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.

Description

Background Art

[0001] IgG4-related disease (IgG4-RD) is a serious, rare, chronic fibro-inflammatory condition that often affects multiple organs, leading to significant organ dysfunction and failure, and even death if the condition is not recognized and treated in time. The disease often affects major organs such as the pancreas, liver, kidneys, lungs, and eyes; pancreatic-hepatobiliary disease is present in about half of cases (Wallace et al., 2019). Patients may present with single organ involvement, but more often with multiple organ involvement. As the disease progresses and patients experience new or worsening signs / symptoms (attacks), additional organs become diseased, and the cellular inflammation that characterizes early disease moves toward a more fibrotic stage, leading to significant tissue damage and ultimately to organ failure (Perugino 2016). For example, cholangitis caused by IgG4-RD may lead to liver failure, IgG4-related (type 1) autoimmune pancreatitis may lead to failure of either or both of the endocrine and exocrine pancreas, and IgG4-related aortitis may lead to aneurysms and / or aortic dissection. Current therapies used for 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 the use of CD19 antibodies (e.g., obexelimab) to improve the treatment of human patients with active (persistent onset) IgG4-RD and to prevent the recurrence (recurrence) of IgG4-RD. The present disclosure relates to the use of CD19 antibodies (e.g., obexelimab) to improve the treatment of human patients with active IgG-RD and to prevent the recurrence of IgG4-RD. The present disclosure also relates to methods for preventing the recurrence of IgG4-RD using CD19 antibodies (e.g., obexelimab). In addition, the present disclosure provides CD19 antibodies (e.g., obexelimab) in adult human patients (i.e., 18 years of age or older) with IgG4-RD (including patients with new, recurrent or refractory IgG4-RD) to treat, improve, stabilize or reduce one or more symptoms of IgG4-RD, such as methods, compositions and uses for reducing the incidence of disease attacks.

[0003] In some aspects, the present disclosure provides methods, compositions, and uses of CD19 antibodies (e.g., obelizumab) for treating, ameliorating, stabilizing, or reducing one or more symptoms of IgG4-RD, such as reducing the incidence or severity of disease attacks, in adult human patients (i.e., 18 years of age or older) with IgG4-RD, including patients with new, relapsed, or refractory IgG4-RD.

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

[0005] In some embodiments, the method comprises administering obelimonab subcutaneously twice a week at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously twice a week at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously every 3 days at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously every 7 days at a dose of 250 mg.

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

[0007] In some embodiments, obelimonab is administered with a liquid formulation comprising 125mg / mL obelimonab. In some embodiments, obelimonab is administered with 2x 1mL injection or 1x 2mL injection. In some embodiments, obelimonab is administered with 2x 1mL injection or 1x 2mL injection, and the total dose is 250mg. In some embodiments, obelimonab injection is administered simultaneously. In some embodiments, obelimonab injection is 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, obelimonab injection is 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, obelimonab is administered as 4x0.25mL injections with a liquid formulation comprising 125mg / mL obelimonab. In some embodiments, obelimonab is administered as 4x 0.25mL injections with a liquid formulation comprising 125mg / mL obelimonab, and the total dose is 250mg. In some embodiments, obelimonab injections are administered simultaneously. In some embodiments, obelimonab injections 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, obelimonab injections 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.

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

[0010] In some embodiments, obelimonab is self-injected by the patient. In some embodiments, obelimonab is injected by a person who is not the patient (e.g., a caregiver). In some embodiments, obelimonab is administered under the supervision of a clinician.

[0011] In some embodiments, the obelizumab is administered in a liquid formulation comprising 125 mg / mL obelizumab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at a pH of 5.5. In some embodiments, the obelizumab is administered in a liquid formulation comprising 100 mg / mL obelizumab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at a pH of 5.5. In some embodiments, the anti-CD19 antibody (e.g., obelizumab) is formulated at a concentration of 80-200 mg / mL obelizumab, 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 at a pH of 5.0-6.0.

[0012] In some embodiments, the methods encompass administration of an anti-CD19 antibody (e.g., obelimonab) to a human patient who has received glucocorticoid (GC) therapy. In some embodiments, the methods encompass administration of an anti-CD19 antibody (e.g., obelimonab) to a human patient who has not yet received glucocorticoid (GC) therapy.

[0013] In some embodiments, the GC therapy is administered at a dose of 20-60 mg / day prednisone or an equivalent. In some embodiments, the GC therapy is administered at a dose of 10-100 mg / day prednisone or an equivalent. 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 prednisone or an equivalent. 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.

[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. 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.

[0015] In some embodiments, the GC therapy is administered at a 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 of prednisone or an equivalent.

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

[0017] In some embodiments, the GC therapy is administered at a dose of up to 1 mg / kg / day of prednisone or an equivalent. 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 high doses of prednisone or equivalent. In some embodiments, the patient has been administered high doses of GC therapy and is unlikely to respond to any therapeutic therapy. In some embodiments, the patient has not responded to previous therapy prior to administration of an anti-CD19 antibody (e.g., obelimonab).

[0020] In some embodiments, the GC therapy is continued during treatment with obelimonab. In some embodiments, the GC therapy is reduced during treatment with obelimonab. In some embodiments, the GC therapy is reduced prior to treatment with obelimonab. In some embodiments, the GC therapy is reduced to complete discontinuation. In some embodiments, obelimonab is administered in combination with GC therapy. In some embodiments, obelimonab is administered without GC therapy.

[0021] In some embodiments, obelizumab is administered for a period of time sufficient to treat, ameliorate, stabilize or alleviate one or more symptoms of IgG4-RD relative to a control. In some embodiments, the at least one symptom is manifested in an organ selected from the group consisting of 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, obelizumab is administered to the patient until complete remission. In some embodiments, obelizumab is administered to the human patient during a relapse-free period to prevent relapse.

[0023] In some embodiments, obelizumab is administered to the patient until complete remission or until the patient is deemed clinically free of evidence of an onset of disease by the physician. In some embodiments, obelizumab is administered until the patient is deemed clinically free of evidence of an onset of disease by the physician. In some embodiments, obelizumab is administered until the patient is clinically free of evidence of an onset of disease by the physician.

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

[0025] In some embodiments, the relapse-free period is determined by the number of days of disease onset. 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 obelimonab. 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 183 days, at least 184 days, at least 186 days, at least 187 days, at least 188 days, at least 189 days, at least 190 days, at least 191 days, at least 192 days, at least 193 days, at least 194 days, at least 195 days, at least 196 days, at least 197 days, at least 198 days, at least 199 days, at least 200 days, at least 201 days, at least 202 days, at least 203 days, at least 204 days, at least 205 days, at least 206 days, at least 207 days, at least 208 days, at least 209 days, at least 210 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.

[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 obelimonab. 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 obelimonab.

[0027] In some embodiments, the relapse-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 5 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. In some embodiments, the relapse-free period is at least 52 weeks from the first administration of obelimonab. In some embodiments, the relapse-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 obelimonab. In some embodiments, the relapse-free period is at least 52 weeks from the administration of obelimonab.

[0028] In some embodiments, the relapse-free period is up to 40 weeks, up to 45 weeks, up to 50 weeks, up to 52 weeks, up to 55 weeks, up to 60 weeks from the first administration of obelizumab. In some embodiments, the relapse-free period is up to 52 weeks from the first administration of obelizumab.

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

[0030] In some embodiments, the relapse-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 obelizumab.

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

[0032] In some embodiments, the relapse-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 obelizumab.

[0033] In some embodiments, obelimonab is used as maintenance therapy. In some embodiments, the patient has no recurrence when taking obelimonab. In some embodiments, the patient has no recurrence when taking obelimonab once a week at a dosage of 250mg. In some embodiments, the recurrence-free period is until obelimonab is discontinued. In some embodiments, the recurrence-free period is at least 7 days after discontinuing obelimonab. In some embodiments, the recurrence-free period is at least 14 days after discontinuing obelimonab. In some embodiments, the recurrence-free period is at least 21 days after discontinuing obelimonab. In some embodiments, the recurrence-free period is at least 28 days after discontinuing obelimonab.

[0034] In some embodiments, obelizumab is administered to the patient until the patient has an active IgG4-RD disease episode. In some embodiments, obelizumab is administered to the patient until the patient has an active IgG4-RD disease episode requiring initiation of rescue therapy. In some embodiments, obelizumab is administered while the patient has an active IgG4-RD disease episode.

[0035] In some embodiments, the rescue therapy comprises administering GC therapy. In some embodiments, the rescue therapy involves initiating a non-GC therapy that controls the symptoms of the attack.

[0036] In some embodiments, the human patient has relapsed or refractory disease to a prior treatment for IgG4-RD. In some embodiments, the human patient has relapsed or refractory disease to rituximab. In some embodiments, the human patient has relapsed or refractory disease to another CD19 therapy.

[0037] In some embodiments, the disease activity of the human patient is assessed using the IgG4-RD reaction index (RI). In some embodiments, the human patient achieves a IgG4-RD RI reduction of ≥2 points from the first day of administration of obelimonab. In some embodiments, the human patient has an American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria IgG4-RD score (IgG4-RD score) > 20 before administration of obelimonab.

[0038] In some embodiments, relative to the control, obelimonab is applied for a period of time sufficient to improve, stabilize or alleviate one or more symptoms of IgG4-RD. In some embodiments, the at least one symptom is manifested in an organ selected from the following: lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, hearts, pericardium, orbits, nasal cavity, lungs, bile ducts, salivary glands and pancreas. In some embodiments, obelimonab is applied to the patient until complete remission. In some embodiments, obelimonab is applied to the patient at an interval during the no-recurrence period. In some embodiments, the no-recurrence period is determined by the number of days of the onset of the disease. In some embodiments, the no-recurrence period is at least 30 days, 40 days, 50 days, 60 days, 70 days, 80 days or 90 days from the first application of obelimonab. In some embodiments, the no-recurrence period is greater than 90 days. In some embodiments, the no-recurrence period is at most 40 weeks, at most 45 weeks, at most 50 weeks, at most 52 weeks from the first application of obelimonab.

[0039] In some embodiments, obelimonab is administered to the patient until the patient has an active IgG4-RD episode requiring initiation of salvage therapy. In some embodiments, the salvage therapy comprises administering GC therapy. In some embodiments, the salvage therapy comprises administering GC therapy in combination with obelimonab. In some embodiments, the patient has relapsed or refractory disease to prior treatment for IgG4-RD. In some embodiments, the patient has relapsed or refractory disease to rituximab.

[0040] In some embodiments, the patient presents with IgG4-RD manifestations selected from the group consisting of: IgG4-related sialadenitis (chronic sclerosing sialadenitis, Kuttner's tumour, Mikulicz's disease), IgG4-related dacryoadenitis (Mikulicz's disease), IgG4-related ophthalmopathy (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic sinusitis IgG4-related hypophysitis (IgG4-related panhypophysitis, IgG4-related adenohypophysitis, IgG4-related infundibular neurohypophysitis, autoimmune hypophysitis), IgG4-related pachymeningitis, IgG4-related leptomeningitis (idiopathic hypertrophic pachymeningitis), IgG4-related pancreatitis (autoimmune pancreatitis type 1, IgG4-related AIP, lymphospermic sclerosing pancreatitis, chronic pancreatitis with aortic IgG4-related pulmonary disease (pneumonic pseudotumor), IgG4-related pleurisy, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortic aneurysm), IgG4-related periaortitis (chronic periaortitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrinous mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis, Albaran-Ormond syndrome) syndrome), Ormond's disease (retroperitoneal fibrosis), perirenal fasciitis, Gerota's fasciitis / syndrome, fibrosing periureteritis, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, nonspecific retroperitoneal inflammation, sclerosing retroperitoneitis, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related mesenteritis (subtypes are: mesenteric panniculitis, mesenteric lipodystrophy, and retractile mesenteritis) (sclerosing mesenteritis, systemic nodular panniculitis, liposclerosing mesenteritis, mesenteric Weber-Christian disease (Weber-Christian disease)disease), mesenteric lipogranuloma, xanthogranulomatous mesenteritis), 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 peripheral fibrosis (chronic testicular pain), IgG4-related paratesticular pseudotumor, IgG4-related epididymo-orchitis ( Paratesticular fibrous pseudotumor, inflammatory pseudotumor of the spermatic cord, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, hyperplastic spermatic corditis, chronic hyperplastic orchitis, fibromatous orchitis, nodular orchitis, reactive orchitis, fibromesothelioma), IgG4-related lymphadenopathy, IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineural disease, and IgG4-related thyroid disease (Reidel's thyroiditis), inflammatory pseudotumor, and multifocal fibrosclerosis.

[0041] In some embodiments, the patient presents with IgG4-RD manifestations selected from the group consisting of autoimmune pancreatitis (lymphoplasmic sclerosing pancreatitis), eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract), fibrosing mediastinitis, idiopathic hypertrophic pachymeningitis, idiopathic tubulointerstitial nephritis, inflammatory pseudotumor, Kuttner tumor, Miguel's disease, fibrosclerosis, periaortitis, periarteritis, inflammatory aortic multifocal aneurysm, Ormond's disease (retroperitoneal fibrosis), Riddle's thyroiditis, and sclerosing mesenteritis. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 is a graph showing a PK simulation of obelizumab plasma concentration-time profiles following weekly subcutaneous administration of obelizumab doses.

[0043] Figure 2 is a graph showing a simulation of the change from baseline in absolute B cell counts following weekly subcutaneous administration of obelizumab doses.

[0044] Figure 3 is a graph showing simulation of CD19 receptor occupancy after weekly subcutaneous administration of obelizumab DETAILED DESCRIPTION

[0045] In addition, the present invention provides methods of treating IgG4-related diseases by administering an anti-CD19 antibody to a human patient >18 years of age in need of treatment at a therapeutically effective dose and administration interval for a treatment period sufficient to improve, stabilize, or alleviate one or more symptoms of the IgG4-related disease relative to a control (e.g., start of treatment).

[0046] In one aspect, the present invention provides a method for reducing the risk of recurrence in an adult patient. In one aspect, the present invention provides a method for reducing the risk of recurrence in an adult patient with IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obelimonab 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 obelimonab to the patient.

[0047] In one aspect, the present invention provides a method for preventing recurrence in an adult patient. In one aspect, the present invention provides a method for preventing recurrence in an adult patient with IgG4-RD (immunoglobulin G4-related disease), the method comprising administering obelimonab 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 obelimonab to the patient.

[0048] In some embodiments, the method comprises administering obelimonab at a dose of 250 mg. In some embodiments, the method comprises administering obelimonab every 7 days at a dose of 250 mg. In some embodiments, the method comprises administering obelimonab to an adult patient (e.g., a patient at least 18 years old) every 7 days at a dose of 250 mg. In some embodiments, the method comprises administering obelimonab subcutaneously.

[0049] In one aspect, the invention provides a method of reducing the risk of recurrence in an adult patient, the method comprising subcutaneously administering obelizumab to the adult patient at a dose of 250 mg every 7 days.

[0050] Various aspects of the present invention are described in detail in the following sections. The use of 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".

[0051] definition

[0052] Several definitions are described herein. Such definitions are intended to encompass grammatical equivalents.

[0053] Antibody: The term "antibody" herein is intended to include proteins consisting of one or more polypeptides that are substantially encoded by all or part of the immunoglobulin genes identified. For example, the immunoglobulin genes identified in humans include κ (K), λ (l) and heavy chain genetic loci, which together contain numerous variable region genes, and constant region genes mu (u), δ (d), γ (y), σ (s) and α (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 may refer to natural antibodies from any organism, engineered antibodies, or antibodies recombinantly produced for experimental, therapeutic or other purposes.

[0054] CD32b + FcγRllb + Cell: As used herein, the term "CD32b + cell" or "FcγRllb + “Cell” means any cell or cell type expressing CD32b (FcγRIIb). CD32b+ cells include, but are not limited to, B cells, plasma cells, dendritic cells, macrophages, neutrophils, mast cells, basophils or eosinophils.

[0055] 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 bound antibody on a target cell and subsequently cause lysis of the target cell.

[0056] Effector function: As used herein, the term "effector function" means a biochemical event caused by the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include effector functions mediated by FcγR, such as ADCC and ADCP, and effector functions mediated by complement, such as CDC. In addition, effector functions include effector functions mediated by FcγRIlb, such as inhibitory functions (e.g., downregulation, reduction, inhibition, etc., B cell responses, e.g., humoral immune responses).

[0057] Effector cells: As used herein, the term "effector cell" means a cell of the immune system that expresses one or more Fc and / or complement receptors and mediates one or more effector functions. 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 gd T cells, and may be from any organism, including, but not limited to, humans, mice, rats, rabbits, and monkeys.

[0058] Fc or Fc region: As used herein, the term "Fc" or "Fc region" means a polypeptide comprising the constant region of an antibody excluding the first constant region immunoglobulin domain and, in some cases, 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, and the flexible hinge at the N-termini of these domains. For IgA and IgM, Fc may include the J chain. For IgG, Fc comprises the immunoglobulin domains Cγ2 and Cγ3 (Og2 and C3) as well as Cγ1 The hinge between Cγ2 (Cy2). Although the boundaries of the Fc region can vary, the human IgG heavy chain Fc region is generally defined as comprising residues C226 or P230 at its carboxyl terminus, wherein numbering is according to the EU index as in Kabat. Fc may refer to this region in isolation, or to this region in the context of an Fc polypeptide, as described below.

[0059] Fcγ receptor or FcγR: As used herein, the term "Fcγ receptor" or "FcγR" means any member of the family of proteins that bind to the Fc region of an IgG antibody and are substantially encoded by an FcγR gene. In humans, this family includes, but is not limited to, FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIla (including allotypes H131 and R131), FcγRIIb (including FcγRllb-1 and FcγRllb-2), and FcγRIIc; and FcγRI 11 (CD16), including isoforms FcγRIlla (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRlllb-NA1 and FcγRllb-NA2) (Jefferis et al., 2002, Immunol. Lett) 82: 57-65, which is incorporated by reference in its entirety), as well as any undiscovered human FcγR or FcγR isoform or allotype. FcγRs can be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcγRs include but are not limited to FcγRI (CD64), FcγRII (CD32), FcγR 111 (CD16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγR or FcγR isoform or allotype.

[0060] Episode: In the case of IgG4-RD, the term "episode" is defined as the recurrence of previous signs / symptoms or the appearance of new signs / symptoms of IgG4-RD. In certain embodiments, in the case of IgG4-RD, an "episode" is the recurrence of previous signs / symptoms of IgG4-RD or the appearance of new signs / symptoms that, in the opinion of the investigator and adjudication committee, warrants the initiation of rescue therapy. In some embodiments, an IgG4-RD episode is the recurrence of previous signs / symptoms of IgG4-RD or the appearance of new signs / symptoms that meet the criteria for an IgG4-RD episode.

[0061] Modification: The term "modification" as used herein refers to changes in the physical, chemical or sequence properties of a protein, polypeptide, antibody or immunoglobulin. The modifications described herein include amino acid modifications and glycoform modifications.

[0062] Target antigen: As used herein, the term "target antigen" means a molecule bound by the variable region of a given antibody or the fusion partner of an Fc fusion. A target antigen can be a protein, carbohydrate, lipid, or other chemical 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 obelimonab is CD19.

[0063] Target cell: As used herein, the term "target cell" means a cell that expresses a target antigen.

[0064] Obelimumab: As used herein, the term "Obelimumab" is an Fc-engineered humanized monoclonal antibody (mAb) that binds to the human B-cell restricted surface antigen CD19 and has enhanced Receptor IIb The molecule is an IgG1 immunoglobulin with a kappa light chain and 2 amino acid substitutions in the constant portion of the heavy chain. Obelimonab is a monoclonal antibody with an estimated mass of approximately 147,426 Da based on the amino acid sequence. The heavy and light chains of Obelimonab are given by SEQ ID NO: 10 and SEQ ID NO: 9, respectively.

[0065] Relapse-free period: As used herein, the term "relapse-free period" is defined as the time interval between the start of administration of an anti-CD19 antibody (eg, obelizumab) and the time of recurrence of the disease.

[0066] Salvage therapy: As used herein, the term "salvage therapy" refers to the use of therapy to treat a suspected recurrent disease attack or worsening of disease symptoms. In some embodiments, the salvage therapy is a different approved therapy. In some embodiments, the salvage therapy is any therapy that can be used to alleviate the symptoms associated with an IgG4-RD disease attack. A common salvage therapy for IgG4-RD is glucocorticoid (GC) salvage therapy. Other salvage therapies include rituximab and other anti-CD19 antibody therapies, to name a few.

[0067] Obelimumab and its variants

[0068] According to the present invention, obelimonab and its variants are used to treat human patients suffering from IgG4-RD. Obelimonab is a non-cytolytic CD-19 directed antibody used to treat active IgG4-RD (immunoglobulin G4-related disease) in adult patients and reduce the risk of recurrence. On the one hand, the present invention provides a method of administering obelimonab to reduce the risk of recurrence in adult patients. On the one hand, the present invention provides a method of administering obelimonab to reduce the risk of recurrence in adult patients suffering from IgG4-RD (immunoglobulin G4-related disease). On the one hand, the present invention provides a method of administering obelimonab to treat active IgG4-RD (immunoglobulin G4-related disease) in adult patients and reduce the risk of recurrence.

[0069] Obelimumab is a monoclonal antibody specific for CD19, comprising: a light chain comprising a variable region having:

[0070] CDR1, said CDR1 comprising RSSKSLQNVNGNTYLY (SEQ ID NO: 2),

[0071] CDR2, said CDR2 comprising RMSNLNS (SEQ ID NO: 3) and

[0072] CDR3 comprising MQHLEYPIT (SEQ ID NO:4); and

[0073] A heavy chain comprising a variable region having

[0074] CDR1, said CDR1 comprising SYVMH (SEQ ID NO:5),

[0075] CDR2, comprising WIGYINPYNDGTKY (SEQ ID NO: 6) and

[0076] CDR3, said CDR3 comprising GTYYYGTRVFDY (SEQ ID NO: 7),

[0077] wherein the heavy chain comprises amino acid substitutions located in the Fc region S267E and L328F compared to: SEQ ID NO: 8:

[0078] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP

[0079] AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT

[0080] CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV

[0081] DGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE

[0082] KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP

[0083] ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ IDNO:8),

[0084] Therein numbering is according to the EU index as in Kabat.

[0085] In one embodiment, obelizumab comprises: a light chain comprising the amino acid sequence of (SEQ ID NO:9), and a heavy chain comprising the amino acid sequence of (SEQ ID NO:10), as given in Table 1.

[0086] Table 1: Sequences of the heavy and light chain amino acid sequences of obelizumab

[0087]

[0088] In one embodiment, obelizumab comprises: a light chain variable region comprising SEQ ID NO:11, and a heavy chain variable region comprising SEQ ID NO:12.

[0089] Obelimumab works by utilizing the regulation of B cell receptor (BCR) signaling by FcγRIIB1. Obelimumab binds to CD19 of the BCR complex, and its Fc is engineered to increase its affinity for inhibitory FcγRIIB. Since CD19 is associated with BCR, CD19 is tethered to the Obelimumab of FcγRIIB on the same cell so that the BCR complex inhibits antigen-induced BCR aggregation. Obelimumab utilizes the natural inhibitory mechanism of the only Fc receptor FcγRIIb expressed by B cells, which acts as a negative regulator under conditions of antigen excess and immune complex formation (Chu et al., 2014). Compared with B cell depletion antibodies, since Obelimumab may not mediate B cell killing, Obelimumab may also have an improved safety profile.

[0090] Variants

[0091] In one embodiment, a variant of obelizumab is an immunoglobulin specific for CD19, comprising: a light chain comprising a variable region having a CDR1 comprising SEQ ID NO:2, a CDR2 comprising SEQ ID NO:3, and a CDR3 comprising SEQ ID NO:4; and a heavy chain comprising a variable region having a CDR1 comprising SEQ ID NO:5, a CDR2 comprising SEQ ID NO:6, and a CDR3 comprising SEQ ID NO:7, wherein the heavy chain comprises amino acid substitutions in S267E and L328F in the Fc region compared to SEQ ID NO:8, wherein numbering is according to the EU index as in Kabat.

[0092] In some embodiments, the variant of obelizumab comprises a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the heavy chain variable region and / or the light chain variable region comprises 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 no more than 1, 2, 3, 4 or 5 amino acid residues.

[0093] In one embodiment, a variant of obelizumab comprises: a light chain comprising an amino acid sequence that is 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99% identical to SEQ ID NO:9 and / or amino acid substitutions in S267E and L328F in the Fc region compared to SEQ ID NO:10, wherein numbering is according to the EU index, as in Kabat.

[0094] In some embodiments, suitable variants of obelizumab bind to the same epitope on human CD19 as an antibody comprising a light chain of SEQ ID NO: 9 and a heavy chain of SEQ ID NO: 10. Epitope binding can be determined by methods known in the art.

[0095] In some embodiments, suitable variants of obelimonab compete with antibodies comprising a light chain of SEQ ID NO: 9 and a heavy chain of SEQ ID NO: 10 for binding to human CD19 under a library assay known in the art. As used herein, library assay refers to any method of mapping the epitope bound by an antibody regionally. Standard methods for characterizing such antibodies, also referred to as epitope libraries, generally involve surface plasmon resonance (SPR) technology. Using SPR, monoclonal antibody candidates are screened in pairs to bind to a target protein. Other standard methods involve ELISA-based screening, and may require the synthesis of overlapping peptide groups corresponding to the protein of interest.

[0096] In some embodiments, human CD19 comprises the amino acid sequence of SEQ ID NO: 1: (SEQ ID NO: 1)

[0097] Fc receptor binding properties

[0098] Anti-CD19 antibodies disclosed herein (e.g., obelimonab) include Fc variants having enhanced Fc binding to inhibitory Fcγ receptor IIb (FcγRIIb). FcγRIIb is the only FcR on B cells, which acts as an antibody-induced down-regulator of humoral immunity naturally involved in immune complexes. When sufficient antibodies are produced for a given antigen, specific immune complexes form FcγRIIb and B cell receptors (BCRs) and co-engage with them with high affinity, thereby selectively inhibiting only B cells that recognize homologous antigens. In addition, FcγRIIb regulates the activity of other B cell stimulators including interleukin (IL) -4, LPS and BAFF, which amplifies BCR-driven proliferation and differentiation. By simultaneously binding CD19 and FcγRIIb, obelimonab (and variants described herein) mimics the effects of antigen-antibody complexes and down-regulates B cell activity.

[0099] The Fc variants disclosed herein can be optimized for various Fc receptor binding properties. Fc variants that are engineered or predicted to show one or more optimized properties are referred to herein as "optimized Fc variants". The 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 inhibitory receptor FcγRIlb. In other embodiments, the immunoglobulins disclosed herein provide enhanced affinity for FcγRIlb, but the affinity for one or more activated FcγRs including, for example, FcγRI, FcγRIla, FcγRIIIa and / or FcγRIIIb is reduced. 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 FcγRIlb.

[0100] Fc variants include one or more amino acid modifications relative to the parent Fc polypeptide, wherein the one or more amino acid modifications provide one or more optimized properties. The Fc variants disclosed herein are different from their parents in amino acid sequence due to at least one amino acid modification. Therefore, compared with the parent, the Fc variants disclosed herein have at least one amino acid modification. Alternatively, compared with the parent, the Fc variants disclosed herein can have more than one amino acid modification, such as about two to fifty amino acid modifications, such as about two to ten amino acid modifications, about two to about five amino acid modifications, etc. Therefore, the sequence of the Fc variant and the sequence of the parent Fc polypeptide are substantially homologous. For example, the variant Fc variant sequence herein will have about 80% homology with the parent Fc variant sequence, such as at least about 90% homology, at least about 95% homology, at least about 98% homology, at least about 99% homology, etc. Modifications disclosed herein include amino acid modifications, which include insertions, deletions and substitutions. Modifications disclosed herein also include glycoform modifications.

[0101] Modification may be made genetically using molecular biology, or may be made enzymatically or chemically.

[0102] Fc variants disclosed herein are defined according to the amino acid modifications that constitute them. Thus, for example, S267E is an Fc variant having the substitution S267E relative to a parent Fc polypeptide. Similarly, S267E / L328F defines an Fc variant having the substitutions S267E and L328F relative to a parent Fc polypeptide. The identity of the WT amino acids may be unspecified, in which case the aforementioned variant is referred to as 267E / 328F. It should be noted that the order in which the substitutions are provided is arbitrary, that is, for example, 267E / 328F is the same Fc variant as 328F / 267E, and so on. Unless otherwise indicated, the positions discussed herein are numbered according to the EU index as described in Kabat (Kabat et al., 1991, "Sequences of Proteins of Immunological Interest in Immunology", 5th edition, United States Public Health Service, National Institute of Health, Bethesda, which is hereby incorporated by reference in its entirety). In short, EU is the name of the first antibody molecule whose entire amino acid sequence is 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 has become the standard numbering scheme for heavy chain constant regions. EU protein has become a standard reference for defining numbering. Kabat et al. list EU sequences in a set of indexes, which are compared with other antibody sequences, thereby serving as a necessary tool for comparing antibodies with the EU numbering scheme. Thus, as will be appreciated 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., as this places the EU in the context of antibodies of other variable domain lengths. Thus, as used herein, "EU index as in Kabat" or "numbering is according to the EU index, as in Kabat" refers to the numbering of EU antibodies as described in Kabat.

[0103] In certain embodiments, the Fc variants disclosed herein are based on human IgG sequences, and therefore human IgG sequences are used as "base" sequences for comparison with other sequences, including but not limited to sequences from other organisms, such as rodent and primate sequences. Immunoglobulin can also include sequences from other immunoglobulin classes such as IgA, IgE, IgGD, IgGM. It is conceivable that, although the Fc variants disclosed herein are engineered in the case of a parent IgG, variants can be engineered or "transferred" to the parent IgG in the case of another second parent IgG. This is accomplished by determining the "equivalent" or "corresponding" residues and substitutions between the first and second IgGs, usually based on the sequence or structural homology between the sequences of the first and second IgGs. In order to establish homology, the amino acid sequence of the first IgG outlined herein is directly compared with the sequence of the second IgG. After the alignment sequence, one or more of the homology alignment programs known in the art (e.g., using conserved residues between species) are used to allow necessary insertions and deletions to maintain the alignment (i.e., avoiding elimination of conserved residues by arbitrary deletions and insertions), and residues equivalent to the specific amino acids in the primary sequence of the first immunoglobulin are defined. The alignment of conserved residues can conserve 100% of such residues. However, the alignment of conserved residues greater than 75% or as low as 50% is also sufficient to define equivalent residues. Equivalent residues can also be defined by determining the structural homology between the first and second IgGs at the tertiary structure level of the IgG whose structure has been determined. In this case, equivalent residues are defined as those residues whose atomic coordinates of two or more of the main chain atoms of the specific amino acid residues (N on N, CA on CA, C on C and O on O) of the parent or precursor after alignment are within about 0.13nm. In another embodiment, equivalent residues are within about 0.1nm after alignment. Alignment is achieved after the optimal model has been oriented and positioned to give 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 prepared, it is intended to convey that the discovered Fc variants as disclosed herein can be engineered into any second parent IgG having significant sequence or structural homology with the Fc variant. Thus, for example, if a variant antibody is generated by using the above method or other methods for determining equivalent residues, wherein the parent antibody is human IgG1, then the variant antibody can be engineered in another IgG1 parent antibody that binds to a different antigen, a human IgG2 parent antibody, a human IgA parent antibody, a mouse IgG2a or IgG2b parent antibody, etc. Similarly, as described above, the background of the parent Fc variant does not affect the ability to transfer the Fc variants disclosed herein to other parent IgGs.

[0104] As used herein, the term "greater affinity" or "improved affinity" or "enhanced affinity" or "better affinity" than a parent Fc polypeptide means that when the amounts of the variant and the parent polypeptide in the binding assay are substantially the same, the Fc variant binds to the Fc receptor with a significantly higher equilibrium association constant (KA or Ka) or a lower equilibrium dissociation constant (KD or Kd) than the parent Fc polypeptide. For example, an Fc variant with improved Fc receptor binding affinity can show 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 parent Fc polypeptide, wherein the Fc receptor binding affinity is determined by a person skilled in the art, for example, by a binding method disclosed herein, including but not limited to Biacore. Thus, "reduced affinity" means that the Fc variant binds to the Fc receptor with a significantly lower KA or higher KD than the parent Fc polypeptide, compared to the parent Fc polypeptide as used herein. Greater or reduced affinity can also be defined relative to absolute affinity levels. 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. In addition, some Fc variants described herein bind to FcγRIIb with an affinity that is about 10 times that of 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.

[0105] In one embodiment, the Fc variant provides a selectively enhanced affinity for FcγRIIb relative to one or more activating receptors. Selectively enhanced affinity means that the Fc variant has an improved affinity for FcγRIIb relative to one or more activating receptors compared to the parent Fc polypeptide, but has a reduced affinity for one or more activating receptors compared to the parent Fc polypeptide, or this means that the Fc variant has an improved affinity for both FcγRIIb and activating receptors compared to the parent Fc polypeptide, but the improvement in affinity for FcγRIIb is greater than the improvement in affinity for one or more activating receptors. In alternative embodiments, the Fc variant reduces or eliminates binding to one or more activating FcγRs, reduces or eliminates binding to one or more complement proteins, reduces or eliminates one or more effector functions mediated by FcγRs, and / or reduces or eliminates one or more effector functions mediated by complement.

[0106] The presence of different polymorphic forms of FcγRs provides yet another parameter that influences the therapeutic utility of the Fc variants disclosed herein. While the specificity and selectivity of a given Fc variant for different classes of FcγRs significantly influences the ability of the Fc variant to target a given antigen to treat a given disease, the specificity or selectivity of the Fc variant for different polymorphic forms of these receptors can partially determine which studies or preclinical experiments may be suitable for testing, and ultimately which patient populations may or may not respond to treatment. Therefore, 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 research and preclinical experiments, clinical trial design, patient selection, dose dependency, and / or selection of other aspects of clinical trials.

[0107] The Fc variants disclosed herein may comprise modifications that modulate interactions with Fc receptors other than FcγR, including but not limited to complement proteins, FcRn, and Fc receptor homologs (FcRHs). FcRHs include but are not limited to FcRFH, FcRH2, FcRH3, FcRH4, FcRH5, and FcRH6 (Davis et al., 2002, Immunol. Reviews 190: 123-136).

[0108] An important parameter for determining the most beneficial selectivity of a given Fc variant for treating a given disease is the background of the Fc variant. Therefore, the Fc receptor selectivity or specificity of a given Fc variant will provide different properties depending on whether it constitutes an antibody, an Fc fusion or an Fc variant with the fusion partner to which it is coupled. In one embodiment, the Fc receptor specificity of the Fc variant disclosed herein will determine its therapeutic utility. The utility of a given Fc variant for therapeutic purposes will depend on the epitope or form of the target antigen and the disease or indication being treated. For some targets and indications, greater FcγRIIb affinity and reduced activation of FcγR-mediated effector functions may be beneficial. For other target antigens and therapeutic applications, increasing affinity for FcγRIIb or increasing affinity for both FcγRIIb and activating receptors may be beneficial.

[0109] Formulations and pharmaceutical compositions

[0110] The present invention provides pharmaceutical compositions and formulations of anti-CD19 antibodies (e.g., obelimonab). The formulations of anti-CD19 antibodies disclosed herein are prepared by mixing the antibody having the desired degree of purity with an optional pharmaceutically acceptable carrier, excipient or stabilizer (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed., 1980, which is incorporated by reference in its entirety) in the form of a lyophilized formulation or an aqueous solution for storage.

[0111] In some embodiments, the pharmaceutical compositions of interest include anti-CD19 antibodies (e.g., obelimonab) at various concentrations. In some embodiments, suitable formulations may include an antibody of interest 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).

[0112] In some embodiments, suitable formulations can comprise an anti-CD 19 antibody at a concentration ranging from 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).

[0113] In some embodiments, formulations suitable for subcutaneous administration may contain a protein of interest 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.

[0114] 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) sodium chloride in 5 mM sodium phosphate at pH 7.0) and sugar solutions (e.g., up to 3% (e.g., up to 2.4%, 2.0%, 1.5%, 1.0%) sucrose in 5 mM sodium phosphate at pH 7.0). In some embodiments, suitable formulation compositions are saline (e.g., 150 mM NaCl in water).

[0115] Many therapeutic agents, and in particular the antibodies of the invention, require controlled pH and specific excipients to maintain their solubility and stability in the pharmaceutical compositions of the invention.

[0116] The pH of the pharmaceutical composition is another factor that can change the solubility of anti-CD19 antibodies (e.g., obelimonab) in aqueous pharmaceutical compositions. In certain embodiments, the pharmaceutical composition of the present invention contains one or more buffers. In certain embodiments, the composition according to the present invention contains an amount of a 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 comprises sodium phosphate at most about 50mM (e.g., at most about 45mM, 40mM, 35mM, 30mM, 25mM, 20mM, 15mM, 10mM, 5mM). Suitable buffers include, for example, acetate, succinate, citrate, phosphate, other organic acids, and tris (hydroxymethyl) aminomethane ("Tris").

[0117] Suitable buffer concentrations can be from about 1 mM to about 100 mM, or from about 3 mM to about 20 mM, depending, for example, on the desired isotonicity of the buffer and 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.

[0118] In some embodiments, the formulation contains an isotonic agent to keep the formulation isotonic. Exemplary isotonic agents include, but are not limited to, glycine, sorbitol, mannitol, sodium chloride, and arginine. In some embodiments, a suitable isotonic agent can be present in the formulation at a concentration of about 0.01-5% by weight (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% by weight).

[0119] In some embodiments, the formulation may contain a stabilizer to protect the antibody. Typically, a suitable stabilizer is a non-reducing sugar, such as sucrose, raffinose, trehalose or an amino acid, such as glycine, arginine and methionine. The amount of the stabilizer in the formulation is generally such that the formulation will be isotonic. However, hypertonic formulations may also be suitable. In addition, the amount of the stabilizer must not be too low to cause unacceptable degradation / aggregation of the antibody. The range of exemplary stabilizer concentrations in the formulation may be from about 1mM to about 400mM (e.g., from about 30mM to about 300mM and from about 50mM to about 100mM), or alternatively, 0.1 wt % to 15 wt % (e.g., from 1 wt % to 10 wt %, from 5 wt % to 15 wt %, from 5 wt % to 10 wt %). In some embodiments, the ratio of the mass amount of the stabilizer to the therapeutic agent is about 1:1. In other embodiments, the ratio of the mass amount 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, stabilizers suitable for lyophilization are also lyoprotectants.

[0120] The pharmaceutical compositions, formulations and related methods of the present invention can be used to deliver anti-CD19 antibodies (e.g., subcutaneously) and for treating related diseases. The pharmaceutical compositions of the present invention are particularly useful for delivering anti-CD19 antibodies (e.g., obelimonab) to patients suffering from IgG4-RD.

[0121] 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); poloxamer (e.g., poloxamer 188); Triton; sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glucoside; lauryl-, myristyl-, linoleoyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleoyl-, or stearyl-sarcosine; linoleoyl-, myristyl-, or cetyl-betaine; lauramidopropyl-, cocamidopropyl-, linoleamidopropyl- , myristamidopropyl-, palmitamidopropyl- or isostearamidopropyl-betaine (e.g., lauroylamidopropyl); myristamidopropyl-, palmitamidopropyl- or isostearamidopropyl-dimethylamine; sodium methyl cocoyl- or disodium methyl mercapto-taurine; and MONAQUATTM series (Mona Industries, Inc., Paterson, NJ), polyethylene glycol, polypropylene glycol and copolymers of ethylene and propylene glycol (e.g., Pluronics, PF68, etc.). Typically, the amount of surfactant added is such that it reduces protein aggregation and minimizes particle or effervescent formation. For example, the surfactant can 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%). Specifically, the surfactant may be present in the formulation at a concentration of about 0.005%, 0.01%, 0.02%, 0.1%, 0.2%, 0.3%, 0.4% or 0.5%, etc.

[0122] In some embodiments, suitable formulations may further include one or more fillers, particularly for freeze-dried formylation. A "filler" is a compound that increases the quality of the freeze-dried mixture and contributes to the physical structure of the freeze-dried cake. For example, a filler can improve the appearance of the freeze-dried cake (e.g., substantially uniform freeze-dried cake). Suitable fillers include, but are not limited to, sodium chloride, lactose, mannitol, glycine, sucrose, trehalose, hydroxyethyl starch. An exemplary concentration of a filler is 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%).

[0123] The formulations according to the present invention can be evaluated based on product quality analysis, reconstitution time (if lyophilized), reconstitution quality (if 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, turbidimetry, 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 (liquid or cake appearance).

[0124] Typically, formulations (lyophilized or aqueous) can be stored at room temperature for extended periods of time. Storage temperatures can typically range from 0°C to 45°C (e.g., 4°C, 20°C, 25°C, 45°C, etc.). Formulations can be stored for periods of months to years. Storage times will typically be 24 months, 12 months, 6 months, 4.5 months, 3 months, 2 months, or 1 month. Formulations can be stored directly in containers for administration, thereby eliminating transfer steps.

[0125] The formulation can be stored directly in the lyophilization container (if lyophilized), which can also serve as the reconstitution container, thereby eliminating the transfer step. Alternatively, the lyophilized product formulation can be measured out in smaller increments for storage. Storage should generally avoid conditions 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.

[0126] In some embodiments, the formulation according to the present invention is in liquid or aqueous form. In some embodiments, the formulation of the present invention is lyophilized. Such lyophilized formulations can be reconstituted by adding one or more diluents thereto before being administered to a patient. Suitable diluents include, but are not limited to, sterile water, antibacterial water for injection, and sterile saline solution. Preferably, when reconstituted, the antibodies contained therein are stable, soluble, and exhibit tolerance when administered to a patient.

[0127] The pharmaceutical compositions of the present invention are characterized by their tolerability. As used herein, the terms "tolerable" and "tolerability" refer to the ability of a pharmaceutical composition of the present invention to not cause adverse reactions in a patient to whom such a composition is administered, or alternatively, to not cause serious adverse reactions in a patient to whom such a composition is administered. In some embodiments, the pharmaceutical compositions of the present invention are well tolerated by a patient to whom such a composition is administered.

[0128] Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, acetate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethylammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, alum, , 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 dextrose; 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; colorants; salts forming counterions such as sodium; metal complexes (e.g., Zn protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0129] In some embodiments, pharmaceutical compositions comprising the antibodies disclosed herein may be in a water-soluble form, such as as a pharmaceutically acceptable salt, which is intended to include both acid and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to salts formed from inorganic acids and organic acids that retain the biological effectiveness of the free base and are not biologically or otherwise undesirable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; 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.

[0130] "Pharmaceutically acceptable base addition salts" include base addition salts derived from inorganic bases, such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. 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, secondary, 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.

[0131] Formulations for in vivo administration (eg, subcutaneous administration) may be sterile. In some embodiments, the formulations are sterilized by filtration through sterile filtration membranes.

[0132] In some embodiments, the anti-CD19 antibody disclosed herein (e.g., obelimonab) is formulated for subcutaneous (SC) administration. In some embodiments, the anti-CD19 antibody (e.g., obelimonab) formulation for SC administration comprises one or more buffers, one or more tension modifiers, one or more solvents, and one or more surfactants. Non-limiting examples of buffers include phosphates, citrates, acetates, glutamates, carbonates, tartrates, triethanolamine (TRIS), diglycine, histidine, glycine, lysine, arginine, and other organic acids. More specifically, non-limiting examples of buffers include HEPES sodium, MES, potassium phosphate, potassium thiocyanate, sterilants, TAE, TBE, ammonium sulfate / HEPES, BuffAR, sodium acetate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate, sodium hydrogen phosphate, and sodium phosphate. In addition, the buffer can be in various hydrate forms. For example, the buffer can be a monohydrate, a dihydrate, a trihydrate, a tetrahydrate, a pentahydrate, a hexahydrate, a heptahydrate, an octahydrate, a nonahydrate, a decahydrate, an undecahydrate, and a dodecahydrate. Occasionally, the hydrate can be a fractional, such as a hemihydrate or a sesquihydrate. Non-limiting examples of tonicity modifications 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, tetraethylene glycol, Solketal TM , glycerol formal, acetone, tetrahydrofurfuryl alcohol, diethylene glycol dimethyl ether, dimethyl isosorbide and ethyl lactate. Non-limiting examples of solvents include polysorbates (e.g., polysorbate-20, polysorbate-80), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monooleate polyoxyethylene sorbitan monolaurate (Tween 20), sorbitan trioleate (Span 85), lecithin and polyoxyethylene polyoxypropylene copolymer (Pluronic, Pluronic F-68).

[0133] The amount of anti-CD19 antibody (e.g., obelizumab), buffer, tonicity modifier, solvent, and surfactant can vary. In some embodiments, the anti-CD19 antibody (e.g., obelizumab) is formulated at a concentration of 125 mg / mL obelizumab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid (density 1.053 g / mL), 30 mg / mL L-proline, and 0.1 mg / mL polysorbate 80 at a pH of 5.5. In some embodiments, the anti-CD19 antibody (e.g., obelizumab) is formulated at a concentration of 80-200 mg / mL obelizumab, 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, and 0.05-0.2 mg / mL polysorbate 80 at a pH of 5.0-6.0. In some embodiments, the anti-CD19 antibody (e.g., obelizumab) is formulated at a concentration of 122-127 mg / mL obelizumab, 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 at a pH of 5.0-6.0.

[0134] In certain embodiments, the subcutaneous (SC) formulation comprises an anti-CD19 antibody (e.g., obelimonab), one or more buffers, one or more tension 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 tension modifier can be acetic acid, L-proline, and combinations thereof. In another embodiment, the solvent is water.

[0135] In some embodiments, the surfactant is a polysorbate. In some embodiments, the polysorbate is polysorbate-80. In some embodiments, the SC formulation comprises an anti-CD19 antibody (e.g., obelimonab), sodium acetate trihydrate, acetic acid and L-proline, water and polysorbate-80.

[0136] In some embodiments, the subcutaneous (SC) formulation comprises an anti-CD 19 antibody (e.g., obelizumab) 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 per 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., obelizumab) 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 per ml.

[0137] Anti-CD19 antibodies disclosed herein (e.g., obelimonab) can also be formulated into immunoliposomes. Liposomes are vesicles that contain various types of lipids, phospholipids and / or surfactants that can be used to deliver anti-CD19 antibodies (e.g., obelimonab) to mammals. Liposomes containing anti-CD19 antibodies (e.g., obelimonab) are prepared by methods known in the art. Liposomes with enhanced circulation time are disclosed in US 5,013,556, which is incorporated by reference as a whole. In certain embodiments, anti-CD19 antibodies (e.g., obelimonab) are formulated in liposomes generated by a reverse phase evaporation method using a lipid composition comprising phosphatidylcholine, cholesterol and PEG-derived phosphatidylethanolamine (PEG-PE). Liposomes are extruded through a filter with a limited pore size to produce liposomes with a desired diameter.

[0138] In some embodiments, the anti-CD19 antibody (e.g., obelizumab) is entrapped in microcapsules prepared by methods including, but not limited to, coagulation techniques, interfacial polymerization (e.g., using hydroxymethylcellulose or gelatin-microcapsules or poly-(methyl methacrylate) 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.

[0139] In some embodiments, anti-CD19 antibody (e.g., obelimonab) sustained-release formulations can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers in the form of shaped articles, such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methyl acrylate) or poly(vinyl alcohol)), polylactic acid (US 3,773,919, fully incorporated by reference), copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, such as Lupron. (which are injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), poly D-(-)-3-hydroxybutyric acid and (commercially available from Alkermes), which is a microsphere-based delivery system consisting of the desired bioactive molecule incorporated into a poly-DL-lactide-co-glycoside (PLG) matrix.

[0140] Containers for injection

[0141] The present invention provides a container for injecting a pharmaceutical composition and formulation of an anti-CD19 antibody (e.g., obelimonab). On the one hand, the container comprises a liquid pharmaceutical composition comprising obelimonab. Suitable containers include, but are not limited to, syringes, automatic injectors, vials, infusion bottles, ampoules, carpoules, syringes equipped with a needle protection system, and carpoules in injection pens.

[0142] In some embodiments, the container containing the liquid pharmaceutical composition is a prefilled syringe, a vial, or an auto-injector. In some embodiments, the container is a prefilled syringe. In some embodiments, the container is an auto-injector.

[0143] In some embodiments, the container is a prefilled syringe or autoinjector containing a liquid pharmaceutical composition comprising:

[0144] a.122-127mg / mL obelizumab,

[0145] b. 2.0-2.5 mg / mL sodium acetate trihydrate at pH 5.0-6.0,

[0146] c. 0.15-0.19 mg / mL acetic acid (density 1.053 g / mL),

[0147] d.25-35mg / mL L-proline,

[0148] e. 0.05-0.15 mg / mL polysorbate 80.

[0149] In some embodiments, the prefilled syringe or the autoinjector comprises a liquid drug composition comprising: a liquid drug composition comprising approximately 125 mg / mL obelizumab, 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 a pH of 5.5.

[0150] In some embodiments, the prefilled syringe or the autoinjector facilitates subcutaneous or intradermal delivery of a pharmaceutical composition. In some embodiments, the methods of treating IgG4-RD described herein comprise administering a formulation comprising obelizumab to the patient's bloodstream following a single or multiple subcutaneous injection into the patient's abdomen using a prefilled syringe or an autoinjector.

[0151] 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.

[0152] IgG4-Related Disease (IgG4-RD)

[0153] IgG4-RD is a serious, rare chronic fibroinflammatory disease, usually affecting multiple organs, causing significant organ dysfunction and failure, and even death when the disease is not identified and treated in time. In certain embodiments, the disease usually affects major organs, such as pancreas, liver, kidney, lung and eyes. In certain embodiments, the patient may show a single organ involvement, but more often shows multiple organ involvement. Along with disease progression and patient experience new or worsening signs / symptoms (attacks), other organs are lesioned, and the cell inflammation characterizing early stage disease moves towards a more fibrotic stage, thereby causing major tissue damage, and ultimately leading to organ failure. For example, the cholangitis caused by IgG4-RD may cause liver failure, IgG4-related (type 1) autoimmune pancreatitis may cause failure of either or both of the endocrine and exocrine pancreas, and IgG4-related aortitis may cause aneurysm and / or aortic dissection.

[0154] Several B cell subsets have been described to be elevated in the peripheral blood of IgG4-RD patients by flow cytometry (Wallace 2015, Mattoo 2014), and CD19+ plasmablasts have been shown to actively contribute to tissue fibrosis (Della-Torre 2019). The histopathological features of IgG4-RD include lymphoplasmacytic infiltration, storiform fibrosis, and occlusive phlebitis (Carruthers 2015). The hallmark of IgG4-RD is the infiltration of IgG4-positive plasma cells in the affected organs (Cheuk 2010, Floreani 2020).

[0155] Clinical symptoms and disease course depend on the organ or organs affected and, therefore, may be evaluated and treated by a number of different medical specialties, including rheumatologists, gastroenterologists, nephrologists, and ophthalmologists. Despite increasing awareness of the disease and key advances in understanding its pathophysiology, there are still no approved medications. In fact, no randomized, double-blind, placebo-controlled trials have ever been published for IgG4-RD. Treatment is based on consensus expert opinion (Khosroshahi 2015), but therapeutic options remain sparse and are often limited by the common comorbidities of patients with IgG4-RD (e.g., advanced age, diabetes, obesity, hypertension) and the fact that the disease often targets organs such as the pancreas, exacerbating treatment complications associated with glucocorticoids.

[0156] B cells, including plasmablast-directed therapies with CD19 monoclonal antibodies such as obelimonab (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 obelimonab, which simultaneously binds to CD19 and FcγRIIb and downregulates B cell activity, has been demonstrated in vitro and in vivo, including in classic animal models of autoimmune disease.

[0157] IgG4-RD is currently incurable. The goal of treatment is to reduce inflammation and swelling in the organs, prevent or reverse (if possible) fibrosis and increase glandular secretion. When vital organs are involved, immediate treatment is required to prevent organ failure. For example, cholangitis caused by IgG4-RD may lead to liver failure, IgG4-related (type 1) autoimmune pancreatitis may lead to failure of either or both of the endocrine and exocrine pancreas, and IgG4-related aortitis may lead to aneurysm and / or aortic dissection. Currently, glucocorticoids are the first line of therapy. Although this approach is initially effective in most patients, the recurrence rate when reduced or discontinued is high (Khosroshahi et al. 2015). In addition, long-term use of glucocorticoids causes toxicity in patients, especially in the elderly population including osteoporosis, hypertension and diabetes.

[0158] The pathogenesis of IgG4-RD suggests that B cell-targeted therapies may be useful therapeutic disease interventions. For example, results from 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 result in long-term B cell depletion for 6 months or longer, which puts patients at risk for opportunistic infections and may reduce responses to vaccines. Therefore, new therapies that do not deplete B cells but rather downregulate their activity are needed.

[0159] The IgG4-related diseases for treatment in the present disclosure can be selected from the group consisting of: IgG4-related sialadenitis (chronic sclerosing sialadenitis, Kuttner's tumor, Miguel's disease), IgG4-related dacryoadenitis (Miguel's disease), IgG4-related eye disease (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic sinusitis, eosinophilic angiocentric fibrosis, IgG4-related hypophysitis (IgG4-related panhypophysitis, IgG4-related adenohypophysitis, IgG4-related infundibulohypophysitis, autoimmune hypophysitis), IgG4-related pachymeningitis, IgG4-related leptomeningitis (idiopathic hypertrophic pachymeningitis), IgG4-related pancreatitis (autoimmune pancreatitis type 1, IgG4-related AIP, lymphosesclerosing pancreatitis, chronic pancreatitis with diffuse irregular stenosis of the main pancreatic duct), IgG4-related lung disease (pneumonic pseudotumor), IgG4-related pleurisy, IgG4-related liver disease, IgG4-related sclerosing pancreatitis ... IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortic aneurysm), IgG4-related periaortitis (chronic periaortitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrinous mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis, Albaran-Ormond syndrome, Ormond disease (retroperitoneal fibrosis), perirenal fasciitis, Jeremy's fasciitis / syndrome, fibrous periureteritis, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, nonspecific retroperitoneal inflammation, sclerosing retroperitoneal cavity inflammation, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related mesenteritis (subtypes are: mesenteric fat membrane inflammation, mesenteric fat dystrophy and retractile mesenteritis) (sclerosing mesenteritis, systemic nodular fat membrane inflammation, liposclerosing mesenteritis, mesenteric Weber-Christian disease (Weber-Christian disease)disease), mesenteric lipogranuloma, xanthogranulomatous mesenteritis), 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 peripheral fibrosis (chronic testicular pain), IgG4-related paratesticular pseudotumor, IgG4-related epididymo-orchitis (paratesticular fibrous pseudotumor, spermatic cord pseudotumor Tumors, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, hyperplastic spermatic corditis, chronic hyperplastic orchitis, fibromatous orchitis, nodular orchitis, reactive orchitis, fibromesothelioma), IgG4-related lymphadenopathy, IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineural disease and IgG4-related thyroid disease (Riddle's thyroiditis), eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract), inflammatory pseudotumors, and multifocal fibrosclerosis.

[0160] Additionally, in some embodiments, the present disclosure also includes methods of treating IgG4-RD manifestations selected from the group consisting of autoimmune pancreatitis (lymphoplasmic sclerosing pancreatitis), eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract), fibrosing mediastinitis, idiopathic hypertrophic pachymeningitis, idiopathic tubulointerstitial nephritis, inflammatory pseudotumors, Kuttner tumors, Miguel's disease, fibrosclerosis, periaortitis, periarteritis, inflammatory aortic multifocal aneurysm, Ormond's disease (retroperitoneal fibrosis), Riddle's thyroiditis, and sclerosing mesenteritis.

[0161] Human patient population

[0162] According to the present invention, qualified human patients selected to receive obelimonab are 18 years of age or older with active IgG4-RD. In some embodiments, qualified patients have active IgG4-RD signs / symptoms (e.g., attacks) that require initiation of therapy. In some embodiments, the patient population is adults (≥18 years of age) with active IgG4-RD. In some embodiments, patients are first evaluated for the following factors:

[0163] ●1 organ affected versus >1 organ affected

[0164] ●Newly diagnosed disease meets classification criteria for participation in clinical trials for IgG4-RD compared with relapsed disease.

[0165] In some embodiments, the patient has recently suffered from an active disease requiring GC therapy. In some embodiments, the therapeutic efficacy of obelizumab is determined by reducing the risk of attacks compared to placebo control. Qualified patients may have ≥1 organ involvement. In some embodiments, the affected organ in IgG4-RD is a lung. In some embodiments, the affected organ in IgG4-RD is an aorta. In some embodiments, the affected organ in IgG4-RD is retroperitoneum. In some embodiments, the affected organ in IgG4-RD is dura mater. In some embodiments, the affected organ in IgG4-RD is a thyroid gland. In some embodiments, the affected organ in IgG4-RD is at least one eye socket. In some embodiments, the affected organ in IgG4-RD is a lacrimal gland. In some embodiments, the organ in IgG4-RD is a salivary gland. In some embodiments, the affected organ in IgG4-RD is a liver. In some embodiments, the affected organ in IgG4-RD is a bile duct. In some embodiments, the affected organ in IgG4-RD is a pancreas. In some embodiments, the affected organ in IgG4-RD is a kidney. In some embodiments, the affected organ in IgG4-RD is a skin. In some embodiments, the affected organ in IgG4-RD is a thyroid gland. In certain embodiments, the organ affected in IgG4-RD is a pituitary gland. In certain embodiments, the organ affected in IgG4-RD is a lymph node. Patients with disease in only one organ system can be excluded, and its main manifestation is fibrosis (i.e., retroperitoneal fibrosis without aortitis, Riedel's thyroiditis, fibrosing mediastinitis, sclerosing mesenteritis, etc.). In certain embodiments, organ involvement refers to the enlargement or tumor-like mass in the affected organ, except (1) bile duct, which tends to narrow, (2) aorta, in which wall thickening or aneurysmal dilatation is typical, and (3) lung, which relates to the thickening of bronchovascular bundles.

[0166] In some embodiments, the prior therapy is GC therapy and / or an augmentation of background long-term GC therapy.

[0167] In some embodiments, the qualified patients have received at least 2 weeks of GC treatment. In some embodiments, the qualified patients according to the present invention need to receive at least 3 weeks of GC treatment. In some embodiments, the qualified patients according to the present invention need to receive more than 3 weeks of GC treatment. In some embodiments, the qualified patients according to the present invention need to receive up to 6 weeks of GC treatment. In some embodiments, GC treatment is administered at a dose of 30-50 mg / day prednisone or equivalent. In some embodiments, GC treatment is administered at a dose of 10-70 mg / day prednisone or equivalent. In some embodiments, GC treatment is administered at a dose of 20-60 mg / day prednisone or equivalent. Table 3 shows exemplary GC equivalent doses.

[0168] In some embodiments, in qualified patients according to the present invention, GC therapy is administered together with obelimonab. In some embodiments, the GC therapy is tapered prior to starting obelimonab therapy. An exemplary tapering regimen involves administering 0.6–1.0 mg / kg of corticosteroids daily for 2–4 weeks, followed by tapering (Khosroshahi 2015). In some exemplary embodiments, GC is completely tapered to discontinuation within 8–12 weeks. In some embodiments, tapering requires less than 8 weeks. In some embodiments, tapering requires greater than 12 weeks. In some exemplary embodiments, GC therapy is allowed to continue long-term at low to moderate doses of 2.5-10.0 mg per day (Kamisawa 2017).

[0169] In some embodiments, qualified patients according to the present invention may have plasmablast levels of greater than 100 cells / mL, greater than 200 cells / mL, greater than 300 cells / mL, greater than 400 cells / mL, greater than 500 cells / mL, greater than 600 cells / mL, greater than 700 cells / mL, greater than 800 cells / mL, greater than 900 cells / mL, greater than 1000 cells / mL, greater than 2000 cells / mL, greater than 3000 cells / mL, greater than 4000 cells / mL, or greater than 5000 cells / mL.

[0170] In some embodiments, the 2019 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria IgG4-RD score for qualified patients according to the present invention can be ≥20. The ACR / EULAR scoring system was developed by an international multi-specialty group of 86 physicians assembled by ACR and EULAR. The scoring system uses consensus exercises, existing literature, derivation and validation groups, and multi-criteria decision analysis of 1,879 patients (1,086 cases, 793 simulators) to identify, weight, and test potential classification criteria.

[0171] In some embodiments, eligible patients according to the present invention have a recent active flare requiring treatment. In some embodiments, patients who experience a flare receive corticosteroids followed by a protocol-specified taper on the day of randomization.

[0172] In some embodiments, eligible patients according to the present invention may have at least 1 organ involved. In some embodiments, patients according to the present invention may have more than 1 organ involved. In some embodiments, patients with disease in only 1 organ system will be excluded, and their primary manifestation is fibrosis (i.e., retroperitoneal fibrosis without involvement of aortitis, Riedel's thyroiditis, fibrosing mediastinitis, sclerosing mesenteritis, etc.).

[0173] Treating IgG4-RD with obelizumab

[0174] There are no approved treatments for IgG4-RD, and the goal of treatment is to prevent inflammation, which can lead to fibrosis and associated organ failure. Obelimumab (XmAb5871) is a humanized anti-CD19 monoclonal antibody whose Fc portion is engineered to increase affinity for FcγRIIb, the only receptor on B cells.

[0175] In some embodiments, administration of obelizumab in a subcutaneous (SC) formulation minimizes the risk of acute administration-related reactions.

[0176] In some embodiments, obelimonab is administered subcutaneously at a concentration of 125 mg / ml as 2x 1 ml injections at 250 mg per week. In some embodiments, obelimonab is administered subcutaneously at a concentration of 125 mg / ml as 1x 2 ml injections at 250 mg per week. In some embodiments, obelimonab is administered subcutaneously at 200 mg per week. In some embodiments, obelimonab is administered subcutaneously at 150 mg per week. In some embodiments, obelimonab is administered subcutaneously at 100 mg per week. In some embodiments, obelimonab is administered as a single injection. In some embodiments, obelimonab is administered as more than 2 injections, for example, obelimonab is administered as 3 injections or 4 injections or more. In some embodiments, the concentration of obelimonab is 100 mg / ml. In some embodiments, the concentration of obelimonab is 50 mg / ml. In some embodiments, obelimonab is administered subcutaneously at a concentration of 100 mg / ml as 2x 1 ml injections.

[0177] In one aspect, the present invention provides a method of treating IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obelizumab at a dose of 250 mg weekly to a human patient ≥18 years of age.

[0178] In some embodiments, the method comprises administering obelimonab subcutaneously twice a week at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously twice a week at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously every 3 days at a dose of 125 mg. In some embodiments, the method comprises administering obelimonab subcutaneously every 7 days at a dose of 250 mg.

[0179] In some embodiments, obelimonab can be administered subcutaneously once a week to human patients >18 years of age at a dose of 200 mg. In some embodiments, obelimonab can be administered subcutaneously twice a week to human patients >18 years of age at a dose of 125 mg. In some embodiments, obelimonab is administered subcutaneously twice a week to human patients >18 years of age at a dose of 100 mg. In some embodiments, obelimonab is administered subcutaneously once a week to human patients >18 years of age at a dose of 300 mg. In some embodiments, obelimonab is administered subcutaneously twice a week to human patients >18 years of age at a dose of 150 mg.

[0180] In some embodiments, obelimonab is administered with a liquid formulation comprising 125mg / mL obelimonab. In some embodiments, obelimonab is administered as 2x 1mL injections. In some embodiments, obelimonab is administered with 2x 1mL injections, with a total dose of 250mg. In some embodiments, obelimonab injections are administered simultaneously. In some embodiments, obelimonab injections 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, obelimonab injections 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.

[0181] In some embodiments, obelimonab is administered as 4x0.25mL injections with a liquid formulation comprising 125mg / mL obelimonab. In some embodiments, obelimonab is administered as 4x 0.25mL injections with a liquid formulation comprising 125mg / mL obelimonab, and the total dose is 250mg. In some embodiments, obelimonab injections are administered simultaneously. In some embodiments, obelimonab injections 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, obelimonab injections 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.

[0182] In some embodiments, obelizumab is administered as a single injection in a liquid formulation. In some embodiments, obelizumab is administered as a single injection in a liquid formulation with a total dose of 250 mg.

[0183] In some embodiments, obelimonab is administered at a dose of about 100-500 mg per week. In some embodiments, obelimonab 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, obelimonab 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.

[0184] In certain embodiments, weekly dose can be once injected or divided into two or more injections in a whole week. In certain embodiments, weekly dose is divided into 2 injections, 3 injections, 4 injections, 5 injections, 6 injections or daily injections. In certain embodiments, weekly dose is equally distributed. In certain embodiments, weekly dose is unequally divided. In certain embodiments, weekly dose is divided into so that it is used every other day, every 2 days or every 3 days.

[0185] In some embodiments, a suitable dosage range is 20-40 mg per day, 25-40 mg per day, or 30-40 mg per day. In some embodiments, a suitable dosage is 35 mg per day.

[0186] In some embodiments, obelimonab is administered at a dose of 500 mg every two weeks. In some embodiments, obelimonab is administered every 2 weeks, and the dose can be injected once or divided into two or more injections. In some embodiments, the dose is divided into 2 injections, 3 injections, 4 injections, 5 injections, 6 injections or more injections.

[0187] In some embodiments, the patient receives 1000 mg of obelizumab per month. In some embodiments, the 1000 mg monthly dose can be injected once or divided into 4 or more injections. In some embodiments, the dose is divided into 4 injections, 5 injections, 6 injections, 7 injections, 8 injections or more injections.

[0188] IgG4-RD flare-ups

[0189] In certain embodiments, IgG4-RD attack criteria are used to determine IgG4-RD attack. In certain embodiments, IgG4-RD attack criteria are an objective organ-specific instrument that details the assessment and discovery required for supporting organ-specific attack diagnosis based on patient-reported symptoms, physical examination, biopsy, imaging, and laboratory findings. In certain embodiments, IgG4-RD attack criteria minimize the subjectivity of the researcher's identification of disease attack. In certain embodiments, IgG4-RD attack is evaluated using methods known in the art. In certain embodiments, the attack is diagnosed by analyzing serum IgG4 values, which may be normal in some patients suffering from IgG4-RD. In certain embodiments, IgG4-RD attack criteria include data collection for the following attack evaluation.

[0190] In certain embodiments, the recurrence-free period compared to placebo or before the treatment is started is evaluated. In certain embodiments, the increase in the recurrence-free period is considered as a positive result. As explained above, the recurrence-free period can be determined by the number of days of the onset of disease development.

[0191] Time to disease onset (TDF)

[0192] In some embodiments, the time of disease onset is the primary endpoint. In some embodiments, the time to the first IgG4-RD attack needs to start rescue therapy. In some embodiments, during clinical trials, TDF is the time from the start of treatment to the reappearance of previous signs / symptoms of IgG4-RD or the appearance of new signs / symptoms without recurrence. For example, if the subject has another attack of IgG4-RD 3 weeks after the start of obelimonab treatment, the TDF of the subject is 3 weeks. In some embodiments, TDF is thus measured until the 52nd week. In some embodiments, TDF is an assessment of the effect of weekly subcutaneous administration of obelimonab on reducing the risk of attacks in patients with active IgG4-RD. In some embodiments, compared with patients receiving placebo, in patients treated with obelimonab, TDF is significantly longer.

[0193] In some embodiments, the recurrence-free period is one week. In some embodiments, the recurrence-free period is one week. In some embodiments, the recurrence-free period is two weeks. In some embodiments, the recurrence-free period is three weeks. In some embodiments, the recurrence-free period is four weeks. In some embodiments, the recurrence-free period is one week. In some embodiments, the recurrence-free period is one month. In some embodiments, the recurrence-free period is one week. In some embodiments, the recurrence-free period is two months. In some embodiments, the recurrence-free period is three months. In some embodiments, the recurrence-free period is four months. In some embodiments, the recurrence-free period is five months. In some embodiments, the recurrence-free period is six months. In some embodiments, the recurrence-free period is seven months. In some embodiments, the recurrence-free period is nine months. In some embodiments, the recurrence-free period is ten months. In some embodiments, the recurrence-free period is eleven months. In some embodiments, the recurrence-free period is one year or more.

[0194] Collect seizure assessment data (seizure criteria)

[0195] In some embodiments, the administration of obelimonab reduces recurrence. Although the onset can be treated with GC, steroids cannot prevent disease recurrence after discontinuation (Kamisawa 2017, Raina 2009). In some embodiments, the onset of IgG4-RD is assessed during a clinical visit. In some embodiments, if the patient exhibits recurrence or new signs / symptoms of previous signs / symptoms of IgG4-RD, a physical examination, imaging, and / or biochemical parameters specific to the onset area should be obtained. In addition to testing serum IgG4 levels, the investigator also provides a comprehensive description of the assessment and information. Exemplary assessment data include, but are not limited to:

[0196] Earliest onset of signs / symptoms

[0197] ●Organ-specific seizure evaluation:

[0198] ○ Symptoms reported by patients

[0199] ○Physical examination revealed

[0200] ○ Laboratory discovery

[0201] ○ Imaging findings

[0202] ○ Biopsy findings

[0203] ○ Incidental discovery during surgery

[0204] ● Investigator's decision on whether an episode requiring rescue therapy occurred

[0205] ●Processing

[0206] ○ Treatment started (yes / no)

[0207] ○ Treatment start date

[0208] ○ Treatment Type

[0209] Glucocorticoid steroids

[0210] Immunosuppressants other than steroids

[0211] ●Surgical intervention, including stent placement

[0212] Duration of treatment

[0213] ●Treatment outcome compared to pre-attack baseline

[0214] ○Has resolved, no sequelae

[0215] ○ Subsided, with sequelae

[0216] ○ Improved but still exists

[0217] ○Unchanged

[0218] ○ Worsening since treatment

[0219] ●Describe the entire incident, including a description of current signs and symptoms, and any relevant historical data.

[0220] Remedial therapy

[0221] In the event of an attack, rescue therapy may be administered to the patient to acutely treat the attack. Rescue therapy involves the administration of GC therapy. In some embodiments, rescue therapy involves the administration of <40 mg / day of prednisone or equivalent at a dose of 250 mg every 7 days for <8 weeks in combination with obelimax.

[0222] In some embodiments, the GC therapy is administered at a dose of 20-60 mg / day prednisone or an equivalent. In some embodiments, the GC therapy is administered at a dose of 10-100 mg / day prednisone or an equivalent. 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 prednisone or an equivalent. 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.

[0223] 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. 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.

[0224] In some embodiments, the GC therapy is administered at a 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 of prednisone or an equivalent.

[0225] In some embodiments, the GC therapy is administered at a dose of 0.1-1 mg / kg / day, a dose of 0.1-0.8 mg / kg / day, a dose of 0.1-0.7 mg / kg / day, a dose of 0.1-0.6 mg / kg / day, a dose of 0.1-0.5 mg / kg / day, a dose of 0.1-0.4 mg / kg / day, a dose of 0.1-0.3 mg / kg / day, a dose of 0.1-0.2 mg / kg / day, or a dose of 0.05-0.1 mg / kg / day of prednisone or an equivalent.

[0226] In some embodiments, the GC therapy is administered at a dose of up to 1 mg / kg / day of prednisone or an equivalent. 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.

[0227] In some embodiments, the prednisone equivalent dose is determined as shown in Table 3.

[0228] In some embodiments, the GC therapy is administered with high doses of prednisone or equivalent. In some embodiments, the patient has been administered high doses of GC therapy and is unlikely to respond to any therapeutic therapy. In some embodiments, the patient has not responded to previous therapy prior to administration of an anti-CD19 antibody (e.g., obelimonab).

[0229] In some embodiments, the GC therapy is continued during treatment with obelimonab. In some embodiments, the GC therapy is reduced during treatment with obelimonab. In some embodiments, the GC therapy is reduced prior to treatment with obelimonab. In some embodiments, the GC therapy is reduced to complete discontinuation. In some embodiments, obelimonab is administered in combination with GC therapy.

[0230] IgG4-RD Reaction Index

[0231] Develop IgG4-RD reaction index (RI) to help researchers evaluate the efficacy of treatment in a structured manner. In certain embodiments, IgG4-RD RI is used to measure efficacy. IgG4-RD RI is a tool designed to detect the change of disease activity, and identifies the improvement and deterioration of the same or different organ systems compared with placebo or when compared with the beginning of treatment. The validation of the index is carried out by 26 doctors-investigators, including representatives from 6 specialized fields and 9 countries (Carruthers 2012, Wallace 2018). IgG4-RD RI uses a scoring system for each organ system or position, and requires clinicians to score disease activity and degree of damage when encountering clinically. Original IgG4-RD RI has been modified to eliminate serum IgG4 concentration as a part of the instrument, and the score is improved or worsened relative to the baseline, and lymph node involvement is eliminated, and the assessment of the damage caused by IgG4-RD in each affected organ (Carruthers 2012) is included. The total IgG4-RD RI activity score includes the sum of the numerical values ​​in the activity column.

[0232] In certain embodiments, the doctor scores each of the organ systems as 0-3 based on the first 28 days. In certain embodiments, urgent organ involvement (i.e., requiring urgent treatment) receives double scores. The organ can be selected from, but not limited to, lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, hearts, pericardium, orbits, nasal cavities, lungs, bile ducts, salivary glands, and pancreas. In certain embodiments, the organ or organ site is selected from, dura mater, pituitary gland, orbits and lacrimal glands, salivary glands, thyroid gland, lymph nodes, lungs, aorta and great vessels, retroperitoneum, mediastinum and mesentery, pancreas, bile ducts, and liver, kidneys, skin, and other sclerosis / mass formation. In certain embodiments, the organ or organ site is selected from, dura mater, pituitary gland, orbits, lacrimal glands, salivary glands, lymph nodes, lungs, aorta, retroperitoneum, pancreas, bile ducts, liver, kidneys, and skin.

[0233] At each follow-up assessment, the physician entered a score of 0-3 after the listed organ / site.

[0234] 0 = Normal or resolved

[0235] 1 = Improved since last assessment but still present, or improved relative to initial assessment but unchanged relative to previous assessment

[0236] 2 = No change in disease activity from previous assessment

[0237] Once an organ or site has improved or worsened, a score of 2 will no longer be used for that organ / site, i.e., the improved organ / system will maintain a score of 1 until it regresses (score of 0) or worsens (score of 3).

[0238] In some embodiments, no change relative to a previous assessment refers to disease manifestations that require subsequent imaging to accurately assess, i.e., disease manifestations that can be assessed only by imaging will be assumed to be unchanged until such time as repeat imaging demonstrates improvement, worsening, or regression.

[0239] 3 = Worsening or new disease manifestation since last assessment and requiring additional therapy (intent to treat).

[0240] The compiled scores give a snapshot of disease activity at that time point compared to the previous visit. The proportion of patients achieving complete remission by Week 52, defined as an IgG4-RDRI score of 0. In some embodiments, patients achieve complete remission after administration of obelizumab. In some embodiments, complete remission is defined as an IgG4-RDRI score of 0, no AC-determined flare, and no flare-directed treatment by Week 52.

[0241] In some embodiments, the patient achieves a complete remission after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0. In some embodiments, the patient achieves a complete remission after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0, no AC-confirmed flares, and no flare-directed treatment. In some embodiments, the patient achieves a complete remission after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0, no AC-confirmed flares, and no flare-directed treatment.

[0242] In some embodiments, the IgG4-RD RI includes the serum IgG4 concentration of the subject. In some embodiments, the IgG4-RD RI does not include the serum IgG4 concentration of the subject.

[0243] On the one hand, the invention provides a method for treating IgG4 related diseases (IgG4-RD), the method comprising administering obelimonab subcutaneously to a human patient once a week at a dosage of 250 mg. In certain embodiments, the method further comprises determining the IgG4-RD RI. In certain embodiments, the IgG4-RD RI is determined before treatment with obelimonab (e.g., baseline). In certain embodiments, the IgG4-RD RI is determined after administering obelimonab. In certain embodiments, the IgG4-RD RI is maintained relative to baseline. In certain embodiments, the IgG4-RD RI is reduced relative to baseline, wherein the baseline is the IgG4-RD RI score before starting treatment.

[0244] In some embodiments, obelizumab is administered to a subject to improve or prevent worsening of signs or symptoms of IgG4-RD. In some embodiments, the improvement or prevention of worsening of signs or symptoms of IgG4-RD is measured using the IgG4-RD RI.

[0245] In some embodiments, the range of IgG4-RD-RI score is 0-30. In some embodiments, the range of IgG4-RD-RI score is 0-5. In some embodiments, the range of IgG4-RD-RI score is 0-10. In some embodiments, the range of IgG4-RD-RI score is 0-15. In some embodiments, the range of IgG4-RD-RI score is 0-20. In some embodiments, the range of IgG4-RD-RI score is 0-25.

[0246] In some embodiments, the IgG4-RD-RI score is a decrease from baseline of 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. In some embodiments, the IgG4-RD-RI score is a decrease from baseline of 1-5, 2-5, 3-5, 4-5.

[0247] In some embodiments, the IgG4-RD-RI score is decreased by at least 1 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 3 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 4 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 5 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 6 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 7 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 8 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 9 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 10 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 11 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 12 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 13 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 14 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 15 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 16 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 17 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 18 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 19 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased by at least 20 relative to baseline. In some embodiments, the IgG4-RD-RI score is decreased to 0.

[0248] In some embodiments, within 1 week after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 2 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 3 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 4 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 5 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 6 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 7 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 8 weeks after administration of obelizumab, the IgG4-RD-RI score is decreased by at least 2 relative to baseline. In some embodiments, within 9 weeks after administration of obelizumab, the IgG4-RD-RI score is reduced by at least 2 relative to baseline. In some embodiments, within 10 weeks after administration of obelizumab, the IgG4-RD-RI score is reduced by at least 2 relative to baseline.

[0249] In some embodiments, the patient achieves complete remission at the 25th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at the 26th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at the 27th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at the 28th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at the 29th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at the 30th week after the administration of obelimonab, wherein complete remission includes an IgG4-RD RI score of 0, and there is no treatment for an attack. In some embodiments, the patient achieves complete remission at week 40 after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0 and no treatment for an attack. In some embodiments, the patient achieves complete remission at week 45 after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0 and no treatment for an attack. In some embodiments, the patient achieves complete remission at week 50 after administration of obelizumab, wherein the complete remission comprises an IgG4-RD RI score of 0 and no treatment for an attack.

[0250] Glucocorticoid toxicity index (GTI)

[0251] GTI is a toxicity measure related to the use of GC reported by a doctor. This is a weighted outcome measure that scores changes in steroid toxicity over time. The index is a measure of corticosteroid toxicity over time, and 9 domains (body mass index [BMI], glucose tolerance, blood pressure, lipids, bone density, steroid myopathy, skin toxicity, neuropsychiatric toxicity and infection) are utilized using 31 projects. GTI was developed by a group of 19 experts in corticosteroid use using multi-criteria decision analysis, and is intended to provide a reliable measurement of the steroid retention capacity of new therapeutic agents (Stone 2022). GTI has been used as an important efficacy endpoint for other clinical studies (Jayne 2021, McDowell 2021). GTI is described in Stone JH et al. "Semin Arthritis Rheum." August 2022; 55: 152010. PMID: 35486995, the document is hereby incorporated by reference in its entirety.

[0252] In one aspect, the invention provides a method for treating IgG4-related disease (IgG4-RD), the method comprising administering obelimonab subcutaneously to a human patient once a week at a dose of 250 mg. In an embodiment, subcutaneous administration of obelimonab achieves a change in glucocorticoid-related toxicity as measured by the GTI score.

[0253] In some embodiments, the 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 before the administration of obelimonab. In some embodiments, the toxicity associated with the use of corticosteroids is determined after the administration of obelimonab. In some embodiments, the toxicity associated with the use of corticosteroids is reduced after the administration of obelimonab.

[0254] In some embodiments, toxicity associated with the use of corticosteroids is determined using GTI. In some embodiments, the range of GTI scores is 346 to +439. In some embodiments, the GTI score shows a GTI worsening change corresponding to ≥10 points, ≥20 points, and ≥30 points. In some embodiments, the GTI score decreases after administration of obelimonab. In some embodiments, the GTI score decreases by at least 10 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 15 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 20 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 25 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 30 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 35 after administration of obelimonab. In some embodiments, the GTI score decreases by at least 40 after administration of obelimonab. In some embodiments, after administration of obelimonab, the GTI score decreases by at least 45.

[0255] GTI Scoring Factors

[0256] In some embodiments, the GTI score is measured by a change in BMI of at least -5 BMI units or greater than about 5 BMI units. In some embodiments, the GTI score is measured by changes in glucose metabolism produced by improvements in HbA1c and / or reductions in medications or increases in HbA1c and / or increases in medications. In some embodiments, the GTI score is measured by changes in blood pressure produced by improvements in blood pressure and / or reductions in medications or increases in blood pressure and / or increases in medications. In some embodiments, the GTI score is measured by changes in hyperlipidemia as measured by reductions in LDL and / or reductions in medications or by increases in hyperlipidemia as measured by reductions in LDL and / or increases in medications. In some embodiments, the GTI score is measured by changes in steroid myopathy as measured by moderate weakness to no weakness with or without functional limitations or no to mild weakness with or without functional limitations. In some embodiments, the GTI score is measured by skin steroid-related toxicity as measured by a reduction or increase in skin steroid toxicity. In some embodiments, the GTI score is measured by neuropsychiatric (NP)-steroid related symptoms as measured by a decrease or increase in NP toxicity. In some embodiments, the GTI score is measured by infection as measured by oral and / or vaginal candidiasis and / or other grade 3, 4 or 5 infections.

[0257] The GTI is measured at baseline and then every three or six months for periods called GTI intervals. The GTI is scored by comparing the domain value at the beginning of each GTI interval to the score at the end of each GTI interval. The CWS and AIS are calculated for each GTI interval, and the interval scores are then summed.

[0258] Examples

[0259] Example 1: Patient selection and inclusion criteria

[0260] This example describes the selection of patients with IgG4-RD for treatment with CD19 antibodies. In a 20-patient Phase II, open-label, single-arm clinical study (XmAb5871-03) conducted in patients with active IgG4-RD, obelimonab showed a strong and rapid improvement in disease activity. This study included up to 4 weeks of screening, followed by 12 doses (24 weeks) every 14 days, plus 6 weeks of follow-up. At a certain time point during the study, 14 (93%) of the 15 patients treated with obelimonab 5mg / kg intravenously for 14 days achieved a decrease in the IgG4-RD reaction index (RI) of ≥2, and all 14 patients decreased by 5 points or more. It is worth noting that the baseline IgG4-RD RI score of 1 patient was 2, but the RI score was still reduced by 50% (RI=1) by the end of the study.

[0261] In summary, the role of CD19+ B cells in the pathogenesis of IgG4-RD, the effects of B cell depletion observed in previous studies of IgG4-RD (Khosroshahi 2010), and the strong efficacy and safety observed in the phase 2 IgG4-RD study with obelizumab provide a strong rationale for the continued development of obelizumab in a pivotal, double-blind, randomized study of IgG4-RD.

[0262] The study consists of a screening period (day -28 to day -1) and a 52-week randomized controlled period (RCP), during which obelizumab or placebo will be administered as a subcutaneous injection every 7 days (52 doses), followed by an open-label extension period. Eligible patients will meet the 2019 American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) IgG4-RD classification criteria and must have active IgG4-RD signs / symptoms (i.e., attacks) that require the initiation of glucocorticoid (GC) therapy or the increase of background long-term GC therapy. The primary endpoint is the time to IgG4-RD onset (TDF). The time to IgG4-RD onset (TDF) is the recurrence of previous signs / symptoms of IgG4-RD or the appearance of new signs / symptoms from randomization to week 52.

[0263] Prior to randomization, all patients will receive GC treatment with a dose of 20 to 60 mg / day prednisone equivalents for ≥3 weeks and up to 6 weeks. The required GC therapy will be a newly started or an increase in long-term GC therapy (i.e., the patient previously received a dose of ≤10 mg / day prednisone equivalents). During the screening period, before randomization, the exact dose and reduction schedule will be determined by the investigator, preferably within 0-8 weeks. On the day of randomization, the patient must reach a dose of 20 mg / day prednisone equivalents and start the reduction specified in the protocol to discontinuation before the 8th week.

[0264] At the 1st day visit, eligible patients will be stratified according to the number of organs affected (1 or>1) and whether the disease is newly diagnosed with recurrent disease, because the risk of recurrence may be different between the patients. Patients will be randomized 1:1 to receive obelimonab or placebo, and the first SC dose of obelimonab / placebo will be administered at the trial center. Table 2 shows the dosage and formulation of obelimonab. All patients will be observed for at least 2 hours, during which safety assessments will be performed. The disease activity and AEs of the patients will be evaluated weekly.

[0265] Placebo

[0266] A placebo containing no active substance will also be provided as a solution for subcutaneous injection. The placebo formulation is: 2.35 mg / mL sodium acetate trihydrate at pH 5.5, 0.17 mg / mL acetic acid (density 1.053 g / mL), 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80, 115 mg / mL dextran-40.

[0267] The SC formulation of placebo is a sterile liquid product supplied in a disposable glass vial. Each 2-mL glass vial is filled with 1.2 mL of placebo. The disposable glass vial is shielded to make it indistinguishable from obelimonab. Table 6 shows the dosage regimen and formulation of obelimonab.

[0268] Table 6: Investigational Product: Obelimumab and Dosage

[0269]

[0270]

[0271] During the randomized controlled period (RCP), patients will be evaluated for efficacy, safety, PK, pharmacodynamics (PD), and immunogenicity at study visits specified in the schedule of assessments (SoA). Adverse events (AEs), serious adverse events (SAEs), and treatment-emergent adverse events (TEAEs) or clinically significant safety laboratory abnormalities will be evaluated.

[0272] Inclusion criteria

[0273] Patients were eligible for inclusion in this study only if they met all of the following criteria:

[0274] 1. Males and females aged ≥ 18 years old when signing the informed consent

[0275] 2. Patients must meet the 2019 ACR / EULAR IgG4-RD classification criteria with a score of ≥20

[0276] 3. Patients must have active IgG4-RD signs / symptoms (i.e., flare) requiring initiation of GC therapy or increase in background long-term GC therapy (if previously receiving a stable dose of ≤10 mg / day prednisone equivalents) as assessed by the investigator

[0277] 4. The total duration of GC treatment at a dose of 20 to 60 mg / day before randomization must be ≥ 3 weeks and a maximum of 6 weeks

[0278] 5. Female patients are eligible to participate if they are not pregnant (see Appendix 4), not breastfeeding, and at least 1 of the following conditions applies:

[0279] a. Not a woman of childbearing potential (WOCBP)

[0280] or

[0281] b. WOCBP, who agrees to follow contraceptive guidelines after the last dose of study medication

[0282] 6. Male patients must:

[0283] a. agree to (i) refrain from sexual intercourse or (ii) use contraception for at least 1 month (i.e., approximately 5 half-lives) after the last IP dose or (iii) be surgically sterilized during the study, and

[0284] b. Agree to refrain from donating sperm for at least 1 month (approximately 5 half-lives) after the last IP dose

[0285] 7. WOCBP must have a negative serum pregnancy test at Screening and a negative urine test prior to the first dose of study drug and at all time points specified in the SoA.

[0286] Exclusion criteria

[0287] Patients were excluded from the study if any of the following criteria applied:

[0288] 1. Any exclusion criteria listed in the ACR / EULAR IgG4-RD classification criteria

[0289] 2. In patients with disease in only 1 organ system, the predominant manifestation is fibrosis (ie, retroperitoneal fibrosis without involvement of aortitis, Riedel's thyroiditis, fibrosing mediastinitis, sclerosing mesenteritis, etc.).

[0290] 3. Oral administration of prednisone equivalents at a dose greater than 60 mg / day within 4 weeks prior to screening or during the screening period.

[0291] 4. Unable to tolerate 20 mg / day on the first day.

[0292] 5. Failure to taper GC therapy 8 weeks after randomization.

[0293] 6. Use of B-cell depleting, B-cell targeted, or other biologic immunomodulatory agents within 6 months prior to randomization. Patients who received B-cell targeted therapy within 6 to 12 months prior to randomization must have B-cell counts within the laboratory reference range at screening, as measured by a central laboratory.

[0294] 7. Received non-biological, disease-modifying anti-rheumatic drugs or immunosuppressants other than GC within 4 weeks before screening

[0295] 8. Has received investigational treatment or direct medical intervention in another clinical study within 12 weeks or <5 half-lives of investigational treatment prior to screening, whichever is shorter.

[0296] 9. Vaccination with live vaccines or live therapeutic infectious agents within 2 weeks prior to screening.

[0297] 10. Acute hepatitis B infection (HBsAg positive), active hepatitis C virus, or HIV infection. A positive test for hepatitis B is the detection of (a) HBsAg or (b) HBsAg; and in Japan only (c) HBsAg.

[0298] 11. Evidence of active pulmonary tuberculosis (TB) or being at high risk for TB based on:

[0299] a. History of active TB or latent TB, unless completion of treatment according to local guidelines is documented.

[0300] b. Positive interferon-γ release assay result at screening, unless treatment is documented.

[0301] c. Signs and symptoms that may represent active TB.

[0302] d. Chest X-ray, computed tomography (CT), or magnetic resonance imaging (MRI)

[0303] Indicates a possible diagnosis of TB.

[0304] 12. History or evidence of clinically unstable / uncontrolled disorders, conditions, or diseases other than IgG4-RD (including but not limited to cardiopulmonary, neoplastic, renal, hepatic, metabolic, hematologic, psychiatric, active infection) that, in the investigator's opinion, would pose a risk to patient safety or interfere with study evaluations, procedures, or completion.

[0305] 13. Malignant tumor within 5 years (except successfully treated cervical cancer in situ, excised squamous cell or basal cell carcinoma of the skin, breast cancer with no recurrence for ≥ 5 years after treatment, or prostate cancer with no recurrence for ≥ 3 years after prostatectomy)

[0306] 14. Any known allergy to monoclonal antibody therapy.

[0307] 15. Hematology or clinical chemistry parameters that meet any of the following criteria at screening:

[0308] a. White blood cell count <2.5×10 3 / μL

[0309] b. Absolute neutrophil count <1.0×10 3 / μL

[0310] c. Elevated serum creatinine > 2.5 × upper limit of normal (ULN) or estimated creatinine

[0311] Clearance calculated by the Cockrock-Gault formula at screening < 40 mL / min

[0312] d. Hemoglobin <10 g / dL

[0313] e. Platelet count <75×10 3 / μL

[0314] 16. Abnormal liver function tests meeting any of the following criteria:

[0315] a. In the absence of hepatobiliary activity:

[0316] i. Alanine aminotransferase (ALT)>2×ULN

[0317] ii. Aspartate aminotransferase (AST)>2×ULN

[0318] iii. Total bilirubin > 2×ULN

[0319] b. In the presence of hepatobiliary activity:

[0320] i.ALT>10×ULN

[0321] ii.AST>10×ULN

[0322] iii. Total bilirubin > 5×ULN

[0323] Patients receiving obelizumab experienced significantly fewer flare-ups compared with patients receiving placebo.

[0324] Example 2: Existing Glucocorticoid Therapy

[0325] Prior to randomization, all patients will receive ≥3 weeks and up to 6 weeks of GC therapy at a dose of 20 to 60 mg / day prednisone equivalents (Table 3). GC therapy can be a new start or an increase in long-term GC therapy (e.g., an increase from a previous stable dose of ≤10 mg / day prednisone equivalents).

[0326] Table 3 - Prednisone equivalence

[0327]

[0328]

[0329] The exact dose and schedule prior to randomization, including a tapering schedule if deemed necessary, is at the discretion of the investigator. However, patients must receive 20 mg / day of prednisone equivalents on the day of randomization and receive GC therapy at the dose indicated on Day 1. Patients will taper off over 8 weeks, reducing the dose by 5 mg equivalents every 2 weeks (Table 4).

[0330] Table 4 - Glucocorticoid Tapering*

[0331] Weekly dose of oral prednisone (or equivalent) Dosage of oral prednisone (or equivalent) Week 0 (Day 1) to end of Week 1 20 mg / day Week 2 to end of week 3 15 mg / day Week 4 to end of week 5 10 mg / day Week 6 to end of week 7 5 mg / day

[0332] * Patients must be receiving 20 mg / day of prednisone equivalents at Week 0 (Day 1) and will undergo required GC taper to cessation over 8 weeks, decreasing the dose by 5 mg equivalents every 2 weeks.

[0333] Example 3: Efficacy analysis and analysis

[0334] The primary efficacy endpoint (primary analysis) was time to IgG4-RD flare (TDF), which was the recurrence of previous signs / symptoms of IgG4-RD or the onset of new signs / symptoms requiring initiation of rescue therapy from randomization to Week 52. The proportion of patients achieving complete remission by Week 52 was defined as having an IgG4-RD RI score of 0 by Week 52 and not being involved in a flare and not having flare-directed treatment.

[0335] The date of IgG4-RD onset was defined as the start date of any onset treatment required for disease onset (new GC treatment, other immunotherapy, or interventional procedure). A hazard ratio of 0.37 was used as the threshold for trial success. A hazard ratio of 0.37 corresponded to 35% of patients in the placebo group expected to have disease onset by week 52 (and 30 such patients were required) and 15% of patients in the obelimonab group expected to have disease onset by week 52 (13 such patients were required).

[0336] An extension of the Kaplan-Meier (KM) estimate (Aalen and Johansen 1978) and the log-rank test (Gray 1988) will be used for intention-to-treat comparisons of obelizumab and placebo over the entire observed follow-up period. The extension accommodates adjustment for stratification and competing risks (if necessary), where stratification is 1 organ versus >1 organ, and newly diagnosed versus relapsed and competing risks are four possible types:

[0337] 1. Death may be partially attributed to IgG4-RD,

[0338] 2. Withdrawal due to perceived lack of efficacy, and

[0339] 3. Withdrawal due to side effects or intolerance to study drug

[0340] 4. Because the Adjudication Committee (AC) disagrees with the investigator's initiation of rescue therapy.

[0341] Estimates of flare incidence are limited to less than 100% in the presence of competing risks, so competing risks need to reflect the reality that these events are alternatives to and occur before the detection of flares and are hopefully infrequent. Two possible sources of competing risk, namely, related deaths and withdrawals due to lack of efficacy, are unlikely to occur before the identification of an IgG4-RD flare but could occur before an flare in the absence of data on flare-repair therapy. In the actual clinical setting, such events could occur before the identification of an flare due to less extensive patient monitoring than occurs during clinical studies.

[0342] If competing risk events are frequent, or if dates are frequently missing that require interval censoring, then tipping point analysis will be used to explore the robustness of the analysis. For example, if the primary outcome is statistically significant, conditions under which the outcome may become nonsignificant will be explored. For interval censoring (episode rescue treatment dates are unknown, but there are minimum and maximum dates), this will require assigning a different number of such outcomes to the minimum date in the obelizumab group and the maximum date in the placebo group. For competing risks, this will require reassigning a different number of such events as episode events in the obelizumab group, and right censoring for the placebo group.

[0343] In addition to the primary analysis, a sensitivity analysis will be performed using a proportional hazard model to evaluate the treatment effect adjusted for prognostic factors and baseline covariates. The model will use time to disease onset (TDF) as the response variable, with treatment group, stratification factors, subgroup variables, and continuous variables (e.g., age) as covariates. Table 5 summarizes the secondary endpoints.

[0344] Table 5 - Summary of Secondary Efficacy Endpoints and Analyses

[0345]

[0346]

[0347] Example 4: PK / PD analysis of subcutaneous administration of obelizumab

[0348] This example describes an exemplary PK / PD analysis of subcutaneous administration of obelimonab. Simulation experiments show that a dose of 250 mg of obelimonab administered subcutaneously every 7 days achieves a maximum inhibition of the absolute B cell count of about 50% of the baseline and 100% receptor occupancy of CD19 during the entire dosing interval. When compared with the PK of the previous intravenous study, the PK and PD simulations of 250 mg subcutaneously every 7 days support sufficient safety coverage (lower concentration maximum [C maximum] and area under the curve [AUC]), while maintaining higher trough concentrations for target engagement. The average steady-state C maximum and AUC (normalized relative to 336 hours) of 250 mg subcutaneously every 7 days are 1 / 11 and 1 / 2.5 of the average steady-state C maximum and AUC of 10 mg / kg intravenously every 14 days, respectively. All mAb treatments given by the intravenous route are associated with the risk of non-allergic (cytokine release syndrome) and allergic (hypersensitivity) infusion-related reactions.

[0349] However, the mean steady-state trough concentration was 4.6-fold higher with 250 mg subcutaneously every 7 days, which may provide better maintenance of target engagement and maximal PD effect. These data suggest that treatment of IgG4-RD with obelizumab will provide a reduction in the risk and frequency of disease flares.

[0350] Example 5: PK / PD simulation model validation of obelizumab dosing in patients with immunoglobulin G4-related disease (IgG4-RD)

[0351] This example demonstrates the validation of an appropriate obelizumab dose for the treatment of patients with immunoglobulin G4-related disease (IgG4-RD) using PK / PD.

[0352] A population PK / PD model was established based on 4 studies (two Phase I studies and two Phase 2 studies) that describes the exposure-response (ER) relationship of obelizumab plasma PK and plasma obelizumab concentrations to absolute B cell (ABC) counts or CD19 receptor occupancy (RO) after single and multiple intravenous (IV) or subcutaneous (SC) administration to healthy subjects and patients with RA or IgG4-RD. The PK model was a two-compartment model with first-order absorption and first-order elimination for subcutaneous administration. Two covariates were included in the PK model - dose and disease state.

[0353] ● Dosage as in E 最大值 Model Covariates on the scaling factors in the PK model describing the nonlinear PK of obelizumab observed at low doses were included.

[0354] • Disease status was included as a covariate for the elimination rate of obelizumab from the central compartment. The final ABC count PK / PD model was an indirect response model.

[0355] By S-Shaped 最大值 The function describes the increase in ABC disappearance rate by obelizumab (K out The CD19 RO PK / PD model is an S-shaped 最大值 Table 6 lists the parameters estimated by the PK, ABC PK / PD, and CD19 RO PK / PD models.

[0356] Table 6 - Parameters estimated from the PK / PD model.

[0357]

[0358]

[0359] IIV = inter-individual variability; PK model: kel = elimination rate constant, V2 = volume of distribution in the plasma compartment, Q = inter-compartmental clearance, V3 = volume of distribution in the peripheral compartment, ka = absorption rate constant for subcutaneous administration, F1 = bioavailability of the subcutaneous dose, Vmax = proportionality constant between the intravenous dose and the scaling factor for the intravenous dose, sc = scaling factor for the dose administered intravenously, Km = intravenous dose that achieves 50% saturation of the binding sites, RA on kel = study 2 of ABC counts Rheumatoid arthritis patients in PK / PD model: Kin = zero-order rate constant describing the formation of ABC counts, Kout0 = first-order rate constant describing the disappearance of ABC counts, EC50 = plasma obelizumab concentration that achieves half of the maximal reduction in ABC counts, Emax = maximum effect associated with plasma obelizumab concentration for CD19 RO PK / PD model: Emax = maximum fractional change from baseline in CD19 RO, EC50 = plasma obelizumab concentration that achieves half of the maximal reduction in CD19 RO = sigmoid parameter controlling the steepness of the ER relationship

[0360] The population PK / PD model was used to simulate the PK exposure values ​​of obelizumab after various subcutaneous doses and the changes in ABC counts and CD19 RO. Table 7 lists the predicted 10th, 25th, 50th, 75th and 90th percentiles of the minimum plasma obelizumab concentration (Cmin), maximum plasma obelizumab concentration (Cmax), mean plasma obelizumab concentration (Cmean) and area under the plasma concentration-time curve (AUC) in the first week and at steady state after various weekly subcutaneous doses. Figure 1-3 Shown are plasma obelizumab concentration-time profiles, ABC relative to baseline, and CD19 RO over time.

[0361] Based on plasma obelimax C 最大值，稳态 Based on the simulated 90th percentile of , 90% of subjects receiving 250 mg of obelizumab once weekly would have plasma obelizumab concentrations less than 39,265 ng / mL, which is 1 / 6.9 of the mean Cmax (272,832 ng / mL) observed at 10 mg / kg IV from Study XmAb5871-02.

[0362] Based on plasma obelimax C 最小值，稳态 At the simulated 10th percentile, 90% of subjects receiving 250 mg of obelizumab once weekly would have plasma obelizumab concentrations greater than 8376 ng / mL ( Figure 1), the plasma obelimonab concentration was at least 85.0 times the EC50 and 9.44 times the EC90 value of ABC counts. The reduction in ABC counts with plasma obelimonab exposure was rapid, and a maximum reduction of approximately 50% of the baseline ABC count value was achieved. The magnitude of the effect of once-weekly subcutaneous administration of 15.625, 31.25, 62.5, 125 and 250 mg of obelimonab on ABC counts was similar during dosing intervals with different recovery phases after dosing was stopped. Once obelimonab 250 mg weekly dosing was stopped, ABC counts took approximately 10 weeks to return to baseline levels ( Figure 2 ).

[0363] Based on plasma obelimax C 最小值，稳态 At the simulated 10th percentile, 90% of subjects receiving 250 mg of obelizumab once weekly would have plasma obelizumab concentrations greater than 8376 ng / mL ( Figure 1 ), the plasma obelimonab concentration was at least 112 times the EC50 and 37.1 times the EC90 value of CD19 RO. The increase in CD19 RO with plasma obelimonab exposure was rapid, and approximately 100% RO was achieved. During the dosing interval, the magnitude of the effect of 15.625, 31.25, 62.5, 125 and 250 mg of obelimonab administered subcutaneously once a week on CD19 RO was similar, and after stopping dosing, returned to baseline with different recovery times. After stopping weekly dosing of 250 mg obelimonab, CD19 RO took approximately 8 weeks to return to baseline levels ( Figure 3 ).

[0364] Table 7 - Population PK model predictions and steady-state plasma obelizumab concentrations in the first week following once-weekly subcutaneous administration of 125 and 250 mg doses

[0365]

[0366] Cmin: minimum plasma concentration; Cmean: mean plasma concentration; Cmax: maximum plasma concentration;

[0367] AUC0-168h: area under the plasma concentration-time curve from time 0 to 168 hours; Cmin, steady-state: minimum plasma concentration at steady-state

[0368] concentration; Cmean, steady state: mean plasma concentration; Cmax, steady state: maximum plasma concentration at steady state

[0369] Concentration; AUCtau: area under the plasma concentration-time curve during the dosing interval at steady state (tau = 168 hours)

[0370] Based on PK / PD simulations, it was observed that a higher C was achieved with 250 mg subcutaneous administration once weekly. 最小值 In addition, weekly subcutaneous dosing of 250 mg provided higher AUC and C compared with subcutaneous 250 mg every two weeks. 最大值 At the same time, an adequate safety margin was maintained based on data from clinical and nonclinical studies.

[0371] Table 8 - Summary of subcutaneous delivery of obelizumab administered biweekly compared to weekly and safety margin

[0372]

[0373] a: Based on 12-week study with weekly GLP: Cmax of 5,900 μg / mL at the NOAEL of 100 mg / kg IV once weekly, and AUC of 52,000 μg / mL*day or 1,250,000 μg / mL*hour (mean from male and female monkeys) (2,500,000 μg / mL*hour AUC if normalized to 14 days for comparison to once every two weeks); b: Based on Study XmAb5871-02: Cmax

[0374] The subcutaneous (SC) dose was observed to achieve better PK exposure than that observed at 250 mg SC every two weeks while maintaining adequate safety coverage (see Table 8).

Claims

1. A method of treating IgG4-related disease (IgG4-RD), the method comprising subcutaneously administering obexelimab to a human patient at least 18 years of age at a dose of 250 mg once a week.

2. The method of claim 1, wherein the obelizumab is administered as 2X 1 mL injections or 1X 2 mL injections.

3. The method of claim 1 or 2, wherein the obelizumab is administered in a liquid formulation comprising 125 mg / mL obelizumab, 2.35 mg / mL sodium acetate trihydrate, 0.17 mg / mL acetic acid, 30 mg / mL L-proline, 0.1 mg / mL polysorbate 80 at a pH of 5.

5.

4. according to the method described in any one of the preceding claims, wherein the human patient has received glucocorticoid (GC) therapy.

5. The method of claim 4, wherein the GC therapy is administered at a dose of 20-60 mg / day of prednisone or equivalent.

6. The method of claim 4 or 5, wherein the GC therapy is continued during treatment with obelizumab.

7. The method of claim 4 or 5, wherein the GC therapy is curtailed.

8. The method of claim 7, wherein the GC therapy is reduced to complete cessation.

9. The method of any one of claims 1 to 3, wherein the obelizumab is administered in combination with GC therapy.

10. The method of any one of the preceding claims, wherein obelizumab is administered for a period sufficient to improve, stabilize, or reduce one or more symptoms of IgG4-RD relative to a control.

11. The method of claim 10, wherein at least one symptom is manifested in an organ selected from the group consisting of lymph nodes, submandibular glands, parotid glands, lacrimal glands, kidneys, heart, pericardium, orbits, nasal cavity, lungs, liver or bile ducts, salivary glands, and pancreas.

12. The method according to any one of the preceding claims, wherein obelizumab is administered to the patient to improve clinical symptoms.

13. The method of any one of the preceding claims, wherein obelizumab is administered to the human patient during a relapse-free period to prevent relapse.

14. The method of claim 13, wherein the relapse-free period is determined by the number of days from disease onset.

15. The method of claim 14, wherein the relapse-free period is at least 60 days, 70 days, 80 days or 90 days from the first administration of obelizumab.

16. The method of claim 15, wherein the relapse-free period is up to 40 weeks, up to 45 weeks, up to 50 weeks, up to 52 weeks from the first administration of obelizumab.

17. The method of any one of the preceding claims, wherein obelizumab is administered to the patient until the patient has an active IgG4-RD disease flare requiring initiation of rescue therapy.

18. The method of claim 17, wherein the salvage therapy comprises administering GC therapy.

19. The method of any one of the preceding claims, wherein the human patient is relapsed or refractory to prior treatment for IgG4-RD.

20. The method of claim 19, wherein the human patient is relapsed or refractory to rituximab.

21. The method according to any one of the preceding claims, wherein the disease activity of the human patient is assessed using the IgG4-RD Reaction Index (RI).

22. The method of any one of the preceding claims, wherein the human patient achieves a reduction in IgG4-RD RI of ≥ 2 points from day 1 of administration of obelizumab.

23. The method according to any one of the preceding claims, wherein the human patient has an American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria IgG4-RD score (IgG4-RD score) ≥ 20 prior to administration of obelizumab.

24. The method according to any of the preceding claims, wherein the human patient presents with IgG4-RD manifestations selected from the group consisting of: IgG4-related sialadenitis (chronic sclerosing sialadenitis, Kuttner's tumor, Mikulicz's disease), IgG4-related dacryoadenitis (Mikulicz's disease), IgG4-related ophthalmopathy (idiopathic orbital inflammatory disease, orbital pseudotumor), chronic sinusitis IgG4-related hypophysitis (IgG4-related panhypophysitis, IgG4-related adenohypophysitis, IgG4-related infundibular neurohypophysitis, autoimmune hypophysitis), IgG4-related pachymeningitis, IgG4-related leptomeningitis (idiopathic hypertrophic pachymeningitis), IgG4-related pancreatitis (autoimmune pancreatitis type 1, IgG4-related AIP, lymphospermic sclerosing pancreatitis, chronic pancreatitis with main pancreatic IgG4-related pulmonary disease (pneumonic pseudotumor), IgG4-related pleurisy, IgG4-related hepatopathy, IgG4-related sclerosing cholangitis, IgG4-related cholecystitis, IgG4-related aortitis (inflammatory aortic aneurysm), IgG4-related periaortitis (chronic periaortitis), IgG4-related periarteritis, IgG4-related pericarditis, IgG4-related mediastinitis (fibrinous mediastinitis), IgG4-related retroperitoneal fibrosis (retroperitoneal fibrosis), Albarran-Ormond syndrome, Ormond's diseasedisease)(retroperitoneal fibrosis), perirenal fasciitis, Gerota's fasciitis / syndrome, fibrous periureteritis, sclerosing lipogranuloma, sclerosing retroperitoneal granuloma, nonspecific retroperitoneal inflammation, sclerosing retroperitoneal cavity inflammation, retroperitoneal vasculitis with perivascular fibrosis), IgG4-related mesenteritis (subtypes are: mesenteric fat membrane inflammation, mesenteric fat dystrophy and retractile mesenteritis) (sclerosing mesenteritis, systemic nodular fat membrane inflammation, liposclerosing mesenteritis, mesenteric Weber-Christian disease, mesenteric fat granuloma, xanthogranulomatous mesenteritis), 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 peripheral fibrosis (chronic testicular pain), IgG4-related paratesticular pseudotumor, IgG4-related epididymo-orchitis (paratesticular fibrous pseudotumor, inflammatory pseudotumor of the spermatic cord, pseudosarcomatous myofibroblastic proliferation of the spermatic cord, proliferative spermatic corditis, chronic proliferative orchitis, fibromatous orchitis, nodular orchitis, reactive orchitis, fibromesothelioma), IgG4-related lymphadenopathy, IgG4-related skin diseases (angiolymphoid hyperplasia with eosinophilia, cutaneous pseudolymphoma), IgG4-related perineural disease, and IgG4-related thyroid disease (Reidel's thyroiditis), inflammatory pseudotumor, and multifocal fibrosclerosis.

25. The method of any of the preceding claims, wherein the human patient presents with IgG4-RD manifestations selected from the group consisting of autoimmune pancreatitis (lymphoplasmic sclerosing pancreatitis), eosinophilic angiocentric fibrosis (affecting the orbits and upper respiratory tract), fibrosing mediastinitis, idiopathic hypertrophic pachymeningitis, idiopathic tubulointerstitial nephritis, inflammatory pseudotumor, Kuttner tumor, Miguel's disease, fibrosclerosis, periaortitis, periarteritis, inflammatory aortic multifocal aneurysm, Ormond's disease (retroperitoneal fibrosis), Riedel's thyroiditis, and sclerosing mesenteritis.

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