in vivo administration (e.g., subcutaneous administration) may be sterilized. In some embodiments, the formulation is sterilized by filtration through a sterile filtration membrane.

[0108] In some embodiments, the anti-CD19 antibodies (e.g., obexelimab) disclosed herein are formulated for subcutaneous (SC) administration. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) formulation for SC administration comprises one or more buffers, one or more tonicity modifiers, one or more solvents, and one or more surfactants. Non-limiting examples of buffers include phosphates, citrates, acetates, glutamates, carbonates, tartrates, triethanolamine (TRIS), glycylglycine, histidine, glycine, lysine, arginine, and other organic acids. More specifically, non-limiting examples of buffers include sodium HEPES, MES, potassium phosphate, potassium thiocyanate, bactericide, TEE, TEB, ammonium sulfate / HEPES, BuffAR, sodium acetate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate. Further, the buffer may be in various hydrated forms. For example, the buffer may be a monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, undecahydrate, and dodecahydrate. Occasionally, the hydrate may be a fractional separation such as a hemihydrate or a sequihydrate. Non-limiting examples of tonicity modifiers include sodium chloride, acetic acid, L-proline, dextrose, mannitol, potassium chloride, glycerin, and glycerol. Non-limiting examples of solvents include water, propylene glycol, polyethylene glycol, ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycofluor, Solketal™, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, and ethyl lactate.Non-limiting examples of solvents include polysorbates (e.g., polysorbate-20, polysorbate-80), polyoxyethylene sorbitan monooleate (Tween® 80), polyoxyethylene sorbitan monolaurate (Tween® 20), sorbitan trioleate (Span 85), lecithin, and polyoxyethylene polyoxypropylene copolymers (Pluronics®, Pluronic® F-68).

[0109] The amounts of anti-CD19 antibody (e.g., obexelimab), buffer, tonicity modifier, solvent, and surfactant can vary. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 125 mg / mL obexelimab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid (density 1.053 g / mL), 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80, pH 5.5. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 80 - 200 mg / mL obexelimab, 1.5 - 3 mg / mL sodium acetate trihydrate, 0.1 - 0.2 mg / mL acetic acid (density 1.053 g / mL), 10 - 50 mg / mL L-proline, 0.05 - 0.2 mg / mL polysorbate 80, pH 5.0 - 6.0. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated at a concentration of 122 - 127 mg / mL obexelimab, 2.0 - 2.5 mg / mL sodium acetate trihydrate, 0.15 - 0.19 mg / mL acetic acid (density 1.053 g / mL), 25 - 35 mg / mL L-proline, 0.05 - 0.15 mg / mL polysorbate 80, pH 5.0 - 6.0.

[0110] In certain embodiments, the subcutaneous (SC) formulation comprises an anti-CD19 antibody (e.g., obexelimab), one or more buffers, one or more tonicity modifiers, one or more solvents, and one or more surfactants. In some embodiments, the buffer can be a sodium acetate buffer. For example, the buffer can be sodium acetate trihydrate. In one embodiment, the tonicity modifiers can be acetic acid, L-proline, and combinations thereof. In another embodiment, the solvent is water.

[0111] In some embodiments, the surfactant is polysorbate. In some embodiments, the polysorbate is polysorbate-80. In some embodiments, the SC formulation comprises an anti-CD19 antibody (e.g., obexelimab), sodium acetate trihydrate, acetic acid and L-proline, water, and polysorbate-80.

[0112] In some embodiments, the subcutaneous (SC) formulation comprises an anti-CD19 antibody (e.g., obexelimab) in an amount of about 1 mg to about 500 mg per mL, or about 50 mg to about 250 mg per mL, or about 100 mg to about 250 mg per mL, sodium acetate trihydrate in an amount of about 1 to about 10 mg per mL, or about 1 to about 5 mg per mL, or about 1 to about 2.5 mg per mL, acetic acid and L-proline in an amount of about 5 to about 50 mg per mL, or about 10 to about 50 mg per mL, or about 20 to about 40 mg per mL, up to about 1 mL of water, and polysorbate-80 in an amount of about 0.01 mg to about 1 mg / mL, or about 0.01 to about 0.5 mg / mL, or about 0.05 to about 0.2 mg / mL. Specifically, the SC formulation comprises an anti-CD19 antibody (e.g., obexelimab) in an amount of about 100 mg to about 250 mg / ml, sodium acetate trihydrate in an amount of about 1 to about 2.5 mg / ml, acetic acid and L-proline in an amount of about 20 to about 40 mg / ml, water up to about 1 mg / ml, and polysorbate-80 in an amount of about 0.05 to about 0.2 mg / ml.

[0113] The anti-CD19 antibodies (e.g., obexelimab) disclosed herein may also be formulated as immunoliposomes. Liposomes are vesicles containing various types of lipids, phospholipids, and / or surfactants useful for the delivery of anti-CD19 antibodies (e.g., obexelimab) to mammals. Liposomes containing an anti-CD19 antibody (e.g., obexelimab) are prepared by methods known in the art. Liposomes with enhanced circulation times are disclosed in U.S. Patent No. 5,013,556, which is incorporated by reference in its entirety. In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is formulated in liposomes produced by the reverse-phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol, and a PEG-derivatized phosphatidylethanolamine (PEG-PE). The liposomes are extruded through a filter with a defined pore size to obtain liposomes having the desired diameter.

[0114] In some embodiments, the anti-CD19 antibody (e.g., obexelimab) is encapsulated in microcapsules prepared by methods including, but not limited to, coacervation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose or gelatin-microcapsules, or poly-(methylmethacrylate) microcapsules), colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), and macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980, which is incorporated by reference in its entirety.

[0115] In some embodiments, a sustained-release preparation of an anti-CD19 antibody (e.g., obexelimab) may be prepared. Suitable examples of sustained-release preparations include a semipermeable matrix of a solid hydrophobic polymer, which matrix is in the form of a molded article, such as a film, or a microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919, incorporated herein by reference in its entirety), copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as Lupron Depot® (injectable microspheres composed of a copolymer of lactic acid-glycolic acid and leuprolide acetate), poly-D-(-)-3-hydroxybutyric acid, and ProLease® (commercially available from Alkermes), which is a microsphere-based delivery system composed of a desired bioactive molecule incorporated into a matrix of poly-DL-lactide-co-glycolide (PLG). Injection container

[0116] The present invention provides a pharmaceutical composition of an anti-CD19 antibody (e.g., obexelimab) and a container for injecting the formulation. In one aspect, the container contains a liquid pharmaceutical composition containing obexelimab. Suitable containers include, but are not limited to, syringes, autoinjectors, vials, infusion bottles, ampoules, cartridges, syringes with needle protection systems, and cartridges within injection pens.

[0117] In some embodiments, the container containing the liquid pharmaceutical composition is a prefilled syringe, a vial, or an autoinjector. In some embodiments, the container is a prefilled syringe. In some embodiments, the container is an autoinjector.

[0118] In some embodiments, the container is a. obexelimab at 122-127 mg / mL, and b. at pH 5.0 to 6.0, 2.0 to 2.5 mg / mL of sodium acetate trihydrate, and c. 0.15 to 0.19 mg / mL of acetic acid (density 1.053 g / mL), and d. 25 to 35 mg / mL of L - proline, and e. 0.05 to 0.15 mg / mL of polysorbate 80, and is a prefilled syringe or auto - injector containing a liquid pharmaceutical composition.

[0119] In some embodiments, the prefilled syringe or auto - injector contains a liquid pharmaceutical composition, and the liquid pharmaceutical composition contains, at pH 5.5, about 125 mg / mL of obexelimab, 2.35 mg / mL of sodium acetate trihydrate, 0.17 mg / mL of acetic acid, 30 mg / mL of L - proline, and 0.1 mg / mL of polysorbate 80.

[0120] In some embodiments, the prefilled syringe or auto - injector facilitates subcutaneous or intradermal delivery of the pharmaceutical composition. In some embodiments, the method of treating IgG4 - RD described herein involves administering a formulation containing obexelimab into the patient's bloodstream after single or multiple subcutaneous injections into the patient's abdomen using a pre - filled syringe or auto - injector.

[0121] In some embodiments, the composition in the prefilled syringe is stable for at least 3 months when stored at 2 - 8°C. In some embodiments, the composition in the prefilled syringe is stable for at least 6 months when stored at 2 - 8°C. In some embodiments, the composition in the prefilled syringe is stable for at least 6 months when stored at 2 - 8°C. In some embodiments, the composition in the prefilled syringe is stable for at least 1 year when stored at 2 - 8°C. In some embodiments, the composition in the prefilled syringe is stable for at least 2 years when stored at 2 - 8°C. IgG4 - related disease (IgG4 - RD)

[0122] IgG4-RD is a severe and rare chronic fibrosing inflammatory condition that typically affects multiple organs, results in significant organ dysfunction and failure, and can even lead to death if the condition is not recognized and treated in a timely manner. In some embodiments, the disease generally affects major organs such as the pancreas, liver, kidney, lung, and eye. In some embodiments, a patient may present with a single involved organ, but more frequently may present with involvement of multiple organs. As the disease progresses and the patient experiences new or worsening signs / symptoms (flares), additional organs develop lesions, and the cellular inflammation that characterizes early disease moves towards a more fibrotic stage, causing major tissue damage and ultimately organ failure. For example, cholangitis due to IgG4-RD can lead to liver failure, IgG4-related (type 1) autoimmune pancreatitis can lead to failure of either or both the endocrine and exocrine pancreas, and IgG4-related aortitis can lead to aneurysm and / or aortic dissection.

[0123] Several B cell subsets have been described by flow cytometry as being elevated in the peripheral blood of IgG4-RD patients (Wallace 2015, Mattoo 2014), and CD19+ plasmablasts have been shown to contribute actively to tissue fibrosis (Della-Torre 2019). The histopathological features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis (Carruthers 2015). A hallmark of IgG4-RD is infiltration of IgG4-positive plasma cells in the affected organ (Cheuk 2010, Floreani 2020).

[0124] Clinical symptoms and disease course depend on the affected organ(s) and can therefore be evaluated and treated by many different specialties, including rheumatologists, gastroenterologists, nephrologists, and ophthalmologists. Despite increased awareness of this disease and significant progress in understanding its pathophysiology, no approved pharmaceuticals are available. In fact, no randomized, double-blind, placebo-controlled trials have been published for IgG4-RD. Treatment is based on expert opinion consensus (Khosroshahi 2015), but treatment options remain limited and are often restricted by comorbidities common among IgG4-RD patients (e.g., elderly, diabetes, obesity, hypertension), and the fact that the disease frequently targets organs such as the pancreas and exacerbates treatment complications associated with glucocorticoids.

[0125] B cells, including plasmablast-specific therapies using CD19 monoclonal antibodies such as obexelimab (XmAb5871), which co-engages CD19 and FcγRIIb, mimic the natural action of antigen-antibody complexes and downregulate B cell activity. The proposed mechanism of action of obexelimab, which simultaneously binds CD19 and FcγRIIb and downregulates B cell activity, has been demonstrated in vitro and in vivo, including in classical animal models of autoimmune disease.

[0126] IgG4-RD is currently incurable. The aims of treatment are to reduce organ inflammation and swelling, prevent or reverse fibrosis (if possible), and increase glandular secretion. Immediate treatment is required to prevent organ failure when important organs are involved. For example, IgG4-RD-related cholangitis can lead to liver failure, IgG4-related (type 1) autoimmune pancreatitis can lead to failure of either or both the endocrine and exocrine pancreas, and IgG4-related aortitis can lead to aneurysm and / or aortic dissection. Currently, glucocorticoids are the first-line treatment. This approach is initially effective in most patients, but the relapse rate is high upon tapering or discontinuation (Khosroshahi et al. 2015). Furthermore, long-term use of glucocorticoids causes toxicity in patients, especially in the elderly population including osteoporosis, hypertension, and diabetes.

[0127] The etiology of IgG4-RD suggests that B cell-targeted therapy could be a useful therapeutic intervention. For example, the results of a small pilot study of the anti-CD20 monoclonal antibody rituximab in 30 patients with IgG4-RD support this concept (Carruthers 2015). Rituximab and other B cell-depleting agents can prolong B cell depletion for more than 6 months, expose patients to the risk of opportunistic infections, and reduce the response to vaccines. Therefore, there is a need for new therapies that downregulate rather than deplete B cell activity.

[0128] IgG4-related diseases for treatment in the present disclosure include IgG4-related sialadenitis (chronic sclerosing sialadenitis, Kuttner tumor, Mikulicz disease), IgG4-related dacryoadenitis (Mikulicz disease), IgG4-related ophthalmic diseases (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic rhinosinusitis, eosinophilic granulomatosis with polyangiitis, IgG4-related hypophysitis (IgG4-related panhypophysitis, IgG4-related hypopituitarism, IgG4-related Inhibin neuronophysis disease, autoimmune hypothesis), IgG4-related peritonitis, IgG4-related leptomeningitis (idiopathic hypertrophic pachymeningitis), IgG4-related pancreatitis (type 1 autoimmune pancreatitis, IgG4-related AIP, lymphoplasmacytic sclerosing pancreatitis, chronic pancreatitis with diffuse irregular stenosis of the main pancreatic duct), IgG4-related lung diseases (pulmonary inflammatory pseudotumor), IgG4-related pleurisy, IgG4-related liver disorders, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortitis), IgG4-related peritonitis (chronic peritonitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrosing mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis, Albarran - Ormond syndrome, Ormond disease (tetroperitoneal fibrosis)), peripheral fasciitis, Gerota fasciitis / syndrome, fibrous perianeuritis, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, nonspecific retroperitonitis, sclerosing retroperitonitis, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related mesenteritis (subtype:It may be selected from the group consisting of mesenteric pancreatitis, mesenteric lipodystrophy and retroperitoneal mesenteritis (sclerosing mesenteritis, systemic nodular pancreatitis, enteric inflammatory fat sclerosis, enteric Weber-Christian disease, mesenteric fat granuloma, heterogeneous granulomatous enteritis), IgG4-related mastitis (sclerosing mastitis), IgG4-related kidney disease (IgG4-RKD), IgG4-related tubulointerstitial nephritis (IgG4-TIN), IgG4-related membranous glomerulonephritis (idiopathic tubulointerstitial nephritis), IgG4-related prostatitis, IgG4-related perienteric fibrosis (chronic glossodynia), IgG4-related paraintestinal pseudotumor, IgG4-related epididymo-orbital inflammation (intestinal fibrosing pseudotumor, inflammatory pseudotumor of the spermatic cord, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, proliferative balanitis, chronic proliferative perioral dermatitis, fibrosing perioral dermatitis, nodular perioral dermatitis, reactive perioral dermatitis, fibrous mesothelioma), IgG4-related lymphadenopathy, IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineural diseases, and IgG4-related thyroid diseases (Riedel thyroiditis), eosinophilic angiofibrosis (affecting the orbit and upper airway), inflammatory pseudotumor, and multiple sclerosis.

[0129] Furthermore, in some embodiments, the present disclosure also includes a method of treating symptoms of IgG4-RD selected from the group consisting of autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), eosinophilic angiofibrosis (affecting the orbit and upper airway), fibrous mediastinitis, idiopathic hypertrophic pachynsis, idiopathic tubulointerstitial nephritis, inflammatory pseudotumor, Kuttner tumor, Mikulicz disease, fibrous arteriosclerosis, periodontitis, periarteritis, inflammatory aortic multifocal surgery, Ormond disease (retroperitoneal fibrosis), Riedel thyroiditis, and sclerosing enteritis. Human patient population

[0130] According to the present invention, eligible human patients selected for obexelimab administration are 18 years of age or older with active IgG4-RD. In some embodiments, eligible patients have active IgG4-RD signs / symptoms (e.g., flares) that require initiation of therapy. In some embodiments, the patient population is adults (18 years of age or older) with active IgG4-RD. In some embodiments, patients are first evaluated for the following factors. · One organ involvement versus more than one organ involvement · Newly diagnosed and recurrent diseases meet the classification criteria for participation in clinical trials of IgG4-RD.

[0131] In some embodiments, the patient has a recent active disease that requires GC therapy. In some embodiments, the therapeutic efficacy of obexelimab is determined by reducing the risk of relapse compared to a placebo control. Eligible patients may have ≥1 organ involvement. In some embodiments, the affected organ in IgG4-RD is the lung. In some embodiments, the affected organ in IgG4-RD is the aorta. In some embodiments, the affected organ in IgG4-RD is the retroperitoneum. In some embodiments, the affected organ in IgG4-RD is the pachimenin. In some embodiments, the affected organ in IgG4-RD is the thyroid. In some embodiments, the affected organ in IgG4-RD is at least one orbit. In some embodiments, the affected organ in IgG4-RD is the lacrimal gland. In some embodiments, the organ in IgG4-RD is the salivary gland. In some embodiments, the affected organ in IgG4-RD is the liver. In some embodiments, the affected organ in IgG4-RD is the bile duct. In some embodiments, the affected organ in IgG4-RD is the pancreas. In some embodiments, the affected organ in IgG4-RD is the kidney. In some embodiments, the affected organ in IgG4-RD is the skin. In some embodiments, the affected organ in IgG4-RD is the thyroid. In some embodiments, the affected organ in IgG4-RD is the pituitary gland. In some embodiments, the affected organ of IgG4-RD is the lymph node. Patients having a disease of only one organ system with the main symptom being fibrosis (i.e., retroperitoneal fibrosis without aortitis, Riedel thyroiditis, fibrosing mediastinitis, associated with ulcerative colitis, etc.) may be excluded. In some embodiments, organ involvement refers to an enlargement or tumor-like mass in the affected organ, excluding (1) the bile duct where stricture tends to occur, (2) the aorta where wall thickening or aneurysmal dilation is typical, and (3) the lung with thickening of the bronchovascular bundle.

[0132] In some embodiments, the previous therapy is an increase in GC therapy and / or background long-term GC therapy.

[0133] In some embodiments, an eligible patient has received GC treatment for at least two weeks. In some embodiments, an eligible patient according to the present invention needs to receive GC treatment for at least three weeks. In some embodiments, an eligible patient according to the present invention needs to receive GC treatment for more than three weeks. In some embodiments, an eligible patient according to the present invention needs to receive GC treatment for a maximum of six weeks. In some embodiments, GC treatment is administered at 30 - 50 mg / day prednisone or an equivalent dose. In some embodiments, GC treatment is administered at 10 - 70 mg / day prednisone or a corresponding dose. In some embodiments, GC treatment is administered at 20 - 60 mg / day prednisone or an equivalent dose. Table 3 shows exemplary equivalent doses of GC.

[0134] In some embodiments, in an eligible patient according to the present invention, GC therapy is administered together with obexelimab. In some embodiments, GC treatment is tapered before the start of obexelimab therapy. An exemplary tapering protocol includes administering 0.6 - 1.0 mg / kg of corticosteroid daily for 2 - 4 weeks, followed by a gradual taper (Khosroshahi 2015). In some exemplary embodiments, GC is completely tapered within 8 - 12 weeks until discontinuation. In some embodiments, the taper takes less than 8 weeks. In some embodiments, the taper takes more than 12 weeks. In some exemplary embodiments, GC treatment can be continued chronically at a low to medium dose of 2.5 - 10.0 mg per day (Kamisawa 2017).

[0135] In some embodiments, an eligible patient according to the present invention may have a plasmablast level of more than 100 cells / mL, more than 200 cells / mL, more than 300 cells / mL, more than 400 cells / mL, more than 500 cells / mL, more than 600 cells / mL, more than 700 cells / mL, more than 800 cells / mL, more than 900 cells / mL, more than 1000 cells / mL, more than 2000 cells / mL, more than 3000 cells / mL, more than 4000 cells / mL, or more than 5000 cells / mL.

[0136] In some embodiments, eligible patients according to the present invention may have the 2019 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for IgG4-RD with a score of ≧20. The ACR / EULAR scoring system was developed by an international multi-specialty group of 86 physicians assembled by the ACR and EULAR. The scoring system used consensus exercises, existing literature of 1,879 patients (1,086 cases, 793 mimickers), derivation, and validation cohorts, as well as multi-criteria decision analysis to identify, weight, and test potential classification criteria.

[0137] In some embodiments, eligible patients according to the present invention have a recent disease activity flare that requires treatment. In some embodiments, patients who experience a flare are administered corticosteroids, and then a protocol-specified taper continues on the day of randomization.

[0138] In some embodiments, eligible patients according to the present invention may have at least one organ involvement. In some embodiments, patients according to the present invention may have multiple organ involvements. In some embodiments, patients with a disease of only one organ system, whose main symptom is fibrosis (i.e., retroperitoneal fibrosis without aortic arteritis, Riedel's thyroiditis, fibrosing mediastinitis, associated with ulcerative colitis, etc.) are excluded. Treatment of IgG4-RD with obexelimab

[0139] There is no approved treatment for IgG4-RD, and the goal of treatment has been to prevent fibrosis and the inflammation that can lead to associated organ failure. Obexelimab (XmAb5871) is a humanized anti-CD19 monoclonal antibody with an Fc portion engineered to increase affinity for FcγRIIb, the only receptor on B cells.

[0140] In some embodiments, administration of obexelimab in a subcutaneous (SC) formulation minimizes the risk of acute administration-related reactions.

[0141] In some embodiments, obexelimab is administered subcutaneously as 2 × 1 ml injections at a concentration of 125 mg / ml at a dose of 250 mg per week. In some embodiments, obexelimab is administered subcutaneously as 1 × 2 ml injections at a concentration of 125 mg / ml at a dose of 250 mg per week. In some embodiments, obexelimab is administered subcutaneously at a dose of 200 mg per week. In some embodiments, obexelimab is administered subcutaneously at a dose of 150 mg per week. In some embodiments, obexelimab is administered subcutaneously at a dose of 100 mg per week. In some embodiments, obexelimab is administered as a single injection. In some embodiments, obexelimab is administered as more than 2 injections, for example, obexelimab is administered as 3 injections, or as 4 or more injections. In some embodiments, the concentration of obexelimab is 100 mg / ml. In some embodiments, the concentration of obexelimab is 50 mg / ml. In some embodiments, obexelimab is administered subcutaneously as 2 × 1 ml injections at a concentration of 100 mg / ml.

[0142] In one aspect, the present invention provides a method of treating an IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient over 18 years of age at a dose of 250 mg per week.

[0143] In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg twice a week. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg twice a week. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 125 mg every three days. In some embodiments, the method comprises subcutaneously administering obexelimab at a dose of 250 mg every seven days.

[0144] In some embodiments, obexelimab can be administered subcutaneously to human patients over 18 years old at a dose of 200 mg once a week. In some embodiments, obexelimab can be administered subcutaneously to human patients over 18 years old at a dose of 125 mg twice a week. In some embodiments, obexelimab is administered subcutaneously to human patients over 18 years old at a dose of 100 mg twice a week. In some embodiments, obexelimab is administered subcutaneously to human patients over 18 years old at a dose of 300 mg once a week. In some embodiments, obexelimab is administered subcutaneously to human patients over 18 years old at a dose of 150 mg twice a week.

[0145] In some embodiments, obexelimab is administered as a liquid formulation containing 125 mg / mL of obexelimab. In some embodiments, obexelimab is administered as two 1 mL injections. In some embodiments, obexelimab is administered as two 1 mL injections for a total dose of 250 mg. In some embodiments, the obexelimab injections are administered simultaneously. In some embodiments, the obexelimab injection solutions are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or 20 minutes of each other. In some embodiments, the obexelimab injection solutions are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours of each other.

[0146] In some embodiments, obexelimab is administered as a liquid formulation containing obexelimab at 125 mg / mL as 4 × 0.25 mL injections. In some embodiments, obexelimab is administered at a total dose of 250 mg in a liquid formulation containing obexelimab at 125 mg / mL as 4 × 0.25 mL injections. In some embodiments, the obexelimab injections are administered simultaneously. In some embodiments, the obexelimab injection solutions are administered within 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, or 20 minutes of each other. In some embodiments, the obexelimab injection solutions are administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours of each other.

[0147] In some embodiments, obexelimab is administered as a single injection in a liquid formulation. In some embodiments, obexelimab is administered as a single injection in a liquid formulation at a total dose of 250 mg.

[0148] In some embodiments, obexelimab is administered at a dose of about 100 - 500 mg per week. In some embodiments, obexelimab is administered at a dose of about 100 - 200 mg per week, 100 - 300 mg per week, 100 - 400 mg per week, 200 - 400 mg per week, 100 - 300 mg per week, 200 - 350 mg per week, 150 - 300 mg per week, 125 - 275 mg per week, 225 - 275 mg per week, 230 - 260 mg per week, 240 - 260 mg per week, or 245 - 255 mg per week. In some embodiments, obexelimab is administered at a dose of about 100 mg per week, 150 mg per week, 200 mg per week, 250 mg per week, 300 mg per week, 350 mg per week, 400 mg per week, 450 mg per week, or 500 mg per week.

[0149] In some embodiments, the weekly dose may be injected once throughout the week or divided into two or more injections. In some embodiments, the weekly dose is divided into two injections, three injections, four injections, five injections, six injections, or daily injections. In some embodiments, the weekly dose is divided equally. In some embodiments, the weekly dose is divided unequally. In some embodiments, the weekly dose is divided to be administered every other day, every two days, or every three days.

[0150] In some embodiments, a suitable dose ranges from 20 to 40 mg per day, 25 to 40 mg per day, or 30 to 40 mg per day. In some embodiments, a suitable dose is 35 mg per day.

[0151] In some embodiments, obexelimab is administered at a dose of 500 mg every two weeks. In some embodiments, obexelimab is administered every two weeks, and the dose may be injected once or divided into two or more injections. In some embodiments, the dose is divided into two injections, three injections, four injections, five injections, or six or more injections.

[0152] In some embodiments, the patient receives 1000 mg of obexelimab once a month. In some embodiments, the monthly dose of 1000 mg may be injected once or divided into four or more injections. In some embodiments, the dose is divided into four injections, five injections, six injections, seven injections, or eight or more injections. IgG4-RD flare

[0153] In some embodiments, an IgG4-RD flare is determined using IgG4-RD flare criteria. In some embodiments, the IgG4-RD flare criteria are objective organ-specific tools that detail the evaluations and findings necessary to support an organ-specific flare diagnosis based on patient-reported symptoms, physical examination, biopsy, imaging, and clinical laboratory findings. In some embodiments, the IgG4-RD flare criteria minimize subjectivity in the identification of disease flares by the treating investigator. In some embodiments, an IgG4-RD flare is evaluated using methods known in the art. In some embodiments, a flare is diagnosed by analyzing serum IgG4 values that can be normal in some patients with IgG4-RD. In some embodiments, the IgG4-RD flare criteria include the collection of data for flare evaluation as described below.

[0154] In some embodiments, the relapse-free period is evaluated compared to placebo or compared to before treatment initiation. In some embodiments, an increase in the relapse-free period is considered a positive outcome. As described above, the relapse-free period can be determined by the number of days until disease relapse occurs. Time to disease flare (TDF)

[0155] In some embodiments, the time to disease flare is a primary endpoint. In some embodiments, the time to the first IgG4-RD relapse requiring rescue therapy. In some embodiments, during a clinical trial, TDF is the relapse-free time from treatment initiation until the recurrence of previous signs / symptoms or the appearance of new signs / symptoms of IgG4-RD. For example, if a subject has a recurrence of an IgG4-RD flare 3 weeks after initiation of ocrelizumab treatment, the subject's TDF is 3 weeks. In some embodiments, TDF is measured up to week 52. In some embodiments, TDF is an evaluation for assessing the effect of weekly SC administration of ocrelizumab in reducing the risk of relapse in patients with active IgG4-RD. In some embodiments, TDF is significantly longer in patients administered ocrelizumab compared to patients administered placebo.

[0156] In some embodiments, the relapse-free period is one week. In some embodiments, the relapse-free period is one week. In some embodiments, the relapse-free period is two weeks. In some embodiments, the relapse-free period is three weeks. In some embodiments, the relapse-free period is four weeks. In some embodiments, the relapse-free period is one week. In some embodiments, the relapse-free period is one month. In some embodiments, the relapse-free period is one week. In some embodiments, the relapse-free period is two months. In some embodiments, the relapse-free period is three months. In some embodiments, the relapse-free period is four months. In some embodiments, the relapse-free period is five months. In some embodiments, the relapse-free period is six months. In some embodiments, the relapse-free period is seven months. In some embodiments, the relapse-free period is nine months. In some embodiments, the relapse-free period is ten months. In some embodiments, the relapse-free period is eleven months. In some embodiments, the relapse-free period is one year or more. Collection of data for flare assessment (flare criteria)

[0157] In some embodiments, administration of obexelimab results in a reduction in relapse of flare. Flare can be treated with GC, but steroids do not prevent relapse of the disease after discontinuation (Kamisawa 2017, Raina 2009). In some embodiments, IgG4-RD flare is evaluated at clinical visits. In some embodiments, when a patient exhibits recurrence of previous signs / symptoms of IgG4-RD or new signs / symptoms, physical examination, imaging, and / or biochemical parameters specific to the area of flare should be obtained. A comprehensive description of the evaluation and information is provided by the investigator in charge of the clinical trial in addition to testing of serum IgG4 levels. Examples of evaluation data include, but are not limited to, the following. · Earliest onset date of flare signs / symptoms · Organ-specific assessment of flare: o Symptoms reported by the patient o Physical examination findings o Clinical examination findings o Imaging findings o Biopsy findings o Intraoperative incidental findings · Decision of the principal investigator regarding whether a flare requiring rescue treatment has occurred · Treatment o Treatment initiation (Y / N) o Treatment start date o Treatment type · Glucocorticoid steroids · Immunosuppressants other than steroids · Surgical intervention including stent fixation o Treatment duration · Results of treatment compared to the pre-relapse baseline o Resolution without sequelae o Resolution by sequential analysis o Improved but still present o No change o Worsening after treatment · Narrative of the entire event, including description of current signs and symptoms and related past data Rescue treatment

[0158] In the case of a disease flare, the patient may be administered rescue therapy for acute treatment of the flare. The rescue therapy involves administration of GC therapy. In some embodiments, the rescue therapy includes administration of <8 weeks of obexelimab in combination with <40 mg / day of prednisone or equivalent at a dose of 250 mg every 7 days.

[0159] In some embodiments, the GC therapy is administered at a dose of 20 - 60 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of 10 - 100 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of about 1 - 70 mg / day, about 5 - 70 mg / day, about 10 - 70 mg / day, about 15 - 70 mg / day, about 20 - 70 mg / day, about 25 - 70 mg / day, about 30 - 70 mg / day, about 35 - 70 mg / day, about 40 - 70 mg / day of prednisone or a corresponding dose. In some embodiments, the GC therapy is administered at a dose of about 1 - 60 mg / day, about 5 - 60 mg / day, about 10 - 60 mg / day, about 15 - 60 mg / day, about 20 - 60 mg / day, about 25 - 60 mg / day, about 30 - 60 mg / day, about 35 - 60 mg / day, about 40 - 60 mg / day of prednisone or an equivalent dose.

[0160] In some embodiments, the GC therapy is administered at a dose of about 1 - 150 mg / day, about 5 - 150 mg / day, about 10 - 150 mg / day, about 15 - 150 mg / day, about 20 - 150 mg / day, about 25 - 150 mg / day, about 30 - 150 mg / day, about 35 - 150 mg / day, about 40 - 150 mg / day, about 45 - 150 mg / day, about 50 - 150 mg / day, about 55 - 150 mg / day, about 60 - 150 mg / day, about 65 - 150 mg / day, about 70 - 150 mg / day, about 75 - 150 mg / day, about 80 - 150 mg / day, about 90 - 150 mg / day, or about 100 - 150 mg / day of prednisone or an equivalent dose. In some embodiments, the GC therapy is administered at a dose of about 5 - 120 mg / day, about 5 - 110 mg / day, about 10 - 90 mg / day, about 15 - 100 mg / day, about 20 - 100 mg / day, about 25 - 100 mg / day, about 30 - 100 mg / day, about 35 - 100 mg / day, about 40 - 100 mg / day, about 45 - 100 mg / day, about 50 - 100 mg / day, about 55 - 100 mg / day, about 60 - 100 mg / day, about 65 - 100 mg / day, about 70 - 100 mg / day, about 75 - 100 mg / day, about 80 - 100 mg / day, or about 90 - 100 mg / day of prednisone or an equivalent dose.

[0161] In some embodiments, the GC therapy is administered at a prednisone or equivalent dosage of up to about 150 mg / day, up to about 120 mg / day, up to about 110 mg / day, up to about 100 mg / day, up to about 90 mg / day, up to about 80 mg / day, up to about 70 mg / day, up to about 60 mg / day, up to about 50 mg / day, up to about 40 mg / day, up to about 30 mg / day, up to about 20 mg / day, up to about 15 mg / day, up to about 10 mg / day, up to about 5 mg / day, or up to about 1 mg / day.

[0162] In some embodiments, the GC therapy is administered at a prednisone or equivalent dosage of 0.1 - 1 mg / kg / day, 0.1 - 0.8 mg / kg / day, 0.1 - 0.7 mg / kg / day, 0.1 - 0.6 mg / kg / day, 0.1 - 0.5 mg / kg / day, 0.1 - 0.4 mg / kg / day, 0.1 - 0.3 mg / kg / day, 0.1 - 0.2 mg / kg / day, or 0.05 - 0.1 mg / kg / day.

[0163] In some embodiments, the GC therapy is administered at a maximum of 1 mg / kg / day of prednisone or an equivalent dosage. In some embodiments, the GC therapy is administered at a dosage of up to 0.9 mg / kg / day, up to 0.8 mg / kg / day, up to 0.7 mg / kg / day, up to 0.6 mg / kg / day, up to 0.5 mg / kg / day, up to 0.4 mg / kg / day, up to 0.3 mg / kg / day, up to 0.2 mg / kg / day, or up to 0.1 mg / kg / day of prednisone or an equivalent.

[0164] In some embodiments, the prednisone equivalent dosage is determined as shown in Table 3.

[0165] In some embodiments, the GC therapy is administered with a high dosage of prednisone or an equivalent. In some embodiments, the patient has been administered a high dosage of GC therapy and is less likely to respond to any treatment therapy. In some embodiments, the patient has not responded to previous therapies prior to administration of an anti - CD19 antibody (e.g., obexelimab).

[0166] In some embodiments, GC therapy is continued during treatment with obexelimab. In some embodiments, GC therapy is tapered during treatment with obexelimab. In some embodiments, GC therapy is tapered prior to treatment with obexelimab. In some embodiments, GC therapy is tapered to complete discontinuation. In some embodiments, obexelimab is administered in combination with GC therapy. IgG4-RD responder index

[0167] The IgG4-RD responder index (RI) was developed to assist the treating physician in evaluating the effectiveness of treatment in a structured manner. In some embodiments, effectiveness is measured using the IgG4-RD RI. The IgG4-RD RI is a tool designed to detect changes in disease activity and to discriminate improvement and worsening in the same or different organ systems compared to placebo or compared to the start of treatment. Validation of the index was performed by 26 physician-hospitals including representatives from six specialties and nine countries (Carruthers 2012, Wallace 2018). The IgG4-RD RI uses a scoring system for each organ system or site and asks the clinician to assess the degree of disease activity and damage at clinical examination. The original IgG4-RD RI excluded serum IgG4 concentration as part of the tool, scored improvement or worsening from baseline, excluded lymph node involvement, and was modified to include an assessment of damage caused by IgG4-RD in each affected organ (Carruthers 2012). The total IgG4-RD RI activity score includes the sum of the numerical values in the active columns.

[0168] In some embodiments, the physician scores each organ system on a scale of 0 - 3 based on the past 28 days. Emergency organ involvement (i.e., requiring emergency treatment) receives, in some embodiments, double the score. Organs may be selected from, but are not limited to, lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, heart, pericardium, orbits, nasal cavities, lungs, bile ducts, salivary glands, and pancreas. In some embodiments, the organ or organ site is selected from pachymeninx, pituitary gland, orbits and lacrimal glands, salivary glands, thyroid gland, lymph nodes, lungs, aorta and large blood vessels, retroperitoneum, mediastinum, and mesentery, pancreas, bile ducts and liver, kidneys, skin, and other sclerosis / mass formations. In some embodiments, the organ or organ site is selected from pachymeninx, pituitary, orbits, lacrimal glands, salivary glands, lymph nodes, lungs, aorta, retroperitoneum, pancreas, bile ducts, liver, kidneys, and skin.

[0169] In each subsequent evaluation, the physician enters a score of 0 - 3 for the listed organs / sites using the following after the listed organ / site. 0 = Normal or resolved 1 = Improved but still present since previous evaluation or improved from initial evaluation No change from previous evaluation 2 = Disease activity has not changed from previous evaluation When an organ or site improves or worsens, a score of 2 is no longer used for that organ / site, i.e., an improved organ / system maintains a score of 1 until disappearance (score 0) or worsening (score 3). In some embodiments, a change from a previous evaluation does not refer to disease symptoms that require follow-up imaging to accurately assess. That is, it is assumed that disease symptoms that are only evaluable by imaging do not change until imaging indicates improvement, worsening, or disappearance. 3 = Worsening since the last evaluation or new disease manifestation and requirement for additional therapy (treatment intent).

[0170] The compiled score provides a snapshot of the disease activity at that point compared to the previous visit. The percentage of patients who achieved complete remission by week 52, defined as an IgG4-RD RI score of 0. In some embodiments, the patient achieves complete remission after administration of obexelimab. In some embodiments, complete remission is defined as an IgG4-RD RI score of 0, no AC-determined flare, and no treatment of flare by week 52.

[0171] In some embodiments, the patient achieves complete remission after administration of obexelimab, and complete remission includes an IgG4-RD RI score of 0. In some embodiments, the patient achieves complete remission after administration of obexelimab, and complete remission includes an IgG4-RD RI score of 0, no AC-determined flare, and no treatment of flare. In some embodiments, the patient achieves complete remission after administration of obexelimab, and complete remission includes an IgG4-RD RI score of 0 and no treatment of flare.

[0172] In some embodiments, IgG4-RD RI includes the serum IgG4 concentration of the subject. In some embodiments, IgG4-RD RI does not include the serum IgG4 concentration of the subject.

[0173] In one aspect, the present invention provides a method of treating IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient at a dose of 250 mg once a week. In some embodiments, the method further comprises determining IgG4-RD RI. In some embodiments, IgG4-RD RI is determined before treatment with obexelimab (e.g., baseline). In some embodiments, IgG4-RD RI is determined after administration of obexelimab. In some embodiments, IgG4-RD RI is maintained relative to baseline. In some embodiments, IgG4-RD RI is reduced compared to baseline, and baseline is the IgG4-RD RI score before the start of treatment.

[0174] In some embodiments, obexelimab is administered to a subject to improve or prevent worsening of the signs or symptoms of IgG4-RD. In some embodiments, improvement or prevention of worsening of the signs or symptoms of IgG4-RD is measured using IgG4-RD RI.

[0175] In some embodiments, the IgG4-RD-RI score ranges from 0 to 30. In some embodiments, the IgG4-RD-RI score ranges from 0 to 5. In some embodiments, the IgG4-RD-RI score ranges from 0 to 10. In some embodiments, the IgG4-RD-RI score ranges from 0 to 15. In some embodiments, the IgG4-RD-RI score ranges from 0 to 20. In some embodiments, the IgG4-RD-RI score ranges from 0 to 25.

[0176] In some embodiments, the IgG4-RD-RI score decreases by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 28 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by 1-5, 2-5, 3-5, 4-5 compared to the baseline.

[0177] In some embodiments, the IgG4-RD-RI score decreases by at least 1 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 3 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 4 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 5 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 6 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 7 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 8 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 9 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 10 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 11 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 12 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 13 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 14 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 15 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 16 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 17 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 18 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 19 compared to the baseline. In some embodiments, the IgG4-RD-RI score decreases by at least 20 compared to the baseline.In some embodiments, the IgG4-RD-RI score is reduced to 0.

[0178] In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 1 week after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 2 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 3 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 4 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 5 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 6 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 7 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 8 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 9 weeks after administration of obexelimab. In some embodiments, the IgG4-RD-RI score decreases by at least 2 compared to baseline within 10 weeks after administration of obexelimab.

[0179] In some embodiments, the patient achieves complete remission by 25 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by 26 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by week 27 after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by 28 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by week 29 after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by week 30 after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by 40 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by 45 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. In some embodiments, the patient achieves complete remission by 50 weeks after obexelimab administration, where complete remission includes an IgG4-RD RI score of 0 and does not include treatment of flares. Glucocorticoid Toxicity Index (GTI)

[0180] The GTI is a physician-reported measure of toxicity related to GC use. It is a weighted outcome measure that scores the temporal changes in steroid toxicity. The index is a measure of the change in corticosteroid toxicity over time and uses 31 items to address nine domains (body mass index [BMI], glucose tolerance, blood pressure, lipids, bone density, steroid myopathy, skin toxicity, neuropsychiatric toxicity, and infection). The GTI was developed using multicriteria decision analysis by a group of 19 experts in corticosteroid use and is intended to provide a reliable measure of the steroid-sparing ability of new therapeutics (Stone 2022). The GTI has been used as an important efficacy assessment item in other clinical trials (Jayne 2021, McDowell 2021). The GTI is described in Stone JH, et al. Semin Arthritis Rheum. 2022 Aug;55:152010. PMID: 35486995, which is hereby incorporated by reference in its entirety.

[0181] In one aspect, the invention provides a method of treating IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient once a week at a dose of 250 mg. In a plurality of embodiments, the subcutaneous administration of obexelimab achieves a change in glucocorticoid-related toxicity as measured by the GTI score.

[0182] In some embodiments, a method of treating IgG4-related disease (IgG4-RD) comprises determining toxicity associated with the use of corticosteroids. In some embodiments, the toxicity associated with the use of corticosteroids is determined prior to administration of obexelimab. In some embodiments, the toxicity associated with the use of corticosteroids is determined after administration of obexelimab. In some embodiments, the toxicity associated with the use of corticosteroids is reduced after administration of obexelimab.

[0183] In some embodiments, the toxicity associated with the use of corticosteroids is determined using the GTI. In some embodiments, the GTI score has a range of 346 to +439. In some embodiments, the GTI score indicates a worsened change in GTI corresponding to ≧10 points, ≧20 points, and ≧30 points. In some embodiments, the GTI score is reduced after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 10 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 15 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 20 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 25 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 30 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 35 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 40 after administration of obexelimab. In some embodiments, the GTI score is reduced by at least 45 after administration of obexelimab. GTI score factor

[0184] In some embodiments, the GTI score is measured by a change in BMI of at least -5 BMI units or more than about 5 BMI units. In some embodiments, the GTI score is measured by a change in glucose metabolism due to an improvement in HbA1c and / or a decrease in medications or an increase in HbA1c and / or an increase in medications. In some embodiments, the GTI score is measured by a change in blood pressure due to an improvement in blood pressure and / or a decrease in medications or an increase in blood pressure and / or an increase in medications. In some embodiments, the GTI score is measured by a change in hyperlipidemia measured by a decrease in LDL and / or a decrease in medications, or an increase in hyperlipidemia measured by a decrease in LDL and / or an increase in medications. In some embodiments, the GTI score is measured by a change in steroid myopathy measured by no frailty to moderate frailty, with or without functional limitations, or no frailty to moderate frailty with or without functional limitations. In some embodiments, the GTI score is measured by skin steroid-related toxicity measured by a decrease or increase in skin steroid toxicity. In some embodiments, the GTI score is measured by neuropsychiatric (NP)-steroid-related symptoms measured by a decrease or increase in NP toxicity. In some embodiments, the GTI score is measured by an infection measured by oral and / or vaginal candidiasis and / or other grade 3, 4, or 5 infections.

[0185] The GTI is measured at baseline and then every 3 or 6 months, a period known as the GTI interval. The GTI is scored by comparing the domain value at the start of each GTI interval to the score at the end of each GTI interval. Both the CWS and AIS are calculated for each GTI interval and then the interval scores are summed.

Example

[0186] Example Example 1: Patient Selection and Selection Criteria This example describes the selection of patients with active IgG4-RD for treatment with a CD19 antibody. In a Phase II open-label single-group clinical trial (XmAb5871-03) of 20 patients with active IgG4-RD, obexelimab demonstrated a strong and rapid improvement in disease activity. This study included a maximum 4-week screening period, followed by 12 administrations (24 weeks) every 14 days, and a 6-week follow-up. Fourteen out of 15 patients (93%) treated with obexelimab 5 mg / kg IV Q14D achieved a decrease of ≧2 in the IgG4-RD responder index (RI) at some point during the trial, and all 14 patients showed a decrease of 5 points or more. In particular, one patient had a baseline IgG4-RD RI score of 2 but had a 50% decrease in the RI score (RI = 1) by the end of the trial.

[0187] In summary, the role of CD19+ B cells in the etiology of IgG4-RD, the effect of B cell depletion observed in previous studies in IgG4-RD (Khosroshahi 2010), and the strong efficacy and safety observed in the Phase 2 IgG4-RD study using obexelimab provide strong rationales for the continued development of obexelimab in a pivotal, double-blind, randomized study in IgG4-RD.

[0188] This trial consists of a screening period (-28 days to -1 day) and a 52-week randomized control period (RCP), during which obexelimab or placebo is administered as an SC injection every 7 days (52 doses), followed by an open-label extension period. Eligible patients must meet the 2019 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria for IgG4-RD and have active IgG4-RD signs / symptoms (i.e., flares) that require initiation of glucocorticoid (GC) therapy or an increase in background long-term GC therapy. The primary endpoint is the time to flare of IgG4-RD (TDF). The time to flare of IgG4-RD (TDF) is the reappearance of previous signs / symptoms or the appearance of new signs / symptoms of IgG4-RD from randomization to week 52.

[0189] All patients receive GC therapy for ≥ 3 weeks and up to 6 weeks, at a dose of prednisone equivalent of 20 - 60 mg / day, prior to randomization. The required GC therapy is either newly initiated or an increase in long-term GC therapy (i.e., the patient has received a dose of ≤ 10 mg / day prednisone equivalent in the past). During the screening period, the exact dose and tapering schedule prior to randomization are at the discretion of the investigator responsible for the clinical trial, preferably over 0 - 8 weeks. On the day of randomization, the patient must be at a dose of 20 mg / day prednisone equivalent and must initiate tapering to discontinuation as specified in the protocol by week 8.

[0190] On the first visit, eligible patients are stratified based on the number of affected organs (≥ 1) and whether the disease is newly diagnosed or recurrent, as the risk of recurrence is likely to differ between them. Patients are randomized 1:1 and administered obexelimab or placebo, and the first SC administration of obexelimab / placebo is administered at the clinical trial site. Table 2 shows the dose and formulation of obexelimab. All patients are observed for at least 2 hours, during which a safety assessment is performed. Patients are evaluated weekly for disease activity and AEs. Placebo

[0191] A placebo containing no active substance is also supplied as a solution for SC injection. The placebo formulation is sodium acetate trihydrate at 2.35 mg / mL, acetic acid (density 1.053 g / mL) at 0.17 mg / mL, L-proline at 30 mg / mL, polysorbate 80 at 0.1 mg / mL, and Dextran-40 at 115 mg / mL at pH 5.5.

[0192] The SC formulation of placebo is a sterile liquid product supplied in single-use glass vials. Each 2-mL glass vial is filled with 1.2 mL of placebo. The single-use glass vials are masked so as to be indistinguishable from obexelimab. Table 6 shows the dosing regimen and formulation of obexelimab.

Table 6-1

[0193] During the randomization control period (RCP), patients will undergo evaluations of efficacy, safety, PK, pharmacodynamics (PD), and immunogenicity at the study visits as defined in the schedule of assessments (SoA). Adverse events (AE), serious adverse events (SAE), and treatment-emergent adverse events (TEAE), or clinically significant safety laboratory abnormalities will be evaluated. Selection Criteria

[0194] Patients are eligible to participate in the study only if all of the following criteria apply. 1. Males and females 18 years of age or older at the time of signing the informed consent 2. Patients must meet the 2019 ACR / EULAR classification criteria for IgG4-RD with a score of 20 or more 3. Patients must have active IgG4-RD signs / symptoms (i.e., flare) that require initiation of GC therapy or an increase in background long-term GC therapy (if previously administered at a stable dose ≤ 10 mg / day prednisone equivalent), as evaluated by the study physician. 4. The total duration of GC treatment prior to randomization must be ≥ 3 weeks and a maximum of 6 weeks at a dose of 20 - 60 mg / day. 5. Female patients are not pregnant (see Appendix 4), not lactating, and are eligible to participate if at least one of the following conditions applies. a. Are not women of childbearing potential (WOCBP) Or b. WOCBP who agree to follow contraceptive guidance after the last dose of the study drug 6. Male patients must do the following. a. Agree to (i) abstain from sexual intercourse, or (ii) use contraception for at least 1 month after the last dose of IP (i.e., approximately 5 half-lives), or (iii) be surgically sterile during the study period, and b. During this period, agree to refrain from sperm donation for at least 1 month after the final administration of IP (i.e., approximately 5 half-lives). 7. The WOCBP must have a negative serum pregnancy test at screening and a negative urine test before the first dose of the investigational product and at all time points specified in the SoA. Exclusion Criteria

[0195] Patients will be excluded from this study if any of the following criteria apply. 1. Exclusion criteria described in the ACR / EULAR IgG4-RD classification criteria 2. Patients with a disease affecting only one organ system with fibrosis as the primary symptom (i.e., retroperitoneal fibrosis without aortic arteritis, Riedel's thyroiditis, fibrosing mediastinitis, associated with ankylosing enteritis, etc.) 3. Oral administration of prednisone equivalent at a dose exceeding 60 mg / day within 4 weeks before screening or during screening. 4. Unable to tolerate 20 mg / day on Day 1. 5. Unable to taper off GC therapy by 8 weeks after randomization. 6. Use of B cell depletion, B cell targeting, or other biological immunomodulatory agents within 6 months before randomization. Patients who received B cell-targeted therapy within 6 - 12 months before randomization must have B cell counts within the range of clinical laboratory criteria at screening measured by the Central Laboratory. 7. Receiving non-biological, disease-modifying anti-rheumatic drugs or immunosuppressants other than GC within 4 weeks before screening 8. Receiving investigational product or direct medical intervention in another clinical trial within 12 weeks before screening or within the shorter of <5 half-lives of the investigational drug. 9. Receiving live vaccines or live therapeutic infectious agents within 2 weeks before screening. 10. Acute hepatitis B infection (hepatitis B surface antigen positive), active hepatitis C virus, or HIV infection. A positive test for hepatitis B is the detection of either (a) hepatitis B surface antigen or (b) hepatitis B core antibody, or in Japan, (c) the detection of only hepatitis B surface antibody. 11. Evidence of active tuberculosis (TB) or high risk of TB based on the following: a. History of active TB or latent TB, except if completion of treatment according to local guidelines is documented. b. Positive interferon gamma release assay results at screening, unless treatment is documented. c. Signs of symptoms that may represent active TB. d. Chest radiograph, computed tomography (CT), or magnetic resonance imaging (MRI) that suggests the possibility of a TB diagnosis. 12. History or evidence of clinically unstable / uncontrolled disorders, conditions, or diseases other than IgG4-RD (including but not limited to cardiopulmonary, oncology, renal, hepatic, metabolic, hematologic, psychiatric, active infections) that, in the opinion of the responsible investigator, pose a risk to the patient's safety or interfere with the conduct, evaluation, treatment, or completion of the trial. 13. Malignancy within 5 years (excluding successfully treated carcinoma in situ of the cervix, excised squamous or basal cell carcinoma of the skin, breast cancer that does not recur ≥5 years after treatment, or prostate cancer that does not recur ≥3 years after prostatectomy) 14. Any known allergy to monoclonal antibody therapy. 15. Hematologic or clinical chemistry parameters that meet any of the following criteria at screening: a. White blood cell count < 2.5×10 3 / μL b. Absolute neutrophil count < 1.0×10 3 / μL c. Serum creatinine > 2.5× upper limit of normal (ULN) or elevated estimated creatinine clearance < 40 mL / min, calculated by the Cockcroft-Gault formula at screening d. Hemoglobin < 10 g / dL e. Platelet count < 75 × 10 3 / μL 16. Abnormal liver function tests that meet any of the following criteria: a. In the absence of hepatobiliary tract activity: i. Alanine aminotransferase (ALT) > 2 × ULN ii. Aspartate aminotransferase (AST) > 2 × ULN iii. Total bilirubin > 2 × ULN b. In the presence of hepatobiliary duct activity: i. ALT > 10 × ULN ii. AST > 10 × ULN iii. Total bilirubin > 5 × ULN

[0196] Patients administered obexelimab experience a significant reduction in flare occurrence compared to patients administered placebo. Example 2: Previous glucocorticoid therapy

[0197] Prior to randomization, all patients receive GC therapy for ≥ 3 weeks and up to 6 weeks at a dose of prednisone equivalent of 20 - 60 mg / day (Table 3). The GC therapy can be either newly initiated or an increase in long - term GC therapy (e.g., an increase from a previously stable dose of ≤ 10 mg / day prednisone equivalent).

Table 3

[0198] The exact dose and schedule prior to randomization may include a tapering schedule as needed, at the discretion of the principal investigator of the clinical trial. However, patients must be at a dose of prednisone equivalent to 20 mg / day on the day of randomization and receive that dose of GC therapy on day 1. Patients are tapered to discontinuation over 8 weeks with dose reductions of 5 mg equivalents every 2 weeks (Table 4).

Table 4

[0199] The primary efficacy evaluation item (primary analysis) is the time to IgG4-RD relapse (TDF), which is the recurrence of past signs / symptoms or the appearance of new signs / symptoms of IgG4-RD from randomization until week 52 that requires the initiation of rescue therapy. The proportion of patients who achieve complete remission by week 52 is IgG4-RD RI score 0, without relapse and without treatment for relapse by week 52.

[0200] The date of IgG4-RD relapse is defined as the start date of any relapse treatment (new GC treatment, other immunotherapy, or interventional procedure) considered necessary for disease relapse. A hazard ratio of 0.37 is used as the threshold for trial success. A hazard ratio of 0.37 corresponds to 35% of patients predicted to have disease relapse by week 52 in the placebo group (and 30 such patients are required), and 15% of patients predicted to have disease relapse by week 52 in the obexelimab group (13 such patients are required).

[0201] The extended Kaplan-Meier (K-M) estimator (Aalen and Johansen 1978) and log-rank test (Gray 1988) are used to compare the treatment intent of obexelimab and placebo over the entire observed follow-up period. The extension is adapted for adjustment by strata and competing risks (if necessary), with strata being 1 organ vs >1 organ, and the newly diagnosed risk vs recurrence risk and competing risks being the four possible types. 1. Perhaps death due in part to IgG4-RD, 2. Dropout due to lack of recognition of efficacy, and 3. Dropout due to side effects or intolerance of the investigational drug 4. By the adjudication committee (AC) not agreeing to the initiation of rescue therapy by the trial responsible physician.

[0202] The estimation of the recurrence rate is limited to less than 100% in the presence of competing risks. Therefore, the competing risks need to reflect alternative and realistic scenarios that occur before detecting recurrence, and are also expected to be infrequent. Among the possible causes of competing risks, related deaths and dropouts due to lack of efficacy, two of them, are very unlikely to occur before the identification of IgG4-RD recurrence. However, if data for identifying rescue treatment for recurrence are lacking, they may occur before recurrence. In the actual clinical situation, such events may occur before the identification of flares due to lower patient monitoring than during clinical trials.

[0203] When competing risk events occur frequently, or when dates requiring interval cutoffs are frequently missing, use tipping point analysis to explore the robustness of the analysis. For example, if the primary result is statistically significant, explore the conditions under which the result may become non-significant. For interval cutoffs (the date of rescue treatment at recurrence is unknown, but there is a minimum date and a maximum date), it is necessary to place different numbers of results at the minimum date of the obexelimab group and the maximum date of the placebo group. For competing risks, this will involve reassigning different numbers of such events to recurrence events for the obexelimab group and appropriate cutoffs for the placebo group.

[0204] In addition to the primary analysis, perform a sensitivity analysis using a proportional hazards model to evaluate the treatment effect adjusted for influential prognostic factors and baseline covariates. The model uses time to disease recurrence (TDF) as the response variable and treatment group, stratifying factors, subgroup variables, and continuous variables (e.g., age) as covariates. Table 5 summarizes the secondary evaluation items.

Table 5

[0205] This example describes an example of PK / PD analysis of subcutaneously (SC) administered obexelimab. Simulation experiments demonstrated that 250 mg of obexelimab administered SC every 7 days achieved maximal suppression of absolute B cell counts at approximately 50% of baseline and 100% receptor occupancy of CD19 throughout the dosing interval. PK and PD simulations of 250 mg SC every 7 days supported a sufficient safety margin (lower maximum [Cmax] and area under the curve [AUC]) while maintaining a higher trough concentration for target engagement compared to PK from previous studies of intravenous (IV) administration. The mean steady-state Cmax and AUC (normalized over 336 hours) of 250 mg SC every 7 days were 11-fold and 2.5-fold lower, respectively, compared to 10 mg / kg IV every 14 days. All mAb therapeutics administered by the intravenous route are associated with the risk of both non-allergic (cytokine release syndrome) and allergic (anaphylaxis) infusion-related reactions.

[0206] However, the mean steady-state trough concentration of 250 mg SC every 7 days was 4.6-fold higher, which is likely to provide better maintenance of target engagement and maximal PD effect. This data suggests that treatment with obexelimab in IgG4-RD results in a reduction in the risk and frequency of disease relapse. Example 5: Validation of PK / PD simulation model for dosing of obexelimab in patients with immunoglobulin G4-related disease (IgG4-RD)

[0207] This example shows the validation of a suitable obexelimab dose for treating patients with immunoglobulin G4-related disease (IgG4-RD) using PK / PD.

[0208] A population PK / PD model describing the exposure-response (E-R) relationships of obexelimab plasma PK, plasma obexelimab concentration, and absolute B cell (ABC) count or CD19 receptor occupancy (RO) after single and multiple intravenous (IV) or subcutaneous (SC) administrations to healthy subjects and patients with RA or IgG4-RD was established based on four studies (two Phase I trials and two Phase 2 trials). The PK model was a two-compartment model with first-order absorption and first-order elimination for SC administration. The PK model included two covariates: dose and disease state. · The dose was included as a multiplicative covariate in the PK model used to describe the non-linear PK of obexelimab observed at low doses. max · The disease state was included as a covariate for the obexelimab removal rate from the central compartment. The final ABC count PK / PD model was an indirect response model.

[0209] The increase in the ABC disappearance rate (K out ) due to obexelimab was described by a sigmoid E max function. The CD19 RO PK / PD model was a direct response model with a sigmoid E max function. Table 6 lists the parameters estimated for the PK, ABC PK / PD, and CD19 RO PK / PD models.

Table 6-2

[0210] ​Using a population PK / PD model, the PK exposure values of obexelimab and the changes in ABC count and CD19 RO were simulated after various SC dose administrations. Table 7 lists the predicted minimum plasma obexelimab concentration (Cmin), maximum plasma obexelimab concentration (Cmax), mean plasma obexelimab concentration (Cavg), and the 10th, 25th, 50th, 75th, and 90th percentiles of the area under the plasma concentration-time curve (AUC) at week 1 and steady state after various QW SC dose administrations. Figures 1-3 show the plasma obexelimab concentration-time profiles, ABC relative to baseline, and the time-course changes in CD19 RO.

[0211] Plasma obexelimab C max,ss Based on the simulated 90th percentile of plasma obexelimab C, 90% of subjects receiving 250 mg of obexelimab QW had plasma obexelimab concentrations less than 39,265 ng / mL, which is 6.9-fold less than the mean Cmax (272,832 ng / mL) observed from the XmAb5871-02 trial at 10 mg / kg IV.

[0212] Plasma obexelimab C min,ss Based on the simulated 10th percentile of plasma obexelimab C, 90% of subjects receiving 250 mg of obexelimab QW had plasma obexelimab concentrations greater than 8376 ng / mL (Figure 1), which is at least 85.0-fold greater than the EC50 and 9.44-fold greater than the EC90 value of the ABC count. The decrease in ABC count due to plasma obexelimab exposure was rapid and achieved a maximum decrease of approximately 50% of the baseline ABC count value. The magnitude of the effect of obexelimab on ABC count was similar at 15.625, 31.25, 62.5, 125, and 250 mg of SC QW administered during the dosing interval, while the recovery period after dosing cessation was different. When dosing with 250 mg of obexelimab QW weekly was discontinued, it took approximately 10 weeks for the ABC count to return to the baseline level (Figure 2).

[0213] Plasma obexelimab C min,ssBased on the simulated 10th percentile, 90% of the subjects receiving 250 mg of obexelimab QW had plasma obexelimab concentrations greater than 8376 ng / mL (Figure 1), which is at least 112-fold greater than the EC50 and 37.1-fold greater than the EC90 value of CD19 RO. The increase in CD19 RO due to plasma obexelimab exposure was rapid, achieving approximately 100% RO. The magnitude of the effect of obexelimab on CD19 RO was similar at 15.625, 31.25, 62.5, 125, and 250 mg administered SC QW during the dosing interval, but the recovery times to baseline after dosing cessation were different. After cessation of weekly dosing of 250 mg of obexelimab, it took approximately 8 weeks for CD19 RO to return to baseline levels (Figure 3).

Table 7

[0214] From PK / PD simulations, higher C min and equivalent AUCs were observed to be achieved (see Table 8). Furthermore, compared to 250 mg SC Q2W, the weekly 250 mg SC dose could provide higher AUC and C max One the other hand, a sufficient safety margin was maintained based on data from both clinical and non-clinical trials.

Table 8

[0215] The subcutaneous (SC) dose achieved better PK exposure than that observed with 250 mg SC Q2W while maintaining a sufficient safety margin (see Table 8).

Claims

1. A composition for treating IgG4-related disease (IgG4-RD), comprising obexerimab, characterized in that the composition is administered subcutaneously to a human patient at a dose of 250 mg once a week.

2. The composition according to claim 1, wherein the obexerimab is administered as a 2 × 1 mL injection or a 1 × 2 mL injection.

3. The composition according to claim 1, wherein the obexerimab is a liquid formulation containing 125 mg / mL of obexerimab, 2.35 mg / mL of sodium acetate trihydrate, 0.17 mg / mL of acetic acid, 30 mg / mL of L-proline, and 0.1 mg / mL of polysorbate 80 at pH 5.

5.

4. The composition according to claim 1, wherein the human patient is receiving glucocorticoid (GC) therapy.

5. The composition according to claim 4, characterized in that the GC therapy is administered at a dose of 20 to 60 mg / day of prednisone or an equivalent dose.

6. The composition according to claim 4 or 5, wherein the GC therapy is gradually reduced.

7. The composition according to claim 1, characterized in that the composition is administered in combination with GC therapy.

8. The composition according to claim 1, wherein the treatment results in improvement, stabilization, or reduction of one or more symptoms of IgG4-RD compared to a control.

9. The composition according to claim 8, wherein at least one of the symptoms is observed in an organ selected from the lymph nodes, submandibular gland, parotid gland, lacrimal gland, kidney, heart, pericardium, orbit, nasal cavity, lung, liver or bile duct, salivary gland, and pancreas.

10. The composition according to claim 1, characterized in that the composition is administered to the human patient during the relapse-free period in order to prevent recurrence.

11. The composition according to claim 10, wherein the recurrence-free period is determined by the number of days until disease recurrence.

12. The composition according to claim 11, wherein the recurrence-free period is at least 60, 70, 80, or 90 days from the first dose of the composition, or the recurrence-free period is up to 40 weeks, up to 45 weeks, up to 50 weeks, or up to 52 weeks from the first dose of the composition.

13. The composition according to claim 1, characterized in that the composition is administered to the patient until the patient has an active IgG4-RD disease relapse that requires the initiation of rescue treatment.

14. The composition according to claim 13, wherein the rescue therapy includes the administration of GC therapy.

15. The composition according to claim 1, wherein the human patient is relapsed or refractory to prior treatment for IgG4-RD.

16. The composition according to claim 15, wherein the human patient is relapsed or refractory to rituximab.

17. The composition according to claim 1, wherein the human patient achieves a decrease of 2 points or more in IgG4-RD RI from the first day of administration of the composition.

18. The composition according to claim 1, wherein the human patient has an IgG4-RD score of 20 or more (IgG4-RD score) according to the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria prior to administration of the composition.

19. The aforementioned human patients have IgG4-related sialadenitis (chronic ankylosing sialadenitis, Kuttner tumor, Mikulicz disease), IgG4-related dacryodenitis (Mikulicz disease), IgG4-related eye diseases (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic sinusitis, IgG4-related hypophysitis (IgG4-related panhypopititis, IgG4-related hypoglandular dysfunction, IgG4-related inhibitorone uremic disease, autoimmune hypothesis), IgG4-related cilia, IgG4-related molluscum meningitis (idiopathic hypertrophic ciliamyelitis), IgG4-related pancreatitis (type 1 autoimmune pancreatitis, IgG4-related AIP, lymphoplasmacytic sclerosing pancreatitis, chronic pancreatitis with diffuse irregular stenosis of the main pancreatic duct), and IgG4-related lung disease. Patient (inflammatory pseudotumor of the lung), IgG4-related pleuritis, IgG4-related liver injury, IgG4-related ankylosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortitis), IgG4-related peritonitis (chronic peritonitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrous mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis, Albaran-Almond syndrome, Ormond disease (retroperitoneal fibrosis), peripheral fasciitis, Gerota's fasciitis / syndrome, fibrous periteritis, ankylosing lipogranuloma, ankylosing retroperitoneal granuloma, nonspecific retroperitonitis, ankylosing retroperitonitis, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related enteritis (subtype:Mesenteric pancreatitis, mesenteric lipodystrophy and retrograde mesenteritis (ankylosing mesenteritis, systemic nodular pancreatitis, enteritis-induced liposclerosis, enteric-coated Weber-Christian disease, mesenteric lipogranuloma, xenogranulomatous colitis), IgG4-related mastitis (ankylosing mastitis), IgG4-related kidney disease (IgG4-RKD), IgG4-related tubulointerstitial nephritis (IgG4-TIN), IgG4-related membranous glomerulonephritis ( Idiopathic tubulointerstitial nephritis, IgG4-related prostatitis, IgG4-related periileal fibrosis (chronic oral pain), IgG4-related vesicular pseudotumor, IgG4-related epididymitis (intestinal fibrous pseudotumor, inflammatory pseudotumor of the sperm umbilical cord, pseudosarcomatoid myofibroblast proliferation of the sperm umbilical cord, proliferative fungal infection, chronic proliferative perioral inflammation, fibromatous perioral inflammation, nodular perioral inflammation, reactive perioral inflammation, fibrous mesothelioma), IgG4-related lymphadenopathy, The composition according to claim 1, wherein the human patient exhibits IgG4-RD symptoms selected from the group consisting of IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineurial diseases, and IgG4-related thyroid diseases (Reidel's thyroiditis), inflammatory pseudoneoplasms, and multifocal fibrosclerosis, or the human patient exhibits IgG4-RD symptoms selected from the group consisting of autoimmune pancreatitis (lymphoplasmacytic antislipid pancreatitis), eosinophilic angiocentral fibrosis (affecting the orbit and upper respiratory tract), fibrous mediastinitis, idiopathic hypertrophic ciliopilitis, idiopathic tubulointerstitial nephritis, inflammatory pseudoneoplasms, Kuttner tumor, Mikulicz disease, fibrous arteriosclerosis, peridotitis, periarteritis, inflammatory aortic multifocal surgery, Ormond's disease (Tetroperitoneal fibrosis), Reidel's thyroiditis, and ankylosing colitis.

20. The composition according to claim 1, wherein the human patient is at least 18 years old.

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