Extended dosing regimen of anti-CD20 antibodies in treatment of multiple sclerosis

Abstract

The present disclosure relates to treatment regimens for the treatment of multiple sclerosis (MS). These methods include subcutaneous administration of anti-CD20 antibodies and provide efficacy and safety with extended subcutaneous administration intervals.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 588,851, filed October 9, 2023, entitled “Extended dosing regimens for anti-CD20 antibodies in the treatment of multiple sclerosis,” and U.S. Provisional Application No. 63 / 558,544, filed February 27, 2024, entitled “Extended dosing regimens for anti-CD20 antibodies in the treatment of multiple sclerosis,” the contents of each of which are incorporated herein by reference in their entirety.

[0002] Invention Field This disclosure provides a regimen for administering anti-CD20 antibodies at extended dosing intervals (e.g., subcutaneously) in the treatment of multiple sclerosis. Exemplary extended dosing regimens are provided, including an extended dosing regimen for the monoclonal anti-CD20 antibody ofatumumab. Background Technology

[0003] Multiple sclerosis (MS) is a chronic, immune-mediated central nervous system disease characterized by inflammation, demyelination, and axonal / neuronal destruction, ultimately leading to severe disability. Relapsing MS (RMS) is the most common form of MS.

[0004] Anti-CD20 monoclonal antibodies target CD20 expressed on B cells, which are believed to play a crucial role in myelin and axonal damage in MS, thereby suppressing disease-related inflammatory activity. Exemplary anti-CD20 antibodies used in clinical practice to treat MS include ocrelizumab (KESIMPTA® / BONSPRI®), ocrelizumab (OCREVUS®), rituximab (RITUXAN® / MABTHERA®), and ublituximab (BRIUMVI®).

[0005] Ofatumumab (also known as OMB157) is a fully human immunoglobulin 1 (IgG1κ) monoclonal antibody. Subcutaneous (sc) administration of ofatumumab causes rapid frequency- and dose-dependent B-cell vasoconstriction. Phase III clinical trials COMB157G2301 and COMB157G2302 (Hauser SL, Bar-Or A, Cohen JA et al. (2020) Ofatumumabversus Teriflunomide in Multiple Sclerosis. N Engl J Med; 383(6):546-57) demonstrated that subcutaneous ofatumumab at a subsequent (maintenance) dose of 20 mg every 4 weeks (i.e., monthly) after an initial dose of 20 mg on days 1, 7, and 14 (weeks 0, 1, and 2) effectively suppressed disease inflammatory activity in patients with relapsed MS. Based on this data, ofatumumab has been approved for the treatment of adult patients with RMS in more than 80 countries.

[0006] The treatment of MS requires safe and effective extended dosing regimens of oflamb and other anti-CD20 antibodies. However, such regimens are particularly difficult to provide due to the complex nature of MS and the important role of drug targets (i.e., B cells) in both health and disease. Summary of the Invention

[0007] While monthly subcutaneous 20 mg of low-dose oflamumab has proven to be highly effective and safe, less frequent follow-up dosing can further improve patient experience and clinical outcomes. For example, less frequent follow-up injections can further reduce the risk of any local injection site reactions, such as bruising, skin irritation, tissue damage, or infection, thereby improving patient experience. Furthermore, less frequent follow-up dosing reduces the treatment burden on patients and their caregivers. This, in turn, can increase adherence to prescribed treatment regimens and improve clinical outcomes. Less frequent administration also reduces delivery costs and the environmental footprint of delivery.

[0008] While less frequent administration may provide these and other benefits, prolonged dosing intervals may reduce the ability to tightly control B-cell depletion levels and, consequently, the ability to interrupt MS treatment to replenish B-cells sufficiently quickly when needed (e.g., in the presence of infection or at risk of infection, or in the event of other adverse events / conditions that may pose a risk to patient safety, such as malignancy, pregnancy, or when switching MS therapy). Furthermore, prolonged dosing regimens should provide at least non-inferiority in clinical efficacy and safety to any previously approved regimen.

[0009] Another challenge in developing extended dosing regimens is the delicate interaction between the regimen (i.e., antibody dose, route of administration, and frequency of administration) and the antibody formulation. For extended dosing regimens to achieve clinical efficacy that is non-inferior to any previously approved regimen, the antibody dose should be high enough to maintain exposure throughout the dosing interval and thus sustain B-cell depletion levels between doses. However, high antibody doses can lead to formulation instability, particularly when formulated for subcutaneous administration, as subcutaneous formulations are typically volume-limited. Currently, a preferred volume for subcutaneous injection is considered to be about 2 mL or less; larger volumes generally require additional agents that locally degrade the extracellular matrix (e.g., endoglucosidases, such as hyaluronidase). Reforming higher doses of antibody in smaller volumes can cause changes in viscosity and stability, which can lead to aggregation, particle formation, and adverse events (e.g., injection-related reactions).

[0010] Therefore, developing a clinically effective extended dosing regimen for subcutaneous administration of anti-CD20 antibodies in the treatment of MS requires careful balancing of the pharmacokinetic and pharmacodynamic profiles of the regimen with its formulation characteristics.

[0011] This disclosure provides a novel and advantageous extended dosing regimen for subcutaneous (sc) administration of an anti-CD20 antibody (e.g., ofamumumab) in the treatment of MS. Using pharmacokinetic and pharmacodynamic population B-cell modeling, the inventors identified advantageous combinations of anti-CD20 antibody (e.g., ofamumumab) dosages and dosing intervals that reduce the treatment burden on patients without compromising the safety and / or efficacy of the treatment.

[0012] Specifically, the inventors have demonstrated that a follow-up (e.g., maintenance) dosing regimen of 135 mg of ofamumumab administered subcutaneously every two months (Q2M) provides a less frequent but safe and effective ofamumumab dosing option for patients with MS. Estimated pharmacokinetic and pharmacodynamic morphologies of the 135 mg subcutaneous Q2M regimen indicate that it provides at least similar (e.g., non-inferior) exposure coverage over the entire two-month dosing interval compared to the approved 20 mg of ofamumumab subcutaneously once monthly (Q1M) follow-up (e.g., maintenance) dosing regimen. The inventors evaluated numerous different regimens and found, unexpectedly, that the 135 mg subcutaneous Q2M regimen disclosed herein is a particularly advantageous maintenance regimen because it provides similar or even better sustained B-cell depletion levels compared to the approved once-monthly maintenance regimen. Therefore, the Q2M dosing regimen provided herein allows for extended follow-up (e.g., maintenance) dosing while preserving the ability to rapidly replenish B-cells through treatment interruption when necessary, thus retaining a tightly controlled capacity for B-cell levels.

[0013] According to certain embodiments described herein, a subsequent regimen of 135 mg of ofamumumab subcutaneously every two months, following three consecutive weeks (e.g., at weeks 0, 1, and 2) of initial (e.g., loading) 20 mg subcutaneous doses over two months, is estimated to deplete B-cell levels to ≤10 cells / μL and maintain B-cell levels below this threshold during each full two-month interval between injections, and in some patients even below the B-cell levels achieved using a Q1M regimen. The B-cell levels achieved at the end of each 135 mg Q2M interval are similar to those achieved at the end of each 20 mg Q1M interval. Therefore, the 135 mg Q2M interval preserves the aforementioned tight control of B-cell levels and allows for replenishment by discontinuing treatment if necessary. Furthermore, the 135 mg dose can be formulated into a stable, small-volume formulation suitable for subcutaneous administration.

[0014] As demonstrated in the phase 2 subcutaneous oflavumab study (OMS112831-MIRROR study) in patients with relapsed MS, lower peripheral B-cell levels resulted in smaller lesion volumes (Gd+T1). In the B-cell-Gd+T1 lesion modeling of data from the OMS112831 study, used for dose selection in a phase 3 dosing regimen, a B-cell count cutoff of 8 cells / μL was established. Subsequent analyses based on COMB157G2301 and COMB157G2302 data (ASCLEPIOS I and II) used a B-cell count cutoff of 10 cells / μL to assess the extent of B-cell depletion in the entire experimental population. Both cutoffs correspond to a reduction of approximately 95% in peripheral B-cell count compared to a typical baseline B-cell count of 200 cells / μL.

[0015] Therefore, the level of B-cell depletion associated with the 135 mg subcutaneous Q2M regimen is expected to produce at least non-inferiority clinical efficacy compared to the 20 mg subcutaneous Q1M regimen.

[0016] Therefore, the extended dosing regimens disclosed in this article for the treatment of multiple sclerosis produce similar (or even improved) clinical efficacy, as well as improved patient experience and other advantages.

[0017] Therefore, this article provides a method for stabilizing (e.g., maintaining) B-cell counts in a subject in need during dosing intervals, the method comprising administering oframumab to the subject at two-month intervals to stabilize (e.g., maintain) the B-cell count in the subject. In one embodiment, oframumab is administered subcutaneously to the subject at two-month intervals (e.g., every two months (Q2M)). In some embodiments, the method maintains the subject's B-cell count to ≤10 cells / μL. In one embodiment, the subject has multiple sclerosis (MS).

[0018] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0019] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0020] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0021] Therefore, this article provides a method for treating multiple sclerosis (MS) in subjects of need, the method comprising administering an anti-CD20 antibody (e.g., ofumumab) subcutaneously to the subject approximately every two months (Q2M) at a dose of approximately 100-150 mg (e.g., approximately 110 mg or approximately 130 mg), approximately 120-150 mg, or approximately 130-140 mg (e.g., approximately 135 mg) of ofumumab.

[0022] In some aspects, methods of treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) include (a) administering oframumab subcutaneously to the subject during an initial (e.g., loading) dosing regimen of about 19 mg to about 21 mg (e.g., about 20 mg, e.g., at week 0, week 1, and week 2) once weekly for three consecutive weeks (e.g., at week 0, week 1, and week 2), followed by (b) administering oframumab subcutaneously to the subject during a subsequent (e.g., maintenance) dosing regimen of about 130 mg to about 140 mg (e.g., about 135 mg, e.g., at week 4) once every two months thereafter (or once every eight weeks thereafter; Q2M).

[0023] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0024] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0025] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0026] In some aspects of the invention, a method is provided for treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) by administering a subsequent (e.g., maintenance) dose regimen of oframumab to a subject who has received an initial (e.g., loading) dose regimen, wherein (a) the loading dose regimen comprises a weekly loading dose of about 20 mg (e.g., 20 mg) of oframumab three times consecutively, and (b) the maintenance dose regimen comprises administering about 130 mg to about 140 mg (e.g., 130-140 mg, e.g., about 135 mg, e.g., 135 mg) of oframumab every two months (or every eight weeks; Q2M). In some embodiments, the loading and maintenance doses are administered subcutaneously.

[0027] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0028] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0029] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0030] In some aspects, the present invention includes a method of treating MS (e.g., RMS, RRMS, PPMS, SPMS, or CIS) by administering about 130 mg to about 140 mg (e.g., 130-140 mg, e.g., about 135 mg, e.g., 135 mg) of oflamumab once every two months (or once every eight weeks; Q2M). In some embodiments, the administration is subcutaneous.

[0031] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0032] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0033] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0034] In some embodiments of any of the preceding aspects, the method consumes and / or maintains the subject’s B cell count (e.g., circulating B cell count or peripheral B cell count) to about ≤10 cells / μL, for example ≤10 cells / μL.

[0035] In some embodiments of any of the preceding aspects, oframumab is administered in the form of a pharmaceutical composition having a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0, e.g., pH 5.3 to 5.7, e.g., 5.4 to 5.6, e.g., about pH 5.5, about pH 5.2, about pH 5.3, about pH 5.4, about pH 5.6, about pH 5.7, or about pH 5.8), e.g., about pH 5.5. As used herein and in the following aspects, embodiments, and claims, a pH of about 5.5 encompasses, for example, pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), e.g., pH 5.3-5.8, e.g., pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), e.g., pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), e.g., pH 5.5. In some embodiments, a pH value of 5.5 ± 0.2 (5.3–5.7) is acceptable from a manufacturing perspective. In some embodiments, a pH range of 5.3–5.8 (or 5.2–5.8) is acceptable for the release of the composition (pharmaceutical product) for clinical use.

[0036] In some embodiments, the pharmaceutical composition further includes arginine, sodium acetate, sodium chloride, and polysorbate (e.g., polysorbate 80), optionally including EDTA. In some embodiments, the pharmaceutical composition includes about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally including about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.5 (e.g., pH 5.5), and optionally the pharmaceutical composition further comprises about 0.05 mM (e.g., 0.05 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.5 (e.g., pH 5.5), and a viscosity of not more than about 3 cP (e.g., not more than 3 cP), such as about 2 cP to about 3 cP (e.g., about 2.3 cP, such as 2.3 cP). In some embodiments, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.5 (e.g., pH 5.5).In some embodiments, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.5 (e.g., pH 5.5), and a viscosity of not more than about 3 cP (e.g., not more than 3 cP), such as about 2 cP to about 3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).

[0037] In some embodiments of any of the prior pharmaceutical compositions, the pharmaceutical composition contains no more than about 0.2% (w / v) (e.g., 0.2% (w / v)) of polysorbate (e.g., polysorbate 80). Alternatively, the pharmaceutical composition does not contain methionine.

[0038] In some embodiments, a subsequent (e.g., maintenance) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of about 80-100 mg / mL (e.g., 80-100 mg / mL, e.g., about 90 mg / mL, e.g., 90 mg / mL). In some embodiments, a subsequent (e.g., maintenance) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of about 80-100 mg / mL (e.g., 80-100 mg / mL, e.g., about 90 mg / mL, e.g., 90 mg / mL), wherein the viscosity of the pharmaceutical composition is not more than about 3 cP (e.g., not more than 3 cP), e.g., about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).

[0039] In some embodiments of any of the preceding aspects, oframumab is administered in the form of a pharmaceutical composition that does not contain an endoglucosidase, such as hyaluronidase.

[0040] In some embodiments of any of the preceding aspects, oframumab is administered using a prefilled pen (autoinjector). In some embodiments, the prefilled pen contains a fixed single unit dose of approximately 135 mg (e.g., 135 mg) of oframumab.

[0041] In some embodiments of any of the preceding aspects, the method causes one or more of the following: (a) a decrease in the number of Gd+ T1 lesions relative to baseline; (b) a decrease in the number of new or enlarged T2 lesions relative to baseline; and / or (c) a decrease in the annualized recurrence rate (ARR) relative to baseline. Therefore, the method provided herein may cause one or more of the following: (a) a Gd+ T1 lesion rate ≤ 0.03; (b) an annualized rate of new or enlarged T2 lesions ≤ 0.72; and / or (c) an annualized recurrence rate (ARR) ≤ 0.11.

[0042] In some embodiments, the Q2M maintenance regimen described herein (e.g., 135 mg oframumab subcutaneous Q2M) is non-inferior to a reference maintenance regimen (e.g., a maintenance regimen of 20 mg oframumab subcutaneous Q1M) in one or more of the following aspects: (a) a reduction in the number of Gd+ T1 lesions; (b) a reduction in the number of new or enlarged T2 lesions; (c) a reduction in ARR relative to the reference maintenance regimen; (d) the number and / or severity of injection-related reactions (IRRs); and / or (e) immunogenicity (e.g., the incidence of anti-drug antibodies (ADAs)). In some embodiments, the non-inferiority IRR number or severity is an injection-related systemic reaction, which is a reaction or symptom occurring within 24 hours after oframumab administration. In some embodiments, injection-related systemic reactions occur in less than 24.1% of subjects receiving the Q2M maintenance regimen described herein (e.g., 135 mg oframumab subcutaneous Q2M). In some implementations, injection-related systemic reactions occurred in less than 16.1% of subjects receiving the Q2M maintenance regimen described herein (e.g., 135 mg of ofamumab subcutaneous Q2M).

[0043] In some embodiments of any of the preceding aspects, the method further includes administration of concomitant therapy, such as that selected from corticosteroids, antihistamines, and acetaminophen. In some cases, the concomitant therapy is administered approximately 30 to 60 minutes before the administration of oframumab, for example, approximately 30 to 60 minutes prior to the administration of oframumab.

[0044] This document also provides a solution for injection, such as the solution described in the pharmaceutical compositions disclosed herein, containing about 120-150 mg, for example about 130-140 mg (e.g., about 135 mg) of an anti-CD20 antibody (e.g., oflamumab). The solution for injection is intended for subcutaneous administration. In some embodiments, the solution for injection has a pH of about 5.0 to about 7.0, for example, pH 5.0-7.0, for example, pH about 5.5, for example, pH 5.5.

[0045] In some embodiments, the solution for injection further includes arginine, sodium acetate, sodium chloride, and polysorbate (e.g., polysorbate 80), optionally containing EDTA. In some embodiments, the solution for injection contains about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), optionally containing about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA. In some embodiments, the solution comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.5 (e.g., pH 5.5), optionally further comprising about 0.05 mM (e.g., 0.05 mM) EDTA. In some embodiments, the solution comprises oframumab at a concentration of about 80-100 mg / mL (e.g., 80-100 mg / mL, e.g., about 90 mg / mL, e.g., 90 mg / mL). In some embodiments, the viscosity of the above-described solution for injection is not more than about 3 cP (e.g., not more than 3 cP), e.g., about 2-3 cP (e.g., about 2.3 cP, e.g., 2.3 cP).

[0046] In some aspects of the invention, a prefilled syringe or prefilled pen (e.g., an autoinjector containing a prefilled syringe) contains, for example, a solution as described above, formulated for subcutaneous administration, for example, a total volume of about 1.5 mL (e.g., 1.5 mL).

[0047] This article also provides a prefilled syringe or prefilled pen (autoinjector) containing about 120-150 mg, for example about 130-140 mg (e.g. about 135 mg) of anti-CD20 antibody (e.g., ofamumab), for example about 1.5 mL, for example 1.5 mL (e.g., a concentration of about 90 mg (e.g., 90 mg) of ofamumab per milliliter, for example a total volume of about 1.5 mL (e.g., 1.5 mL)).

[0048] This article also provides a kit containing one or more fixed single-unit doses of anti-CD20 antibody (e.g., ofamumab) each of about 120-150 mg (e.g., about 130-140 mg (e.g., about 135 mg)).

[0049] This document also provides a kit comprising one or more pre-filled syringes or pre-filled pens (autoinjectors), each containing a fixed single-unit dose of an anti-CD20 antibody (e.g., ofamumab) of about 120-150 mg (e.g., about 130-140 mg (e.g., about 135 mg)). Optionally, the kit may also include three pre-filled syringes or pre-filled pens (autoinjectors), each containing a fixed single-unit dose of an anti-CD20 antibody (e.g., ofamumab) of about 18-22 mg (e.g., about 19-21 mg (e.g., about 20 mg)). The kit provided herein may also include instructions for use, such as instructions for use including any of the methods for treating MS described herein.

[0050] These and other aspects of this disclosure, as well as implementation methods, are further described below. Attached Figure Description

[0051] Figure 1 The diagram shows simulated population B-cell morphology for subsequent dosing regimens (maintenance dose regimen) of subcutaneous 40 mg oframumab every two months (Q2M) versus subcutaneous 20 mg oframumab monthly (Q1M). Both subsequent dosing regimens were initiated at week 4 following the initial dosing regimen of 20 mg oframumab at weeks 0, 1, and 2 (loading dose regimen). Black line = median B-cell morphology for the 20 mg Q1M subsequent dosing regimen; dark gray shaded area = 5%–95% of the simulated B-cell data for that regimen. Dark gray line = median B-cell morphology for the 40 mg Q2M subsequent dosing regimen; light gray shaded area = 5%–95% of the simulated B-cell data for that regimen. Arrows point to the 95th percentile (shaded area) and median (solid line).

[0052] Figure 2The simulated population pharmacokinetic (PK) patterns are shown for the 40 mg oframumab subcutaneous Q2M follow-up regimen compared to the 20 mg oframumab subcutaneous Q1M follow-up regimen. Both follow-up dosing regimens began at week 4 after three consecutive doses of 20 mg oframumab (logarithmic scale) at weeks 0, 1, and 2. Black line = median PK pattern for 20 mg Q1M; dark gray shaded area = 5-95% of the simulated concentration data for the regimen. Dark gray line = median PK pattern for the 40 mg Q2M follow-up regimen; light gray shaded area = 5-95% of the simulated concentration data for the regimen. Arrows point to the 95th percentile (shaded area) and median (solid line). The vertical axis shows the concentration of oframumab (mg / mL), while the horizontal axis shows the time from the administration of the first dose of oframumab.

[0053] Figure 3 The simulated population B-cell morphology is shown for the follow-up dosing regimen (maintenance dose regimen) of 80 mg oframumab subcutaneously every two months (Q2M) versus 20 mg oframumab subcutaneously once a month (Q1M). Both follow-up dosing regimens were initiated at week 4 after three consecutive doses of the initial 20 mg oframumab regimen (load dose regimen) at weeks 0, 1, and 2. Black line = median B-cell morphology for the 20 mg Q1M follow-up dosing regimen; dark gray shaded area = 5%–95% of the simulated B-cell data for that regimen. Light gray line = median B-cell morphology for the 80 mg Q2M follow-up dosing regimen; light gray shaded area = 5%–95% of the simulated B-cell data for that regimen. Arrows point to the 95th percentile (shaded area) and median (solid line).

[0054] Figure 4 The simulated population pharmacokinetic (PK) patterns are shown for the 80 mg oframumab subcutaneous Q2M follow-up regimen compared to the 20 mg oframumab subcutaneous Q1M follow-up regimen. Both follow-up dosing regimens began at week 4 after three consecutive doses of 20 mg oframumab (logarithmic scale) at weeks 0, 1, and 2. Black line = median PK pattern for 20 mg Q1M; dark gray shaded area = 5-95% of the simulated concentration data for the regimen. Dark gray line = median PK pattern for the 80 mg Q2M follow-up regimen; light gray shaded area = 5-95% of the simulated concentration data for the regimen. Arrows point to the 95th percentile (shaded area) and median (solid line). The vertical axis shows the concentration of oframumab (mg / mL), while the horizontal axis shows the time from the administration of the first dose of oframumab.

[0055] Figure 5The simulated population B-cell morphology is shown for the follow-up dosing regimen (maintenance dose regimen) of 135 mg oframumab subcutaneously every two months (Q2M) versus 20 mg oframumab subcutaneously once a month (Q1M). Both follow-up dosing regimens were initiated at week 4 after three consecutive doses of 20 mg oframumab at weeks 0, 1, and 2 (load dose regimen). Black line = median B-cell morphology for the 20 mg Q1M follow-up dosing regimen; light gray shaded area = 5%–95% interval of simulated B-cell data for the regimen. Light gray line = median B-cell morphology for the 135 mg Q2M follow-up dosing regimen; dark gray shaded area = 5%–95% interval of simulated B-cell data for the regimen. Arrows point to the 95th percentile (shaded area) and median (solid line).

[0056] Figure 6 The simulated population pharmacokinetic (PK) patterns are shown for the 135 mg oframumab subcutaneous Q2M follow-up regimen compared to the 20 mg oframumab subcutaneous Q1M follow-up regimen. Both follow-up dosing regimens began at week 4 after three consecutive doses of 20 mg oframumab (logarithmic scale) at weeks 0, 1, and 2. Black line = median PK pattern for 20 mg Q1M; dark gray shaded area = 5-95% percentile of simulated concentration data for the regimen. Dark gray line = median PK pattern for the 135 mg Q2M follow-up regimen; light gray shaded area = 5-95% percentile of simulated concentration data for the regimen. Arrows point to the 95th percentile (shaded area) and median (solid line). The vertical axis shows the concentration of oframumab (mg / mL), while the horizontal axis shows the time from the first dose of oframumab.

[0057] Figure 7 This paper outlines the study design for a Phase III clinical trial comparing subsequent dosing regimens of ofamumumab 135 mg subcutaneously (auto-injector) Q2M versus ofamumumab 20 mg subcutaneously (auto-injector) Q1M. Eligible study participants were randomized to one of the two treatment groups at a 1:1 randomization ratio on day 1 visit. The study consisted of two parts: a core part and an extension part. At the end of the parallel group portion, patients in the 20 mg Q1M group were switched to start receiving 135 mg Q2M at week 12. Detailed Implementation

[0058] Anti-CD20 antibody The antibody used in the method disclosed herein is an anti-CD20 antibody. The anti-CD20 antibody can induce the consumption of CD20-positive B cells. The antibody is a monoclonal anti-CD20 antibody.

[0059] In some embodiments, the anti-CD20 antibody is a full-length antibody. In some embodiments, the anti-CD20 antibody is a full-length IgG1 antibody containing the human Fc region. In some embodiments, the anti-CD20 antibody is a completely human antibody. In some embodiments, the anti-CD20 antibody is humanized. In other embodiments, the anti-CD20 antibody is a chimeric antibody.

[0060] In one embodiment, the anti-CD20 antibody is olfamumab or a variant thereof as defined below (i.e., a similar antibody). In another embodiment, the anti-CD20 antibody is olprexaumab or a variant thereof as defined below (i.e., a similar antibody). In yet another embodiment, the anti-CD20 antibody is utuximab or a variant thereof as defined below (i.e., a similar antibody). Based on the content of this disclosure, those skilled in the art can provide anti-CD20 antibodies suitable for use in the disclosed methods.

[0061] Ophamumab In a preferred embodiment, the anti-CD20 antibody is oframumab. oframumab (OMB157) is a fully human immunoglobulin type 1 G1κ (IgG1κ) monoclonal antibody (mAb) that targets CD20 expressed on B cells and has been developed for the treatment of MS, particularly relapsed MS (RMS). oframumab specifically recognizes a conformational (i.e., discontinuous) epitope encompassing a large and small extracellular loop on the human CD20 molecule, which allows oframumab to bind very close to the plasma membrane. oframumab binding to CD20 induces B cell lysis primarily through complement-dependent cytotoxicity (CDC) and to a minor extent through antibody-dependent cell-mediated cytotoxicity (ADCC). The pharmacokinetics (PK) of oframumab have been reported to include low clearance, small volume of distribution, and a relatively long half-life (T1 / 2) of 16 days. It has been reported that binding to human B cells occurs at a drug concentration of 287 ng / mL with a half-maximal response (EC50). The theoretical molecular weight is 146 kDa, calculated from the amino acid composition deduced from the DNA sequence. Ofamumumab is typically produced in mouse cell lines (NS0). Ofamumumab is defined by SEQ ID No. 1-10 (Table 9). As those skilled in the art will know, post-translational modifications, including glycosylation and C-terminal lysine cleavage of the heavy chain, may occur during its production in cell cultures (such as NSO cells).

[0062] In some embodiments, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and light chain complementarity-determining regions SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8. In some embodiments, the anti-CD20 antibody comprises a variable heavy chain sequence of SEQ ID NO: 4 and a variable light chain sequence of SEQ ID NO: 9, or sequences that are at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 4 and / or SEQ ID NO: 9. In some embodiments, the anti-CD20 antibody comprises a heavy chain sequence of SEQ ID NO: 5 and a light chain sequence of SEQ ID NO: 10, or sequences that are at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5 and / or SEQ ID NO: 10. In other embodiments, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and light chain complementarity-determining regions SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8, wherein the variable heavy chain sequence excluding CDR is at least 90%, at least 95%, at least 97% or at least 99% identical to SEQ ID NO: 4, and the variable light chain sequence excluding CDR is at least 90%, at least 95%, at least 97% or at least 99% identical to SEQ ID NO: 9. In another embodiment, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and light chain complementarity-determining regions SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, wherein the heavy chain sequence excluding CDR is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 5, and the light chain sequence excluding CDR is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 10. Any of these anti-CD20 antibodies may be considered similar to oflambumab, the complete sequence of which is defined by SEQ ID NOs 5 and 10.

[0063] Those skilled in the art will understand that the percentage of sequence identity, as used herein, refers to the percentage of identical amino acid residues when two sequences are aligned and compared along their full length. Therefore, the percentage of sequence identity can be calculated using a global pairwise sequence alignment tool (end-to-end alignment of the sequences to be aligned), such as Needle (EMBOSS), which uses the Needleman-Wunsch algorithm to form the optimal global alignment of two sequences. The default settings are: BLOSUM62 matrix, vacancy open penalty of 10, vacancy extension penalty of 0.5, terminal vacancy penalty (no), terminal vacancy open penalty of 10, and terminal vacancy extension penalty of 0.5.

[0064] Orizumab Ogrizumab (also known as 2H7) is a humanized monoclonal antibody based on a human immunoglobulin G1 (IgG1) framework containing heavy chain VHIII and light chain VκI subsequence sequences. Ogrizumab selectively targets CD20-expressing B cells. Upon binding to the cell surface, osgrizumab selectively consumes CD20-expressing B cells through antibody-dependent phagocytosis (ADCP), antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis.

[0065] Oreganotumab has reportedly a half-life of approximately 26 days. The complete molecular formula of ozoglucon is C1. 6482 H 9952 N 1712 O 2014 S 46 The calculated molecular weight of the fully deglycosylated olizumab is approximately 145,564 Da (peptide chain only, without heavy chain C-terminal lysine residues). Oolizumab is typically produced in Chinese hamster ovary cells using recombinant DNA technology. Oolizumab is defined by SEQ ID NO 11-20 (Table 9).

[0066] In some embodiments, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and light chain complementarity-determining regions SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18. In some embodiments, the anti-CD20 antibody comprises a variable heavy chain sequence of SEQ ID NO: 14 and a variable light chain sequence of SEQ ID NO: 19, or sequences that are at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 14 and / or SEQ ID NO: 19. In some embodiments, the anti-CD20 antibody comprises a heavy chain sequence of SEQ ID NO: 15 and a light chain sequence of SEQ ID NO: 20, or sequences that are at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15 and / or SEQ ID NO: 20. In other embodiments, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13, and light chain complementarity-determining regions SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the variable heavy chain sequence excluding CDR is at least 90%, at least 95%, at least 97% or at least 99% identical to SEQ ID NO: 14, and the variable light chain sequence excluding CDR is at least 90%, at least 95%, at least 97% or at least 99% identical to SEQ ID NO: 19. In another embodiment, the anti-CD20 antibody comprises heavy chain complementarity-determining regions SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, and light chain complementarity-determining regions SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, wherein the heavy chain sequence excluding CDR is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 15, and the light chain sequence excluding CDR is at least 90%, at least 95%, at least 97%, or at least 99% identical to SEQ ID NO: 20. Any of these anti-CD20 antibodies may be considered similar to oligrin, the complete sequence of which is defined by SEQ ID NO 15 and 20.

[0067] Utoximab Ultuximab is a chimeric monoclonal antibody. It is produced in the rat cell line YB2 / 0. Ultuximab selectively targets and induces the lysis of CD20-expressing B cells. Ultuximab depletes B cells through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

[0068] Utuximab has reportedly an evaluation half-life of approximately 22 days. The complete molecular formula of utuximab is C2. 6418 H 9866 N 1702 O 2006 S 48 The calculated molecular weight of utuximab is 144,504 Da.

[0069] In some embodiments, the anti-CD20 antibody comprises the heavy chain sequence of SEQ ID NO: 21 and the light chain sequence of SEQ ID NO: 22, or the same sequence as SEQ ID NO: 21 and / or SEQ ID NO: 22 by at least 90%, at least 95%, at least 97%, or at least 99%.

[0070] plan This document provides a method for treating multiple sclerosis (MS) in a subject in need, comprising administering an anti-CD20 antibody subcutaneously to the subject at a dose of approximately 100-600 mg (e.g., approximately 600 mg, approximately 200 mg, or approximately 135 mg) every approximately 2 months. This document also provides a method for treating multiple sclerosis in a subject in need, comprising administering an anti-CD20 antibody subcutaneously to the subject at a dose of approximately 100-600 mg every approximately 2-6 months. In some embodiments, the anti-CD20 antibody is administered subcutaneously to the subject every 2 months (Q2M). In some embodiments, the anti-CD20 antibody is administered subcutaneously to the subject at a dose of approximately 135 mg. Unless otherwise specifically stated or apparent from the context, those skilled in the art will understand, with reference to the embodiments described herein, that the term “4 weeks” is equivalent to “1 month,” the term “12 weeks” is equivalent to “3 months,” and the term “24 weeks” is equivalent to “6 months.” Skilled personnel will also understand that in clinical practice, "about 2 months" can mean between 6 and 10 weeks, and "2 months" can mean between 7 and 9 weeks, usually 8 weeks. Similarly, skilled personnel will understand that in clinical practice, "about 6 months" can mean between 20 and 28 weeks, and "6 months" can mean between 22 and 26 weeks, usually 24 weeks. Skilled personnel will also understand that unless otherwise specifically stated or obvious from the context, the term "every 2 months" means "once every 2 months," and "every about 2 months" means "once every about 2 months," and so on.

[0071] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0072] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0073] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0074] Therefore, in some implementations, anti-CD20 antibodies are administered at a dose of approximately 100-600 mg every 6-28 weeks.

[0075] In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 100-170 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 110-160 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 120-150 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 130-140 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 135 mg every 6-10 weeks (approximately 2 months). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0076] In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 100-170 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 110-160 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 120-150 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 130-140 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered at a dose of approximately 135 mg every 7-9 weeks (2 months). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0077] In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered every 8 weeks (2 months) at a dose of approximately 100-170 mg. In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered every 8 weeks (2 months) at a dose of approximately 110-160 mg. In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered every 8 weeks (2 months) at a dose of approximately 120-150 mg. In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered every 8 weeks (2 months) at a dose of approximately 130-140 mg. In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered every 8 weeks (2 months) at a dose of approximately 135 mg. These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0078] In a preferred embodiment, this article provides a method for treating multiple sclerosis in a subject of need, the method comprising subcutaneously administering oframumab at a dose of about 130-140 mg every 2 months.

[0079] In one particular implementation, this article provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneously administering oframumab at a dose of approximately 135 mg every 2 months.

[0080] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0081] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0082] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0083] The inventors have further discovered that combining an initial (lower) dose regimen (i.e., a loading dose regimen) prior to the aforementioned subsequent (higher) dosing regimen (i.e., the maintenance dose regimen) provides a particularly effective and safe treatment because the initial regimen effectively, safely, and rapidly depletes B-cell levels before administration of the first subsequent (higher) dose. This initial regimen further reduces the risk of any systemic injection-related reactions (IRR). Without being bound by any theory, it is believed that the severity of the IRR may be related to a relatively high number of circulating B cells available for depletion upon administration of oflambumab. Those skilled in the art will understand that the initial dosing regimen may refer to a loading dose regimen, and the subsequent dosing regimen may refer to a maintenance dose regimen.

[0084] Therefore, this document also provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneously administering an anti-CD20 antibody to the subject sequentially during an initial dosing regimen and subsequent dosing regimens as disclosed herein. Thus, this disclosure covers subcutaneously administering one or more doses of an anti-CD20 antibody (e.g., ofamumab) to a subject at specific time intervals during an initial dosing regimen, followed by subcutaneous administration of the anti-CD20 antibody to the subject at specific time intervals during subsequent dosing regimens. In some embodiments, the initial dosing regimen includes administering three doses of the anti-CD20 antibody at weeks 0, 1, and 2. In some embodiments, subsequent dosings of the anti-CD20 antibody are administered in addition to the initial dosing. For example, the initial dose of the anti-CD20 antibody may be about 15-25 mg, 16-24 mg, 18-22 mg, 19-21 mg, such as 20 mg. One or more of these initial doses may be administered. In examples, three initial doses are administered. Initial dosing intervals are generally more frequent compared to subsequent dosing intervals. Weekly initial doses are used in examples. Therefore, a specific embodiment of the initial regimen used in the disclosed method is approximately 20 mg of an anti-CD20 antibody (e.g., ofamumab) for three weekly doses (in weeks 0, 1, and 2). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0085] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0086] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0087] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0088] Therefore, this article also provides a method for treating multiple sclerosis (MS) in subjects of need, the method comprising subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during an initial dosing regimen of three separate initial doses at weeks 0, 1, and 2, followed by subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during subsequent dosing regimens beginning at week 4. In some embodiments, the anti-CD20 antibody is administered during an initial dosing regimen of three separate 15-25 mg doses at weeks 0, 1, and 2, followed by subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during week 4 and thereafter during subsequent dosing regimens of approximately 100-170 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 16-24 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 110-160 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 18-22 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 120-150 mg every 6-10 weeks (approximately 2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 19-21 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 130-140 mg every 6-10 weeks (approximately 2 months). In some implementations, an anti-CD20 antibody (e.g., ofamumumab) is administered during an initial dosing regimen of three separate 20 mg doses at weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 135 mg every 6–10 weeks (approximately 2 months). These implementations are particularly suitable for ofamumumab and similar anti-CD20 antibodies.

[0089] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0090] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0091] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0092] In some embodiments, this document provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during an initial dosing regimen of three separate 15-25 mg doses at weeks 0, 1, and 2, followed by subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during week 4 and thereafter during subsequent dosing regimens of approximately 100-170 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 16-24 mg doses at weeks 0, 1, and 2, followed by subsequent dosing regimens of approximately 110-160 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 18-22 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 120-150 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 19-21 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 130-140 mg every 7-9 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 20 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 135 mg every 7-9 weeks (2 months). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0093] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0094] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0095] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0096] In some embodiments, this document provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during an initial dosing regimen of three separate 15-25 mg doses at weeks 0, 1, and 2, followed by subcutaneous administration of an anti-CD20 antibody (e.g., ofamumab) to the subject during week 4 and thereafter during subsequent dosing regimens of approximately 100-170 mg every 8 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 16-24 mg doses at weeks 0, 1, and 2, followed by subsequent dosing regimens of approximately 110-160 mg every 8 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 18-22 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 120-150 mg every 8 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 19-21 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 130-140 mg every 8 weeks (2 months). In some embodiments, an anti-CD20 antibody (e.g., ofamumab) is administered during an initial dosing regimen of three separate 20 mg doses in weeks 0, 1, and 2, followed by a subsequent dosing regimen of approximately 135 mg every 8 weeks (2 months). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0097] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0098] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0099] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0100] In a preferred embodiment, this document provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneously administering oframumab to the subject during an initial dosing regimen of three separate 19-21 mg doses at weeks 0, 1, and 2, followed by subcutaneous administration of oframumab to the subject during a subsequent dosing regimen of approximately 130-140 mg every 2 months thereafter at week 4.

[0101] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0102] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0103] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0104] In one particular embodiment, this document provides a method for treating multiple sclerosis (MS) in a subject of need, the method comprising subcutaneously administering oframumab to the subject during an initial dosing regimen of three separate 20 mg doses over three consecutive weeks (e.g., at week 0, week 1, and week 2), followed by subcutaneous administration of oframumab to the subject during a subsequent dosing regimen of approximately 135 mg every two weeks thereafter, two weeks after the third 20 mg dose (e.g., at week 4) and every two months (e.g., every eight weeks).

[0105] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0106] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0107] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0108] This disclosure also provides extended subcutaneous dosing regimens for use with anti-CD20 antibodies, such as orizumab and similar anti-CD20 antibodies.

[0109] Therefore, this document also provides a method for treating multiple sclerosis in subjects of need, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ospermumab) to the subject approximately every two months. In some embodiments, the anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 100-600 mg (e.g., approximately 600 mg, approximately 200 mg, or approximately 135 mg) approximately every two months. Therefore, in some embodiments, the anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 600 mg approximately every two months. In some embodiments, the anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 200 mg approximately every two months. In some embodiments, the anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 100-170 mg approximately every two months. In some embodiments, the anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 135 mg approximately every two months. In some implementations, for example due to differences in half-life, EC50, potency, etc., subcutaneous dosing regimens for anti-CD20 antibodies (such as ospermumab and similar anti-CD20 antibodies) may require higher doses. Therefore, this document also provides a method for treating multiple sclerosis in subjects of need, the method comprising administering an anti-CD20 antibody (e.g., ospermumab) at a dose of approximately 600-1,200 mg approximately every 6 months. In some implementations, an anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 1,200 mg approximately every 6 months.

[0110] A particularly useful dose of anti-CD20 antibodies (such as ospermumab) is 920 mg. In some embodiments, an anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 920 mg every 20-28 weeks (approximately 6 months). In some embodiments, an anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 920 mg every 22-26 weeks (approximately 6 months). In a particularly useful embodiment, an anti-CD20 antibody (e.g., ospermumab) is administered at a dose of approximately 920 mg every 24 weeks (approximately 6 months). While a dose of approximately 920 mg is typical, these embodiments also cover the use of doses within a reasonable range, particularly 690-1,150 mg, 730-1,110 mg, 820-1,020 mg, and 870-960 mg (e.g., 920 mg) of anti-CD20 antibodies (e.g., ospermumab). These embodiments are particularly suitable for ospermumab and similar anti-CD20 antibodies. Therefore, in a preferred embodiment, this document provides a method for treating multiple sclerosis in a subject in need, the method comprising administering ozoglucon subcutaneously to the subject at a dose of approximately 920 mg approximately every 6 months.

[0111] Therefore, this document also provides a method for treating multiple sclerosis in subjects of need, the method comprising administering an anti-CD20 antibody (e.g., oligrizumab) at a dose of approximately 600 mg every 20–28 weeks (approximately 6 months). In some embodiments, an anti-CD20 antibody (e.g., oligrizumab) is administered subcutaneously to the subject at a dose of approximately 600 mg every 22–26 weeks (6 months). In some embodiments, an anti-CD20 antibody (e.g., oligrizumab) is administered subcutaneously to the subject at a dose of approximately 600 mg every 24 weeks (6 months). While a dose of approximately 600 mg is typical, these embodiments also cover the use of doses within a reasonable range, particularly 450–750 mg, 480–720 mg, 540–660 mg, and 570–630 mg (e.g., 600 mg) of anti-CD20 antibodies. These embodiments are particularly suitable for oligrizumab and similar anti-CD20 antibodies. Therefore, in one particular implementation, this article provides a method for treating multiple sclerosis in a subject in need, the method comprising subcutaneously administering ozoglucon at a dose of approximately 600 mg to the subject every 6 months.

[0112] This disclosure also provides extended subcutaneous dosing regimens for use with anti-CD20 antibodies, such as utuximab and similar anti-CD20 antibodies.

[0113] Therefore, this article also provides a method for treating multiple sclerosis in subjects of need, the method comprising administering an anti-CD20 antibody (e.g., utuximab) subcutaneously to the subject approximately every 2 months. In some embodiments, the anti-CD20 antibody (e.g., utuximab) is administered at a dose of approximately 100-170 mg approximately every 2 months. In some embodiments, the anti-CD20 antibody (e.g., utuximab) is administered at a dose of approximately 135 mg approximately every 2 months.

[0114] Composition This document also provides compositions comprising an anti-CD20 antibody (e.g., oflamumab) for use in any of the methods of this disclosure, i.e., pharmaceutical compositions. Thus, in some embodiments, the anti-CD20 antibody (e.g., oflamumab) is administered subcutaneously in the form of a pharmaceutical composition.

[0115] antibody concentration In some embodiments, anti-CD20 antibodies are administered subcutaneously in the form of a pharmaceutical composition comprising an anti-CD20 antibody at a concentration of 20 to 400 mg / mL (e.g., 30-350 mg / mL, e.g., 40-300 mg / mL).

[0116] In one exemplary embodiment, the anti-CD20 antibody (e.g., ofamumab) is administered at concentrations of about 65-115 mg / mL, 70-110 mg / mL, 80-100 mg / mL, 85-95 mg / mL, preferably 90 mg / mL (e.g., about 135 mg of antibody in a total volume of about 1.5 mL), during subsequent (e.g., maintenance) dosing regimens, and at concentrations of about 35-65 mg / mL, 40-60 mg / mL, 45-55 mg / mL, 47-53 mg / mL, preferably 50 mg / mL (e.g., about 20 mg of antibody in a total volume of 0.4 mL), during initial (e.g., loading) dosing regimens. In one particular embodiment, one or more initial (e.g., loading) doses of antiCD20 antibody are administered in the form of a pharmaceutical composition comprising an antiCD20 antibody at a concentration of 50 mg / mL, and one or more subsequent (e.g., maintenance) doses of antiCD20 antibody are administered in the form of a pharmaceutical composition comprising an antiCD20 antibody at a concentration of about 90 mg / mL (e.g., 90 mg / mL).

[0117] Therefore, in some embodiments, the pharmaceutical composition used for the initial dosing regimen differs from the pharmaceutical composition used for subsequent dosing regimens. In some embodiments, the pharmaceutical composition used for subsequent (e.g., maintenance) dosing regimens contains a higher concentration of anti-CD20 antibody compared to the pharmaceutical composition used for the initial (e.g., loading) dosing regimen.

[0118] The preferred anti-CD20 antibody is oframumab. Therefore, in some embodiments, oframumab is administered in the form of a pharmaceutical composition containing about 65-115 mg / mL of oframumab. In some embodiments, oframumab is administered in the form of a pharmaceutical composition containing about 70-110 mg / mL of oframumab. In some embodiments, oframumab is administered in the form of a pharmaceutical composition containing about 80-100 mg / mL of oframumab. In some embodiments, oframumab is administered in the form of a pharmaceutical composition containing about 85-95 mg / mL of oframumab. In some embodiments, oframumab is administered in the form of a pharmaceutical composition containing about 90 mg / mL of oframumab (e.g., oframumab is administered in the form of a pharmaceutical composition containing 90 mg / mL of oframumab).

[0119] Therefore, in some embodiments, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising 50 mg / mL of oframumab, and subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 65-115 mg / mL of oframumab. In some embodiments, subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 70-110 mg / mL of oframumab. In some embodiments, subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 80-100 mg / mL of oframumab. In some embodiments, subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 85-95 mg / mL of oframumab. In some embodiments, subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 90 mg / mL of oframumab.

[0120] In some embodiments, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising 35-65 mg / mL of oframumab, and subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 65-115 mg / mL of oframumab. In some embodiments, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising 40-60 mg / mL of oframumab, and subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 70-110 mg / mL of oframumab. In some embodiments, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising 45-55 mg / mL of oframumab, and subsequent (e.g., maintenance) doses of oframumab are administered in the form of a pharmaceutical composition comprising about 80-100 mg / mL of oframumab. In some embodiments, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of 47-53 mg / mL, and a subsequent (e.g., maintenance) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of about 85-95 mg / mL.

[0121] In a preferred embodiment, an initial (e.g., loading) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of 50 mg / mL, and a subsequent (e.g., maintenance) dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of about 90 mg / mL.

[0122] This document also provides pharmaceutical compositions comprising olizumab. In one embodiment, a dose of olizumab is administered in the form of a pharmaceutical composition comprising about 90 mg / mL (e.g., about 135 mg in a 2 mL total volume). In another embodiment, olizumab and other anti-CD20 antibodies may require higher doses and are therefore administered at high concentrations for subcutaneous use (i.e., small injection volumes). In such cases, concentrations can be as high as 400 mg / mL, up to 350 mg / mL, or up to 300 mg / mL (e.g., about 600 mg antibody in a 1.5-2 mL total volume). For example, when co-administering hyaluronidase, larger volumes, such as 5-15 mL, can be used, and the antibody concentration can be about 100-150 mg / mL, such as 120 mg / mL (e.g., about 600 mg in a 5 mL total volume), or 30-50 mg / mL, such as 40 mg / mL (e.g., about 600 mg in a 15 mL total volume). Therefore, in one embodiment, the pharmaceutical composition comprises an anti-CD20 antibody (e.g., oligrin) at a concentration of about 30-150 mg / mL or about 40-120 mg / mL, preferably about 120 mg / mL. In a more preferred embodiment, the concentration of the anti-CD20 antibody (e.g., oligrin) is about 40 mg / mL (e.g., about 920 ml in 23 ml).

[0123] This document also provides pharmaceutical compositions comprising utuximab. In one embodiment, a dose of utuximab is administered in the form of a pharmaceutical composition comprising utuximab at a concentration of 90 mg / ml (e.g., about 135 mg in a total volume of 2 mL).

[0124] Other components in the pharmaceutical composition In addition to anti-CD20 antibodies (such as ofamumab), the pharmaceutical compositions disclosed herein also contain pharmaceutically acceptable excipients, carriers, buffers, stabilizers, or other materials well known to those skilled in the art (such as water for injection). These materials are non-toxic and do not impair the efficacy of the anti-CD20 antibodies.

[0125] In some embodiments, an anti-CD20 antibody (e.g., oframumab) is administered to a subject in the form of a pharmaceutical composition, said pharmaceutical composition further comprising L-arginine, sodium acetate, sodium chloride, and / or (e.g., and) polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0). In some embodiments, the pharmaceutical composition also comprises EDTA. In some embodiments, the composition does not contain EDTA. In some embodiments, the pharmaceutical composition does not contain an endoglucosidase (e.g., hyaluronidase, such as rHupH20). These embodiments are particularly suitable for oframumab and similar anti-CD20 antibodies.

[0126] In some embodiments, the pharmaceutical composition comprises about 10 to about 100 mM (e.g., 10 to 100 mM), about 20 to about 100 mM (e.g., 20 to 100 mM), about 30 to about 100 mM (e.g., 30 to 100 mM), about 40 to about 100 mM (e.g., 40 to 100 mM), about 50 to about 100 mM (e.g., 50 to 100 mM), about 60 to about 100 mM (e.g., 60 to 100 mM), about 70 to about 100 mM (e.g., 70 to 100 mM), about 25 to about 80 mM (e.g., 25 to 80 mM), or about 30 to about 70 mM (e.g., 30 to 70 mM) of sodium acetate. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM), about 40 mM (e.g., 40 mM), about 45 mM (e.g., 45 mM), about 55 mM (e.g., 55 mM), or about 60 mM (e.g., 60 mM) sodium acetate. In a preferred embodiment, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate. Sodium acetate can be conveniently incorporated into the composition using sodium acetate trihydrate. These embodiments are particularly suitable for ofphamumab and similar anti-CD20 antibodies.

[0127] In some embodiments, the pharmaceutical composition comprises about 25 to about 100 mM (e.g., 25 to 100 mM), about 35 to about 90 mM (e.g., 35 to 90 mM), about 45 to about 80 mM (e.g., 45 to 80 mM), about 25 to about 70 mM (e.g., 25 to 70 mM), or about 45 to about 70 mM (e.g., 45 to 70 mM) of sodium chloride. In some embodiments, the pharmaceutical composition comprises about 45 mM (e.g., 45 mM), about 46 mM (e.g., 46 mM), about 47 mM (e.g., 47 mM), about 48 mM (e.g., 48 mM), about 49 mM (e.g., 49 mM), about 50 mM (e.g., 50 mM), about 51 mM (e.g., 51 mM), about 52 mM (e.g., 52 mM), about 53 mM (e.g., 53 mM), about 54 mM (e.g., 54 mM), or about 55 mM (e.g., 55 mM) of sodium chloride. In a preferred embodiment, the pharmaceutical composition comprises about 51 mM (e.g., 51 mM) sodium chloride. These embodiments are particularly suitable for ofphamumab and similar anti-CD20 antibodies.

[0128] In some embodiments, the pharmaceutical composition comprises (w / v) between about 0.5 and about 5.0% (e.g., 0.5 and 5.0%), about 0.5 to about 2.0% (e.g., 0.5 to 2.0%), about 0.5 to about 2.5% (e.g., 0.5 to 2.5%), about 0.5 to about 3.0% (e.g., 0.5 to 3.0%), about 0.5 to about 3.5% (e.g., 0.5 to 3.5%), about 0.5 to about 4.0% (e.g., 0.5 to 4.0%), or about 0.5 to about 4.5% (e.g., 0.5 to 4.5%) of free arginine base (L-arginine). In some embodiments, the pharmaceutical composition comprises (w / v) about 1% (e.g., 1%), about 0.7% (e.g., 0.7%), about 1.3% (e.g., 1.3%), or about 2.0% (e.g., 2.0%) of free arginine base. In a preferred embodiment, the pharmaceutical composition comprises about 1% (w / v) (e.g., 1% (w / v)) of free arginine base. These embodiments are particularly suitable for oflambumab and similar anti-CD20 antibodies.

[0129] In some embodiments, the pharmaceutical composition comprises (w / v) about 0.01 to about 0.2% (e.g., 0.01 to 0.2%), about 0.01 to about 0.15% (e.g., 0.01 to 0.15%), about 0.02 to about 0.2% (e.g., 0.02 to 0.2%), about 0.02 to about 0.15% (e.g., 0.02 to 0.15%), about 0.01 to about 0.25% (e.g., 0.01 to 0.25%), or about 0.01 to about 0.05% (e.g., 0.01 to 0.05%) of polysorbate (e.g., polysorbate 80). In some embodiments, the pharmaceutical composition comprises (w / v) about 0.02% (e.g., 0.02%), about 0.015% (e.g., 0.015%), or about 0.025% (e.g., 0.025%) of polysorbate (e.g., polysorbate 80). In a preferred embodiment, the pharmaceutical composition comprises about 0.02% (w / v) (e.g., 0.02% (w / v) polysorbate (e.g., polysorbate 80). In another embodiment, the pharmaceutical composition comprises about 0.02 to about 0.04% (e.g., 0.02 to 0.04%) (w / v) polysorbate (e.g., polysorbate 80), for example, about 0.04% (e.g., 0.04%) (w / v) polysorbate (e.g., polysorbate 80). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0130] In some embodiments, the pharmaceutical composition comprises about 0.02 mM to about 0.2 mM (e.g., 0.02 to 0.2 mM), about 0.02 mM to about 0.1 mM (e.g., 0.02 mM to 0.1 mM), about 0.02 mM to about 0.15 mM (e.g., 0.02 mM to 0.15 mM), about 0.04 mM to about 0.1 mM (e.g., 0.04 mM to 0.1 mM), about 0.03 mM to about 0.15 mM (e.g., 0.03 mM to 0.15 mM), or about 0.03 mM to about 0.2 mM (e.g., 0.03 mM to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM), about 0.03 mM (e.g., 0.03 mM), about 0.04 mM (e.g., 0.04 mM), or about 0.06 mM (e.g., 0.06 mM) EDTA. In a preferred embodiment, the pharmaceutical composition comprises about 0.05 mM (e.g., 0.05 mM) EDTA. EDTA can be conveniently incorporated into the composition using disodium edetate dihydrate. These embodiments are particularly suitable for oflambumab and similar anti-CD20 antibodies.

[0131] The pharmaceutical compositions disclosed herein (particularly pharmaceutical compositions comprising ofphamumab) may have a pH value of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), such as about pH 5.5, such as pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), such as pH 5.3-5.8, such as pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), such as pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), such as pH 5.5. Therefore, in some embodiments, the pharmaceutical composition is adjusted to a pH of 5.0 to 7.0. In some embodiments, the pharmaceutical composition is adjusted to a pH of 5.0, 5.5, 6.0, 6.5, or 7.0. In a preferred embodiment, the pharmaceutical composition is adjusted to a pH of 5.5. These embodiments are particularly suitable for ofphamumab and similar anti-CD20 antibodies.

[0132] In some embodiments, the pharmaceutical composition may contain about 0.1 mM to about 20 mM (e.g., 0.1 mM to 20 mM), about 1 mM to about 15 mM (e.g., 1 mM to 15 mM), about 2 mM to about 10 mM (e.g., 2 mM to 10 mM), or about 4 mM to about 6 mM (e.g., 4 mM to 6 mM) of methionine (e.g., L-methionine). Therefore, the pharmaceutical composition may contain about 1 mM (e.g., 1 mM), about 5 mM (e.g., 5 mM), about 10 mM (e.g., 10 mM), about 15 mM (e.g., 15 mM), or about 20 mM (e.g., 20 mM) of methionine (e.g., L-methionine). In a preferred embodiment, the pharmaceutical composition contains about 5 mM (e.g., 5 mM) of methionine (e.g., L-methionine). These embodiments are particularly suitable for ofamumab and similar anti-CD20 antibodies.

[0133] In some embodiments, the pharmaceutical composition comprises about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) free arginine base, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) polysorbate (e.g., polysorbate 80), and is adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), and optionally comprises about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA. In some embodiments, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v) polysorbate (e.g., polysorbate 80), and is adjusted to a pH of about 5.5 (e.g., pH 5.5), and optionally contains about 0.05 mM (e.g., 0.05 mM) EDTA.

[0134] In a preferred embodiment, the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), and is adjusted to a pH of about 5.5 (e.g., pH 5.5), and optionally contains about 0.05 mM (e.g., 0.05 mM) EDTA.

[0135] The pharmaceutical compositions described herein include low-viscosity formulations of relatively high concentrations of oframumab, which facilitate subcutaneous administration. In some cases, this document provides pharmaceutical compositions comprising oframumab (e.g., about 90 mg / mL of oframumab, e.g., 90 mg / mL) with a viscosity not exceeding about 3 cP (e.g., not exceeding 3 cP), e.g., about 2.3 centipoise (cP) (e.g., 2.3 cP).

[0136] Therefore, this article provides a pharmaceutical composition comprising about 80-100 mg / mL (e.g., 80-100 mg / mL) (e.g., about 90 mg / mL) of ofumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate, about 25 to about 100 mM of sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0). This composition can be used for the volumetric delivery of approximately 135 mg (e.g., 135 mg) of oflambumab for easy subcutaneous administration.

[0137] This document also provides a pharmaceutical composition comprising: about 80-100 mg / mL (e.g., 80-100 mg / mL) (e.g., about 90 mg / mL) of ofumab; about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate (e.g., sodium acetate trihydrate); about 25 to about 100 mM (e.g., 25 to 100 mM) of sodium chloride; about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base (e.g., L-arginine); about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80); and about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA. (e.g., disodium edetate dihydrate), water for injection, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0) (e.g., with hydrochloric acid). This composition can be used for the subcutaneous delivery of about 135 mg (e.g., 135 mg) of oflamumab.

[0138] In a preferred embodiment, the pharmaceutical composition comprises about 90 mg / mL (e.g., 90 mg / mL) of oframumab, about 50 mM (e.g., 50 mM) of sodium acetate, about 51 mM (e.g., 51 mM) of sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) of free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) of EDTA, and adjusted to a pH of about 5.5 (e.g., pH 5.5). About 1.5 mL (e.g., 1.5 mL) of this composition provides about 135 mg (e.g., 135 mg) of oframumab. For example, the pharmaceutical composition may consist of approximately 90 mg / mL (e.g., 90 mg / mL) of ofumumab, approximately 50 mM (e.g., 50 mM) of sodium acetate (e.g., sodium acetate trihydrate), approximately 51 mM (e.g., 51 mM) of sodium chloride, approximately 1% (w / v) (e.g., 1% (w / v)) of free arginine base (e.g., L-arginine), approximately 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate (e.g., polysorbate 80), approximately 0.05 mM (e.g., 0.05 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to a pH of approximately 5.5 (e.g., pH 5.5) (e.g., with hydrochloric acid). In a suitable, subcutaneously stable formulation, approximately 1.5 mL (e.g., 1.5 mL) of this composition provides approximately 135 mg (e.g., 135 mg) of ofumumab. In fact, as shown in Example 2, this formulation remains stable for at least 6 months under its intended storage conditions (e.g., 5°C ± 3°C).

[0139] In a preferred embodiment, the anti-CD20 antibody is oframumab, and may be present in the composition at any of the concentrations described above, such as about 35-115 mg / mL (e.g., 35-115 mg / mL), such as about 50 mg / mL (e.g., 50 mg / mL), or about 90 mg / mL (e.g., 90 mg / mL). Therefore, this document provides a pharmaceutical composition comprising about 90 mg / mL (e.g., 90 mg / mL) of oframumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL). This document also provides a solution for injection comprising about 90 mg / mL (e.g., 90 mg / mL) of oframumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).

[0140] In other embodiments, the anti-CD20 antibody is oligrizumab. In such embodiments (particularly those using larger volumes, such as about 5-15 mL), the anti-CD20 antibody is typically administered in the form of a pharmaceutical composition that also contains an agent that locally degrades the extracellular matrix, thereby allowing the subcutaneous space to accommodate such a larger volume. In a preferred embodiment, the anti-CD20 antibody (e.g., oligrizumab) is administered in a volume of about 23 mL. An exemplary agent is hyaluronidase, preferably recombinant human hyaluronidase, such as rHuPH20.

[0141] Specifically, the enzyme hyaluronidase can be used to induce local and transient changes in the subcutaneous space by degrading hyaluronic acid (i.e., hyaluronic acid), a naturally occurring glycosaminoglycan present throughout the body. This glycosaminoglycan resists the flow of large volumes of fluid in the extracellular matrix and limits the delivery of large-volume subcutaneous drugs. By degrading hyaluronic acid at the local injection site, hyaluronidase enables the flow of large volumes of fluid in the subcutaneous space and facilitates the delivery of large-volume subcutaneous drugs.

[0142] Purified recombinant human hyaluronidase (recombinant human hyaluronidase [rHuPH20]) has been commercially available in the United States since 2005 (HYLENEX®, recombinant) and has been co-formulated with other therapeutic products using ENHANZE® drug delivery technology. ENHANZE® has been shown to reduce dosing time and frequency and enable rapid subcutaneous injection of large volumes (5 to 15 mL).

[0143] Therefore, in some embodiments, olizumab is administered as a pharmaceutical composition that also contains recombinant human hyaluronidase (e.g., rHupH20) and optionally sodium acetate, trehalose, and polysorbate (e.g., polysorbate 20), typically with a pH of about 5.0-6.0. The olizumab pharmaceutical composition may also contain glacial acetic acid.

[0144] In some embodiments, the pharmaceutical composition comprises about 1,000 to about 16,000 U / mL (e.g., 1,000 to 16,000 U / mL) of hyaluronidase (e.g., rHupH20), wherein based on a hypothetical specific activity of about 100,000 U / mg (e.g., 100,000 U / mg), said amount corresponds to about 0.01 mg to 0.15 mg of hyaluronidase. In some embodiments, the pharmaceutical composition comprises about 1,500 to about 12,000 U / mL (e.g., 1,500 to 12,000 U / mL) of hyaluronidase (e.g., rHupH20). In some embodiments, the pharmaceutical composition comprises about 2,000 to about 12,000 U / mL (e.g., 2,000 to 12,000 U / mL) of hyaluronidase (e.g., rHupH20).

[0145] In some embodiments, the pharmaceutical composition comprises about 1 mM to about 15 mM (e.g., 1 mM to 15 mM) of glacial acetic acid, about 2 mM to about 10 mM (e.g., 2 mM to 10 mM) of glacial acetic acid, or about 3 mM to about 5 mM (e.g., 3 mM to 5 mM) of glacial acetic acid. In a preferred embodiment, the pharmaceutical composition comprises about 4 mM (e.g., 4 mM) of glacial acetic acid.

[0146] In some embodiments, the pharmaceutical composition comprises about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w / v) (e.g., 0.01-0.1% (w / v)) polysorbate 20 and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3).

[0147] In some embodiments, the pharmaceutical composition comprises about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate 20 and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3).

[0148] In some embodiments, olizumab is administered in the form of a pharmaceutical composition comprising about 30-350 mg / mL (e.g., 30-350 mg / mL) of olizumab, about 1-100 mM (e.g., 1-100 mM) of sodium acetate, about 15-250 mM (e.g., 15-250 mM) of trehalose, about 0.01-0.1% (w / v) (e.g., 0.01-0.1% (w / v)) of polysorbate 20, and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3). For example, the pharmaceutical composition may contain about 30-350 mg / mL (e.g., 30-350 mg / mL (e.g., about 120 mg / mL)) of oligrin, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose dihydrate, about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate 20 and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) of rHuPH20, with a pH of about 5.3 (e.g., pH 5.3).

[0149] In some embodiments, olizumab is administered in the form of a pharmaceutical composition comprising about 30-150 mg / mL (e.g., 30-150 mg / mL) (e.g., about 40-120 mg / mL), preferably about 120 mg / mL olizumab, about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w / v) (e.g., 0.01-0.1% (w / v)) polysorbate 20, and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3). In some embodiments, the pharmaceutical composition comprises about 30-150 mg / mL (e.g., 30-150 mg / mL) (e.g., about 40-120 mg / mL), preferably about 120 mg / mL of oligrin, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose dihydrate, about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate 20, and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) of hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3).

[0150] In a more preferred embodiment, olizumab is administered in the form of a pharmaceutical composition comprising about 40 mg / mL olizumab, about 1-100 mM (e.g., 1-100 mM) sodium acetate, about 15-250 mM (e.g., 15-250 mM) trehalose, about 0.01-0.1% (w / v) (e.g., 0.01-0.1% (w / v)) polysorbate 20, and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3). In some embodiments, the pharmaceutical composition comprises about 40 mg / mL (e.g., 40 mg / mL) of oligrin, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose dihydrate, about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate 20, and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) of hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3). This pharmaceutical composition is particularly useful for treating multiple sclerosis in subjects of need.

[0151] One particularly useful pharmaceutical composition comprises about 40 mg / mL of olizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w / v)) polysorbate 20, about 1,500 U / ml (e.g., 1,500 U / ml) of hyaluronidase (e.g., rhuPH20), at a pH of about 5.3 (e.g., pH 5.3). Another particularly useful pharmaceutical composition comprises about 40 mg / mL of olizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose, about 0.02% (e.g., 0.02% (w / v)) polysorbate 20, about 2,300 U / ml (e.g., 2,300 U / ml) of hyaluronidase (e.g., rhuPH20), at a pH of about 5.3 (e.g., pH 5.3). Pharmaceutical compositions containing the following are also particularly useful: approximately 40 mg / mL of orizumab, approximately 30 mM (e.g., 30 mM) sodium acetate, approximately 8% (e.g., 8%) trehalose, approximately 0.02% (e.g., 0.02% (w / v)) polysorbate 20, approximately 3,000 U / ml (e.g., 3,000 U / ml) of hyaluronidase (e.g., rhuPH20), pH approximately 5.3 (e.g., pH 5.3). Another particularly useful pharmaceutical composition contains about 40 mg / ml of orizumab, about 30 mM (e.g., 30 mM) sodium acetate, about 8% (e.g., 8%) trehalose dihydrate, about 0.02% (e.g., 0.02% (w / v)) polysorbate 20, about 12,000 U / ml (e.g., 12,000 U / ml) of hyaluronidase (e.g., rhuPH20), at a pH of about 5.3 (e.g., pH 5.3).

[0152] In some embodiments, the pharmaceutical composition comprises about 120 mg / mL (e.g., 120 mg / mL) of oligrin, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose dihydrate, about 0.02% (e.g., 0.02% (w / v)) of polysorbate 20 and about 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) of hyaluronidase (e.g., rHuPH20), at a pH of about 5.3 (e.g., pH 5.3).

[0153] In some embodiments, the pharmaceutical composition comprises about 50 mg / ml (e.g., 50 mg / ml) of orizumab, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose, about 0.02% (e.g., 0.02% (w / v)) of polysorbate 20, about 1,500 U / ml (e.g., 1,500 U / ml) of hyaluronidase (e.g., rhuPH20), and a pH of about 5.3 (e.g., pH 5.3).

[0154] In some embodiments, the pharmaceutical composition comprises about 100 mg / ml (100 mg / ml) of orizumab, about 30 mM (e.g., 30 mM) of sodium acetate, about 8% (e.g., 8%) of trehalose dihydrate, about 0.02% (e.g., 0.02% (w / v)) of polysorbate 20, about 12,000 U / ml (e.g., 12,000 U / ml) of hyaluronidase (e.g., rhuPH20), and a pH of about 5.3 (e.g., pH 5.3).

[0155] Therefore, this article provides a method for treating multiple sclerosis in subjects of need, comprising subcutaneously administering oligrizumab to the subject at a dose of approximately 920 mg approximately every 6 months, wherein oligrizumab is administered in the form of a formulation comprising: approximately 40 mg / mL oligrizumab, approximately 1-100 mM (e.g., 1-100 mM) sodium acetate, approximately 15-250 mM (e.g., 15-250 mM) trehalose, approximately 0.01-0.1% (w / v) (e.g., 0.01-0.1% (w / v)) polysorbate 20, and approximately 1,500-12,000 U / mL (e.g., 1,500-12,000 U / mL) hyaluronidase (e.g., rHuPH20), at a pH of approximately 5.3 (e.g., pH 5.3). This is a particularly stable pharmaceutical formulation suitable for subcutaneous injection.

[0156] In another embodiment, the anti-CD20 antibody is utuximab.

[0157] In some embodiments, the pharmaceutical composition containing orritumab may also contain about 15-250 mM (e.g., 15-250 mM) or about 150-250 mM (e.g., 150-250 mM) of methionine, such as about 210 mM (e.g., 210 mM) of methionine.

[0158] deliver The anti-CD20 antibody disclosed herein can be administered via any suitable route, but is typically administered subcutaneously (sc), usually by injection.

[0159] In some embodiments, the anti-CD20 antibody is administered via subcutaneous injection. In some embodiments, the initial and / or subsequent doses of the anti-CD20 antibody are administered via subcutaneous injection. In some embodiments, the anti-CD20 antibody is administered in an outpatient setting.

[0160] In some implementations, the anti-CD20 antibody is administered to the subject's abdomen, thigh, or outer upper arm.

[0161] In one embodiment, subcutaneous administration of the anti-CD20 antibody is achieved using a pre-filled syringe. In a preferred embodiment, subcutaneous administration of the anti-CD20 antibody is achieved using a pre-filled pen (i.e., an autoinjector). A non-limiting example of an autoinjector suitable for the uses according to this disclosure is Sensoready. ® Pen. A pre-filled syringe consists of a main pre-filled syringe assembled into a needle safety device. A pre-filled pen consists of a main pre-filled syringe assembled into an autoinjector (AI).

[0162] Therefore, this document provides a pre-filled syringe or pre-filled pen (i.e., an autoinjector) containing an anti-CD20 antibody (e.g., oflamumab or a similar anti-CD20 antibody). In some embodiments, the pre-filled syringe or pre-filled pen (i.e., the autoinjector) contains a single unit dose of anti-CD20 antibody of about 100-170 mg. In some embodiments, the pre-filled syringe or pre-filled pen (i.e., the autoinjector) contains a single unit dose of anti-CD20 antibody of about 110-160 mg. In some embodiments, the pre-filled syringe or pre-filled pen (i.e., the autoinjector) contains a single unit dose of anti-CD20 antibody of about 120-150 mg. In a preferred embodiment, the pre-filled syringe or pre-filled pen (i.e., the autoinjector) contains a single unit dose of anti-CD20 antibody of about 130-140 mg. In another preferred embodiment, the pre-filled syringe or pre-filled pen (i.e., the autoinjector) contains a single unit dose of anti-CD20 antibody of about 135 mg.

[0163] The preferred anti-CD20 antibody is oframumab. Therefore, in some embodiments, the pre-filled syringe or pen (i.e., auto-injector) contains a single unit dose of oframumab of about 100-170 mg. In some embodiments, the pre-filled syringe or pen (i.e., auto-injector) contains a single unit dose of oframumab of about 110-170 mg. In some embodiments, the pre-filled syringe or pen (i.e., auto-injector) contains a single unit dose of oframumab of about 120-150 mg. In some embodiments, the pre-filled syringe or pen (i.e., auto-injector) contains a single unit dose of oframumab of about 130-140 mg. In a preferred embodiment, the pre-filled syringe or pen (i.e., auto-injector) contains a single unit dose of oframumab of about 135 mg.

[0164] Prefilled pens (autoinjectors) are particularly preferred. In one specific embodiment, ofamumab is provided in a prefilled pen (autoinjector) containing a single unit dose of antibody of about 130-140 mg (e.g., about 135 mg, for example). This single unit dose is intended for use in subsequent regimens as described herein.

[0165] In some embodiments, as described herein, the anti-CD20 antibody is administered to a subject in the form of a pharmaceutical composition. In one embodiment, the pharmaceutical composition containing the anti-CD20 antibody is provided in a pre-filled syringe. In a preferred embodiment, the pharmaceutical composition containing the anti-CD20 antibody is provided in a pre-filled pen (i.e., an autoinjector). A non-limiting example of an autoinjector suitable for use according to this disclosure is Sensoready. ® Pen. Preferably, the anti-CD20 antibody is oflavumab.

[0166] Pharmaceutical compositions containing anti-CD20 antibodies can be provided in the form of an injectable solution. In one embodiment, the injectable solution is provided in a pre-filled syringe. In a preferred embodiment, the injectable solution is provided in a pre-filled pen (i.e., an autoinjector). A non-limiting example of an autoinjector suitable for use according to this disclosure is Sensoready. ® Pen. Preferably, the anti-CD20 antibody is oflavumab.

[0167] In some embodiments, the solution for injection contains between about 100 and about 600 mg of anti-CD20 antibody in the pharmaceutical composition disclosed herein. In some embodiments, the solution for injection contains between about 100 and about 170 mg of anti-CD20 antibody in the pharmaceutical composition disclosed herein. In some embodiments, the solution for injection contains about 135 mg of anti-CD20 antibody in the pharmaceutical composition disclosed herein. In some embodiments, the solution for injection contains about 600 mg of anti-CD20 antibody in the pharmaceutical composition disclosed herein.

[0168] The preferred anti-CD20 antibody is oframumab. Therefore, in some embodiments, the solution for injection contains between about 110 and about 160 mg of oframumab in the pharmaceutical composition disclosed herein. In some embodiments, the solution for injection contains between about 120 and about 150 mg of oframumab in the pharmaceutical composition disclosed herein. In some embodiments, the solution for injection contains between about 130 and about 140 mg of oframumab in the pharmaceutical composition disclosed herein. In a preferred embodiment, the solution for injection contains about 135 mg of oframumab in the pharmaceutical composition disclosed herein.

[0169] In some embodiments, the anti-CD20 antibody may be administered in a volume of about 0.4 mL to about 1.5 mL. In some embodiments, an initial dose of the anti-CD20 antibody is administered in a volume of about 0.4 mL. In some embodiments, subsequent doses of the anti-CD20 antibody are administered in a volume of about 1.5 mL.

[0170] In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 0.4 mL of a solution for injection, wherein the solution for injection contains the anti-CD20 antibody in the pharmaceutical composition disclosed herein. In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 0.4 mL of a solution for injection, wherein the solution contains the anti-CD20 antibody at a concentration of about 50 mg / mL. In some embodiments, an initial dose of the anti-CD20 antibody is administered in a pre-filled syringe or pen (i.e., an autoinjector) containing about 0.4 mL of a solution for injection, wherein the solution contains the anti-CD20 antibody at a concentration of about 50 mg / mL.

[0171] In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution for injection contains the anti-CD20 antibody in the pharmaceutical composition disclosed herein. In some embodiments, the anti-CD20 antibody is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains the anti-CD20 antibody at a concentration of about 90 mg / mL. In some embodiments, a subsequent dose of the anti-CD20 antibody is administered in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains the anti-CD20 antibody at a concentration of about 90 mg / mL.

[0172] The preferred anti-CD20 antibody is oframumab. Therefore, the initial dose of oframumab can be administered in a volume of approximately 0.4 mL; subsequent doses of oframumab can be administered in a volume of approximately 1.5 mL.

[0173] In some embodiments, oframumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 0.4 mL of a solution for injection, wherein the solution contains oframumab at a concentration of about 50 mg / mL. In a preferred embodiment, an initial dose of oframumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 0.4 mL of a solution for injection, wherein the solution contains oframumab at a concentration of about 50 mg / mL.

[0174] In some embodiments, oframumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains oframumab at a concentration between about 70 and about 110 mg / mL. In some embodiments, subsequent doses of oframumab are provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains oframumab at a concentration between about 70 and about 110 mg / mL.

[0175] In some embodiments, ofamumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains ofamumab at a concentration between about 80 and about 100 mg / mL. In some embodiments, subsequent doses of ofamumab are provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains ofamumab at a concentration between about 80 and about 100 mg / mL.

[0176] In some embodiments, ofamumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains ofamumab at a concentration between about 85 and about 95 mg / mL. In some embodiments, subsequent doses of ofamumab are provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains ofamumab at a concentration between about 85 and about 95 mg / mL.

[0177] In some embodiments, oframumab is provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution for injection contains oframumab at a concentration of about 90 mg / mL. In a preferred embodiment, subsequent doses of oframumab are provided in a pre-filled syringe or pen (i.e., an autoinjector) containing about 1.5 mL of a solution for injection, wherein the solution contains oframumab at a concentration of about 90 mg / mL.

[0178] Multiple sclerosis This article provides a method for treating multiple sclerosis (MS) in a subject of need, wherein the method includes subcutaneous administration of an anti-CD20 antibody to the subject. In one embodiment, MS is RMS. In one embodiment, MS is RRMS. In one embodiment, MS is PPMS. In one embodiment, MS is SPMS. In one embodiment, MS is CIS.

[0179] Any mention of treatment methods herein also discloses the use of antiCD20 antibodies in said treatment methods, the use of antiCD20 antibodies in said treatment methods, and the use of antiCD20 antibodies in the manufacture of pharmaceutical agents for said treatment.

[0180] Therefore, this article also provides an anti-CD20 antibody for treating multiple sclerosis (MS) in a subject. This article also provides the use of the anti-CD20 antibody for treating multiple sclerosis. Additionally, this article provides the use of the anti-CD20 antibody in the manufacture of a pharmaceutical agent for treating multiple sclerosis.

[0181] In some preferred embodiments, MS is relapsing multiple sclerosis (RMS), including clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS).

[0182] In some implementations, MS refers to relapsing-remitting multiple sclerosis (RRMS). In some implementations, MS refers to active secondary progressive multiple sclerosis (SPMS). In some implementations, MS refers to clinically isolated syndrome (CIS).

[0183] In some embodiments, MS refers to progressive MS, including secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). In some embodiments, MS is secondary progressive multiple sclerosis (SPMS). In some embodiments, MS is primary progressive multiple sclerosis (PPMS).

[0184] In one illustrative embodiment, this document provides a method for treating relapsing multiple sclerosis in a subject of need, the method comprising subcutaneously administering an antiCD20 antibody (e.g., ofamumab) to the subject during an initial dosing regimen of three separate doses of approximately 19-21 mg at weeks 0, 1, and 2, followed by subcutaneous administration of the antiCD20 antibody (e.g., ofamumab) to the subject during week 4 and subsequent dosing regimens of approximately 130-140 mg every 2 months thereafter.

[0185] In another illustrative embodiment, this document provides a method for treating multiple sclerosis in a subject of need, the method comprising subcutaneously administering an anti-CD20 antibody (e.g., ofamumab) to the subject during an initial dosing regimen of three separate doses of approximately 20 mg at weeks 0, 1, and 2, followed by subcutaneous administration of the anti-CD20 antibody (e.g., ofamumab) to the subject during week 4 and subsequent dosing regimens of approximately 135 mg every 2 months thereafter.

[0186] Companion therapy In some embodiments, the methods disclosed herein further include administration of a concomitant therapy, such as that selected from the group consisting of corticosteroids, antihistamines, and acetaminophen. In some embodiments, the concomitant therapy is a corticosteroid. In some embodiments, the concomitant therapy is an antihistamine. In some embodiments, the concomitant therapy is acetaminophen.

[0187] The term 'concomitant therapy' includes administration of an anti-CD20 antibody (e.g., ofamumab) before, during, or after administration, such as before, during, or after administration of a first dose of an anti-CD20 antibody; or administration of another agent (e.g., selected from the group consisting of corticosteroids, antihistamines, and acetaminophen) before, during, or after administration of one or more subsequent doses or each dose of an anti-CD20 antibody.

[0188] In some implementations, concomitant therapy is administered before the administration of the anti-CD20 antibody. In some implementations, concomitant therapy is administered 30 to 60 minutes before the administration of the anti-CD20 antibody.

[0189] In some implementations, concomitant therapy is administered during the administration of the anti-CD20 antibody. In other implementations, concomitant therapy is administered after the administration of the anti-CD20 antibody.

[0190] In some implementations, no pre-medication is administered before the administration of the anti-CD20 antibody.

[0191] In the above implementation scheme, the preferred anti-CD20 antibody is oflambumab.

[0192] Subjects for treatment In some embodiments, the subject is a mammal. In a preferred embodiment, the subject is a human. In some embodiments, the subject is referred to as a patient.

[0193] In some implementations, anti-CD20 antibodies are administered regardless of the subject's weight, sex, age, race, or baseline B-cell count.

[0194] In some implementations, the subjects are adult subjects (e.g., adults). In some implementations, the subjects are 18 to 55 years old (inclusive). In some implementations, the subjects are over 55 years old.

[0195] In some embodiments, the subject has been diagnosed with multiple sclerosis according to the 2017 Revised McDonaldcriteria (see Table 1 of Thompson AJ, Baranzini SE, Geurts J et al. (2018) Multiple sclerosis. Lancet; 391(10130):1622-36). In some embodiments, the subject has a disability status with an Extended Disability Status Scale (EDSS) score of 0 to 5.5 (inclusive). In some embodiments, the subject's B cells have been depleted by any disease-altering MS treatment prior to initiating the therapy disclosed herein, such as prior to administration of oframumab Q2M (e.g., subcutaneously at about 135 mg). Therefore, MS subjects treated by the methods disclosed herein may already have a B cell count of ≤10 cells / μL when the first dose of an antiCD20 antibody (e.g., oframumab) is administered according to this disclosure (e.g., subcutaneously at about 135 mg and thereafter every about two months).

[0196] In some implementation plans, patients are neurologically stable for one month prior to the first administration of an anti-CD20 antibody (e.g., ofamumab). Neurological stability is defined as a clinical state characterized by the absence of changes in mental status or level of consciousness. This state may include control of seizures; the absence of new neurological deficits such as aphasia, ataxia, dysarthria, hemiparesis, paralysis, visual field loss, or blindness, and is defined as neurological stability.

[0197] In some implementations, the subjects are receiving or have received treatment for disease-altering multiple sclerosis, such as oflamumab, glatiramer acetate, olgrizumab, utuximab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate.

[0198] In some implementations, the subject is receiving or has received anti-CD20 antibody therapy. In some implementations, the anti-CD20 antibody is selected from oflavumab, oligrizumab, rituximab, or utuximab. In some implementations, the subject has received at least one dose of the anti-CD20 antibody. In some implementations, the subject has received at least 12 doses of the anti-CD20 antibody. In some implementations, the subject has received at least 1-12 doses of the anti-CD20 antibody.

[0199] In some implementations, the subject is receiving or has received a monthly dose of an anti-CD20 antibody (e.g., oflamumab). In some implementations, the subject has received an initial dose of an anti-CD20 antibody (e.g., oflamumab) at weeks 0, 1, and 2, followed by one or more subsequent monthly doses of the anti-CD20 antibody (e.g., oflamumab) starting at week 4. In some implementations, the subject has received at least one monthly dose of an anti-CD20 antibody (e.g., oflamumab). In some implementations, the subject has received at least 12 monthly doses of an anti-CD20 antibody (e.g., oflamumab). In some implementations, the subject has received 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 monthly doses of an anti-CD20 antibody (e.g., oflamumab).

[0200] In another implementation, the patient is newly diagnosed. The newly diagnosed patient has not received any prior treatment for multiple sclerosis (e.g., disease-modifying therapies).

[0201] In some implementations, the subject had at least one relapse within the year prior to treatment. In some implementations, the subject had at least two relapses within the two years prior to treatment. In some implementations, the subject had one positive Gd-enhanced MRI scan within the year prior to treatment. In some implementations, the subject had active disease, meaning they showed signs of relapse and / or active inflammation on MRI scans.

[0202] In some implementations, patients undergo hepatitis B virus (HBV) screening before initiating anti-CD20 antibody (e.g., ofamumab) therapy. Screening may include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb) testing. This testing may be supplemented with other appropriate markers, depending on local guidelines. In some implementations, patients do not have active HBV infection. For example, a patient does not have active HBV confirmed by a positive result for both hepatitis B surface antigen [HBsAg] and anti-HBV testing. Therefore, patients to be treated have undergone hepatitis B virus (HBV) screening and / or do not have active HBV infection before initiating anti-CD20 antibody (e.g., ofamumab) therapy.

[0203] In some implementations, the patient does not have known IgE-mediated hypersensitivity to anti-CD20 antibodies (e.g., oflamumab). In some implementations, the patient is not allergic to the anti-CD20 antibody (e.g., oflamumab) or any excipient in the anti-CD20 antibody (e.g., oflamumab) formulation. For example, the patient is not allergic to the anti-CD20 antibody (e.g., oflamumab) or to any component of the formulation, including any non-medical ingredient, component, or container.

[0204] In some implementations, patients undergo quantitative serum immunoglobulin screening before initiating anti-CD20 antibody (e.g., ofamumab) therapy. In some implementations, patients do not have a severe immunocompromised state (e.g., significant neutropenia or lymphopenia). Therefore, patients have undergone quantitative serum immunoglobulin screening and / or do not have a severe immunocompromised state before initiating anti-CD20 antibody (e.g., ofamumab) therapy.

[0205] Therefore, according to the present invention, the patient to be treated may have any one or more of the above characteristics. For example, the patient may have one or more of the following characteristics: a) The patient had undergone hepatitis B virus (HBV) screening before starting anti-CD20 antibody (e.g., ofamumab) treatment; b) The patient does not have an active HBV infection; c) The patient underwent quantitative serum immunoglobulin screening before starting anti-CD20 antibody (e.g., ofamumab) treatment; d) The patient does not have a severe immunocompromised state (e.g., significant neutropenia or lymphopenia); e) The patient does not have known IgE-mediated hypersensitivity to anti-CD20 antibodies (e.g., ofamumab); and / or f) The patient is not allergic to any excipient of the anti-CD20 antibody (e.g., ofamumumab) and / or any non-medical ingredient, component, or container of the anti-CD20 antibody preparation (e.g., ofamumumab).

[0206] In some implementations, a target level of B-cell depletion is achieved following treatment according to the methods disclosed herein. Preferably, the methods provided herein deplete and / or maintain the subject's B-cell count to ≤ about 10 cells / μL (e.g., 10 cells / μL).

[0207] Low B-cell counts have been observed to suppress lesions and reduce the risk of recurrence. Therefore, in some implementations, a target level of Gd+T1 lesion rate per MRI scan is achieved.

[0208] In some implementations, the methods described herein (e.g., using ofamumab as an anti-CD20 antibody) cause one or more of the following: a) a decrease in the number of Gd+T1 lesions relative to baseline; b) a decrease in the number of new or enlarged T2 lesions relative to baseline; and / or c) a decrease in the annualized relapse rate (ARR) relative to baseline.

[0209] In some implementations, the methods described herein (e.g., follow-up dosing regimens using 135 mg of oframumab subcutaneously Q2M) are non-inferior to reference maintenance regimens (e.g., follow-up dosing regimens using 20 mg of oframumab subcutaneously Q1M) in one or more of the following aspects: a) a reduction in the number of Gd+ T1 lesions; b) a reduction in the number of new or enlarged T2 lesions; c) a reduction in ARR relative to the reference maintenance regimen; d) the number and / or severity of injection-related reactions (IRR); and / or e) immunogenicity (e.g., the incidence of anti-drug antibodies (ADA)).

[0210] In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of approximately 0.25 or less. In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of <0.1. In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of 0.01–0.05. In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of 0.005–0.05. In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of <0.005. In some embodiments, the method provided herein achieves a Gd+T1 lesion rate of ≤0.02. In a preferred embodiment, the method provided herein achieves a Gd+T1 lesion rate of ≤0.03.

[0211] In some embodiments, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of 4 or less. In some embodiments, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of less than 2. In some embodiments, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of less than 1. In some embodiments, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of less than 0.9. In some embodiments, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of less than 0.8. In a preferred embodiment, the method provided herein achieves an annualized rate of new or enlarged T2 lesions of ≤0.72.

[0212] In some implementations, the method provided herein achieves an annual recurrence rate (ARR) of less than 0.25. In some implementations, the method provided herein achieves an ARR of less than 0.22, less than 0.20, less than 0.15, or less than 0.12. In a preferred implementation, the method provided herein achieves an ARR of ≤0.11.

[0213] Therefore, the methods presented in this article (e.g., using ofamumab as an anti-CD20 antibody) may result in one or more of the following: a) a Gd+ T1 lesion rate of ≤0.03; b) an annualized rate of new or enlarged T2 lesions of ≤0.72; and / or c) an annualized relapse rate (ARR) of ≤0.11.

[0214] In some implementations, injection-related systemic reactions occurred in less than 24.1% of subjects receiving the Q2M maintenance regimen described herein (e.g., 135 mg of ofamumumab subcutaneous Q2M). In some implementations, injection-related systemic reactions occurred in less than 16.1% of subjects receiving the Q2M maintenance regimen described herein (e.g., 135 mg of ofamumumab subcutaneous Q2M).

[0215] In some implementations, the methods provided herein deplete and / or maintain the subject's B-cell count to ≤10 cells / μL, and / or achieve a Gd+T1 lesion rate of 0.01–0.05.

[0216] In some implementations, the methods described herein (e.g., using oligrinumab or utuximab as anti-CD20 antibodies) deplete and / or maintain the subject's B cell count to ≤10 cells / μL, ≤8 cells / μL, or ≤5 cells / μL; and / or achieve a Gd+T1 lesion rate (number of Gd+T1 lesions per MRI scan) of <0.05 or ≤0.02.

[0217] Unit dosage and medicine box This document also provides a fixed single-unit dose of an anti-CD20 antibody. In some embodiments, the fixed single-unit dose comprises about 100 to about 600 mg of anti-CD20 antibody. In some embodiments, the fixed single-unit dose comprises about 100 to about 170 mg of anti-CD20 antibody. In some embodiments, the fixed single-unit dose comprises about 135 mg of anti-CD20 antibody. In some embodiments, the fixed single-unit dose comprises about 600 mg of anti-CD20 antibody.

[0218] The preferred anti-CD20 antibody is oflavumab (or a similar anti-CD20 antibody). Therefore, in some embodiments, each fixed single-unit dose comprises approximately 110-160 mg of oflavumab. In some embodiments, each fixed single-unit dose comprises approximately 120-150 mg of oflavumab. In some embodiments, each fixed single-unit dose comprises approximately 130-140 mg of oflavumab. In a preferred embodiment, each fixed single-unit dose comprises approximately 135 mg of oflavumab. This fixed single-unit dose helps to efficiently deplete and maintain low B-cell levels for up to 2 months.

[0219] In some embodiments, this document provides a fixed single-unit dose of ospermumab (or a similar anti-CD20 antibody). In some embodiments, each fixed single-unit dose comprises about 135 mg of ospermumab. In some embodiments, each fixed single-unit dose comprises about 480-720 mg of ospermumab. In some embodiments, each fixed single-unit dose comprises about 540-660 mg of ospermumab. In some embodiments, each fixed single-unit dose comprises about 600 mg of ospermumab. In some embodiments, each fixed single-unit dose comprises about 730-1,110 mg of ospermumab. In some embodiments, each fixed single-unit dose comprises about 820-1,020 mg. In a preferred embodiment, each fixed single-unit dose comprises about 920 mg of ospermumab.

[0220] In another embodiment, this document provides a fixed single-unit dose of utuximab (or a similar anti-CD20 antibody). In some embodiments, each fixed single-unit dose comprises about 100-170 mg of utuximab. In some embodiments, each fixed single-unit dose comprises about 135 mg of utuximab.

[0221] This document also provides a kit comprising one or more fixed single-unit doses of anti-CD20 antibodies as described above. This document also provides a kit comprising one or more pre-filled pens (i.e., autoinjectors) or pre-filled syringes, each pre-filled pen or syringe containing a fixed single-unit dose of the anti-CD20 antibody as described above. In some embodiments, the kit further includes three pre-filled pens (i.e., autoinjectors) or pre-filled syringes, each pre-filled pen or syringe containing approximately 20 mg of a fixed single-unit dose of anti-CD20 antibody (e.g., oflambumab).

[0222] In some embodiments, each single fixed dose is provided in a total volume of about 0.4 mL. In a preferred embodiment, each single fixed dose is provided in a total volume of about 1.5 mL. In some embodiments, each single fixed dose is provided in a total volume of about 2 mL.

[0223] Neurofilament light chains Neurofilament light chains (NFL) can be used as a biomarker for MS disease progression and responsiveness to treatment. Specifically, higher levels of NFL have been found to be associated with increased T2 and Gd+T1 lesions and increased relapse frequency. Therefore, this article provides for the use of NFL as a prognostic biomarker for MS disease activity in subjects. In some implementations, the subjects are undergoing treatment with anti-CD20 antibodies.

[0224] This article also provides a method for predicting MS relapse in a subject, the method comprising detecting NFL levels (pg / mL). In some embodiments, the method comprises detecting NFL levels in the subject's cerebrospinal fluid or blood. In some embodiments, the subject is undergoing treatment with an anti-CD20 antibody.

[0225] This article also provides a method for treating MS in a subject of need, the method comprising subcutaneously administering an anti-CD20 antibody to the subject, wherein the subject has elevated NFL levels, such as elevated NFL levels in blood or cerebrospinal fluid. In a preferred embodiment, the anti-CD20 antibody is oflambumab.

[0226] This article also provides a method for treating MS in subjects of need, wherein the method includes i) subcutaneous administration of an anti-CD20 antibody to the subject and ii) monitoring the subject's NFL levels. In a preferred embodiment, the anti-CD20 antibody is oflavumab.

[0227] Methods for monitoring disease progression The following describes methods for monitoring disease progression in MS and how these methods can be combined with the treatments disclosed herein.

[0228] Disease progression in subjects with MS can also be assessed using the Extended Disability Status Scale (EDSS), the Symbolic Digit Pattern Test (SDMT), the Rey Auditory Verbal Learning Test (RAVLT), the Brief Visual Spatial Memory Test-Revised (BVMT-R), the 25-foot Timed Walk Test (T25-FW), and the 9-hole pegboard test (9-HPT).

[0229] Another approach to monitoring disease progression in subjects with MS is eye-tracking assessment. Eye-tracking assessment may involve measuring eye movement parameters obtained from fixation, forward saccades, backward saccades, visual smooth tracking, and optokinetic nystagmus tasks. Eye-tracking assessment can serve as an eye-tracking biomarker for disease progression, optionally using digital eye-tracking biomarkers.

[0230] Methods for monitoring disease progression in subjects with MS using eye-tracking assessments may include tracking eye movements. Suitable methods and systems for tracking eye movements have been described in WO2019161503, WO2022232935 (Innodem Neurosciences), US20170276934 (ICSPI Corp.), US20180342066 (Sony Interactive Entertainment), WO2021028858, and WO2007076479 (Alcon), all of which are incorporated herein by reference in their entirety.

[0231] Therefore, this document discloses a method in which a subject may have been treated with or is currently being treated with an anti-CD20 antibody (e.g., oflamumab, for example, during an initial dosing regimen of three separate 20 mg doses at weeks 0, 1, and 2, followed by a subsequent dosing regimen of 20 mg once monthly or 135 mg once every 2 months), and the method includes eye movement assessment as described above. In some embodiments, the anti-CD20 antibody is oflamumab, ospermumab, rituximab, or utuximab. In a preferred embodiment, the anti-CD20 antibody is oflamumab.

[0232] summary Unless otherwise indicated, the practice of this disclosure will employ conventional methods of chemistry, biochemistry, molecular biology, immunology, and pharmacology that are within the technical scope of those skilled in the art.

[0233] Unless the context otherwise indicates, the term “about” in relation to the numerical value x is optional and means, for example, x ± 10%.

[0234] Unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” used in this specification and the appended claims include plural indicators.

[0235] Unless otherwise stated or obvious from the context, as used herein, the term “or” should be understood as inclusive and covers both “or” and “and”.

[0236] Unless otherwise stated or obvious from the context, as used in this specification, the term "day 1" is equivalent to the term "week 0", the term "day 7" is equivalent to "week 1", the term "day 14" is equivalent to "week 2", the term "week 4" is equivalent to "month 1", the term "week 12" is equivalent to "month 3", and the term "week 24" is equivalent to "month 6".

[0237] Skilled practitioners will understand that the term "baseline" refers to baseline measurements recorded before the start of treatment, such as the baseline number of Gd+T1 lesions.

[0238] As used herein, the terms “subject” and “patient” are used interchangeably and refer to a person (e.g., an adult at least 18 years of age).

[0239] As used in this specification, "anti-CD20 antibody" is an antibody that specifically binds to the human CD20 antigen expressed on B cells. CD20 is expressed on late-stage pre-B cells, mature B cells, and memory B cells, but not on lymphoid stem cells or plasma cells. Examples of anti-CD20 antibodies include, but are not limited to, oflamb, rituximab, tositumomab, utuximab, oligrizumab (2H7.vl6), 11B8 or 7D8 (disclosed in WO2004 / 035607), anti-CD20 antibodies (such as C6) disclosed in WO 2005 / 103081, anti-CD20 antibodies (such as IMMU-106 (from Immunomedics)) disclosed in WO2003 / 68821, anti-CD20 antibodies (such as AME-133 (from Applied Molecular Evolution / Lilly)) disclosed in WO2004 / 103404, and anti-CD20 antibodies (such as TRU-015 (from Trubion Pharmaceuticals Inc)) disclosed in US 2003 / 0118592.

[0240] The term "treatment" refers to both therapeutic treatment and preventative or preventative therapy.

[0241] All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, and are commonly used in the field. Publications and other references cited herein to describe the background of the invention and to provide further details on its practice are incorporated herein by reference.

[0242] Other exemplary implementations 1. A method for treating multiple sclerosis in a subject in need, the method comprising administering an anti-CD20 antibody to the subject every two months.

[0243] 2. The method of any of the foregoing embodiments, wherein the anti-CD20 antibody is selected from the group consisting of: olfamumab (e.g., KESIMPTA® / BONSPRI®), olrezhumab (e.g., OCREVUS®), rituximab (e.g., RITUXAN® / MABTHERA®), and utuximab (e.g., BRIUMVI®).

[0244] 3. The method as described in any of the foregoing embodiments, wherein the anti-CD20 antibody is oflavumab.

[0245] 4. The method as described in any of the preceding embodiments, wherein the anti-CD20 antibody (e.g., ofamumab) is administered at a dose of about 130 to about 140 mg every 2 months, for example, 130 to 140 mg (e.g., about 135 mg, for example, 135 mg) every two months.

[0246] 5. The method as described in any of the preceding embodiments, wherein the subject is receiving or has received an anti-CD20 antibody, such as olfamumab (e.g., KESIMPTA® / BONSPRI®), olrezhumab (e.g., OCREVUS®), rituximab (e.g., RITUXAN® / MABTHERA®), or utuximab (e.g., BRIUMVI®), such as olfamumab (e.g., KESIMPTA® / BONSPRI®).

[0247] 6. The method as described in any of the preceding embodiments, wherein the subject is receiving or has received or has received monthly oflamb (e.g., KESIMPTA® / BONSPRI®).

[0248] 7. The method as described in any of the preceding embodiments, wherein the subject has received oframumab (e.g., KESIMPTA® / BONSPRI®) at weeks 0, 1, and 2.

[0249] 8. The method as described in any of the preceding embodiments, wherein the subject has received an initial dose, such as a loading dose of an anti-CD20 antibody, such as oflambumab (e.g., KESIMPTA® / BONSPRI®), at weeks 0, 1, and 2, followed by one or more subsequent (e.g., maintenance) doses of an anti-CD20 antibody, such as oflambumab (e.g., KESIMPTA® / BONSPRI®), once monthly.

[0250] 9. The method as described in any of the preceding embodiments, wherein the subject has received at least 1 to 12 monthly doses of an anti-CD20 antibody, such as oflambumab (e.g., KESIMPTA® / BONSPRI®).

[0251] 10. A solution for injection comprising about 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate, about 25 to about 100 mM of sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), such as pH 5.5.

[0252] 11. The solution for injection as described in Embodiment 10, wherein the solution for injection comprises about 90 mg / mL of ofumab (e.g., 90 mg / mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5). For example, the pH value can be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), such as pH 5.3-5.8, such as pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), such as pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), especially pH 5.3-5.8 or pH 5.3-5.7.

[0253] 12. A solution for injection, said solution comprising: about 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate (e.g., sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) of sodium chloride, about 0.5 to about 5% (w / v) (e.g., 0.5% to 5% (w / v)) of free arginine base (e.g., L-arginine), about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH...). pH 5.0 to 7.0), for example, about pH 5.5 (e.g., with hydrochloric acid).

[0254] 13. The solution for injection as described in Embodiment 12, wherein the solution for injection comprises: about 90 mg / mL (e.g., 90 mg / mL) of ofumumab, about 50 mM (e.g., 50 mM) of sodium acetate (e.g., sodium acetate trihydrate), about 51 mM (e.g., 51 mM) of sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) of free arginine base (e.g., L-arginine), about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g., with hydrochloric acid). For example, the pH value can be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), such as pH 5.3-5.8, such as pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), such as pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), especially pH 5.3-5.8 or pH 5.3-5.7.

[0255] 14. A pharmaceutical composition comprising about 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate, about 25 to about 100 mM of sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), such as about pH 5.5.

[0256] 15. The pharmaceutical composition of embodiment 14, wherein the pharmaceutical composition comprises about 90 mg / mL of ofumab (e.g., 90 mg / mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to about pH 5.5 (e.g., pH 5.5). For example, the pH value can be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), such as pH 5.3-5.8, such as pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), such as pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), especially pH 5.3-5.8 or pH 5.3-5.7.

[0257] 16. A pharmaceutical composition comprising: about 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate (e.g., sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) of sodium chloride, about 0.5 to about 5% (w / v) (e.g., 0.5% to 5% (w / v)) of free arginine base (e.g., L-arginine), about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH...). pH 5.0 to 7.0), for example, about pH 5.5 (e.g., with hydrochloric acid).

[0258] 17. The pharmaceutical composition of embodiment 16, wherein the pharmaceutical composition comprises: about 90 mg / mL (e.g., 90 mg / mL) of ofumumab, about 50 mM (e.g., 50 mM) of sodium acetate (e.g., sodium acetate trihydrate), about 51 mM (e.g., 51 mM) of sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) of free arginine base (e.g., L-arginine), about 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to about pH 5.5 (e.g., pH 5.5) (e.g., with hydrochloric acid). For example, the pH value can be pH 5.5 ± 0.3 (i.e., pH 5.2-5.8), such as pH 5.3-5.8, such as pH 5.5 ± 0.2 (i.e., pH 5.3-5.7), such as pH 5.5 ± 0.1 (i.e., pH 5.4-5.6), especially pH 5.3-5.8 or pH 5.3-5.7.

[0259] Example The following examples are included for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0260] Example 1: B cell morphology and PK exposure method The inventors have discovered that the Q2M dosing interval is particularly suitable for subcutaneous treatment of MS with ofamumumab. It provides the convenience of less frequent dosing while maintaining effective control of B-cell levels without extending the interval so much that the dose of ofamumumab would be too high for comfortable subcutaneous delivery.

[0261] PK-B cell models, established from extensive data obtained in Phase 2 and 3 studies completed as described in (Yu H, Graham G, David OJ et al. (2022) Population Pharmacokinetic-B Cell Modeling for Ofatumumab in Patients with Relapsing Multiple Sclerosis. CNS Drugs; 36(3):283-300), were used to simulate pharmacokinetic (PK)-B cell morphologies for different dosing regimens in RMS patients. PK morphologies for all dosing regimens in the RMS patient population were assessed based on simulations of individual PK morphologies using characteristics of all patients who received subcutaneous administration in the OMS112831, COMB157G2102, COMB157G2301, and COMB157G2302 studies, corresponding to 1461 patients per simulation. This was considered well-representative of the adult RMS population, taking into account similar inclusion / exclusion criteria for future Phase 3 trials.

[0262] PK and B-cell morphology simulations were performed on various potential dosing regimens identified by the inventors. In all simulations presented herein, parameters were evaluated using a subcutaneous autoinjector in the PK-B-cell model. However, the results are not limited to the autoinjector presentation and are also applicable to other forms of administration, such as those via pre-filled syringes. In all simulations, an initial dosing regimen of 20 mg at weeks 0, 1, and 2 was used in conjunction with subsequent dosing regimens starting at week 4. PK and B-cell morphology were simulated after 52 weeks of dosing. The median, 5th percentile, and 95th percentile of the PK and B-cell morphology data are presented.

[0263] result 40 mg of oflamb monoclonal antibody subcutaneous Q2M regimen PK and B cell morphologies were simulated for an extended dosing regimen that included a subsequent administration of 40 mg of oflamumab subcutaneously in Q2M (i.e., twice the Q1M dose of 20 mg of oflamumab).

[0264] Figure 1The B-cell depletion pattern of the 40 mg subcutaneous Q2M regimen compared to the approved 20 mg subcutaneous Q1M regimen is shown. The B-cell depletion pattern was identical for both regimens up to week 4, as they both used the same 20 mg initial dosing regimen (weeks 0, 1, and 2). After week 4, both regimens also exhibited rapid initial B-cell depletion. However, at week 8, subsequent dosing regimens of the 40 mg subcutaneous Q2M regimen began to deviate from the B-cell depletion pattern of the 20 mg subcutaneous Q1M regimen in terms of median B-cell morphology and B-cell distribution in the population.

[0265] Both the 20 mg subcutaneous Q1M and 40 mg subcutaneous Q2M regimens achieved a median CD19+ B cell count of ≤10 cells / μL. However, the median B cell count achieved with the 40 mg subcutaneous Q2M regimen was higher than that achieved with the 20 mg subcutaneous Q1M regimen. This is because the median B cell count with the 40 mg subcutaneous Q2M regimen fluctuated during the two-month dosing interval, while the median B cell count with the 20 mg subcutaneous Q1M regimen remained relatively stable between monthly doses.

[0266] In practice, the median B-cell count of the 40 mg subcutaneous Q2M regimen began to rise approximately 4 weeks after each subsequent dose and peaked before the next subsequent dose. During the first 28 weeks of treatment, the median B-cell count of the 40 mg subcutaneous Q2M regimen increased from approximately 1 cell / μL to between approximately 3 and 2 cells / μL between doses, while the median B-cell count of the 20 mg subcutaneous Q1M regimen remained consistently at approximately 1 cell / μL. Therefore, the 40 mg subcutaneous Q2M regimen demonstrated a higher level of B-cell replenishment between doses compared to the 20 mg subcutaneous Q1M regimen.

[0267] Furthermore, compared to the 95th percentile of the 20 mg Q1M regimen ( Figure 1 Compared to the upper boundary of the dark gray shaded area in the image, the 95th percentile of the 40 mg subcutaneous Q2M regimen ( Figure 1 The upper boundary of the light gray shaded area (as shown in the image) indicates a higher B-cell count. Between doses, the 95th percentile B-cell count peaked above 30 cells / μL with the 40 mg subcutaneous Q2M regimen, while the 95th percentile B-cell count remained ≤10 cells / μL with the 20 mg subcutaneous Q1M regimen. As explained above, a B-cell count ≤10 cells / μL is associated with a lower rate of Gd+T1 lesions and higher therapeutic efficacy. Therefore, the 40 mg subcutaneous Q2M regimen is not expected to achieve the same level of B-cell depletion (and therefore the same level of therapeutic efficacy) in the patient population as the 20 mg subcutaneous Q1M regimen.

[0268] like Figure 2As shown, the 40 mg subcutaneous Q2M dosing regimen also exhibited a less favorable pharmacokinetic pattern. The median concentration of oframumab decreased to below 0.1 mg / L between doses in the 40 mg subcutaneous Q2M regimen, suggesting a risk of insufficient exposure over the two-month dosing interval. Therefore, the 40 mg subcutaneous Q2M dosing regimen provides inferior exposure compared to the currently approved 20 mg subcutaneous Q1M dosing regimen.

[0269] The pharmacokinetic and B-cell profiles evaluated for the 40 mg subcutaneous Q2M regimen indicate that this extended dosing regimen is clinically inferior to the approved 20 mg subcutaneous Q1M regimen.

[0270] 80 mg of oflamb subcutaneous Q2M regimen The subsequent dosing regimen of 80 mg of ofamumab subcutaneously Q2M (i.e., four times the approved Q1M 20 mg dose) was simulated.

[0271] Figure 3 The B-cell depletion pattern of the 80 mg subcutaneous Q2M regimen compared to the approved 20 mg subcutaneous Q1M regimen is shown. As explained above, the B-cell depletion pattern was identical for both regimens up to week 4, as they both used the same 20 mg initial dosing regimen. After week 4, subsequent dosing regimens of 80 mg subcutaneous Q2M showed a good concordance with the 20 mg subcutaneous Q1M pattern in terms of both rapid initial depletion and median B-cell pattern. Specifically, the 80 mg subcutaneous Q2M regimen showed a similar median B-cell count to the 20 mg subcutaneous Q1M regimen, which was maintained over the two-month dosing interval. Similar to the 20 mg subcutaneous Q1M regimen, the 80 mg subcutaneous Q2M regimen was evaluated to achieve the desired median CD19+ B-cell count of ≤10 cells / μL.

[0272] However, compared to the 20 mg subcutaneous Q1M regimen, the 80 mg subcutaneous Q2M regimen showed inferior B-cell distribution in the population. The 95th percentile of the 20 mg subcutaneous Q1M regimen ( Figure 3 Compared to the upper boundary of the dark gray shaded area in the image, the 95th percentile of the 80 mg subcutaneous Q2M regimen ( Figure 3 The upper boundary of the light gray shaded area (as shown in the image) indicates a higher B-cell count. Specifically, during a simulated 52-week treatment period, the 95th percentile B-cell count of the 80 mg subcutaneous Q2M regimen remained above 10 cells / μL. In all patients, the 80 mg subcutaneous regimen failed to achieve a B-cell count ≤10 cells / μL, suggesting that this extended dosing regimen may be clinically inferior to the approved 20 mg subcutaneous Q1M regimen.

[0273] like Figure 4As shown, the pharmacokinetic profile of the 80 mg subcutaneous Q2M regimen is also inferior to that of the 20 mg subcutaneous Q1M regimen. Specifically, the median C-minus (mg / mL) assessed for the 80 mg subcutaneous Q2M regimen is lower than that for the 20 mg subcutaneous Q1M regimen. Therefore, the 80 mg subcutaneous Q2M regimen is expected to provide a lower level of exposure compared to the approved monthly regimen.

[0274] Based on the above-mentioned simulated pharmacokinetics and B-cell depletion patterns, the 80 mg subcutaneous Q2M regimen provides clinical efficacy inferior to previously approved regimens.

[0275] 135 mg of oflamb monoclonal antibody subcutaneous Q2M regimen Of all the extended follow-up dosing regimens tested, the 135 mg subcutaneous Q2M regimen unexpectedly produced a favorable B-cell morphology. Figure 5 The B-cell depletion pattern of the 135 mg subcutaneous Q2M regimen compared to the 20 mg subcutaneous Q1M regimen is shown. The B-cell depletion patterns were identical for both regimens up to week 4, as they both used the same 20 mg initial dosing regimen. After week 4, subsequent dosing of the 135 mg subcutaneous Q2M regimen showed good agreement with the 20 mg Q1M pattern in terms of rapid initial depletion, median B-cell pattern, and B-cell distribution in the population. Specifically, the 135 mg Q2M dosing regimen showed similar or even lower median B-cell counts, which were maintained over the two-month dosing interval. The 135 mg regimen was evaluated to achieve a median CD19+ B-cell count of ≤10 cells / μL, similar to the B-cell counts achieved with a monthly dosing regimen. As previously explained, a B-cell count of ≤10 cells / μL is associated with a lower rate of Gd+T1 lesions and higher therapeutic efficacy.

[0276] The 95th percentile of the 20 mg Q1M regimen ( Figure 5 Compared to the upper boundary of the light gray shaded area in the image, the 95th percentile of the 135 mg subcutaneous Q2M regimen ( Figure 5 The upper boundary of the dark gray shaded area in the image also showed a lower B-cell count. During the intervals between subsequent dose administrations, the 95th percentile B-cell count of the 135 mg subcutaneous Q2M regimen was lower than that of the 20 mg subcutaneous Q1M regimen. Furthermore, after week 12 (i.e., after administration of the second 135 mg follow-up dose), and even at the end of each 2M interval before the next follow-up dose, the 95th percentile of the 135 mg Q2M regimen remained below 10 cells / μL and lower than that of the 20 mg Q1M regimen.

[0277] The 135 mg subcutaneous Q2M regimen also makes B-cell count replenishment less frequent, with B-cell depletion levels peaking every two months instead of monthly, while allowing for replenishment quickly enough when necessary (e.g., in case of infection).

[0278] like Figure 6 As shown, the 135 mg subcutaneous Q2M dosing regimen also exhibits an appropriate pharmacokinetic profile. The minimum C-value was chosen as the most sensitive and clinically relevant target metric to confirm non-inferiority of the new regimen over the entire Q2M dosing interval compared to the 20 mg subcutaneous Q1M regimen. As shown in Table 1 below, the lower 5th percentiles of the minimum C-values ​​for 135 mg subcutaneous Q2M and 20 mg subcutaneous Q1M are similar, thus minimizing the risk of underexposure. Therefore, the 135 mg subcutaneous Q2M dosing regimen is expected to provide at least non-inferior exposure to the approved 20 mg subcutaneous Q1M dosing regimen over the dosing interval.

[0279] Table 1: PK metric AUCτ from the RMS population receiving oflambumab (Week 4-12) The median and (5th and 95th) quantiles of C-maximum (week 5) and C-minimum (week 12 before administration).

[0280] Based on pharmacokinetic and B-cell morphology modeling, the 135 mg subcutaneous Q2M regimen is expected to exhibit a similar safety profile to the 20 mg subcutaneous Q1M regimen. Specifically, the inventors have found that the initial 20 mg subcutaneous regimen, administered in weeks 0, 1, and 2 prior to the initiation of subsequent higher-dose 135 mg subcutaneous Q2M regimens at week 4, further reduces the risk of any systemic injection-related response (IRR), the severity of which may be dose- and B-cell count-related. The initial regimen ensures effective depletion of B cells by week 4 (i.e., prior to administration of the first 135 mg subsequent dose) (as determined in COMB157G2301 and COMB157G2302, the overall proportion of patients treated with ofamumumab with a B-cell count ≤10 cells / μL at week 2 was 81.9% and 91.8% by week 4), thereby reducing the potential risk of increased systemic IRR at higher doses.

[0281] Therefore, compared with the approved 20 mg subcutaneous Q1M dosing regimen, the 135 mg subcutaneous Q2M dosing regimen demonstrates at least a non-inferiority pharmacokinetic pattern and has been evaluated to produce at least similar or even more pronounced B-cell depletion that is maintained over a two-month dosing interval, with fewer patients showing signs of B-cell replenishment prior to each subsequent dose administration, while retaining the ability to replenish B-cell levels sufficiently quickly by interrupting treatment when needed (e.g., in case of infection).

[0282] Furthermore, compared to other tested dosing regimens, including 40 mg subcutaneous Q2M and 80 mg subcutaneous Q2M, the 135 mg subcutaneous Q2M dosing regimen demonstrated superior pharmacokinetics and B-cell depletion patterns. Increasing the approved monthly dose of oframumab (i.e., 20 mg) to two times (i.e., 40 mg) or even four times (i.e., 80 mg) is insufficient to provide an effective dosing regimen for oframumab administered at half the frequency of the approved regimen (Q2M).

[0283] Example 2: Stable high-concentration antibody preparation Ophamumab is available in high-concentration antibody formulations, preferably containing 90 mg / mL of ophamumab (e.g., 135 mg in 1.5 mL). As explained above, such high-concentration antibody formulations may be difficult to prepare due to long-term stability issues. Significant optimization is often required to develop high-concentration antibody formulations that facilitate long-term storage and painless delivery to patients.

[0284] For this reason, the physicochemical stability of ofamumab at a concentration of 90 mg / mL was tested in three alternative formulations (A, B and C) shown in Table 2 below.

[0285] Table 2: Exemplary ofamumab formulations

[0286] Formulation A contains 50 mM sodium acetate, 51 mM sodium chloride, 1% (w / v) free arginine, 0.02% (w / v) polysorbate 80, and 0.05 mM EDTA, adjusted to pH 5.5. Therefore, Formulation A corresponds to the formulation used in the approved offamumab 20 mg / 0.4 mL dosage form. In Formulation B, given the tendency of high-concentration antibody formulations to form aggregates, the concentration of polysorbate 80 (PS80) is doubled to 0.04% (w / v). Methionine is added to Formulation C at a concentration of 5 mM to account for the aggregation, particle formation, and oxidative stress that may be observed in high-concentration antibody formulations.

[0287] The long-term stability of oframumab in these three alternative formulations was tested for up to six months under three different storage conditions: i) Expected conditions (5℃±3℃); ii) Acceleration conditions (25℃±2℃ and 60±5% relative humidity); and iii) Stress conditions (40℃±2℃ and 75±5% relative humidity).

[0288] Throughout the study, all three formulations were stored in the same injection device.

[0289] The purity, aggregates, and relative potency of the formulation were evaluated.

[0290] Purity measured by size exclusion chromatography (SEC) The purity of three different ofamumab formulations was measured by size exclusion chromatography (SEC) during a six-month storage period. Table 3 shows the percentage of purity of each formulation over time under expected, accelerated, and stress conditions.

[0291] Table 3 - Purity as measured by SEC

[0292] As shown in Table 3, the purity of all three formulations was well preserved after six months of storage. Specifically, the purity of all three formulations was: • When measured by size exclusion chromatography, the purity at time point 0 is at least 99%, and: (a) at least 99% after storage at 5°C ± 3°C for 1.5 months; and / or (b) at least 99% after storage at 5°C ± 3°C for 6 months; • When measured by size exclusion chromatography, the purity at time point 0 is at least 99%, and: (a) at least 98% after storage for 1.5 months at 25°C ± 2°C and 60 ± 5% relative humidity; and / or (b) at least 96% after storage for six months at 25°C ± 2°C and 60 ± 5% relative humidity; and • When measured by size exclusion chromatography, the purity at time point 0 is at least 99%, and: (a) at least 96% after storage for 1.5 months at 40°C ± 2°C and 60 ± 5% relative humidity; and / or (b) at least 87% after storage for 6 months at 40°C ± 2°C and 60 ± 5% relative humidity.

[0293] Aggregates measured by size exclusion chromatography (SEC) Aggregate formation in three oflamb formulations after six months of storage was assessed by SEC. Table 4 shows the total aggregates over time for each formulation under expected, accelerated, and stress conditions.

[0294] Table 4 - Sum of aggregates as measured by SEC

[0295] Under both expected and accelerated conditions, all three formulations prevented significant aggregate formation after six months of storage. The size change pattern after six months of storage under expected conditions showed a very small increase in total aggregate size compared to time point 0. Under accelerated conditions, the total aggregate size increased by only about 0.5% after six months of storage.

[0296] Relative complement-dependent cytotoxicity (CDC) The potency of the three formulations after six months of storage was tested using a complement-dependent cytotoxicity assay on CD20-expressing Raji cells. Table 5 shows the relative potency of all three batches after six months of storage under expected, accelerated, and stress conditions.

[0297] Table 5 - Relative complement-dependent cytotoxicity (CDC)

[0298] Table 5 confirms that the relative potency of the three formulations remained stable for at least six months under both expected and accelerated conditions. Specifically, the three formulations exhibited at least 90% relative CDC potency after six months of storage at 5°C ± 3°C.

[0299] Subvisible particles observed by optical obscuration method Particle formation in three alternative formulations was tested using a light obscuration method. The number of subvisible particles per milliliter was measured under expected storage conditions, accelerated storage conditions, and stress storage conditions. Table 6 below shows the number of subvisible particles observed per milliliter of each formulation over time.

[0300] Table 6 - Number of subvisible particles per milliliter

[0301] United States Pharmacopeia (USP) Chapter 787, 'Subvisible Particulate Matter in Therapeutic Protein Injections', requires that ≤6000 particles in a container have a size ≥10 μm, and ≤600 particles have a size ≥25 μm. Formulations A, B, and C fully meet the requirements of USP 787 under all conditions and at all times. After 6 months of storage under expected conditions (5°C ± 3°C), the number of subvisible particles per milliliter did not change significantly in any of the three formulations, and only minor changes were observed under accelerated conditions (25°C ± 2°C).

[0302] in conclusion The above results indicate that the formulation containing 90 mg / mL of oframumab, 50 mM sodium acetate, 51 mM sodium chloride, 1% (w / v) free arginine base, 0.02% (w / v) polysorbate 80, and 0.05 mM EDTA, adjusted to pH 5.5, is a stable antibody formulation. As shown above, this formulation exhibits stability for at least six months under the expected storage conditions (5℃ ± 3℃).

[0303] Surprisingly, this formulation is stable and does not require methionine or an increased surfactant concentration. In fact, the results presented here show that, compared to the approved 20 mg / 0.4 mL formulation of ofemumab (A), neither the addition of 5 mM methionine (C) nor the increase of the PS80 concentration from 0.02% to 0.04% (B) had a detectable effect on long-term stability, although the concentration of ofemumab in the tested formulation (i.e., 90 mg / mL) was 180% of the concentration of ofemumab in the approved formulation (i.e., 50 mg / mL).

[0304] These studies demonstrate that the 135 mg subcutaneous Q2M oframumab regimen produces a PK / PD profile that is at least clinically non-inferior to the previously approved 20 mg subcutaneous Q1M regimen. Furthermore, this extended dosing regimen is supported by the applicant's reformulation of oframumab at a concentration of 90 mg / mL to deliver the full 135 mg of oframumab in a volume suitable for subcutaneous administration. Therefore, the 135 mg subcutaneous oframumab Q2M dosing regimen achieves an effective balance between PK / PD and formulation considerations.

[0305] Example 3: Phase III non-inferiority of subcutaneous 135 mg Q2M of oflavumab compared to subsequent doses of 20 mg Q1M. Sexual randomization open-label parallel group study The primary objective and purpose of this Phase 3 study was to demonstrate the non-inferiority (minimum C-value) profile of the new 135 mg subcutaneous Q2M concentration at week 12 (before administration) compared to the approved 20 mg subcutaneous Q1M subsequent regimen. Minimum C-value was chosen as the most sensitive and clinically relevant target metric to confirm the non-inferiority of the new regimen throughout the Q2M dosing interval. Consistency of the non-inferiority PK profile (exposure) and pharmacodynamic profile (B-cell depletion) with the approved regimen would further support the comparability of less frequent subsequent dosing regimens. Other objectives of this study are described below (Table 7).

[0306] Table 7: Research Objectives and Relevant Endpoints

[0307] sc = subcutaneous; RMS = relapsing multiple sclerosis; IRR = incidence rate ratio Research Design This is a phase III open-label, parallel-group, multicenter study conducted in approximately 180 study participants with RMS. The study consists of two parts—a core portion (up to 52 weeks) and an extension portion (up to 2 years) (see [link to study]). Figure 7 ).

[0308] The core study includes screening, treatment, and safety follow-up periods. The first approximately 100 enrolled study participants will be randomized 1:1 (50 per experimental group) to either the 135 mg Q2M or 20 mg Q1M experimental group in the 12-week parallel-group portion of the study. The primary (PK) non-inferiority (NI) endpoint is based on the minimum plasma C level observed at week 12. At the end of the parallel-group portion, patients in the 20 mg Q1M experimental group will switch to 135 mg Q2M starting at week 12. Patients randomized to the 135 mg Q2M experimental group will continue with this regimen until week 52. After approximately 100 patients have been randomized, approximately 80 more patients will be enrolled in the 135 mg Q2M experimental group (totaling 180 study participants) and safety will be followed for up to 52 weeks. All study participants (regardless of initial treatment allocation) will begin treatment with an initial dosing regimen of three 20 mg subcutaneous doses (in weeks 0, 1, and 2), with the first subsequent dose (135 mg Q2M or 20 mg Q1M) starting in week 4. Safety will be assessed in all study participants throughout the 52-week core phase of the study.

[0309] Participants who complete the core treatment phase of the study (lasting up to 52 weeks) will have the option to participate in the long-term extension of the study and continue receiving oflamumab 135 mg Q2M for up to approximately 2 more years.

[0310] research group The study will involve 180 adult patients with relapsing multiple sclerosis, aged 18–55 years (inclusive), male or female, and with an EDSS score of 0–5.5 (inclusive).

[0311] The main inclusion criteria for patient registration in the study included: written informed consent must be obtained before any assessment is performed; male or female patients aged 18 to 55 years (inclusive) at screening; diagnosed with MS according to the 2017 revised McDonald criteria (Thompson AJ, Baranzini SE, Geurts J et al. (2018) Multiple sclerosis. Lancet; 391(10130):1622-36); relapsing MS: relapsing-remitting course (RRMS) or secondary progressive course with disease activity (SPMS); disability status with an EDSS score of 0 to 5.5 (inclusive) at screening; a history of one relapse within the year prior to screening or two relapses within the two years prior to screening or a positive Gd-enhanced MRI scan prior to randomization; and neurological stability within one month prior to randomization.

[0312] Exclusion criteria Patients will be excluded from the study if they meet any of the following primary exclusion criteria: Patients with primary progressive MS (PPMS) or secondary progressive multiple sclerosis (SPMS) without disease activity (however, publicly available therapies are also intended for these forms of MS and other anti-CD20 antibodies, such as oligrinumab, are authorized for the treatment of these forms of MS and RMS); patients meeting the criteria for neuromyelitis optica; patients with an EDSS score of 2 or lower whose disease duration is greater than 10 years; pregnant or lactating women; women of childbearing potential unless using highly effective contraception during and for 12 months after administration of the study drug; sexually active men unless they consent to the use of condoms while using the study drug; patients with a chronic immune system disease other than MS; patients with neurological outcomes consistent with progressive multifocal leukoencephalopathy (PML) or confirmed PML; patients at risk of developing or reactivating hepatitis: serological markers of hepatitis A, B, C, and E (HA, HB, HC, and HE). A positive screening result indicating acute or chronic infection; a patient with an active systemic infection or known to have HIV or a positive HIV antibody test at screening; a patient at risk of developing syphilis or tuberculosis or reactivation of syphilis or tuberculosis; a patient who has received any live or live attenuated vaccine within 2 months prior to randomization; a patient who has been treated with medications as prescribed or for the prescribed period (e.g., corticosteroids, oflamb, rituximab, ozoglucomancil, alemtuzumab, natetuzumab, cyclophosphamide, teriflunomide, leflunomide, etc.); any other disease or condition that may impair participation in the study according to the study protocol or the patient's ability to cooperate and comply with study procedures; and / or a patient with a pre-existing neurological / psychiatric condition prior to randomization (e.g., suicidal tendencies, substance abuse, or clinically significant CNS disease or neurological symptoms mimicking MS).

[0313] Research on treatment Research drugs and comparative drugs The investigational drug will be provided in an auto-injector containing 135 mg of oframumab for subcutaneous administration. The comparative drug will be provided in an auto-injector containing 20 mg of oframumab for subcutaneous administration.

[0314] All patients will begin with an initial dosing regimen of 20 mg of oframumab on day 1 (week 0), day 7 (week 1), and day 14 (week 2), followed by a subsequent dose of 135 mg of oframumab every 2 months or 20 mg of oframumab monthly, starting at month 1 (week 4) depending on the randomization group.

[0315] Table 8: Details of the study drug and comparative drug regimens

[0316] Treatment experimental group / group On day 1 of the visit, eligible patients were randomized to one of the following two treatment groups at a 1:1 randomization ratio: • An initial dosing regimen of 20 mg of oframumab was administered subcutaneously on day 1 (week 0), day 7 (week 1), and day 14 (week 2), followed by a subsequent regimen of 135 mg of oframumab subcutaneously every two months starting in week 4.

[0317] • An initial dosing regimen of 20 mg of oframumab was administered subcutaneously on day 1 (week 0), day 7 (week 1), and day 14 (week 2), followed by a monthly regimen of 20 mg of oframumab subcutaneously starting in week 4 until week 12.

[0318] At the week 12 visit, study participants in the second treatment group will switch to a follow-up regimen of subcutaneous injection of oflamumab 135 mg every two months before week 12 dosing after completing the primary endpoint assessment.

[0319] Study participants who complete the core 52-week treatment phase will be offered an option to continue receiving subcutaneous oflamimumab 135 mg every two months for approximately 24 months (approximately 2 years).

[0320] Companion therapy In RMS clinical studies, only limited benefits were observed with the use of pre-medications containing corticosteroids, antihistamines, or acetaminophen. Therefore, the use of pre-medications containing corticosteroids, acetaminophen, and / or antihistamines (or equivalents) is optional and may be administered at the investigator's discretion. If the investigator chooses to administer a pre-medication, it should be administered 30 to 60 minutes prior to the injection of the study drug.

[0321] After the first dose of 135 mg, the patient will remain at the facility for observation for approximately 5 hours.

[0322] The decision to treat MS relapse should be based on investigator's judgment and / or local clinical practice. If MS relapse requires treatment, the standard therapy should consist of a short course of corticosteroids for 3–5 days and inpatient or outpatient treatment with up to 1,000 mg of methylprednisolone or an equivalent daily. Standards of care will be followed during treatment.

[0323] Prohibited drugs During the study, the following medications are prohibited: systemic corticosteroids (except when administered for the treatment of MS relapses) and administration of any live or live attenuated vaccines (including for measles) as a precaution when patients are exposed to the study drug (the lasting effects of the study drug should be taken into account).

[0324] Sample size and data analysis The total number of participants planned to be enrolled in the study was 180. The core part of the study randomized the first 100 participants at a 1:1 ratio (50 in each experimental group) to either the 135 mg Q2M or 20 mg Q1M experimental group for the primary analytical purpose.

[0325] This sample size of 100 will have over 90% capability to test the non-inferiority of the 135 mg Q2M regimen compared to the 20 mg Q1M regimen at week 12 with the smallest PK parameter C, using the NI cutoff of log (0.8) and a 2.5% one-sided false positive rate.

[0326] In each experimental group, study participants will have drug concentration samples taken at week 12 prior to administration of the next (week 12) subsequent dose. The primary analysis based on the PK endpoint (C-minimum) will be to confirm that the lower bound of the 95% confidence interval for the difference in mean log-transformed concentration between the 135 mg Q2M and 20 mg Q1M dosing regimens is not less than log(0.8).

[0327] By enrolling approximately 80 more participants in the 135 mg Q2M experimental group (after the completion of approximately 100 participants in the parallel group portion) and by switching patients in the 20 mg Q1M experimental group to the 135 mg Q2M regimen at week 12, the exposure to 135 mg Q2M will be increased.

[0328] With a total sample size of 180 participants (assuming a 10% dropout rate within 1 year), assessing the incidence of any adverse event (AE) would have a 5% margin of error, representing a 10% incidence rate over 52 weeks of exposure.

[0329] The positive results of this study will confirm that administration of ofamumumab with the following dosing regimens is equally or even more effective in treating multiple sclerosis compared to the established dosing regimens which consist of the same initial dosing regimen followed by monthly administration of 20 mg of ofamumumab: a) an initial dosing regimen consisting of administration of 20 mg of ofamumumab at weeks 0, 1 and 2, followed by b) administration of ofamumumab during subsequent dosing regimens consisting of administration of 135 mg of ofamumumab at week 4 and thereafter every 2 months.

[0330] Example 4: Subcutaneous administration of olizumab Oprizumab (OCREVUS®) is approved for the treatment of MS by intravenous infusion. The initial dose of 600 mg is administered as follows: two separate intravenous infusions of 300 mg each, followed by a second 300 mg infusion 2 weeks later, and then a single 600 mg intravenous infusion every 6 months thereafter, with the first 600 mg dose administered 6 months after the initial infusion.

[0331] Oregolumab can be administered subcutaneously every 6 months, for example, at a dose of 600 mg. A particularly useful oregolumab dosing regimen is a subcutaneous administration of 920 mg every 6 months. However, because oregolumab has a higher dose requirement compared to olfamolumab, the inventors recommend using specific formulations to enable subcutaneous administration of oregolumab at 6-month intervals as described herein. In addition to oregolumab, exemplary such formulations also contain 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w / v) polysorbate 20, and 1,500-12,000 U / mL rHuPH20, pH 5.3. Therefore, a particularly useful formulation for subcutaneous administration of ozolizumab contains 40 mg / mL ozolizumab (e.g., 920 mg in 23 mL), 30 mM sodium acetate, 8% trehalose dihydrate, 0.02% (w / v) polysorbate 20, and 1,500–12,000 U / mL rHuPH20 at pH 5.3.

[0332] As described in this article, the administration of ozoglucon is expected to achieve a B cell count of ≤10 cells / μL (e.g., ≤5 cells / μL) or a Gd+T1 lesion rate of ≤0.05 (e.g., ≤0.02).

[0333] Table 9: Sequences

[0334] HCDR = heavy chain complementarity-determining region, LCDR = light chain complementarity-determining region; (K) indicates that the C-terminal lysine residue (Lys452) of the heavy chain can be removed during cell culture by alkaline carboxypeptidase. HCDR and LCDR are described in Kabat mode.

Claims

1. A method of treating multiple sclerosis in a subject in need, the method comprising administering oframumab subcutaneously to the subject at a dose of about 130 mg to about 140 mg every 2 months, for example, 130 to 140 mg every 2 months.

2. The method of claim 1, wherein the method comprises subcutaneously administering oframumab to the subject at a dose of about 135 mg every 2 months, for example, 135 mg every 2 months.

3. The method according to claim 1 or claim 2, wherein the method comprises: a) The subjects were given subcutaneous administration of oflamumab during the initial dosing regimen of three separate 19-21 mg doses in weeks 0, 1, and 2, followed by b) During week 4 and subsequent dosing regimens of 130–140 mg every 2 months thereafter, the subjects were administered olfamomumab subcutaneously.

4. The method according to any one of claims 1-3, the method comprising: a) The subject was given subcutaneous administration of oflamumab during the initial dosing regimen of three separate 20 mg doses at weeks 0, 1, and 2, followed by b) The subject was given olfamomumab subcutaneously during week 4 and thereafter during a follow-up dosing regimen of 135 mg every 2 months.

5. The method according to any one of the preceding claims, wherein the method depletes and / or maintains the subject's (e.g., average) B cell count to ≤10 cells / μL.

6. The method according to any one of the preceding claims, wherein oframumab is administered in the form of a pharmaceutical composition, said pharmaceutical composition further comprising arginine, sodium acetate, sodium chloride, polysorbate (e.g., polysorbate 80), adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), such as about pH 5.5, optionally wherein said pharmaceutical composition further comprises EDTA.

7. The method of claim 6, wherein the pharmaceutical composition comprises about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) arginine, about 10 to about 100 mM (e.g., 10 to 100 mM) sodium acetate, about 25 to about 100 mM (e.g., 25 to 100 mM) sodium chloride, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to about pH 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), for example about pH 5.5, and optionally wherein the pharmaceutical composition further comprises about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) EDTA.

8. The method of claim 7, wherein the pharmaceutical composition comprises about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), adjusted to about pH 5.5 (e.g., pH 5.5), optionally wherein the pharmaceutical composition further comprises about 0.05 mM (e.g., 0.05 mM) EDTA.

9. The method according to any one of the preceding claims, wherein a subsequent dose of oframumab is administered in the form of a pharmaceutical composition comprising oframumab at a concentration of about 80-100 mg / mL (e.g., 80-100 mg / mL), such as about 90 mg / mL (e.g., 90 mg / mL).

10. The method of claim 9, wherein oframumab is administered in the form of a pharmaceutical composition that does not contain hyaluronidase.

11. The method according to any one of the preceding claims, wherein oflamb is administered using a pre-filled pen (autoinjector).

12. The method of claim 11, wherein the prefilled pen contains a fixed single unit dose of about 135 mg (e.g., 135 mg) of oflambumab.

13. The method according to any one of the preceding claims, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).

14. The method of claim 13, wherein the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis with disease activity (SPMS), or clinically isolated syndrome (CIS).

15. The method according to any one of claims 1-12, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS).

16. The method according to any one of the preceding claims, wherein the method causes one or more of the following: a. The number of Gd+T1 lesions decreased relative to baseline; b. The number of new or enlarged T2 lesions decreased relative to baseline; and / or c. The annualized relapse rate (ARR) decreased relative to baseline.

17. The method according to any one of the preceding claims, wherein the method further comprises administering a concomitant therapy, for example, selected from the group consisting of corticosteroids, antihistamines, and acetaminophen.

18. The method of claim 17, wherein the concomitant therapy is administered about 30 to about 60 minutes before the administration of ofumumab, for example, before the administration of ofumumab.

19. A solution for injection, said solution for injection containing about 135 mg (e.g., 135 mg) of oflamb in a pharmaceutical composition as defined, for example, in any one of claims 6-10.

20. The method according to any one of claims 1-18, wherein the subsequent dose of oframumab is administered in the form of a solution for injection as defined in claim 19.

21. A prefilled syringe or prefilled pen (autoinjector) containing, for example, a total volume of about 1.5 mL of the solution as defined in claim 19, for subcutaneous administration.

22. A kit containing one or more fixed single-unit doses of ofamumab, each approximately 135 mg (e.g., 135 mg).

23. A kit comprising one or more pre-filled syringes or pre-filled pens (autoinjectors), each of the one or more pre-filled syringes or pre-filled pens (autoinjectors) containing a fixed single-unit dose of about 135 mg (e.g., 135 mg) of oflamumab, optionally wherein the kit further comprises three pre-filled syringes or pre-filled pens (autoinjectors), each containing a fixed single-unit dose of about 20 mg (e.g., 20 mg) of oflamumab.

24. The kit of claim 22 or claim 23, wherein each fixed single unit dose of oframumab of about 135 mg (e.g., 135 mg) is provided in a prefilled syringe or prefilled pen (autoinjector), for example, the total volume in each prefilled syringe or prefilled pen (autoinjector) is about 1.5 mL.

25. A pharmaceutical composition comprising about 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate, about 25 to about 100 mM of sodium chloride (e.g., 25 to 100 mM), about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base, about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), such as about pH 5.

5.

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises about 90 mg / mL of ofumab (e.g., 90 mg / mL), about 50 mM (e.g., 50 mM) sodium acetate, about 51 mM (e.g., 51 mM) sodium chloride, about 1% (w / v) (e.g., 1% (w / v)) free arginine base, about 0.02% (w / v) (e.g., 0.02% (w / v)) polysorbate (e.g., polysorbate 80), about 0.05 mM (e.g., 0.05 mM) EDTA, and adjusted to a pH of about 5.5 (e.g., pH 5.5).

27. A pharmaceutical composition comprising: About 80 to about 100 mg / mL (e.g., 80 to 100 mg / mL) of ofumumab, about 10 to about 100 mM (e.g., 10 to 100 mM) of sodium acetate (e.g., sodium acetate trihydrate), about 25 to about 100 mM (e.g., 25 to 100 mM) of sodium chloride, about 0.5 to about 5% (w / v) (e.g., 0.5 to 5% (w / v)) of free arginine base (e.g., L-arginine), about 0.01 to about 0.2% (w / v) (e.g., 0.01 to 0.2% (w / v)) of polysorbate (e.g., polysorbate 80), about 0.02 to about 0.2 mM (e.g., 0.02 to 0.2 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to a pH of about 5.0 to about 7.0 (e.g., pH 5.0 to 7.0), e.g., about pH 5.5 (e.g., with hydrochloric acid).

28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition comprises: Approximately 90 mg / mL (e.g., 90 mg / mL) of ofumumab, approximately 50 mM (e.g., 50 mM) of sodium acetate (e.g., sodium acetate trihydrate), approximately 51 mM (e.g., 51 mM) of sodium chloride, approximately 1% (w / v) (e.g., 1% (w / v)) of free arginine base (e.g., L-arginine), approximately 0.02% (w / v) (e.g., 0.02% (w / v)) of polysorbate (e.g., polysorbate 80), approximately 0.05 mM (e.g., 0.05 mM) of EDTA (e.g., disodium edetate dihydrate), water for injection, and adjusted to approximately pH 5.5 (e.g., pH 5.5) (e.g., with hydrochloric acid).

29. A pharmaceutical composition comprising about 80-100 mg / mL (e.g., 80-100 mg / mL) (e.g., about 90 mg / mL, 90 mg / mL) of oflamumab, preferably in a volume of about 1.5 mL (e.g., 1.5 mL).

30. A method of treating multiple sclerosis in a subject in need, the method comprising subcutaneously administering a pharmaceutical composition as described in any one of claims 25 to 29 to the patient.

31. The method of claim 30, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).

32. The method of claim 31, wherein the relapsing multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis with disease activity (SPMS), or clinically isolated syndrome (CIS).

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