Compositions and methods for treating multiple sclerosis

Abstract

The present invention relates to methods for treating multiple sclerosis (MS) in a patient, and in some cases, the methods involve subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg. Compositions, formulations, and articles with instructions for such uses are also included.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480046185.1 (22) Application Date 2024.07.10 (30) Priority Data 63 / 513,109 2023.07.11 US 63 / 588,938 2023.10.09 US (85) PCT International Application Entering National Phase Date 2026.01.08 (86) PCT International Application Application Data PCT / US2024 / 037434 2024.07.10 (87) PCT International Application Publication Data WO2025 / 015081 EN 2025.01.16 (71) Applicant Genentech Inc. Address: California, USA Applicant: Hofmeister Roche Inc. (72) Inventor: H. Kollerzl Xiao Jingzhu (74) Patent Agency: Beijing Kunrui Law Firm 11494 Patent Attorney: Feng Xinqin (51) Int.Cl. A61K 39 / 395 (2006.01) A61P 25 / 00 (2006.01) A61P 25 / 28 (2006.01) A61K 38 / 47 (2006.01) A61K 47 / 26 (2006.01) C07K 16 / 28 (2006.01) (54) Invention Title: Composition and Method for Treating Multiple Sclerosis (57) Abstract: This invention relates to a method for treating patients with multiple sclerosis (MS), in some cases, the method involves using about 920 The anti-CD20 antibody is administered subcutaneously to a patient at a dose of about 920 mg. It also includes compositions, formulations, and articles thereof with instructions for use in this context. Claims: 3 pages; Description: 58 pages; Sequence Listing (electronic publication); Figures: 8 pages. CN 121843712 A 2026.04.10 CN 1 21 84 37 12 A 1. A method of treating a patient with multiple sclerosis, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. 2. The method of claim 1, wherein the patient has not previously undergone intravenous administration of the anti-CD20 antibody at a dose of about 600 mg. 3. The method of claim 1 or claim 2, wherein the patient has not previously received intravenous administration of the anti-CD20 antibody.4. The method of any one of claims 1 to 3, wherein the patient has not previously received subcutaneous administration of the anti-CD20 antibody at a dose of less than about 900 mg. 5. The method of claim 1, wherein the patient has received prior treatment with the anti-CD20 antibody, optionally wherein the prior treatment included intravenous administration of the anti-CD20 antibody, optionally including intravenous administration of the anti-CD20 antibody at a dose of about 300 mg or about 600 mg. 6. The method of any one of claims 1 to 5, wherein the method includes subcutaneous administration of more than one dose of the anti-CD20 antibody, wherein each dose comprises about 920 mg of the anti-CD20 antibody. 7. The method of claim 6, wherein the method includes administering at least two, three, or four doses of the anti-CD20 antibody. 8. The method of any one of claims 1 to 7, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 24 weeks or about once every 24 weeks. 9. The method of any one of claims 1 to 7, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 6 months or about once every 6 months. 10. The method of any one of claims 1 to 9, wherein the anti-CD20 antibody is the only drug administered to the patient for the treatment of multiple sclerosis. 11. The method of any one of claims 1 to 10, wherein the anti-CD20 antibody is in a pharmaceutical formulation comprising: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. about 0.06% (w / v) polysorbate 20; and f. about 1000 U / ml hyaluronidase. 12. The method according to any one of claims 1 to 11, wherein the patient has received oral dexamethasone and an antihistamine shortly before the subcutaneous administration of the antiCD20 antibody, optionally, the oral dexamethasone and antihistamine are administered within 30 minutes, 20 minutes, or 15 minutes before the subcutaneous administration. 13. The method according to any one of claims 1 to 12, wherein the antiCD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11.14. The method according to any one of claims 1 to 13, wherein the anti-CD20 antibody is ozoleizumab. (Claims 1 / 3 page 2 CN 121843712 A) 15. The method according to any one of claims 1 to 14, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). 16. The method according to claim 15, wherein the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). 17. The method according to any one of claims 1 to 14, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS). 18. The method of any one of claims 1 to 17, wherein the treatment achieves at least one of the following: a) results that, as measured by pharmacokinetics (levels in blood, e.g., area under the curve (AUC)) over 12 weeks, are not inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); b) results that, over 12 weeks, show magnetic resonance imaging (MRI) lesion activity in the patient's brain comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); and c) a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). 19. The method of any one of claims 1 to 18, wherein the anti-CD20 antibody is contained in a liquid formulation, and the subcutaneous administration takes no more than about 10 minutes. 20. A liquid formulation comprising: a. about 35 to about 45 mg / mL (e.g., 40 mg / mL) of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.0 to about 5.6 (e.g., pH 5.3); c. about 190 to about 290 mM (e.g., 240 mM) trehalose; d. about 5 to about 15 mM (e.g., 10 mM) methionine; e. about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20; and f. about 1000 U / mL hyaluronidase, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and human IgG1. Constant region.21. The liquid formulation of claim 20, wherein the anti-CD20 antibody is olizumab. 22. The liquid formulation of claim 20 or claim 21, wherein the formulation is for subcutaneous administration. 23. A unit dosage form of an anti-CD20 antibody comprising a sealed vial containing an amount of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the amount is sufficient to deliver a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. 24. The unit dosage form of claim 23, wherein the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 40 mg / ml. 25. The unit dosage form of claim 23 or claim 24, wherein the formulation further comprises a buffer, a stabilizer, and a surfactant, and optionally, wherein the formulation further comprises hyaluronidase. 26. The unit dosage form of claim 25, wherein the buffer comprises sodium acetate, optionally, wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5.3. 27. The unit dosage form of claim 25 or 26, wherein the stabilizer comprises trehalose and / or methionine, optionally, wherein the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine. 28. The unit dosage form of any one of claims 25 to 27, wherein the surfactant comprises polysorbate 20, and optionally, wherein the formulation comprises about 0.06% (w / v) polysorbate 20. 29. The unit dosage form according to any one of claims 25 to 28, wherein the hyaluronidase comprises recombinant human hyaluronidase, optionally, the recombinant human hyaluronidase is rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. 30. An article comprising a single fixed-dose anti-CD20 antibody, said anti-CD20 antibody comprising: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the fixed dose is about 920 mg. 31. The article according to claim 30, comprising a single-use vial.32. The article of claim 30 or 31, comprising a syringe or a device including a needle, optionally wherein the device is a body device. 33. The article of any one of claims 30 to 32, wherein the anti-CD20 antibody is ozoleizumab. 34. The article of any one of claims 30 to 33, further comprising a packaging insert instructing a user to subcutaneously administer a fixed dose of the anti-CD20 antibody to a patient suffering from multiple sclerosis, optionally wherein the user is the patient. 35. A disposable vial containing a measured amount of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the amount is sufficient to deliver a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. 36. The single-use vial of claim 35, wherein the anti-CD20 antibody is olizumab. Claims 3 / 3 Page 4 CN 121843712 A Composition and method for treating multiple sclerosis

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 513,109, filed July 11, 2023, and U.S. Provisional Application No. 63 / 588,938, filed October 9, 2023, the contents of which are incorporated herein by reference in their entirety for all purposes.

[0003] Reference to the electronic sequence listing

[0004] The contents of the electronic sequence listing (146392067140seqlist.xml; size: 11,893 bytes; and creation date: July 3, 2024) are incorporated herein by reference in their entirety. Technical Field

[0005] This disclosure relates to methods for treating patients with multiple sclerosis (MS) and articles thereof with instructions for such use. Background Art

[0006] Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, and degenerative disease of the central nervous system (CNS), affecting approximately 900,000 people in the United States (Wallin et al. (2019) Neurology. 92:e1029-40) and 2.3 million people worldwide (GBD 2016 Multiple Sclerosis Collaborators. (2019) Lancet. 18:269-85).It is primarily a disease that first appears in young adults, with 70% to 80% of patients having an onset age (i.e., initial clinical presentation to a physician) between 20 and 40 years of age (Anderson et al. (1992) Ann Neurol 31:333–336; Noonan et al. (2002) Neurology.58:136–138.), and exhibits a phenotype-influenced sex bias, with 64% to 70% of diagnosed patients being female.

[0007] MS is classified into three clinical phenotypes: relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS) (Lublin et al. (2014) Neurology.83:278–86). Based on the presence or absence of disease activity, these three phenotypes are further subdivided into active and inactive forms, which are defined by the presence of clinical relapse and / or so-called active lesions on magnetic resonance imaging (MRI) scans. Active MRI lesions are gadolinium-enhanced lesions on T1-weighted scans (T1Gd+) or new T2-weighted lesions / enlarged T2-weighted lesions. Recurrent MS (RMS) forms encompass RRMS and active SPMS, while progressive MS (PMS) forms constitute inactive SPMS and PPMS.

[0008] Evidence to date suggests that, despite the potential heterogeneity in the clinical presentation of the disease, PPMS, SPMS, and RRMS belong to the same disease spectrum, and the pathological mechanisms that are the cause of relapse / disease activity and progression are largely the same across the MS spectrum (Lassmann (2018) Cold Spring Harb Perspect Med. 8(3): a028936). Although the mechanisms associated with disease progression are assumed to be present from the onset of the disease (Cree et al. (2019) Curr Opin Neurol. 32: 365-77), clinical disability progression usually appears later in the course of the disease, likely due to the patient's level of brain reserve. Symptom progression associated with MS disability progression can lead to a slow, subtle loss of motor and sensory function, as well as cognitive decline and autonomic dysfunction.

[0009] Disability progression across the MS spectrum may occur due to two concurrent inflammatory mechanisms: acute inflammation and chronic compartmentalized inflammation.Instructions 1 / 58 pages 5 CN 121843712 A

[0010] Acute inflammation (such as T1Gd+ lesions or new T2 lesions / enlarged T2 lesions) may be observed on MRI scans and clinically present as relapse, which may also lead to a gradual increase in disability due to incomplete relapse recovery. Pathophysiologically, relapsed forms of MS (i.e., RMS) are associated with local T-cell and B-cell invasion with blood-brain barrier leakage that produces typical active demyelinating plaques in the white matter. However, RMS also has signs of progressive biology / chronic compartmentalized inflammation.

[0011] In contrast to these acute inflammatory processes, chronic compartmentalized inflammation is the cause of increased disability that occurs independently of relapse or radiological disease activity and is characterized by demyelination and axonal loss (progressive biology). Progressive forms of MS (i.e., PMS) are associated with a chronic and slow accumulation of T cells and B cells in the connective tissue spaces of the brain, without leakage of the blood-brain barrier. Typical formation of subpial demyelinating lesions is present in the cerebral and cerebellar cortex, where pre-existing lesions slowly expand in the white matter and diffuse chronic inflammation is present in the normally appearing white or gray matter.

[0012] Ocrelizumab® (“OCR”) is a recombinant humanized monoclonal IgG1 antibody that selectively targets and depletes CD20-expressing B cells while preserving the ability of B cells to reconstitute and pre-existing humoral immunity. CD20 is a B cell surface molecule that is limited to expression in precursor and mature B cells, but is not expressed in the early stages of B cell development. Orelizumab®, administered via intravenous (IV) infusion at a dose of 600 mg every 6 months, was approved by the U.S. Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with MS. All references cited herein, including patent applications, patent publications, and UniProtKB / Swiss-Prot Registry numbers, are incorporated herein by reference in their entirety, as if each individual reference were specifically and individually indicated as incorporated by reference. Summary of the Invention

[0013] In one aspect, this application provides a method of treating a patient with multiple sclerosis, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH (or VH) domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL (or VL) domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region.In some embodiments, the patient has not previously received an intravenous administration of an anti-CD20 antibody at a dose of about 600 mg. In some embodiments, the patient has not previously received an intravenous administration of an anti-CD20 antibody. In some embodiments, the patient has not previously received a subcutaneous administration of an anti-CD20 antibody at a dose of less than about 900 mg. In some embodiments, the patient has received prior treatment with an anti-CD20 antibody, optionally wherein the prior treatment included an intravenous administration of an anti-CD20 antibody, optionally including an intravenous administration of an anti-CD20 antibody at a dose of about 300 mg or about 600 mg.

[0014] In some embodiments of any method described above or herein, the method includes subcutaneous administration of more than one dose of an anti-CD20 antibody, wherein each dose comprises about 920 mg of the anti-CD20 antibody. In some embodiments, the method includes administering at least two, three, or four doses of the anti-CD20 antibody.

[0015] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is administered at a frequency not exceeding once every 24 weeks or about once every 24 weeks.

[0016] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is administered at a frequency not exceeding once every 6 months or about once every 6 months.

[0017] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is the only drug administered to the patient to treat multiple sclerosis. Instructions for Use, Page 2 / 58, CN 121843712 A

[0018] In some embodiments according to any of the methods described above or herein, the anti-CD20 antibody is in a pharmaceutical formulation comprising: a. about 35 to 45 mg / ml (e.g., 40 mg / ml) of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3); c. about 190 mM to about 290 mM (e.g., 240 mM) trehalose; d. about 5 mM to 15 mM (e.g., 10 mM) methionine; e. about 0.04% to 0.08% (w / v) (e.g., 0.06%) of polysorbate 20; and f. about 1000 U / ml hyaluronidase.In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is in a pharmaceutical formulation comprising: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. about 0.06% (w / v) polysorbate 20; and f. about 1000 U / ml hyaluronidase.

[0019] In some embodiments of any of the methods described above or herein, the patient has received oral dexamethasone (or equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the anti-CD20 antibody, optionally, the oral dexamethasone (or equivalent corticosteroid) and antihistamine are administered 30 minutes, 20 minutes, or 15 minutes prior to subcutaneous administration.

[0020] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11.

[0021] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is ozoleizumab.

[0022] In some embodiments of any of the methods described above or herein, the multiple sclerosis is relapsing multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS).

[0023] In some embodiments of any of the methods described above or herein, the multiple sclerosis is primary progressive multiple sclerosis (PPMS).

[0024] In some embodiments of any of the methods described above or herein, the treatment achieves: a) results that, as measured by pharmacokinetics (the concentration in the blood, e.g., the area under the curve (AUC) in serum), are not inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) within 12 weeks; b) results that, within 12 weeks, have MRI lesion activity in the patient's brain comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); and / or c) a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg).

[0025] In some embodiments of any of the methods described above or herein, the anti-CD20 antibody is contained in a liquid formulation and is administered subcutaneously over a period not exceeding 10 minutes.

[0026] In another aspect, this application provides a liquid formulation comprising: a. about 35 to about 45 mg / mL (e.g., 40 mg / mL) of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.0 to about 5.6 (e.g., pH 5.3); c. about 190 to about 290 mM (e.g., 240 mM) trehalose; d. about 5 to about 15 mM (e.g., 10 mM) methionine; e. about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20; and f. about 1000 U / mL hyaluronidase, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; and a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7. The amino acid sequence shown; and the constant region of human IgG1, page 3 / 58, CN 121843712 A. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the formulation is for subcutaneous administration.

[0027] In another aspect, this application provides a liquid formulation comprising: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. about 0.06% (w / v) polysorbate 20; and f. about 1000 U / ml hyaluronidase, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the formulation is for subcutaneous administration.

[0028] In another aspect, this application provides a unit dosage form of an anti-CD20 antibody comprising a sealed vial containing a quantity of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the quantity is sufficient to deliver a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is contained in a liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, optionally, wherein the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally, wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3). In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase per unit dose.

[0029] In another aspect, this application provides an article containing a single fixed dose of an anti-CD20 antibody comprising: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the fixed dose is about 920 mg. In some embodiments, the article comprises a single-use vial. In some embodiments, the article comprises a syringe or a device including a needle, optionally wherein the device is an on-body device. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the article further comprises a packaging insert instructing a user to administer a fixed dose of the anti-CD20 antibody subcutaneously to a patient with multiple sclerosis, optionally wherein the user is a patient.

[0030] In another aspect, this application provides a single-use vial containing a sufficient amount of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the amount is sufficient to deliver a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is ozoleizumab. Brief Description of the Drawings

[0031] The accompanying drawings illustrate certain features and advantages of this disclosure. These embodiments are not intended to limit the scope of the appended claims in any way.

[0032] Figure 1 provides the following schematic diagram: Phase III, non-inferiority, randomization, open-label, parallel group, multiple specification 4 / 58 pages 8 CN 121843712 A central study to investigate the pharmacokinetics, pharmacodynamics, safety, radiological and clinical effects of subcutaneous (SC) ozenafil in multiple sclerosis.

[0033] Figure 2A depicts the pharmacokinetic results of the OCARINA II study.

[0034] Figure 2B depicts the pharmacokinetic results of the OCARINA II study.

[0035] Figure 3A depicts the radiological and clinical effects of the OCARINA II study.

[0036] Figure 3B depicts the radiological and clinical effects of the OCARINA II study.

[0037] Figure 3C depicts the relapse observed in the OCARINA II study.

[0038] Figure 4 depicts the B cell depletion results of the OCARINA II study.

[0039] Figure 5 depicts the B cell consumption results of the OCARINA I study.Detailed Description

[0040] This application is based, at least in part, on the applicant’s discovery that subcutaneous (SC) administration of an anti-CD20 antibody (e.g., ozretrimumab) at a dose of about 920 mg to individuals with multiple sclerosis (MS), optionally every six months or 24 weeks for at least 12, 18, or 24 months, can achieve exposure levels and / or similar beneficial therapeutic effects as demonstrated by intravenous (IV) administration of ozretrimumab at a dose of 600 mg, which is currently approved. In a Phase III clinical trial, subcutaneous injection of ozretrimumab (e.g., at a dose of about 920 mg) was demonstrated to be non-inferior to ozretrimumab administered via intravenous infusion (IV) (e.g., at a dose of about 600 mg) over 12 weeks, as measured by pharmacokinetics (levels in the blood). In terms of controlling the activity of MRI lesions in the brain within 12 weeks, subcutaneous injection of ozonil (e.g., at a dose of about 920 mg) is comparable to that administered via intravenous infusion (IV) (e.g., at a dose of about 600 mg). The safety profile of subcutaneous injection of ozonil (e.g., at a dose of about 920 mg) is consistent with that of intravenous infusion (IV) (e.g., at a dose of about 600 mg).

[0041] This approach offers several advantages over previous methods of treating multiple sclerosis, such as IV administration of ozonil at a dose of 600 mg. These advantages include more convenient and faster administration time, fewer administrations, the ability to administer at locations lacking additional infusion capabilities or the facilities and experience required for IV infusion, and the potential for administration outside of controlled healthcare settings, such as home administration.

[0042] In some aspects, this application provides a method of treating a patient with multiple sclerosis, the method comprising administering an anti-CD20 antibody, wherein the anti-CD20 antibody is ozretinoin, to the patient subcutaneously every six months or 24 weeks at a dose of about 920 mg.In some embodiments, this application provides a method of treating a patient with multiple sclerosis, the method comprising subcutaneously administering an anti-CD20 antibody (such as ozretrimumab) at a dose of about 920 mg every six months or 24 weeks, achieving one or more of the following: a) results that, as measured by pharmacokinetics (the concentration in blood, e.g., the area under the serum curve (AUC)), are not inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) within 12 weeks; b) results that, within 12 weeks, show magnetic resonance imaging (MRI) lesion activity in the patient's brain comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); and / or c) a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is ozretrimumab.

[0043] I. Definitions

[0044] “B cell” is a mature lymphocyte in the bone marrow, including primitive B cells, memory B cells, or effector B cells (plasma cells). B cells as used herein can be normal or non-malignant B cells. Specification 5 / 58 pages 9 CN 121843712 A

[0045] “B cell surface marker” or “B cell surface antigen” as used herein is an antigen expressed on the surface of a B cell that can be targeted by an antibody that binds to it. Exemplary B cell surface markers include CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD40, CD53, CD72, CD73, CD74, CDw75, CDw76, CD77, CDw78, CD79a, CD79b, CD80, CD81, CD82, CD83, CDw84, CD85, and CD86 leukocyte surface markers (for a description, see The Leukocyte Antigen Facts Book, 2nd edition, 1997, edited by Barclay et al., Academic Press, Harcourt Brace & Co., New York). Other B cell surface markers include RP105, FcRH2, B-cell CR2, CCR6, P2X5, HLA-DOB, CXCR5, FCER2, BR3, Btig, NAG14, SLGC16270, FcRH1, IRTA2, ATWD578, FcRH3, IRTA1, FcRH6, BCMA, and 239287.This article is of particular interest to B cell surface markers that are preferentially expressed on B cells compared to other non-B cell tissues in mammals, and can be expressed on both progenitor and mature B cells. The preferred B cell surface marker in this article is CD20.

[0046] The “CD20” antigen, or “CD20”, is a non-glycosylated phosphoprotein of approximately 35 kDa found on the surface of more than 90% of B cells from peripheral blood or lymphoid organs. CD20 is present on both normal and malignant B cells, but is not expressed on stem cells. Other names for CD20 in the literature include “B lymphocyte-restricted antigen” and “Bp35”. The CD20 antigen is described, for example, by Clark et al., Proc. Natl. Acad. Sci. (USA) 82:1766 (1985).

[0047] An “antibody” is typically a heterotetrameric glycoprotein of about 150,000 Daltons, consisting of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to the heavy chain by a covalent disulfide bond, the number of which varies among heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has a variable domain (VH or VH) at one end, followed by multiple constant domains. Each light chain has a variable domain (VL or VL) at one end and a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. Specific amino acid residues are believed to form an interface between the variable domains of the light and heavy chains.

[0048] The “light chain” of antibodies (immunoglobulins) from mammalian species can be assigned to one of two distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequence of their constant domains.

[0049] The “heavy chain” of antibodies from mammalian species can also be assigned to different categories. There are five major classes of complete antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into “subclasses” (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The constant domains of the heavy chain corresponding to different classes of antibodies are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional configurations of different types of immunoglobulins are well known.

[0050] The terms “orelizumab,” “OCR,” or “Ocrevus®” (CAS Registry No. 637334-45-3) used herein refer to a genetically engineered humanized monoclonal antibody against the CD20 antigen comprising: (a) a light chain comprising the amino acid sequence of SEQ ID NO: 9; and (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. Orelizumab is available from Genentech.

[0051] The term “subject” or “patient” used herein refers to a human subject or patient. Generally, a subject or patient meets the criteria for treatment of multiple sclerosis. For the purposes of this article, eligible subjects or patients are those who: are experiencing, have experienced, or may experience one or more signs, symptoms, or other indications of multiple sclerosis; have been diagnosed with multiple sclerosis, for example, whether newly diagnosed (diagnosed as “newly diagnosed” MS), previously diagnosed with a new relapse or exacerbation, previously diagnosed and in remission, etc.; and / or are at risk of developing multiple sclerosis. Individuals with multiple sclerosis or at risk of developing multiple sclerosis may optionally be identified as having elevated levels of CD20-positive B cells in serum, cerebrospinal fluid (CSF), and / or MS lesions and / or screened using assays detecting autoantibodies, and qualitatively (and preferably quantitatively) assessed. Exemplary autoantibodies associated with multiple sclerosis include antimyelin basic protein (MBP), antimyelin oligodendritic glycoprotein (MOG), antiganglioside, and / or antineurofilament antibodies. Such autoantibodies can be detected in the serum, cerebrospinal fluid (CSF), and / or MS lesions of a subject. "Elevated" autoantibody or B-cell levels as used herein mean levels of such autoantibodies or B-cells significantly exceeding those found in individuals without MS.

[0052] As used herein, "therapeutic" or "treatment" is a method for obtaining beneficial or desired outcomes, including clinical outcomes. For the purposes of this invention, beneficial or desired clinical outcomes include, but are not limited to, one or more of the following: reduction of one or more symptoms caused by the disease, reduction of the severity of the disease, stabilization of the disease (e.g., prevention or delay of disease progression), delay or slowing of disease progression, improvement of disease state, reduction of the dosage of one or more other medications required to treat the disease, and / or improvement of quality of life.

[0053] As used herein, “delaying” or “slowing” the progression of multiple sclerosis means preventing, delaying, hindering, slowing, blocking, stabilizing, and / or postponing the development of the disease. Such delay can have different durations depending on the medical history and / or the individual to be treated.

[0054] “Symptoms” of MS are any pathological phenomena or deviations from normal function, structure, or sensation experienced by the subject that indicate MS.

[0055] “Multiple sclerosis” refers to a chronic inflammatory (usually disabling) disease of the central nervous system characterized by demyelination and neurodegeneration. There are three internationally recognized forms of MS: primary progressive multiple sclerosis (PPMS), relapsing-remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS).

[0056] As used herein, “progressive multiple sclerosis” refers to both primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS). In some embodiments, progressive multiple sclerosis is characterized by a documented irreversible loss of neurological function lasting ≥ 6 months that is not attributable to clinical relapse.

[0057] “Primary progressive multiple sclerosis” or “PPMS” is characterized by the gradual progression of the disease from its onset with few superimposed relapses and remissions. There may be periods of flattening disease activity and several good and bad days or weeks. PPMS differs from RRMS and SPMS in that onset generally occurs in the late thirties or early forties, men are just as likely to develop PPMS as women, and the initial disease activity is usually in the spinal cord rather than in the brain. PPMS disease activity may also be observed (or found) in the brain. PPMS is a subtype of MS that is least likely to show inflammatory (gadolinium-enhanced) lesions on MRI scans. The primary progressive form of the disease affects approximately 15% of all people with multiple sclerosis. PPMS can be defined according to the criteria in: Thompson et al. (2018) Lancet 7(2):162-173. The PPMS subjects treated in this article were generally those who had a possible or confirmed diagnosis of PPMS.

[0058] “Relapsing-remitting multiple sclerosis” or “RRMS” is characterized by relapses (also known as exacerbations) during which new symptoms may appear and old symptoms may reappear or worsen. Relapses are followed by remission periods, during which the individual recovers fully or partially from the deficits acquired during the relapse. Relapses may last for days, weeks, or months, and recovery may be slow and gradual or almost instantaneous. The vast majority (approximately 85%) of patients presenting with MS are first diagnosed with RRMS. This usually happens in their twenties or thirties, however, diagnoses are known to occur much earlier or much later. Women are twice as likely as men to present with this subtype of MS. During relapses, the myelin sheath (the protective insulating sheath surrounding nerve fibers (neurons) in the white matter of the central nervous system (CNS)) may be damaged in an inflammatory response of the body's autoimmune system.This leads to a variety of neurological symptoms that vary greatly depending on the area of ​​CNS damage. After a relapse, the inflammatory response immediately disappears, and a special type of glial cell in the CNS (called oligodendrocytes) facilitates myelin regeneration—the process by which the myelin sheath surrounding the axon can be repaired. It is this myelin regeneration that may be the cause of remission. Approximately 50% of patients with RRMS develop SPMS within 10 years of the onset of the disease. After 30 years, this number rises to 90%. At one point, the relapse-remission form of the disease accounted for about 55% of all patients with MS.

[0059] In some embodiments, the initial or first “antibody dose” refers to contact or exposure to the antibody described herein during one or more infusions administered over a period of time of about 1 to 20 days. During this exposure period, infusions may be given once or at fixed or irregular intervals. As detailed herein, initial and later (e.g., second or third) antibody doses are time-separated from each other. In some embodiments, the initial or first “antibody dose” refers to subcutaneous administration.

[0060] As used herein, the “interval” between antibody doses refers to the time period between an earlier antibody dose and a later antibody dose.

[0061] A “stable” formulation is one in which the protein substantially retains its physical stability and / or chemical stability and / or biological activity during storage. Preferably, the formulation substantially retains its physical and chemical stability and its biological activity during storage. The storage period is typically selected based on the expected shelf life of the formulation. Various analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in the following literature: Peptide and Protein Drug Delivery, 247-301, edited by Vincent Lee, Marcel Dekker, Inc., New York, NY, Publishers. (1991) and Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured over a selected time period at a selected temperature. Stability can be assessed qualitatively and / or quantitatively in various ways, including assessing aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity and / or by visual inspection); assessing charge heterogeneity using cation exchange chromatography, imaging capillary isoelectric focusing (icIEF), or capillary zone electrophoresis; N-terminal or C-terminal sequence analysis; mass spectrometry; SDS-PAGE analysis for comparing reduced and intact antibodies; peptide mapping (e.g., trypsin or LYS-C) analysis; and assessing antibody bioactivity or antigen-binding function.Instability may involve one or more of the following: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), shearing / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine ​​residues, N-terminal extension, C-terminal treatment, differential glycosylation, etc.

[0062] If a protein in a pharmaceutical formulation does not show or shows very few signs of aggregation, precipitation, and / or denaturation when visually inspected for color and / or clarity, or when measured by UV light scattering or by size exclusion chromatography, then the protein “retains its physical stability.”

[0063] If a protein in a pharmaceutical formulation exhibits chemical stability at a given time such that it can be considered to retain its biological activity as defined below, then the protein “retains its chemical stability.” Chemical stability can be evaluated by detecting and quantifying the chemical changes in a protein. Chemical alterations may involve size changes (e.g., shearing), which can be assessed using, for example, size exclusion chromatography, SDS-PAGE, and / or matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). Other types of chemical alterations include charge changes (e.g., changes due to deamidation), which can be assessed using, for example, ion exchange chromatography or icIEF.

[0064] As determined in an assay (e.g., antigen binding assay), an antibody “retains its biological activity” if the biological activity of the antibody in the pharmaceutical formulation at a given time is at least about 60% (within the error of the assay) of the biological activity exhibited when the pharmaceutical formulation was prepared. Other “biological activity” assays of antibodies are described in detail below.

[0065] As used herein, the “biological activity” of a monoclonal antibody includes the ability of the antibody to bind to an antigen and produce a measurable biological response, which can be measured in vitro or in vivo.

[0066] "Corticosteroids" refers to any of several synthetic or naturally occurring substances having the general chemical structure of steroids that mimic or enhance the effects of naturally occurring corticosteroids. Examples of synthetic corticosteroids include prednisone, prednisolone (including methylprednisolone), dexamethasone, glucocorticoids, and betamethasone.

[0067] "Packaging insert" is used to refer to instructions commonly included in the commercial packaging of therapeutic products, containing information on indications, usage, dosage, administration, contraindications, other therapeutic products in combination with the packaged product, and / or warnings regarding the use of such therapeutic products.

[0068] The term "label" is used herein to refer to information commonly included with the commercial packaging of pharmaceutical preparations, including containers (such as vials) and packaging inserts, as well as other types of packaging.

[0069] References to “about” values ​​or parameters herein include (and describe) variations relating to the value or parameter itself. For example, a description relating to “about X” includes a description of “X”. In some embodiments, “about” values ​​or parameters describe a range of 50% to 150%, 60% to 140%, 70% to 130%, 80% to 120%, 90% to 110%, or 95% to 105% of the value or parameter.

[0070] As used herein and in the appended claims, the singular forms “a,” “or,” and “the / said” include plural pronouns unless the context explicitly specifies otherwise. It should be understood that aspects and variations of the invention described herein include “consisting of aspects and variations” and / or “essentially consisting of aspects and variations.”

[0071] It should be understood that one, a portion, or all of the features of the various embodiments described herein may be combined to form other embodiments of the invention. These and other aspects of the invention will be apparent to those skilled in the art.

[0072] All references cited herein (including patent applications and publications) are incorporated herein by reference in their entirety.

[0073] II. Treatment Methods

[0074] The various aspects and embodiments described in this section in the context of treatment methods also apply to anti-CD20 antibodies used according to the methods described herein. Similarly, the various aspects and embodiments described in this section in the context of treatment methods also apply to anti-CD20 antibodies used with a delivery device according to the methods described herein, and anti-CD20 antibodies used in combination with a delivery device according to the methods described herein, and anti-CD20 antibodies used according to the methods described herein, wherein the anti-CD20 antibody is administered via a delivery device (e.g., an on-the-body device).

[0075] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the patient has not previously received administration of the anti-CD20 antibody. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS).In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has taken or has been given oral dexamethasone (or equivalent corticosteroid) and / or antihistamines shortly before subcutaneous administration of the antiCD20 antibody; optionally, the oral dexamethasone (or equivalent corticosteroid) and antihistamines are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration. In some embodiments, the antiCD20 antibody is the only drug administered to the patient to treat multiple sclerosis. In some embodiments, the antiCD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml. The formulation further contains buffers, stabilizers, and surfactants; optionally, the formulation further contains hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5.3. In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally, as described on page 9 / 58 of CN 121843712 A, wherein the formulation comprises about 0.06% (w / v) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is contained in a liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, and optionally, the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, and optionally, the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3).In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the subcutaneous application is carried out over a period not exceeding 10 minutes. In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (blood concentrations, e.g., area under the serum curve (AUC)). In some embodiments, treatment achieves MRI lesion activity in the patient's brain that is comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, treatment achieves rapid, complete, and sustained B-cell depletion. In some embodiments, treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the preparation is 23 mL.

[0076] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the patient has not previously experienced administration of the anti-CD20 antibody (e.g., at a dose of about 600 mg). In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has received oral dexamethasone (or equivalent corticosteroid) and antihistamines shortly before subcutaneous administration of the antiCD20 antibody; optionally, the oral dexamethasone (or equivalent corticosteroid) and antihistamines are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration. In some embodiments, the antiCD20 antibody is the only medication administered to the patient to treat multiple sclerosis. In some embodiments, the antiCD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml. The formulation further comprises a buffer, a stabilizer, and a surfactant, and optionally, the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, and optionally, the formulation comprises about 20 mM sodium acetate providing a pH of about 5.3. In some embodiments, the stabilizer comprises trehalose and / or methionine, and optionally, the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine.In some embodiments, the surfactant comprises polysorbate 20, and optionally, the formulation comprises about 0.06% (w / v) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, optionally, wherein the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally, wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3). In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the subcutaneous application is carried out over a period not exceeding 10 minutes. In some embodiments, the treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (blood concentrations, e.g., area under the serum curve (AUC)). In some embodiments, the treatment achieves MRI lesion activity in the patient's brain that is comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, the treatment achieves rapid, complete, and sustained B-cell depletion. In some embodiments, the treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg).In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the preparation is 23 mL.

[0077] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the patient has previously received an anti-CD20 antibody (e.g., at a dose of about 600 mg) (e.g., previously administered intravenously). In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the antiCD20 antibody; optionally, the oral dexamethasone (or an equivalent corticosteroid) and antihistamine are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration.In some embodiments, the anti-CD20 antibody is the only drug administered to a patient for the treatment of multiple sclerosis. In some embodiments, the anti-CD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml. The formulation further comprises a buffer, a stabilizer, and a surfactant, and optionally, the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, and optionally, the formulation comprises about 20 mM sodium acetate providing a pH of about 5.3. In some embodiments, the stabilizer comprises trehalose and / or methionine, and optionally, the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally, the formulation comprises about 0.06% (w / v) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, optionally wherein the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3). In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally, the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) of polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml of hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, subcutaneous application is performed over a period not exceeding 10 minutes.In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (blood concentrations, e.g., area under the serum curve (AUC)). In some embodiments, treatment achieves MRI lesion activity in the patient's brain that is comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, treatment achieves rapid, complete, and sustained B-cell depletion. In some embodiments, treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the preparation is 23 mL.

[0078] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at one dose or at least two doses (such as two, three, or four doses) of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the patient has not previously received a subcutaneous administration of the anti-CD20 antibody at a dose of less than about 900 mg. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS).In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the antiCD20 antibody; optionally, the oral dexamethasone (or an equivalent corticosteroid) and antihistamine are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration. In some embodiments, the antiCD20 antibody is the only drug administered to the patient to treat multiple sclerosis. In some embodiments, the antiCD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml. The formulation further contains buffers, stabilizers, and surfactants; optionally, the formulation further contains hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5.3. In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.06% (w / v) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, and optionally, the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, and optionally, the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3).In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the subcutaneous application is carried out over a period not exceeding 10 minutes. In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (blood concentrations, e.g., area under the serum curve (AUC)). In some embodiments, treatment achieves MRI lesion activity in the patient's brain that is comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, treatment achieves rapid, complete, and sustained B-cell depletion. In some embodiments, treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the anti-CD20 antibody is supplied in a 50 mL single-dose vial. In some embodiments, the volume of the preparation is 23 mL.

[0079] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at at least two, three, or four doses of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 24 weeks or about once every 24 weeks, or at a frequency not exceeding once every 6 months or about once every 6 months. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the antiCD20 antibody; optionally, the oral dexamethasone (or an equivalent corticosteroid) and antihistamine are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration. In some embodiments, the antiCD20 antibody is the only drug administered to the patient to treat multiple sclerosis. In some embodiments, the antiCD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml. The formulation further contains buffers, stabilizers, and surfactants; optionally, the formulation further contains hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally wherein the formulation comprises about 20 mM sodium acetate, which provides a pH of about 5.3. In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine.In some embodiments, the surfactant comprises polysorbate 20, and optionally, the formulation comprises about 0.06% (w / v) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 35 to 45 mg / ml (e.g., 40 mg / ml). In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, optionally, wherein the formulation further comprises hyaluronidase. In some embodiments, the buffer comprises sodium acetate, optionally, wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3). In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 190 mM to about 290 mM (e.g., 240 mM) trehalose and b) about 5 mM to about 15 mM (e.g., 10 mM) methionine. In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) polysorbate 20. In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the subcutaneous application is carried out over a period not exceeding 10 minutes. In some embodiments, the treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (the concentration in the blood, e.g., the area under the serum curve (AUC)). In some embodiments, the treatment achieves results that result in MRI lesion activity in the patient's brain comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, the treatment achieves results that result in rapid, complete, and sustained depletion of B cells. In some embodiments, the treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg, see specification page 14 / 58, 18 CN 121843712 A).In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the preparation is 23 mL.

[0080] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient in at least two, three, or four doses of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, the anti-CD20 antibody being in a pharmaceutical formulation comprising: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. about 0.06% (w / v) polysorbate 20; and f. about 1000 U / ml hyaluronidase. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS).In some embodiments, the patient has received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the antiCD20 antibody, optionally within 30, 20, or 15 minutes prior to subcutaneous administration. In some embodiments, the antiCD20 antibody is the only drug administered to the patient for the treatment of multiple sclerosis. In some embodiments, subcutaneous administration takes no more than 10 minutes. In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the antiCD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (the concentration in the blood, e.g., the area under the serum curve (AUC)). In some embodiments, treatment achieves results that, within 12 weeks, MRI lesion activity in the patient's brain is comparable to that of intravenous infusion of the antiCD20 antibody (e.g., at a dose of 600 mg). In some embodiments, treatment achieves results that result in rapid, complete, and sustained depletion of B cells. In some embodiments, the treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical formulation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the formulation is 23 mL.

[0081] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient in at least two, three, or four doses of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 24 weeks or about once every 24 weeks, or at a frequency not exceeding once every 6 months or about once every 6 months, wherein the pharmaceutical formulation comprises: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. Approximately 0.06% (w / v) polysorbate 20; and f. approximately 1000 U / ml hyaluronidase. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the anti-CD20 antibody; optionally, the oral dexamethasone (or an equivalent corticosteroid) and antihistamine are administered 30 minutes, 20 minutes, or 15 minutes before subcutaneous administration. In some embodiments, the anti-CD20 antibody is the only medication administered to the patient to treat multiple sclerosis. In some embodiments, subcutaneous administration is administered within 10 minutes.In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (blood concentrations, e.g., area under the serum curve (AUC)). In some embodiments, treatment achieves MRI lesion activity in the patient's brain that is comparable to that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg) over 12 weeks. In some embodiments, treatment achieves rapid, complete, and sustained B-cell depletion. In some embodiments, treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the preparation is 23 mL.

[0082] In some embodiments, a method of treating a patient with multiple sclerosis is provided, the method comprising subcutaneously administering an anti-CD20 antibody to the patient in at least two, three, or four doses of about 920 mg, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region, the anti-CD20 antibody being in a pharmaceutical formulation comprising: a. about 40 mg / ml of anti-CD20 antibody; b. about 20 mM sodium acetate providing a pH of about 5.3; c. about 240 mM trehalose; d. about 10 mM methionine; e. about 0.06% (w / v) polysorbate 20; and f. about 1000 U / ml hyaluronidase, wherein the anti-CD20 antibody is administered at a dose not exceeding 24 mg / ml. Apply once a week or about once every 24 weeks, or at a frequency not exceeding once every 6 months or about once every 6 months.In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the multiple sclerosis is relapsing-remitting multiple sclerosis (RMS). In some embodiments, the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS). In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has already received oral dexamethasone (or an equivalent corticosteroid) and an antihistamine shortly before subcutaneous administration of the antiCD20 antibody, optionally within 30, 20, or 15 minutes prior to subcutaneous administration. In some embodiments, the antiCD20 antibody is the only drug administered to the patient for the treatment of multiple sclerosis. In some embodiments, treatment achieves results that are non-inferior to intravenous infusion of the antiCD20 antibody (e.g., at a dose of 600 mg) over 12 weeks, as measured by pharmacokinetics (the concentration in the blood, e.g., the area under the serum curve (AUC)). In some embodiments, treatment achieves results that, within 12 weeks, MRI lesion activity in the patient's brain is comparable to that of intravenous infusion of the antiCD20 antibody (e.g., at a dose of 600 mg). In some embodiments, treatment achieves results that result in rapid, complete, and sustained B-cell depletion. In some embodiments, the treatment achieves a safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg). In some embodiments, the anti-CD20 antibody is in a pharmaceutical preparation comprising about 920 mg of the anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3.In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the formulation is 23 mL.

[0083] In some embodiments, the treatment produces non-inferiority efficacy compared to the efficacy of alternative treatments comprising intravenous administration of the anti-CD20 antibody. In some embodiments, the dose of the anti-CD20 antibody for alternative intravenous administration is about 600 mg. In some embodiments, 600 mg of the anti-CD20 antibody is administered in two divided doses of 300 mg each, wherein the two divided doses are spaced two weeks apart or at least two weeks apart.

[0084] In some embodiments, non-inferiority efficacy is determined by assessing the overall exposure to the anti-CD20 antibody. In some embodiments, the overall exposure to the anti-CD20 antibody is measured by the area under the serum curve (AUC) of the anti-CD20 antibody in the first 12 weeks after administration. In some embodiments, non-inferiority is determined when the lower end of the two-sided 90% confidence interval (GMR) of the geometric mean ratio (AUC) is >0.8.

[0085] In some embodiments, the outcome of treatment is a serum area under the curve (AUC) of anti-CD20 antibody not less than about 1100, 1125, 1150, or 1175 days*mcg / mL in the first 12 weeks after administration. In some embodiments, the outcome of treatment is a serum area under the curve (AUC) of anti-CD20 antibody not less than about 1100, 1125, 1150, 1175, or 1200 days*mcg / mL in the first 24 weeks after administration.

[0086] In some embodiments, the outcome of treatment is a serum area under the curve (AUC) of anti-CD20 antibody not greater than about 7000, 6750, 6500, 6250, or 6000 days*mcg / mL in the first 12 weeks after administration. In some embodiments, the result of treatment is that the area under the curve (AUC) of the anti-CD20 antibody in the first 12 weeks after administration is not greater than about 7500, 7250, 7000, or 6750 days*mcg / mL.

[0087] In some embodiments, the result of treatment is that the area under the curve (AUC) of the anti-CD20 antibody in the first 12 weeks after administration is about 1200 days*mcg / mL to 6000 days*mcg / mL.

[0088] In some embodiments, the result of treatment is that the area under the curve (AUC) of the anti-CD20 antibody in the first 24 weeks after administration is about 1200 days*mcg / mL to 6600 days*mcg / mL.

[0089] In some embodiments, the result of treatment is that the Cmax of the anti-CD20 antibody is not less than about 20, 25, 30, or 35 mcg / mL. In some embodiments, the result of treatment is that the Cmax of the anti-CD20 antibody is not greater than about 230, 225, 220, 215, or 210 mcg / mL. In some embodiments, the result of treatment is that the Cmax of the anti-CD20 antibody is about 35 to 210 mcg / mL.

[0090] In some embodiments, the result of treatment is durable B cell depletion (e.g., at least about 60%, 70%, 80%, 90%, or 95% of B cells are depleted) from about 2 weeks after administration to about 4, 8, 12, 16, 20, or 24 weeks after administration. In some embodiments, the outcome of treatment is complete B-cell depletion (at least 95%, 96%, 97%, 98%, or 99% of B cells are depleted) from approximately 2 weeks to approximately 12 or 15 weeks after administration. In some embodiments, the outcome of treatment is at least 80% B-cell depletion from approximately 2 weeks to approximately 24 weeks after administration. In some embodiments, the outcome of treatment is at least 95%, 96%, 97%, 98%, or 99% B-cell depletion at approximately 2, 4, 8, 12, or 16 weeks after administration. In some embodiments, the outcome of treatment is at least 80% B-cell depletion at approximately 2, 4, 8, 12, 16, 20, or 24 weeks after administration. In some embodiments, the patient has previously undergone B-cell depletion therapy (e.g., anti-CD20 antibody therapy). In some embodiments, the patient has not previously undergone B-cell depletion therapy (e.g., anti-CD20 antibody therapy).

[0091] In some embodiments, this treatment produces a comparable B-cell depletion effect (such as those described above) compared to the B-cell depletion effect of alternative therapies comprising intravenous administration of anti-CD20 antibodies. In some embodiments, the dose of anti-CD20 antibody for alternative intravenous administration is about 600 mg. In some embodiments, the 600 mg of anti-CD20 antibody is administered in two divided doses of 300 mg each, wherein the two divided doses are spaced two weeks apart from each other or at least two weeks apart.

[0092] In some embodiments, the result of the treatment is complete suppression of MRI lesions (e.g., previous T1Gd+ lesions, e.g., new or enlarged T2 lesions) at weeks 8, 12, 16, 20, and 24 after administration.In some embodiments, the outcome of treatment is zero relapse at least 4, 8, 12, 16, 20, or 24 weeks after administration.

[0093] In some embodiments, the treatment produces a comparable radiological effect to the efficacy of alternative treatments comprising intravenous administration of antiCD20 antibodies. In some embodiments, the dose of antiCD20 antibody for alternative intravenous administration is about 600 mg. In some embodiments, the 600 mg of antiCD20 antibody is administered in two divided doses of 300 mg each, wherein the two divided doses are spaced two weeks apart from each other or at least two weeks apart. In some embodiments, the radiological effect comprises the total number of T1Gd+ lesions detected by brain MRI as in previous scans, such as at week 8 and / or week 24. In some embodiments, the radiological effect comprises the total number of new or enlarged T2 lesions detected by brain MRI as in week 12 and / or week 24.

[0094] In some embodiments, this treatment produces a comparable safety profile compared to the safety profile of alternative treatments including intravenous administration of anti-CD20 antibodies. In some embodiments, the dose of the anti-CD20 antibody for alternative intravenous administration is about 600 mg. In some embodiments, the 600 mg of anti-CD20 antibody is administered in two divided doses of 300 mg each, wherein the two divided doses are spaced two weeks apart from each other or at least two weeks apart. In some embodiments, a comparable safety profile is determined by a similar lack of anti-drug antibodies (e.g., antibodies against anti-CD20 antibodies, such as antibodies against rHuPH20) in the subject after treatment. In some embodiments, a comparable safety profile is determined by a similar risk of serious adverse events (e.g., based on previous clinical trial results, such as a similar rate of SAEs after treatment). In some embodiments, a comparable safety profile is determined by the absence of safety considerations based on previous clinical trial results, such as a similar rate of SAEs after treatment.

[0095] A. Antibodies and their production

[0096] The methods and articles of this application use or incorporate antibodies that bind to B cell surface markers, particularly antibodies that bind to CD20. Therefore, methods for producing such antibodies are described herein.Specification 18 / 58 pages 22 CN 121843712 A

[0097] In some embodiments, the anti-CD20 antibody used in the methods described herein is produced by a method comprising: expressing a nucleic acid encoding a humanized antibody in a host cell, the humanized antibody comprising the heavy chain and light chain amino acid sequences of SEQ ID NO: 10 or 11 and SEQ ID NO: 9, respectively; and restoring the expression of the humanized antibody or an antigen-binding fragment thereof in the host cell. In some embodiments, the host cell is a mammalian cell (e.g., CHO cell), an insect cell, or a plant cell. In some embodiments, the host cell is a bacterial cell. The method of producing anti-CD20 is further described in detail, for example, in U.S. Patent No. 7,799,900.

[0098] The B cell surface marker to be used for producing or screening antibodies may be, for example, a marker in a soluble form containing a desired epitope or a portion thereof. Alternatively or additionally, cells expressing the marker at their cell surface may be used to produce or screen antibodies. Other forms of B cell surface markers that can be used to produce antibodies will be apparent to those skilled in the art.

[0099] The following is a description of exemplary techniques for producing antibodies used according to this application.

[0100] Humanized Antibodies

[0101] Methods for humanizing non-human antibodies have been described in the art. In some embodiments, the humanized antibody has one or more amino acid residues introduced from a non-human source. These non-human amino acid residues are generally referred to as “introduced” residues and are typically derived from an “introduced” variable domain. Humanization can be performed essentially as described by Winter and colleagues (Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)), by replacing the corresponding sequence of the human antibody with a highly variable region sequence. Therefore, such “humanized” antibodies are chimeric antibodies (US Patent No. 4,816,567), in which essentially less than the complete human variable domain has been replaced by a corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies, with some of their hypervariable residues and possibly some FR residues replaced by residues at similar sites in rodent antibodies.

[0102] The selection of the light and heavy chains of the human variable domain used to prepare humanized antibodies is crucial for reducing antigenicity. Sequences of the variable domains of rodent antibodies are screened against a whole library of known human variable domain sequences according to a so-called “best fit” method.Then, the human sequence closest to the rodent sequence is accepted as the human framework region (FR) of the human antibody (Sims et al., J. Immunol. 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987)). Another approach uses a specific framework region of a common sequence from a specific subgroup of the variable region of the light chain or heavy chain of all human antibodies. The same framework can be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993)).

[0103] It is even more important to humanize the antibody while retaining high affinity for the antigen and other advantageous biological properties. To achieve this objective, in some embodiments of the method, humanized antibodies are prepared by analyzing parental sequences and various conceptual humanized products using three-dimensional models of parental and humanized sequences. Three-dimensional immunoglobulin models are routinely available and well-known to those skilled in the art. Computer programs are provided that illustrate and display possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. Examination of these displays allows analysis of the possible roles of residues in the function of the candidate immunoglobulin sequences, i.e., analysis of residues that affect the ability of the candidate immunoglobulin to bind its antigens. In this way, FR residues can be selected from and bound to the receptor and the delivery sequence to obtain desired antibody properties, such as increased affinity for the target antigen. Typically, hypervariable region residues are directly and maximally involved in influencing antigen binding.

[0104] In some embodiments, the anti-CD20 antibody comprises a humanized anti-CD20 antibody. In some embodiments, the humanized anti-CD20 antibody comprises: a light chain variable region comprising: CDR L1 having the amino acid sequence shown on page 19 / 58 of the specification in SEQ ID NO: 1, CN 121843712 A; CDR L2 having the amino acid sequence shown in SEQ ID NO: 2; and CDR L3 having the amino acid sequence shown in SEQ ID NO: 3; and a heavy chain variable region comprising: CDR H1 having the amino acid sequence shown in SEQ ID NO: 4; CDR H2 having the amino acid sequence shown in SEQ ID NO: 5; and CDR H3 having the amino acid sequence shown in SEQ ID NO: 6; and optionally a human IgG1 constant region.

[0105] In some embodiments, the anti-CD20 antibody comprises: a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; and a human IgG1 constant region.

[0106] In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence shown in SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 10; and a human IgG1 constant region.

[0107] In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence shown in SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11; and a human IgG1 constant region.

[0108] In some embodiments, the anti-CD20 antibody is ozoleizumab.

[0109] In some embodiments, the lysine amino acid at the C-terminus of the heavy chain of the anti-CD20 antibody is absent.

[0110] B. Patient

[0111] In some aspects, the present invention provides a method for treating MS in a patient.

[0112] In some embodiments, the patient has an EDSS score of 0 to 6.5. In some embodiments, the patient has a disease duration of no more than 15 years from the onset of MS symptoms. In some embodiments, the patient has an EDSS score of less than 2. EDSS is a commonly used measure for quantifying the change in disability over time in patients with MS. EDSS is a disability scale that ranges from 0 (normal) to 10.0 (death) in 0.5 increments (see Kurtzke (1983) Neurol 1983;33:1444-52; and Kappos (2011) Neurology, University Hospital Basel, Switzerland: Neurostatus Scoring Definitions). The EDSS is based on standard neurological examinations; integrating functional systems (visual, brainstem, pyramidal, cerebellum, sensory, gut and bladder, and cerebrum [or mental]), which are rated and then assigned as the FSS (Functional System Score); and gait, which is assigned as the gait score. Each FSS is an ordinal clinical rating scale ranging from 0 to 5 or 6, and gait scores are rated from 0 to 16. These ratings are then combined with observations and information, related gait and assistive devices used to determine the total EDSS score.In some embodiments, EDSS is applied according to the criteria described below and calculated according to the algorithm described below: D' Souza M, Yaldizli Ö, John R, et al. Neurostatus e-Scoring improves consistency of Expanded Disability Status Scale assessments: A proof of concept study. Mult Scler Houndmills Basingstoke Engl. 2017;(4):597–603.

[0113] In some embodiments, the individual has primary progressive multiple sclerosis (PPMS). In some embodiments, the individual has relapsing form of MS (RMS). In some embodiments, MS is active or inactive form of MS based on the presence or absence of disease activity.

[0114] In some embodiments, the patient is not infected with active hepatitis B. In some embodiments, the patient is screened for hepatitis B virus (HBV) before initiating treatment with the anti-CD20 antibody described herein. In some embodiments, the patient is negative for surface antigen [HBsAg] and negative for HB core antibody [HBcAb+]. In some embodiments, the patient is negative for hepatitis B surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or is a carrier of HBV [HBsAg+]. In some embodiments, the patient is based on a) not being infected with active hepatitis B, b) being negative for hepatitis B surface antigen [HBsAg] and negative for HB core antibody [HBcAb+], and / Specification 20 / 58 page 24 CN 121843712 A or c) being negative for hepatitis B surface antigen [HBsAg] and positive for HB core antibody [HBcAb+], or being a carrier of HBV [HBsAg+].

[0115] Relapsing Multiple Sclerosis (RMS)

[0116] In some embodiments, multiple sclerosis is relapsing multiple sclerosis (RMS). In some embodiments, the patient has been diagnosed with RMS according to the criteria described in the following: Thompson et al. (2018) Lancet Neurol. 17:162–73. In some embodiments, the patient has RMS and the treatment described herein achieves one or more of the outcomes described herein (e.g., non-inferiority as measured by pharmacokinetics, control of MRI lesion activity in the brain, B cell depletion, consistent safety profile).

[0117] In some embodiments, the patient has been diagnosed with RMS according to the 2017 revised McDonald guidelines (Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 McDonald guidelines revised. Lancet Neurol 2018;17:162–73). In some embodiments, the patient with RMS has not received prior treatment with an anti-CD20 antibody or has not received prior anti-CD20 antibody treatment within the past two years. In some embodiments, the patient with RMS has received prior treatment with an anti-CD20 antibody, and the last dose of anti-CD20 antibody was administered more than approximately two years prior to the start of treatment according to the methods described herein. In some embodiments, the patient with RMS has received prior treatment with an anti-CD20 antibody, and the patient has a normal B-cell count. In some embodiments, the patient with RMS has received prior treatment with an anti-CD20 antibody, and treatment was not interrupted due to lack of efficacy and / or adverse events. In some embodiments, patients with RMS have received prior treatment with rituximab, ozoglucillin, obinutuzumab, veltuzumab, tositumomab, ibritumomab, and / or ofatumumab. In some embodiments, patients with RMS have not received prior treatment with mitoxantrone, cladribine, atacicept, and / or alemtuzumab.

[0118] Progressive Multiple Sclerosis (PPMS)

[0119] In some embodiments, the multiple sclerosis is primary progressive multiple sclerosis (PPMS). In some embodiments, the patient has been diagnosed with PPMS according to the criteria described in the following: Thompson et al. (2018) Lancet Neurol. 17:162–73. In some embodiments, the patient has PPMS and the treatment described herein achieves one or more of the outcomes described herein (e.g., non-inferiority as measured by pharmacokinetics, control of MRI lesion activity in the brain, B cell depletion, consistent safety profile). In some embodiments, the patient is at least 18 years of age.

[0120] In some embodiments, a patient with PPMS has not received prior treatment with an anti-CD20 antibody or has not received prior anti-CD20 antibody treatment within the past two years. In some embodiments, a patient with PPMS has received prior treatment with an anti-CD20 antibody, and the last dose of anti-CD20 antibody was administered more than approximately two years prior to the start of treatment according to the methods described herein. In some embodiments, a patient with PPMS has received prior treatment with an anti-CD20 antibody, and the patient has a normal B-cell count. In some embodiments, a patient with PPMS has received prior treatment with an anti-CD20 antibody, and treatment was not interrupted due to lack of efficacy and / or adverse events. In some embodiments, a patient with PPMS has received prior treatment with ourelizumab. In some embodiments, a patient with RMS has received prior treatment with rituximab, ourelizumab, obinuzumab, vetuzumab, tosimoumab, tiimozumab, orfamumab. In some embodiments, patients with RMS have not received prior treatment with mitoxantrone, cladribine, atacicept, and / or alemtuzumab.

[0121] In some embodiments, the patient has been diagnosed with PPMS according to the 2017 revised McDonald guidelines (Thompson AJ, Banwell BL, Barkhof F et al. Diagnosis of multiple sclerosis: 2017 McDonald guidelines revised. Lancet Neurol 2018;17:162–73). In some embodiments, the patient has an EDSS score between 3 and 6.5 (inclusive) at the start of treatment (e.g., before the first dose of anti-CD20 antibody). In some embodiments, the patient has a score ≥ 2.0 on the Functional System of the Pyramidal System (FS) scale based on lower extremity findings. In some embodiments, the patient has a disease duration of less than about 15 years from the onset of MS symptoms, and an EDSS score > 5.0 at the start of treatment (e.g., before the first dose of anti-CD20 antibody). In some embodiments, the patient has a disease duration of less than about 10 years from the onset of MS symptoms, and an EDSS score ≤ 5.0 at screening.In some embodiments, the patient has documented evidence of the presence of cerebrospinal fluid-specific oligoclonal bands.

[0122] C. Dosing Regimen

[0123] The following sections describe various aspects of the dosing and treatment regimen (examples), any and all of which are applicable to the methods described herein.

[0124] In one aspect, this application provides a method of treating an individual with multiple sclerosis, the method comprising subcutaneously administering an effective amount of anti-CD20 antibody every six months or 24 weeks. In some embodiments, about 850 mg to about 1000 mg, about 900 mg to about 950 mg, or about 920 mg of anti-CD20 antibody is administered. In some embodiments, about 920 mg of anti-CD20 antibody is administered.

[0125] In some embodiments, the anti-CD20 antibody is administered subcutaneously to the individual by a healthcare professional using a manual syringe or infusion pump. In some embodiments, the anti-CD20 antibody is administered about every six months or 24 weeks via an SC infusion device into the abdominal SC space, excluding a 5 cm area directly around the umbilicus. In some embodiments, the subcutaneous doses of the anti-CD20 antibody are maintained for at least about 22 weeks or about five months. In some embodiments, the anti-CD20 antibody is administered at home. In some embodiments, the anti-CD20 antibody is administered at a healthcare facility.

[0126] Additional SC intervals may be used for SC administration. These intervals include the outer region of the upper arm, the front of the thigh, the middle of the outer thigh, the middle to upper side (4 inches below the top of the thigh to 4 inches above the knee), the upper back, and the upper region of the buttocks, just behind the hip bone in the lower back (which has the slowest absorption rate among these sites).

[0127] In some embodiments, this document provides a method of treating an individual suffering from MS, the method comprising administering to the individual an effective amount of an antibody that binds to CD20, the antibody comprising a variable heavy chain (VH) and a variable light chain (VL), wherein the VH comprises: CDRL1, which comprises the amino acid sequence shown in SEQ ID NO: 1; CDRL2, which comprises the amino acid sequence shown in SEQ ID NO: 2; CDRL3, which comprises the amino acid sequence shown in SEQ ID NO: 3; CDRH1, which comprises the amino acid sequence shown in SEQ ID NO: 4; CDRH2, which comprises the amino acid sequence shown in SEQ ID NO: 5; and CDRH3, which comprises the amino acid sequence shown in SEQ ID NO: 6.In some embodiments, the CD20 antibody has: a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the antibody comprises: a light chain comprising the amino acid sequence shown in SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 10. In some embodiments, the antibody is ozoleizumab (CAS Registry No. 637334-45-3). In some embodiments, the antibody has an IgG1 isotype. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody binding to CD20 inhibits CD20. In some embodiments, the antibody binding to CD20 selectively targets and consumes B cells expressing CD-20 while preserving the ability of B cell remodeling and pre-existing humoral immunity. In some embodiments, the antibody binding to CD20 is administered at a dose of approximately 920 mg. In some embodiments, the antibody binding to CD20, as described on page 22 / 58 of the specification (CN 121843712 A), is administered approximately every 6 months or 24 weeks. In some embodiments, the antibody binding to CD20 is administered at least two, at least three, at least four, or at least five times. In some embodiments, the antibody binding to CD20 is administered approximately every six months or approximately every 24 weeks for approximately 24 months. In some embodiments, the individual has secondary progressive multiple sclerosis (SPMS). In some embodiments, the individual has relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the individual has relapsing-remitting MS (RMS).

[0128] In some embodiments, to reduce potential injection reactions, approximately 20 mg of dexamethasone (or an equivalent corticosteroid) and / or approximately 5 mg of desloratadine are administered to the individual before subcutaneous administration of the anti-CD20 antibody. In some embodiments, 20 mg of dexamethasone (or an equivalent corticosteroid) and 5 mg of desloratadine are administered to the individual over a period of approximately 30 to 60 minutes, approximately 30 to 40 minutes, approximately 40 to 50 minutes, or approximately 50 to 60 minutes prior to subcutaneous administration of the anti-CD20 antibody. In some embodiments, an equivalent dose of an alternative steroid or antihistamine is administered to the individual prior to subcutaneous administration of the anti-CD20 antibody.

[0129] In some embodiments, the anti-CD20 antibody is administered in a formulation suitable for subcutaneous administration. In some embodiments, the anti-CD20 antibody is formulated with any of the formulations described herein.In some embodiments, the anti-CD20 antibody is present in a pharmaceutical formulation comprising about: 30 to 350 mg / ml (e.g., about 40 mg / ml) of anti-CD20 antibody; about 1 to 100 mM of buffer (e.g., 20 mM sodium acetate) providing a pH of about 3.5 to 7.5 (e.g., about 5.3); about 1 to 500 mM of stabilizer or a mixture of two or more stabilizers (e.g., about 240 mM trehalose and / or about 10 mM methionine); about 0.01% to 0.1% (w / v) of nonionic surfactant (e.g., 0.06% (w / v) polysorbate 20); and optionally an effective amount of at least one hyaluronidase (e.g., about 1000 U / ml of hyaluronidase). In some embodiments, the pharmaceutical formulation further comprises recombinant human hyaluronidase. In some embodiments, the recombinant human hyaluronidase comprises rHuPH20. In some embodiments, the anti-CD20 antibody is in a pharmaceutical formulation comprising about 920 mg of anti-CD20 antibody, about 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the volume of the formulation is 23 mL.

[0130] In some embodiments, the anti-CD20 antibody is administered multiple times (e.g., at least two or at least three times) over a period of 12 months or longer. In some embodiments, the anti-CD20 antibody is administered multiple times (e.g., at least two, three, or four times) over a period of 18 months or longer. In some embodiments, the anti-CD20 antibody is administered multiple times (e.g., at least two, three, four, or five times) over a period of 24 months or longer.

[0131] It may be advantageous to deliver the anti-CD20 antibody to an individual more than once. For example, in some embodiments, the anti-CD20 antibody is administered at least two, at least three, at least four, or at least five times. For example, in some embodiments, the anti-CD20 antibody is administered two, three, four, or five times. In some embodiments, the anti-CD20 antibody is administered multiple times over a period of 24 months, one to 24 months, six to 24 months, or 12 to 24 months.

[0132] In some aspects, this document provides a method of treating an individual with MS, the method comprising administering an anti-CD20 antibody subcutaneously to the individual approximately every six months or 24 weeks for a period of at least 12 months, at least 18 months, or at least 24 months; wherein each administration of the anti-CD20 antibody comprises administering approximately 920 mg of the anti-CD20 antibody subcutaneously.

[0133] In some embodiments, the method includes (i) administering an anti-CD20 antibody subcutaneously to the individual on day 0, (ii) administering a second dose of the anti-CD20 antibody subcutaneously after approximately 6 months (e.g., 180, 181, 182, 183, 184, or 185 days), (iii) administering a third dose of the anti-CD20 antibody subcutaneously after approximately 12 months, (iv) administering a fourth dose of the anti-CD20 antibody subcutaneously after approximately 18 months, and (v) administering a fifth dose of the anti-CD20 antibody subcutaneously after approximately 24 months. In some embodiments, approximately 920 mg of the anti-CD20 antibody is administered during each dose period.

[0134] In some embodiments, the anti-CD20 antibody is the only drug administered to the individual for the treatment of multiple sclerosis. In some embodiments, the anti-CD20 antibody is the sole disease-modifying therapy (DMT) administered to a patient to treat multiple sclerosis. For example, in some embodiments, the anti-CD20 antibody is administered in combination with one or more of the following: methylprednisolone (or its equivalent); an antihistamine (e.g., diphenhydramine or its equivalent); an analgesic (e.g., acetaminophen); and an antipyretic.

[0135] In some embodiments, the anti-CD20 antibody is administered via a device suitable for subcutaneous administration of at least 20 mL. In some embodiments, the anti-CD20 antibody is administered via a device suitable for subcutaneous administration of about 23 mL. In some embodiments, the device includes an infusion pump. In some embodiments, the device includes a CRONO mobile infusion pump. In some embodiments, the device includes a Lapas patch pump. In some embodiments, the device includes an enFuse® on-body platform. In some embodiments, the device includes a wearable syringe or wearable injection device. In some embodiments, the device includes a drug delivery system®. See, for example, Badkar et al., Drug Des Devel Ther. January 13, 2021; 15:159–170.

[0136] In some embodiments, this document provides a method for treating an individual with multiple sclerosis by subcutaneously administering an anti-CD20 antibody to the individual, wherein each subcutaneous anti-CD20 antibody administration comprises SC delivery of about 920 mg of the anti-CD20 antibody. In some embodiments, the individual has secondary progressive multiple sclerosis (SPMS). In some embodiments, the individual has relapsing-remitting multiple sclerosis (RRMS). In some embodiments, the individual has relapsing-remitting MS (RMS).

[0137] This document also provides a method for treating an individual with MS, the method comprising a dosing schedule of at least 24 months, the dosing schedule comprising SC delivery of about 920 mg of the anti-CD20 antibody about every 6 months or 24 weeks. In some embodiments, consecutive doses of the anti-CD20 antibody are administered at intervals of at least about 22 weeks or about five months.

[0138] In some embodiments, the method comprises administering the anti-CD20 antibody at weeks 0, 26, 52, 78, and 104. In some embodiments, the method includes administering an anti-CD20 antibody at weeks 0, 24, 48, 72, and 96. In some embodiments, administering the anti-CD20 antibody includes subcutaneous injection to the individual by a healthcare professional using a manual syringe or infusion pump. In some embodiments, the subcutaneous administration of the anti-CD20 antibody comprises about 920 mg of the anti-CD20 antibody.

[0139] In some embodiments, this document provides a method of treating an individual with MS, the method comprising subcutaneous administration of an anti-CD20 antibody, wherein the anti-CD20 antibody administration comprises subcutaneously delivering about 920 mg of the anti-CD20 antibody to the individual during an anti-CD20 antibody delivery period, wherein during the anti-CD20 antibody delivery period, an effective amount of the anti-CD20 antibody for treating MS is present in the individual's serum.

[0140] In some embodiments, the anti-CD20 antibody is administered subcutaneously as a composition comprising a volume of 23 mL of the anti-CD20 antibody (e.g., with a pre-filled syringe or device comprising a needle). In some embodiments, the anti-CD20 antibody is administered subcutaneously as a composition comprising 23 mL of anti-CD20 antibody, wherein the formulation comprises 920 mg of ozretinoin and 23,000 units of hyaluronidase. In some embodiments, the anti-CD20 antibody is administered into the abdominal SC space, except for a 5 cm area directly around the navel. In some embodiments, the subcutaneous administration takes approximately 10 minutes. In some embodiments, the anti-CD20 antibody is administered every 6 months or 24 weeks. In some embodiments, consecutive doses of the anti-CD20 antibody are administered at intervals of at least approximately 22 weeks or approximately 5 months.In some embodiments, the anti-CD20 antibody is administered subcutaneously as a composition comprising 23 mL of anti-CD20 antibody, wherein the composition comprises 920 mg of ozoleizumab and 23,000 units of hyaluronidase, and the anti-CD20 antibody is administered into the abdominal SC space, except for a 5 cm area directly around the navel (page 24 / 58 of the specification, CN 121843712 A), wherein the administration takes approximately 10 minutes, and the anti-CD20 antibody is administered approximately every 6 months or 24 weeks.

[0141] D. Pre-treatment

[0142] In some embodiments, the patient undergoes pre-treatment prior to (e.g., shortly before) the subcutaneous administration of the anti-CD20 antibody (e.g., any anti-CD20 antibody described herein). In some cases, administering one or more pre-treatments to a patient “shortly” before subcutaneous administration means administering one or more pre-treatments approximately 2 hours, 1 hour, 45 minutes, 30 minutes, 20 minutes, 15 minutes, 10 minutes, or 5 minutes before subcutaneous administration of the anti-CD20 antibody.

[0143] In some embodiments, the patient is pre-treated with methylprednisolone (or an equivalent, such as an alternative steroid) approximately 30 minutes to one hour before each subcutaneous administration of the anti-CD20 antibody. In some embodiments, the patient is pre-treated with methylprednisolone (or an equivalent) approximately 30 minutes before each subcutaneous administration of the anti-CD20 antibody (e.g., approximately 20 minutes or 15 minutes). In some embodiments, the patient is pre-treated with 100 mg IV methylprednisolone (or an equivalent) approximately 30 minutes to one hour before each subcutaneous administration of the anti-CD20 antibody. In some embodiments, the patient pre-administers 100 mg IV methylprednisolone (or its equivalent) approximately 30 minutes before each subcutaneous administration of the anti-CD20 antibody (e.g., approximately 20 or 15 minutes).

[0144] In some embodiments, the patient additionally (or alternatively) pre-administers an antihistamine (e.g., diphenhydramine) approximately 30 to 60 minutes before each subcutaneous administration of the anti-CD20 antibody. In some embodiments, the patient additionally (or alternatively) pre-administers an antihistamine (e.g., diphenhydramine) approximately 30 minutes before each subcutaneous administration of the anti-CD20 antibody (e.g., approximately 20 or 15 minutes). In some embodiments, the patient additionally (or alternatively) pre-administers an antipyretic (e.g., acetaminophen / paracetamol) approximately 30 to 60 minutes before each subcutaneous administration of the anti-CD20 antibody.In some embodiments, the patient may additionally (or alternatively) pre-administer an antipyretic (e.g., acetaminophen / paracetamol) within approximately 30 minutes (e.g., approximately 20 minutes or 15 minutes) before each subcutaneous administration of the anti-CD20 antibody.

[0145] E. Prior Treatment

[0146] In some embodiments, the patient has received prior treatment for MS.

[0147] In some embodiments, the patient has not received prior treatment for MS.

[0148] In some embodiments, the patient has not received prior intravenous administration of an anti-CD20 antibody (such as any anti-CD20 antibody described herein) at a dose of approximately 600 mg. In some embodiments, the patient has not received prior intravenous administration of an anti-CD20 antibody (such as any anti-CD20 antibody described herein).

[0149] In some embodiments, the patient has not received prior subcutaneous administration of an anti-CD20 antibody (such as any anti-CD20 antibody described herein) at a dose less than approximately 900 mg.

[0150] In some embodiments, the patient has not previously received an anti-CD20 antibody (such as any anti-CD20 antibody described herein). In some embodiments, the patient has not previously received an anti-CD20 antibody (such as any anti-CD20 antibody described herein) within 2 years prior to starting treatment with the anti-CD20 antibody described herein. In some embodiments, the anti-CD20 antibody is ozoleizumab.

[0151] In some embodiments, the patient has received prior treatment with an anti-CD20 antibody. In some embodiments, the prior treatment includes intravenous administration of an anti-CD20 antibody. In some embodiments, the prior treatment includes intravenous administration of an anti-CD20 antibody at a dose of about 600 mg. In some embodiments, the prior treatment occurred at least about 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months prior to the time described herein.

[0152] In some embodiments, the patient has not previously received treatment with cladribine, asceticipase, or alemtuzumab. In some embodiments, the patient has not received prior treatment with fingolimod, siponimod, ponesimod, or ozanimod within 6 weeks prior to the method comprising subcutaneous administration of the anti-CD20 antibody described herein.

[0154] In some embodiments, the patient has not received prior treatment with interferon beta (1a or 1b) or glatiramer acetate within 2 weeks prior to the method comprising subcutaneous administration of the anti-CD20 antibody described herein.

[0155] In some embodiments, the patient has not received prior treatment with natalizumab within 4.5 months prior to the method comprising subcutaneous administration of the anti-CD20 antibody described herein.

[0156] In some embodiments, the patient has not received prior treatment with mitoxantrone within 2 years prior to the method comprising subcutaneous administration of the anti-CD20 antibody described herein.

[0157] F. Combination Therapy

[0158] While anti-CD20 antibodies may be the only drug administered to a patient to treat multiple sclerosis, a second drug may optionally be administered, such as a second multiple sclerosis disease modifier (DMT), such as a cytotoxic agent, chemotherapeutic agent, immunosuppressant, cytokine, cytokine antagonist or antibody, growth factor, hormone, integrin, integrin antagonist or antibody (e.g., LFA-1 antibody or α4 integrin antibody (such as nastatinumab (TYSABRI®) available from Biogen Idec / Elan Pharmaceuticals, Inc.)), and antibodies that bind to B cell surface markers (e.g., and anti-CD20 antibodies).

[0159] In some embodiments, the antibody is combined with the following: interferon drugs, such as IFN-β-1a (REBIF® and AVONEX®) or IFN-β-1b (BETASERON®); oligopeptides, such as glatiramer acetate (COPAXONE®); cytotoxic agents, such as mitoxantrone (NOVANTRONE®), methotrexate, cyclophosphamide, chlorambucil, azathioprine; intravenous immunoglobulins (γ-globulins); lymphocyte-depleting therapy (e.g., mitoxantrone, cyclophosphamide, alemtuzumab (Campath®, LEMTRADA™), anti-CD4, cladribine, whole-body irradiation, bone marrow transplantation); corticosteroids (e.g., methylprednisolone, prednisone, dexamethasone, or glucocorticoids), including systemic corticosteroid therapy; and non-lymphocyte-depleting immunosuppressive therapy (e.g., mycophenolate mofetil (MMF)). Or cyclosporine); "statin" cholesterol-lowering drugs, including cerivastatin (BAYCOL®), fluvastatin (LESCOL®), atorvastatin (LIPITOR®), lovastatin (MEVACOR®), pravastatin (PRAVACHOL®), simvastatin (ZOCOR®); estradiol; testosterone (optionally at elevated doses; Stuve et al. Neurology 8:290–301 (2002)); hormone replacement therapy; treatment for symptoms secondary to or associated with MS (e.g., cramps, incontinence, pain, fatigue); TNF Inhibitors; Disease-modifying antirheumatic drugs (DMARDs); Nonsteroidal anti-inflammatory drugs (NSAIDs); Plasma evacuation; Levothyroxine; Cyclosporine A; Somatostatin analogs; Cytokines or cytokine receptor antagonists; Antimetabolites; Immunosuppressants; Rehabilitation surgery; Radioactive iodine; Thyroidectomy; Another B cell surface antagonist / antibody; etc.

[0160] In some embodiments, the second drug is administered together with one or more anti-CD20 antibody administrations, such combined administration including co-administration, using a separate formulation or a single drug formulation, and sequential administration in any order, wherein preferably, there is a period of time during which both (or all) active agents exert their biological activity simultaneously.

[0161] In some embodiments, the anti-CD20 antibody is the only drug administered to a patient to treat multiple sclerosis. In some embodiments, the anti-CD20 antibody is the only disease-modifying therapy (DMT) administered to a patient to treat multiple sclerosis.For example, in some embodiments, the anti-CD20 antibody is administered in combination with one or more of the following: methylprednisolone (or its equivalent); an antihistamine (e.g., diphenhydramine or its equivalent); an analgesic (e.g., acetaminophen); and an antipyretic.

[0162] In some embodiments, the anti-CD20 antibody is not used in conjunction with a non-live vaccine. In some embodiments, the non-live vaccine is a tetanus toxoid vaccine, a pneumococcal polysaccharide, a pneumococcal conjugate vaccine, or a seasonal inactivated influenza vaccine.

[0163] In some embodiments, the administration of a live vaccine or a live attenuated vaccine occurs at least 4 weeks before the start of treatment with the anti-CD20 antibody.

[0164] G. Side Effects

[0165] In one aspect, this application provides a method of treating a patient with multiple sclerosis, the method comprising subcutaneously administering an effective amount of an anti-CD20 antibody at a dose of about 920 mg, wherein the patient does not develop significant side effects, substantial adverse drug reactions, or a safety profile comparable or more favorable than that following intravenous administration of the anti-CD20 antibody at a dose of about 600 mg. In some embodiments, the risk of the patient developing a moderately severe reaction (e.g., an injection reaction) is no greater than about 20%, 18%, or 15%. In some embodiments, the patient does not develop a severe injection reaction. In some embodiments, when the patient does develop an injection reaction, the risk of the patient developing a moderately severe injection reaction is no greater than about 20%, 18%, or 15%.

[0166] In some embodiments, side effects include infusion-related reactions (IRR). All CD20-consuming agents, including ozretinoin, are associated with acute IRR. Symptoms associated with IRR include, but are not limited to, itching, rash, hives, erythema, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, fever, fatigue, headache, dizziness, nausea, tachycardia, and allergic reactions. In some embodiments, the methods described herein produce a reduced incidence of IRR compared to intravenous administration of antiCD20 antibodies at a dose of approximately 600 mg.

[0167] In some embodiments, side effects include injection site reactions (ISR). In some embodiments, injection site reactions may occur during any subcutaneous administration of antiCD20 antibodies. In some embodiments, injection site reactions may include injection site erythema, pain, swelling, bruising, itching, allergies, and / or hives. In some embodiments, patients are pre-treated to reduce the risk of injection site reactions.In some embodiments, the methods described herein produce a reduced incidence of ISR compared to intravenous administration of anti-CD20 antibodies at a dose of about 600 mg.

[0168] In some embodiments, side effects include infection. In some embodiments, infection may include mild to moderate respiratory infection. In some embodiments, infection may be opportunistic infection. In some embodiments, infection may be non-disseminated herpesvirus-associated infection. In some embodiments, infection may be hepatitis B virus infection. In some embodiments, patients are less likely to develop infection after subcutaneous administration of anti-CD20 antibodies compared to intravenous administration of anti-CD20 antibodies at a dose of about 600 mg.

[0169] In some embodiments, a side effect is a decrease in total immunoglobulin (Ig) during a control period of treatment with anti-CD20 antibodies (e.g., 24 weeks prior to treatment). In some embodiments, the decrease in total immunoglobulin is primarily driven by a reduction in IgM. In some embodiments, the proportion of patients with total immunoglobulin below the lower limit of normal (LLN) increases over time and with subsequent administration of anti-CD20 antibodies. In some embodiments, patients are less likely to develop a decrease in total immunoglobulins after subcutaneous administration of antiCD20 antibodies compared to intravenous administration of antiCD20 antibodies at a dose of about 600 mg.

[0170] In some embodiments, side effects include systemic injection reactions, progressive multifocal leukoencephalopathy, allergic reactions, malignancies, and / or neutropenia. In some embodiments, patients experience a lower risk or incidence of developing any of the side effects described above or herein compared to intravenous administration of antiCD20 antibodies at a dose of about 600 mg.

[0171] H. Technical Effects Specification 27 / 58 pages 31 CN 121843712 A

[0172] This application provides a method for achieving non-inferiority pharmacokinetic (PK) results compared to approved MS treatment administered via IV at a dose of 600 mg of ozoleizumab. In some embodiments, this document provides a method of treating a patient with multiple sclerosis, comprising subcutaneously administering an anti-CD20 antibody at a dose of about 920 mg, optionally once every 6 months or 24 weeks for about 12, 18, or 24 months, wherein the serum area under the concentration-time curve (AUCW1-12) from day 1 to week 12 following subcutaneous administration of the anti-CD20 antibody described herein at a dose of about 920 mg is comparable to that of an IV administration of an anti-CD20 antibody (e.g., ozenalinumab) at a dose of 600 mg.In some embodiments, the 25th percentile of the exposure (AUCt) distribution associated with the methods described herein corresponds to an IV administration of an anti-CD20 antibody (e.g., ozenafil) at a dose of 600 mg. In some cases, “corresponding” as used herein means when the value falls within the range of about 50% to about 200%, about 60% to about 170%, about 70% to about 150%, about 75% to about 135%, about 80% to about 120%, or 90% to about 110% of the comparative or reference value.

[0173] III. Compositions, Formulations, and Unit Dosage Forms

[0174] Therapeutic formulations of antibodies used according to the invention for storage are prepared by mixing antibodies of desired purity with optional pharmaceutical carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. Edited (1980)) in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the doses and concentrations used and include: buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexahydroxy quaternary ammonium chloride; phenylenediamine chloride; benzaldehyde chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) peptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, etc. Histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming ions, such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants, such as TWEEN™, PLURONICS™, or polyethylene glycol (PEG).

[0175] Lyophilized formulations suitable for subcutaneous administration are described in U.S. Patent No. 6,267,958 (Andya et al.). Such lyophilized formulations can be reconstituted to high protein concentrations with a suitable diluent, and the reconstituted formulation can be subcutaneously administered to the mammals to be treated herein.

[0176] Antibodies or crystalline forms of antibodies are also contemplated. See, for example, US 2002 / 0136719A1 (Shenoy et al.).

[0177] The formulations described herein may also contain more than one active compound required for the specific indication being treated, and in some embodiments, those compounds having complementary activities that do not adversely affect each other. For example, it may be desirable to further provide in the formulation: cytotoxic agents; chemotherapeutic agents; immunosuppressants; cytokines; cytokine antagonists or antibodies; growth factors; hormones; integrins; integrin antagonists or antibodies available from Biogen Idec / Elan Pharmaceuticals, Inc. (e.g., LFA-1 antibodies or α4 integrin antibodies (such as nastatin / TYSABRI®)); interferon drugs, such as IFN-β-1a (REBIF® and AVONEX®) or IFN-β-1b (BETASERON®); oligopeptides, such as glatiramer acetate (COPAXONE®); cytotoxic agents, such as mitoxantrone (NOVANTRONE®), methotrexate, cyclophosphamide, chlorambucil, or azathioprine; intravenous immunoglobulins (γ-globulins); lymphocyte-depleting drugs (e.g., mitoxantrone, cyclophosphamide, Camppath, anti-CD4). Or cladribine); non-lymphocyte-depleting immunosuppressants (e.g., mycophenolate mofetil (MMF) or cyclosporine); "statins" cholesterol-lowering drugs; estradiol; testosterone; hormone replacement therapy; drugs for the treatment of secondary MS or related symptoms (e.g., cramps, incontinence, pain, fatigue); TNF inhibitors; disease-modifying antirheumatic drugs (DMARDs); nonsteroidal anti-inflammatory drugs (NSAIDs); corticosteroids (e.g., methylprednisolone, prednisone, dexamethasone, or glucocorticoids); levothyroxine; cyclosporine A; somatostatin analogs; cytokine antagonists; antimetabolites; immunosuppressants; integrin antagonists or antibodies (e.g., LFA-1 antibodies, such as efalizumab or α4 integrin antibodies, such as natezilumab); or another B Cell surface antagonists / antibodies, etc. For example, the type and effective amount of these other agents depend on the amount of antibody present in the formulation, the type of multiple sclerosis being treated, and the patient's clinical parameters. These are typically used at the same dosage and route of administration as those used above, or at about 1% to 99% of the dosage used to date.

[0178] The active ingredient may be encapsulated in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared by, for example, cohesive drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or coarse drop emulsions prepared by, for example, cohesive drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules).These techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., ed. (1980).

[0179] Sustained-release preparations can be prepared. Suitable examples of sustained-release formulations include a semi-permeable matrix of a solid hydrophobic polymer containing an antibody, which is in the form of a shaped article, such as a membrane or microcapsule. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide (US Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers (such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate)), and poly-D-(-)-3-hydroxybutyric acid.

[0180] The formulation intended for in vivo administration must be sterile. This can be easily achieved by filtration through a sterile filter membrane.

[0181] In some embodiments, the formulation comprises one or more of the group consisting of sodium acetate, trehalose, methionine, polysorbate 20, and hyaluronidase. In some embodiments, the sodium acetate is a sodium acetate buffer with a pH of about 5.3. Examples of formulations suitable for administering anti-CD20 antibodies can be found in Andya et al., US2006 / 0088523, WO98 / 56418, and US20210054092A1, which are incorporated herein by reference in their entirety.

[0182] In some embodiments, a pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody suitable for subcutaneous administration is provided, the pharmaceutical formulation comprising: about 30 mg / ml to 350 mg / ml, for example about 30 mg / ml to 100 mg / ml (including about 30 mg / ml, about 50 mg / ml or about 100 mg / ml) of the anti-CD20 antibody described herein (e.g., ozolelizumab); about 1 to 100 mM of a buffer (e.g., sodium acetate) providing a pH of 5.5 ± 2.0 (e.g., pH 5.3); about 15 to 250 mM of a stabilizer or a mixture of two or more stabilizers (including trehalose, for example, about 8% trehalose dihydrate); about 0.01% to 0.1% (w / v) of a nonionic surfactant; and optionally an effective amount of at least one hyaluronidase (e.g., rhHUPH20), preferably in an amount of about 1,500 U / ml. Approximately 12,000 U / ml.

[0183] In some embodiments, the formulations provided herein are liquid single-dose or multi-dose formulations comprising: about 30 to 50 mg / mL (e.g., about 40 mg / mL) of an anti-CD20 antibody; about 15 to 25 mM (e.g., 20 mM) of sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3); about 220 mM to about 260 mM (e.g., 240 mM) of trehalose; about 5 mM to 15 mM (e.g., 10 mM) of methionine; about 0.05 to 0.07% (w / v) (e.g., 0.06%) of polysorbate 20; and about 800 to 1200 U / ml (e.g., 1000 U / ml) of hyaluronidase, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; and a VL domain comprising the amino acid sequence shown in SEQ ID NO: 8. NO: 7 shows the amino acid sequence; and the human IgG1 constant region. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the formulation is for subcutaneous administration. In some embodiments, the formulation has a minimum shelf life of two years when stored at 2°C to 8°C. In some embodiments, the formulation provided herein is a liquid formulation comprising: about 35 to about 45 mg / mL (e.g., about 40 mg / mL) of anti-CD20 antibody; about 20 mM sodium acetate providing a pH of about 5 to about 5.6 (e.g., 5.3); about 190 mM to about 290 mM (e.g., 240 mM) trehalose; about 5 mM to 15 mM (e.g., 10 mM) methionine; about 0.04% to 0.08% (w / v) (e.g., 0.06%) polysorbate 20; and about 1000 U / mL hyaluronidase, wherein the anti-CD20 antibody comprises: a VH domain containing the amino acid sequence shown in SEQ ID NO: 8; a VL domain containing the amino acid sequence shown in SEQ ID NO: 7; and human IgG1. Constant region. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the formulation is for subcutaneous administration. In some embodiments, the formulation has a minimum shelf life of two years when stored at 2°C to 8°C.

[0184] In some embodiments, a pharmaceutical formulation of a pharmaceutically active anti-CD20 antibody suitable for subcutaneous administration is provided, the pharmaceutical formulation comprising an anti-CD20 antibody, sodium acetate, trehalose, methionine, polysorbate 20, and hyaluronidase, optionally wherein a) the concentration of the antibody and sodium acetate is about 35 to 45 mg / mL (e.g., about 40 mg / mL): 20 mM; b) the concentration of the antibody and trehalose is about 35 to 45 mg / mL (e.g., about 40 mg / mL): about 190 mM to about 290 mM (e.g., 240 mM); c) the concentration of the antibody and methionine is about 35 to 45 mg / mL (e.g., about 40 mg / mL): 5 mM to 15 mM (e.g., 10 mM); d) the concentration of the antibody and polysorbate 20 is about 35 to 45 mg / mL. mg / mL (e.g., about 40 mg / mL): 0.04% to 0.08% (w / v) (e.g., 0.06%), and / or e) the concentration of antibody and hyaluronidase is about 35 to 45 mg / mL (e.g., about 40 mg / mL): about 1000 U / mL. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase. In some embodiments, the concentrations of anti-CD20 antibody, sodium acetate, trehalose, methionine, polysorbate 20, and hyaluronidase are 40 mg / mL: 20 mM: 240 mM: 10 mM: 0.06% (w / v): 1000 U / mL. In some embodiments, the anti-CD20 antibody comprises: a VH domain containing the amino acid sequence shown in SEQ ID NO: 8; a VL domain containing the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is olizumab. In some embodiments, the formulation has a minimum shelf life of two years when stored at 2°C to 8°C.

[0185] In some embodiments, the anti-CD20 antibody is in a pharmaceutical formulation comprising about 920 mg of anti-CD20 antibody, 23,000 units of hyaluronidase, about 2.088 g of α,α-trehalose dihydrate, about 5.5 mg of glacial acetic acid, about 34.4 mg of L-methionine, about 13.8 mg of polysorbate 20, about 50.1 mg of sodium acetate trihydrate, and water for injection at a pH of about 5.3, wherein the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is ozoleizumab. In some embodiments, the anti-CD20 antibody is supplied in 50 mL single-dose vials. In some embodiments, the formulation is for subcutaneous administration. In some embodiments, the formulation is stored at about 2°C to 8°C. In some embodiments, the antibody formulation is stored at about 25°C or above for no more than 12 hours. In some embodiments, each vial is prepared for a single subcutaneous injection. In some embodiments, the contents of the vial are undiluted.

[0186] In some embodiments, a recombinant humanized 2H7 antiCD20 antibody (such as 2H7.v16 disclosed in WO 2006 / 084264, which is incorporated herein by reference in its entirety) is used in the compositions or formulations described herein.

[0187] Lyophilized formulations suitable for subcutaneous administration are described in WO97 / 04801, which is incorporated herein by reference in its entirety. Such lyophilized formulations can be reconstituted to a high protein concentration with a suitable diluent, and the reconstituted formulation can be subcutaneously administered to the mammals to be treated herein.

[0188] In some embodiments, the antibody in the formulation is stable at -20°C for at least about 6 months, at least about 12 months, at least about 18 months, at least 2 years, at least 3 years, or at least 4 years. In some embodiments, the antibody in the formulation is stable at 2°C to 8°C for at least about 1, 2, 3, or 6 months. In some embodiments, after storage, the antibody retains at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the biological activity (e.g., binding to the target or therapeutic titer) it exhibited before storage (i.e., at the time of preparation of the pharmaceutical formulation).In some embodiments, stability is as follows:

[0189] In some embodiments, the antibody in the formulation is stable at 2°C to 8°C for at least about 1, 2, 3, 4, 5, or 6 months.

[0190] In some embodiments, the antibody formulation is stored at about 25°C or above for no more than 12 hours.

[0191] In some embodiments, the antibody formulation after storage does not have, compared to before storage, a) an increase in the acidic region greater than about 20% or 17.5%, as assessed by ion-exchange high-performance liquid chromatography (IE-HPLC); b) a decrease in the main peak greater than about 25%, 22%, or 20%, as assessed by IE-HPLC; and / or c) an increase in the basic region greater than 3% or 2%, as assessed by IE-HPLC. In some embodiments, the antibody preparation after storage does not exhibit, compared to before storage, a) an increase in the sum of high molecular weight forms (HWM) greater than about 0.2% or 0.1%, as assessed by size exclusion ultra-high performance liquid chromatography (SE-UHPLC); and / or b) a decrease in the main peak greater than 1%, 0.8%, 0.7%, or 0.6%, as assessed by SE-UHPLC. In some embodiments, the antibody preparation after storage does not exhibit, compared to before storage, a) an increase in the sum of low molecular weight forms (LWM) greater than about 3%, 2.7%, or 2.5%, as assessed by non-reducing capillary electrophoresis with sodium dodecyl sulfate (NR CE-SDS); and / or b) a decrease in the main peak greater than 3%, as assessed by NR CE-SDS. In some embodiments, the antibody preparation after storage does not exhibit, compared to before storage, any of the following: a) an increase in HC-M257 oxidation greater than 0.7% or 0.6%, as assessed by peptide mapping; b) an increase in HC-M433 oxidation greater than 0.1%, as assessed by peptide mapping; and / or c) an increase in HC-W107 oxidation greater than 0.1%, as assessed by peptide mapping. In some embodiments, the antibody preparation after storage does not exhibit a decrease in rHuPH20 activity greater than about 500 U / mL or 450 U / mL. In some embodiments, the antibody preparation after storage does not exhibit a decrease in titer greater than 0.25 e4 U / mg by CDC bioassay. In some embodiments, the antibody preparation is stored at about 2°C to about 8°C for at least about 1, 2, 3, or 6 months. In some embodiments, the antibody preparation is stored at about 25°C and 60% relative humidity for at least about 0.5, 1, 2, 3, or 6 months.

[0192] In some embodiments, the antibody formulation exhibits better stability in terms of size variants (such as HMWS by SE-UPLC and / or LMWS by NR CE-SES) compared to a reference antibody formulation (e.g., an IV antibody formulation) of the anti-CD20 antibody after exposure to stress conditions. In some embodiments, the reference antibody formulation comprises 30 mg / mL anti-CD20 antibody, 20 mM sodium acetate, 106 mM trehalose, 0.2 mg / mL PS20, and has a pH of 5.3. In some embodiments, the stress conditions comprise exposing the antibody formulation to about 40°C and 75% relative humidity for about 4 weeks.

[0193] In some embodiments, the antibody formulation does not exhibit a change in the main peak reduction greater than about 0.6% after exposure to stress conditions, as measured by SE-UHPLC. In some embodiments, the antibody formulation exhibits a comparable change in the percentage of the main peak (e.g., a decrease of about 0.6%) compared to a reference antibody formulation exposed to the same stress conditions after exposure to stress conditions, as measured by SE-UHPLC. In some embodiments, the antibody formulation does not exhibit a change in the percentage of high molecular weight species (HMWS) after exposure to stress conditions, as measured by SE-UHPLC. In some embodiments, the antibody formulation exhibits better stability than a reference antibody after exposure to similar stress conditions, characterized by a small change in the percentage of HMWS as measured by SE-UHPLC (no change for the antibody formulation, but an increase of 0.1% for the reference antibody formulation). In some embodiments, the antibody formulation does not exhibit a change in the percentage of low molecular weight species (LMWS) greater than 0.4% after exposure to stress conditions, as measured by SE-UHPLC. In some embodiments, the antibody formulation exhibits a comparable change in the percentage of low molecular weight species (LMWS) compared to a reference antibody formulation exposed to the same stress conditions after exposure to stress conditions (e.g., an increase of about 0.4%), as measured by SE-UHPLC. In some embodiments described on pages 31 / 58 of a specification (CN 121843712 A), the antibody formulation exhibits a comparable change (e.g., about 0.02%) in the daily percentage of the main peak after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions (determined by linear regression), as measured by SE-UHPLC. In some embodiments, the antibody formulation does not exhibit a change greater than 0.003% in the daily HMWS peak after exposure to stress conditions (determined by linear regression), as measured by SE-UHPLC.In some embodiments, the antibody formulation exhibits better stability after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions, characterized by a smaller daily percentage change in the HMWS peak as measured by SE-UHPLC (determined by linear regression) (0.003% daily change for the antibody formulation and 0.006% daily change for the reference antibody formulation). In some embodiments, the reference antibody formulation comprises 30 mg / mL anti-CD20 antibody, 20 mM sodium acetate, 106 mM trehalose, 0.2 mg / mL PS20, and has a pH of 5.3. In some embodiments, the stress conditions comprise exposing the antibody formulation to about 40°C and 75% relative humidity for about 4 weeks.

[0194] In some embodiments, the antibody formulation does not exhibit a change in the main peak reduction greater than about 2.5% (e.g., a reduction of about 2.1%) after exposure to stress conditions, as measured by non-reducing CE-SDS. In some embodiments, the antibody formulation exhibits better stability after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions, characterized by a small change in the percentage of the main peak as measured by non-reducing CE-SDS (a decrease of 2.1% for the antibody formulation and a decrease of 2.7% for the reference antibody formulation). In some embodiments, the antibody formulation does not have a change in the sum of peaks before the stress conditions greater than about 2.5% (e.g., 2.2%), as measured by non-reducing CE-SDS. In some embodiments, the antibody formulation exhibits better stability after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions, characterized by a small change in the percentage of the sum of peaks before the stress conditions as measured by non-reducing CE-SDS (an increase of 2.2% for the antibody formulation and an increase of 2.5% for the reference antibody formulation). In some embodiments, the antibody formulation does not have a change in the main peak greater than about -0.1% per day (determined by linear regression) after exposure to stress conditions, as measured by non-reducing CE-SDS. In some embodiments, the antibody formulation exhibits a comparable change in the daily percentage of the main peak after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions (determined by linear regression), as measured by non-reducing CE-SDS. In some embodiments, the antibody formulation does not exhibit a daily change in the sum of the pre-peak values ​​greater than 0.1% after exposure to stress conditions (determined by linear regression), as measured by non-reducing CE-SDS.In some embodiments, the antibody formulation exhibits a comparable change in the total daily percentage of peaks before exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions (determined by linear regression), as measured by non-reducing CE-SDS. In some embodiments, the antibody formulation exhibits a comparable electrophoretic pattern after exposure to stress conditions compared to a reference antibody formulation exposed to the same stress conditions, as measured by non-reducing CE-SDS. In some embodiments, the reference antibody formulation comprises 30 mg / mL anti-CD20 antibody, 20 mM sodium acetate, 106 mM trehalose, 0.2 mg / mL PS20, and has a pH of 5.3. In some embodiments, the stress conditions comprise exposing the antibody formulation to approximately 40°C and 75% relative humidity for approximately 4 weeks.

[0195] In some embodiments, the antibody formulation does not exhibit a change in the main peak greater than approximately 25% (e.g., a decrease of approximately 23%) after exposure to stress conditions, as measured by IE-HPLC. In some embodiments, the antibody formulation, after exposure to stress conditions, exhibits a comparable change in the percentage of the main peak compared to a reference antibody formulation exposed to the same stress conditions, as measured by IE-HPLC (a decrease of 22.9% for the antibody formulation and a decrease of 23.5% for the reference antibody formulation). In some embodiments, the antibody formulation does not exhibit a change in the acidic region greater than about 25% (e.g., an increase of about 22%) after exposure to stress conditions, as measured by IE-HPLC. In some embodiments, the antibody formulation, after exposure to stress conditions, exhibits a comparable change in the percentage of the acidic region compared to a reference antibody formulation exposed to the same stress conditions, as measured by IE-HPLC (an increase of 22.2% for the antibody formulation and an increase of 22.2% for the reference antibody formulation). In some embodiments, the antibody formulation does not exhibit a change in the main peak greater than about -1% (e.g., -0.8%) per day after exposure to stress conditions (determined by linear regression), as measured by IE-HPLC. In some embodiments, the antibody formulation, after exposure to stress conditions, exhibits a comparable change in the percentage of the main peak as measured by IE-HPLC (determined by linear regression) compared to a reference antibody formulation exposed to the same stress conditions (e.g., -0.8% vs. -0.8%). In some embodiments, the antibody formulation has a comparable chromatogram compared to a reference antibody formulation exposed to the same stress conditions.In some embodiments, the reference antibody formulation comprises 30 mg / mL anti-CD20 antibody, 20 mM sodium acetate, 106 mM trehalose, 0.2 mg / mL PS20, and has a pH of 5.3. In some embodiments, the stress conditions comprise exposing the antibody formulation to about 40°C and 75% relative humidity for about 4 weeks.

[0196] In some embodiments, the antibody formulation does not have a change in titer per CDC bioassay greater than about 0.2 x 10⁴ U / mg after exposure to stress conditions. In some embodiments, the antibody formulation has a comparable change in titer per CDC bioassay compared to a reference antibody formulation exposed to the same stress conditions after exposure to stress conditions.

[0197] In some embodiments, the antibody formulation has a shelf life of at least 12 months, 24 months, or 36 months.

[0198] Unit Dosage

[0199] In another aspect, this application provides a unit dosage form of an anti-CD20 antibody comprising a sealed vial containing a quantity of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the quantity is sufficient to deliver a dose of about 920 mg. In some embodiments, the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is contained in a liquid formulation at a concentration of about 30 to 50 mg / ml (e.g., 40 mg / ml). In some embodiments, the anti-CD20 antibody is contained in a liquid formulation at a concentration of about 40 mg / ml.

[0200] In some embodiments, the formulation further comprises a buffer, a stabilizer, and a surfactant, optionally wherein the formulation further comprises hyaluronidase.

[0201] In some embodiments, the buffer comprises sodium acetate, optionally wherein the formulation comprises about 15 to 25 mM (e.g., 20 mM) sodium acetate, which provides a pH of about 5 to 5.6 (e.g., pH 5.3).

[0202] In some embodiments, the stabilizer comprises trehalose and / or methionine, optionally wherein the formulation comprises a) about 200 mM to about 300 mM (e.g., about 240 mM) trehalose and / or b) about 8 to 12 mM methionine (e.g., 10 mM) methionine.

[0203] In some embodiments, the surfactant comprises polysorbate 20, and optionally wherein the formulation comprises about 0.04% to 0.08% (e.g., 0.06%) (w / v) polysorbate 20.

[0204] In some embodiments, the hyaluronidase comprises recombinant human hyaluronidase, optionally rHuPH20, and further optionally, the formulation comprises about 800 to 1200 U / ml (e.g., 1000 U / ml) of rHuPH20. In some embodiments, the formulation comprises about 23,000 units of hyaluronidase.

[0205] IV. Articles

[0206] The present invention further provides articles or kits (such as component kits) containing materials that can be used to treat multiple sclerosis (e.g., relapsing multiple sclerosis or primary progressive multiple sclerosis) as described herein. In some embodiments, the article comprises a pharmaceutical composition packaged together with a label indicating that the antiCD20 antibody or pharmaceutical composition is suitable for treating a patient with multiple sclerosis (e.g., RMS or PPMS) according to the methods described herein.

[0207] In some embodiments, the product or kit comprises a pharmaceutical composition and label packaged together, the pharmaceutical composition comprising an anti-CD20 antibody and a pharmaceutical carrier, the label indicating that the anti-CD20 antibody or pharmaceutical composition is suitable for treating patients with multiple sclerosis and inhibiting disability progression in patients with multiple sclerosis. In some embodiments, the product or kit comprises a pharmaceutical composition and label packaged together, the pharmaceutical composition comprising an anti-CD20 antibody and a pharmaceutical carrier, the label indicating that the anti-CD20 antibody or pharmaceutical composition is suitable for treating patients with multiple sclerosis (e.g., RMS or PPMS). In some embodiments, the label provides instructions for subcutaneously administering an effective amount of the anti-CD20 antibody to a patient at a dose of about 920 mg. In some embodiments, the label indicates that the anti-CD20 antibody is administered subcutaneously every 6 months for about 12, 18, or 24 months. In some embodiments, the label indicates that the anti-CD20 antibody is administered subcutaneously every 24 weeks for approximately 12, 18, or 24 months. In some embodiments, the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11.

[0208] In some embodiments, the article or kit includes a container and a label or packaging insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes (e.g., pre-filled syringes), etc. Containers can be formed from a variety of materials such as glass or plastic. Containers may contain or contain a composition effective for treating multiple sclerosis and may have a sterile inlet (e.g., the container may be an intravenous solution bag or vial with a stopper that can be punctured by a subcutaneous injection needle). At least one active agent in the composition is an antibody. In some embodiments, the container contains about 920 mg of anti-CD20 antibody.

[0209] In some embodiments, the article or kit includes a device suitable for subcutaneous administration of at least 20 mL (e.g., about 23 mL or about 24 mL), the device comprising a needle. In some embodiments, the article or kit includes a device suitable for subcutaneous administration of about 23 mL, the device comprising a needle. In some embodiments, the device is an on-body syringe. In some embodiments, the device includes an infusion pump. In some embodiments, the device includes a CRONO mobile infusion pump. In some embodiments, the device includes a Lapas patch pump. In some embodiments, the device includes an enFuse body platform. In some embodiments, the device includes a wearable syringe or wearable injection device. In some embodiments, the device includes a drug delivery system. See, for example, Badkar et al., Drug Des Devel Ther. January 13, 2021; 15:159-170.

[0210] The label or packaging insert indicates that the composition is intended for the treatment of multiple sclerosis in patients with multiple sclerosis, and provides specific instructions regarding the dosage and interval of the antibody and any other medications provided. The article may further include a second container containing a pharmaceutical dilution buffer, such as antibacterial water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextran solution. The article may further include other substances required from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0211] Optionally, the articles or kits provided herein further include a container (containing a pharmaceutical agent other than an antibody for treatment) and further include instructions for treating patients with such a pharmaceutical agent, which is preferably: a chemotherapeutic agent or immunosuppressant, an interferon (such as IFN-β-1a (REBIF® and AVONEX®) or IFN-β-1b (BETASERON®)); an oligopeptide, such as glatiramer acetate (COPAXONE®); a cytotoxic agent, such as mitoxantrone (NOVANTRONE®), methotrexate, cyclophosphamide, chlorambucil, or azathioprine; intravenous immunoglobulin (γ-globulin); a lymphocyte-depleting agent (e.g., mitoxantrone, cyclophosphamide, Camppath, anti-CD4, or cladribine); or a non-lymphocyte-depleting immunosuppressant (e.g., mycophenolate mofetil (MMF)). Or cyclosporine); statins; estradiol; hormone replacement therapy; medications for the treatment of symptoms secondary to or associated with MS (e.g., cramps, incontinence, pain, fatigue); TNF inhibitors; disease-modifying antirheumatic drugs (DMARDs); nonsteroidal anti-inflammatory drugs (NSAIDs); corticosteroids (e.g., methylprednisolone, prednisone, dexamethasone, or glucocorticoids); levothyroxine; cyclosporine A; somatostatin analogs; cytokines or cytokine receptor antagonists; antimetabolites; immunosuppressants; integrin antagonists or antibodies (e.g., LFA-1 antibodies, such as efalizumab or α4 integrin antibodies (such as natezumab)); and another B cell surface marker antibody, etc.

[0212] In some embodiments, the article comprises a single-use vial containing a quantity of anti-CD20 antibody suitable for subcutaneous administration to a patient, wherein the quantity is sufficient to deliver a dose of about 920 mg. In some embodiments, the anti-CD20 antibody comprises: a VH domain comprising the amino acid sequence shown in SEQ ID NO: 8; a VL domain comprising the amino acid sequence shown in SEQ ID NO: 7; and a human IgG1 constant region. In some embodiments, the anti-CD20 antibody is ozoleizumab.

[0213] Examples

[0214] The following examples are included for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0215] Example 1: Orelizumab SC drug product as a liquid formulation of ozretinoin for subcutaneous administration used in clinical trials (see Examples 2 and 3 below)

[0216] The drug product consisted of 40 mg / mL ozretinoin and 1000 U / mL rHuPH20 (standard formulation) in 20 mM sodium acetate, 240 mM trehalose, 10 mM L-methionine, and 0.06% (w / v) polysorbate 20 (HP grade for this study) at pH 5.3.

[0217] Part A. Robustness of the ozretinoin SC formulation

[0218] The purpose of this study was to determine the robustness of the ozretinoin subcutaneous (SC) drug product (DP) formulation (hereinafter referred to as ozretinoin SC).

[0219] Table 1 summarizes the formulation components to be studied, as well as their component ranges and the study ranges of each formulation parameter, as part of the robustness study of ozretrolizumab SC DP formulations. Four ozretrolizumab SC formulations were prepared for each of Table 2 in this study. These formulations were designed to assess the robustness of the DP formulations and characterize the stability of ozretrolizumab SC within the study ranges of parameters.

[0220] Table 1. Target and range of ozretrolizumab SC formulation components

[0221]

[0222] Table 2. Study design specification for determining the robustness of ozretrolizumab SC DP formulations 35 / 58 pages 39 CN 121843712 A

[0223]

[0224] Results

[0225] 1. Stability at 2°C to 8°C

[0226] The results of the study of the four DP formulations for up to six months under the recommended storage conditions (2°C to 8°C) are shown in Tables 3 and 4. Table 5 summarizes the degradation rates over a period of six months from 2°C to 8°C. Almost no differences were observed between F2 and F3 and the target formulations (F1 and F4) in any of the tested product quality attributes. The high molecular weight (HMW) form and main peak plots obtained by size exclusion ultra-high performance liquid chromatography (SE-UHPLC), the low molecular weight (LMW) form and main peak summation obtained by size exclusion ultra-high performance liquid chromatography (NR CE-SDS), the acidic region, basic region and main peak obtained by size exclusion ultra-high performance liquid chromatography (IE HPLC), PS20, and rHuPH20 activity were measured, and some data are summarized in Table 9.

[0227] The variation in formulation range resulted in a stability pattern similar to the target formulation, with stability data available up to 6 months from 2°C to 8°C (the study lasted up to 36 months).After being stored at 2°C to 8°C for 24 months, all formulations should meet end-of-life specifications.

[0228] Table 3 Stability data of robust ozolelizumab SC DP formulations (F1 and F2) stored at 2°C to 8°C

[0229]

[0230] Note: Values ​​are rounded; therefore, the total may not equal 100%. NT = Not tested. Instructions for Use, Pages 36 / 58, 40 CN 121843712 A

[0231] Table 3 Stability data of robust formulations of olarelizumab SC DP stored at 2°C to 8°C (F1 and F2) (continued)

[0232]

[0233] Table 4 Stability data of robust formulations of olarelizumab SC DP stored at 2°C to 8°C (F3 and F4)

[0234] Instructions for Use, Pages 37 / 58, 41 CN 121843712 A

[0235] Note: Values ​​are rounded; therefore, the total may not equal 100%.

[0236] Table 4 Stability data of ozretrimumab SC DP robust formulations (F3 and F4) stored at 2°C to 8°C (continued)

[0237]

[0238] Table 5 Degradation rate of ozretrimumab SC DP robust formulations at 2°C to 8°C

[0239]

[0240] a. Almost no change was observed at 2°C to 8°C.

[0241] 2. Stability at 25°C / 60% relative humidity (RH) 38 / 58 pages 42 CN 121843712 A

[0242] The results of the four DP formulations studied under accelerated storage conditions (25°C / 60% RH) for up to six months (final time point) are shown in Tables 6 and 7. Table 8 summarizes the degradation rate of ozretrimumab SC DP robust formulations at 25°C / 60% RH.

[0243] Changes in the quality of ourelizumab products were observed in all four formulations at 25°C for up to 6 months and are summarized in Table 9:

[0244] As expected, pH had the greatest impact on the stability of the ourelizumab SC drug product. As the formulation pH increased from 5.3 (F2) to 5.8 (F3):

[0245] The loss of rHuPH20 activity decreased.

[0246] The formation of acidic regions and the loss of the main peak increased.

[0247] Changes in acidic variants are associated with asparagine deamidation in both CDR (primarily at HC Asn104) and non-CDR (primarily at HC Asn330 and HC Asn389 / Asn394), where the amide functional group of the asparagine residue is hydrolyzed to form aspartic acid, isoaspartic acid, or the corresponding succinimide intermediate. The nature of the modification causes the deamidated variants to be classified into the IE-HPLC acidic region.

[0248] Changes in charge variants at the rHuPH20 activity and pH edge during the dispensing time (less than 8 days for pharmaceutical products) at 25°C are acceptable and produce sufficiently similar product quality (e.g., meeting end-of-shelf acceptance criteria and storage at 2°C to 8°C) (see degradation rates in Table 8).

[0249] The HMW form and main peak obtained by SE-UHPLC, the sum of the LMW form and main peak obtained by NR CE-SDS, the acidic region, basic region and main peak obtained by IE-HPLC, PS20, and rHuPH20 activity were measured, and some data are summarized in Table 9.

[0250] In all other product quality attributes, almost no differences were observed between F2 and F3 and the target formulations (F1 and F4).

[0251] Table 6 Stability data of robust formulations of ozretrimumab SC DP stored at 25℃ / 60% RH (F1 and F2) 39 / 58 pages, 43 CN 121843712 A

[0252]

[0253] Table 6 Stability data of robust formulations of ozretrimumab SC DP stored at 25℃ / 60% RH (F1 and F2) (continued) 40 / 58 pages, 44 CN 121843712 A

[0254]

[0255] Table 7 Stability data of robust formulations of ozretrimumab SC DP stored at 25℃ / 60% RH (F3 and F4) 41 / 58 pages, 45 CN 121843712 A

[0256] Table 7 Stability data of robust formulations of ozretrimumab SC DP stored at 25℃ / 60% RH Stability data of DP robust formulations (F3 and F4) (continued) Instructions for use 42 / 58 pages 46 CN 121843712 A

[0257]

[0258] Table 8 Degradation rate of ozretinoin SC DP robust formulations at 25°C

[0259]

[0260] a Almost no change was observed at 25°C / 60% RH.

[0261] Table 9 Summary of observed changes of olrelizumab SC drug product after 6 months at 25°C / 60% RH 43 / 58 pages 47 CN 121843712 A

[0262]

[0263] Conclusion

[0264] This report analyzes and summarizes data obtained from this study over a period of six months. This study demonstrates that the commercial olrelizumab SC drug product formulation is stable across the formulation range. Although changes were observed at 25°C, the observed degradation of the target formulation was similar to that between formulations F2 and F3 (i.e., making the product quality acceptable and meeting end-of-shelf specifications). Changes across the formulation robustness range produce similar product quality and meet end-of-shelf specifications, including permissible deviations; thus demonstrating the robustness of the formulation.

[0265] Part B. Comparability assessment of ozretrimumab SC 920 mg / 23 mL drug product (DP) and ozretrimumab IV 300 mg / 10 mL drug product

[0266] Materials and Methods

[0267] The Phase III formulation of ozretrimumab SC consisted of 40 mg / mL ozretrimumab at pH 5.3 in 20 mM sodium acetate, 240 mM trehalose, 0.6 mg / mL PS20, and 10 mM L-methionine, along with 1000 U / mL rHuPH20. The formulation of ozretrimumab IV DP consisted of 30 mg / mL ozretrimumab at pH 5.3 in 20 mM sodium acetate, 106 mM trehalose, and 0.2 mg / mL PS20. In this study, the two formulations were placed side by side at 40°C / 75% RH for stress comparability assessment.

[0268] The quality of the samples was determined by color, clarity / opalescence, pH, protein content, visible particles, visually invisible particles, size exclusion high performance liquid chromatography (SE-UPLC), ion exchange high performance liquid chromatography (IE-HPLC), non-reducing capillary electrophoresis sodium dodecyl sulfate (TAMRA NR CE-SDS), polysorbate 20 content and potency.

[0269] Results Description 44 / 58 pages 48 CN 121843712 A

[0270] The stability results after storage at 40°C / 75% relative humidity for 28 days (Table 10) show that:

[0271] After storage at 40°C / 75% relative humidity for 28 days, almost no changes were observed in the two different vial configurations in terms of pH, color / opalescent / clarity (COC), protein content, visible particles, polysorbate 20 content, and visually invisible particles.

[0272] As measured by SE-UHPLC, the molecular size distribution changed with increasing exposure at 40°C: In the main peak, a decrease of 0.6% was observed in the SC formulation and a decrease of 0.6% in the IV formulation between the T0 and T28D time points. For HMWS, no change was observed in the SC formulation and an increase of 0.1% was observed in the IV formulation between the T0 and T28D time points. For LMWS, an increase of 0.4% was observed in both the SC and IV formulations between the T0 and T28D time points. Similarity of change rates of the main peak determined by linear regression was observed, which was -0.02% per day for the SC formulation and -0.02% per day for the IV formulation. Change rate of the HMWS peak determined by linear regression was observed, which was 0.003% per day for the SC formulation and 0.006% per day for the IV formulation. Slightly preferred stability was observed for the SC formulation. The chromatograms of the two formulations showed similar peak shapes and rankings; no new peaks were observed. (Data not shown.)

[0273] As measured by non-reducing CE-SDS, the molecular size distribution changed with increasing exposure at 40°C: In the main peak, a 2.1% decrease was observed in the SC formulation and a 2.7% decrease in the IV formulation between time points T0 and T28D. For the sum before the peak, an increase of 2.2% was observed in the SC formulation and an increase of 2.5% in the IV formulation between time points T0 and T28D. The rate of change of the main peak determined by linear regression was observed to be -0.1% per day for the SC formulation and -0.1% per day for the IV formulation. The rate of change of the sum before the peak determined by linear regression was observed to be 0.1% per day for the SC formulation and 0.1% per day for the IV formulation. The electrophoretic chromatograms of the two formulations showed similar peak shapes and rankings; no new peaks were observed.

[0274] The distribution of charge variants, as measured by IE-HPLC, changed with increasing exposure at 40°C: In the main peak, a 22.9% decrease was observed in the SC formulation and a 23.5% decrease in the IV formulation between the T0 and T28D time points. In the acidic region, a 22.2% increase was observed in both the SC and IV formulations between the T0 and T28D time points. The rate of change of the main peak, determined by linear regression, was -0.8% per day for the SC formulation and -0.8% per day for the IV formulation.The rate of change in the acidic region determined by linear regression was observed to be 0.8% per day for the SC formulation and 0.8% per day for the IV formulation. Chromatograms of the two formulations showed similar peak shapes and ranking; no new peaks were observed.

[0275] From T0 to T28D, a potency decrease of 0.19 x 10⁴ U / mg was observed for the SC formulation and a decrease of 0.21 x 10⁴ U / mg was observed for the IV formulation.

[0276] The SC formulation appears to show slightly preferred stability in terms of size variants (e.g., HMWS obtained by SE-UPLC and LMWS obtained by NR CE-SDS). Overall, the degradation rates of ozretrimumab SC DP vials and ozretrimumab IV DP vials were very similar.

[0277] Table 10. Stability data of ozretrimumab IV and SC formulations at 40°C. Instructions for Use, Pages 45 / 58, 49, CN 121843712 A

[0278]

[0279] COC = Clarity, Opacity, Color; PS20 = Polysorbate 20; ELSD = Evaporative Light Scattering Detector; NT = Not Tested; PFFP = Almost Particle-Free; The nominal fill volume for IV DP is 10 mL, and for SC DP it is 23 mL.

[0280] Conclusion

[0281] The data provided indicate that ozretinoin SC and ozretinoin IV have comparable stability under stress conditions of 40°C / 75% relative humidity. Therefore, the shelf life of ozretinoin SC and ozretinoin IV should be comparable to each other.

[0282] Part C. Stability of the pharmaceutical product ozretinoin SC under long-term conditions.

[0283] This study provides representative stability data for the Phase III ozretinoin SC pharmaceutical product. Tables 11 and 12 contain information from batch X of the olizumab SC drug product. The drug product consists of 40 mg / mL olizumab (see product information page 46 / 58, CN 121843712 A) and 1000 U / mL rHuPH20 (standard formulation) in 20 mM sodium acetate, 240 mM trehalose, 10 mM L-methionine, and 0.06% (w / v) polysorbate 20 at pH 5.3. The drug product used in this study was configured as a nominal 10 mL vial filled with a 20 cc glass vial.

[0284] The ozretrimumab SC drug product was analyzed as follows: color, opalescence and clarity, pH, strength, weight osmotic concentration, visible particles, enhanced visual inspection, visually invisible particles, PS20 content, SE-HPLC / SE-UPLC, IE-HPLC, non-reducing CE-SDS (using TAMRA dye), reduced CE-SDS (using TAMRA dye), potency (CDC and ADCC activities), oxidation, methionine content, and rHuPH20 activity.

[0285] Conclusion: The ozretrimumab SC drug product exhibits acceptable stability over a period of 36 months at 2°C to 8°C. Therefore, for clinical use, the shelf life of the drug product is set at 36 months.

[0286] Table 11. Stability data of ozretrimumab SC drug product batch X under long-term conditions at 5°C

[0287]

[0288] This study provides representative stability data for the Phase III ozretrimumab SC drug product. Tables 11 and 12 contain information from batch X of the ozretrimumab SC drug product. The drug product consists of 40 mg / mL ozretrimumab and 1000 U / mL rHuPH20 (standard formulation) in 20 mM sodium acetate, 240 mM trehalose, 10 mM L-methionine, and 0.06% (w / v) polysorbate 20 at pH 5.3. The drug product used in this study was configured as nominal 10 mL filled into 20 cc

[0289] . The ozretrimumab SC drug product was analyzed as follows: color, opalescence and clarity, pH, strength, weight osmotic concentration, visible particles, enhanced visual inspection, visually invisible particles, PS20 content, SE-HPLC / SE-UPLC, IE-HPLC, non-reduced CE-SDS (using TAMRA dye), reduced CE-SDS (using TAMRA dye), potency (CDC and ADCC activities), oxidation, methionine content, and rHuPH20 activity.

[0290] Conclusion: The ozretrimumab SC drug product exhibits acceptable stability over a period of 36 months at 2°C to 8°C. Therefore, for clinical use, the shelf life of the drug product is set at 36 months.

[0291] Table 11. Stability data of ozretrimumab SC technical batch X under long-term conditions at 5°C (continued) Instructions for Use 47 / 58 pages 51 CN 121843712 A

[0292]

[0293] Table 12. Stability data of drug product technical batch X under accelerated conditions (25°C)

[0294]

[0295] Table 12. Stability data of drug product technical batch X under accelerated conditions (25°C) (continued)

[0296]

[0297] Example 2: Phase Ib study to investigate the pharmacokinetics, safety and tolerability of subcutaneous ozretrimumab administration in patients with multiple sclerosis

[0298] This study evaluated the pharmacokinetics, safety and tolerability, and immunogenicity of subcutaneous ozretrimumab administration to patients with MS. The specific objectives and corresponding endpoints of the study are outlined in the following sections. Instructions for Use, Pages 48 / 58, 52, CN 121843712 A

[0299] The primary pharmacokinetic (PK) objective of this study was to compare the PK characteristics of SC ozretrimumab and IV ozretrimumab based on the following endpoints: a) the serum concentration of ozretrimumab at a specified time point after a single SC administration, determined by the area under the concentration-time curve (AUC); b) the serum concentration of ozretrimumab at a specified time point after a single IV administration (i.e., AUC).

[0300] The safety objectives of this study were to assess and compare the safety and tolerability of SC ozrelizumab versus 600 mg IV ozrelizumab in patients with MS based on the following endpoints during the study duration: a) incidence and severity of adverse events, where severity was determined according to the National Cancer Institute CTCAE v5.0 guidelines for adverse events; b) changes in target vital signs relative to baseline; c) changes in ECG parameters relative to baseline; d) incidence and severity of clinical laboratory abnormalities; e) incidence of local pain and local injection site reaction (ISR) at the injection site, assessed using the Visual Analogue Scale (VAS) and the Local Injection Site Symptom Assessment (LISSA).

[0301] The immunogenicity objective of this study was to evaluate the formation of anti-drug antibody (ADA) in ozoglucilzumab administered via SC and IV, as well as the formation of ADA in rHuPH20, based on the following endpoints: a) the incidence of ADA present during treatment relative to baseline during the duration of the study; b) the relationship between ADA status and pharmacokinetics and safety.

[0302] Dose Escalation Phase

[0303] Group A (patients pretreated with ozretrimumab) involved non-randomized cohorts, e.g., cohorts A1 through A4. Cohort A1: 40 mg SC ozretrimumab; Cohort A2: 200 mg SC ozretrimumab; Cohort A3: 600 mg SC ozretrimumab; Cohort A4: 1200 mg SC ozretrimumab. In the non-randomized sub-phase, participants in cohort A5 received a single intraperitoneal injection of a co-mixture of ozretrimumab and rHuPH20. For cohort AA, participants received a single 600-mg dose of ozretrimumab via intravenous (IV) infusion.

[0304] Patients in Group B (participants who had not received prior ozretinoin treatment) received a single intraperitoneal injection of a mixture of ozretinoin and rHuPH20. Specifically, Cohort B1: 40 mg of ozretinoin. Cohort B2: 200 mg of ozretinoin. Cohort B3: 600 mg of ozretinoin. Cohort B4: 1200 mg of ozretinoin.

[0305] To reduce the IRR and the frequency and severity of systemic injection reactions or ISRs, patients were pre-medicated with corticosteroids and antihistamines prior to ozretinoin administration.

[0306] The emerging safety profile of injection reactions (primarily local and partially systemic) was characterized by mild to moderate severity and a decreasing incidence after the first injection. If a reaction occurs, it can be managed according to current guidelines for handling serious systemic injection reactions, including potential anaphylaxis / hypersensitivity reactions. In this study, the most common systemic injection reaction symptom was headache. The median and mean time to onset of systemic injection reaction symptoms after administration of ozretizumab SC were approximately 5 hours and 6 hours, respectively.

[0307] Given these data and to improve patient experience and limit on-site time, it is considered that a 1 to 2-hour wait is no longer necessary between administration of the oral pre-treatment and the ozretizumab SC injection. In some cases, the oral pre-treatment was administered shortly before initiating the ozretizumab SC injection.

[0308] Safety information from the study showed a decreasing incidence of local and systemic injection reactions after the first ozretizumab SC injection. All local reactions to date were CTCAE grade 1 to 2 and were not severe.Systemic injection reactions occurring less than 1 hour after the start of injection were mild to moderate in intensity, not serious, and resolved with standard treatment. No grade 3 systemic reactions were observed from the second injection onwards. Data from this study did not indicate a "window" of maximum risk following SC administration.

[0309] Based on the PK and safety data obtained in this study, a dose of 920 mg SC was selected for the study described in Example 3. In this study, doses of up to 1200 mg SC were administered, and these doses were safe and well-tolerated. The estimated bioavailability of SC was 72%. Rapid B-cell depletion was observed in patients who had not previously received ozoleizumab after 1200 mg SC, and maintenance of B-cell depletion was achieved throughout the six-month dosing interval in pre-treated patients. See, for example, Figure 5, which shows that treatment with OCR SC resulted in rapid and sustained B-cell depletion between doses in previously treated and untreated patients.

[0310] In cohort A (n=53 OCR SC; n=35 OCR IV) and cohort B (n=46) of OCR SC, the majority were female (72.7% / 63.0%); the mean age at baseline (standard deviation) was 45.7 (10.2) and 39.7 (9.2) years, respectively. OCR SC was well tolerated across all tested doses during the dose escalation phase. Initially, 1200 mg was selected as the candidate SC dose, but subsequently 920 mg was selected as the final SC dose based on all available data. The median duration of treatment with OCR SC 1200 mg or 920 mg was 96 weeks, with 94.7% receiving ≥3 doses. Injection site reactions were the most common adverse events, with erythema, pain, and swelling being the most common symptoms, all of which were mild / moderate.

[0311] A SC dose of 920 mg was chosen so that the ozretinoin exposure of patients after SC administration matched the exposure after an approved and marketed 600 mg IV dose. Because the variability after SC administration is greater than that after IV administration, a SC dose of 920 mg was chosen so that the 25th percentile of the exposure (AUCt) distribution matched the 25th percentile of the exposure distribution after IV 600 mg administration. This ensured that patients in the lower range of the exposure distribution had adequate exposure.

[0312] For IV administration, the initial 600 mg dose was divided into 2 x 300 mg doses.SC administration was not necessary because a single dose of up to 1200 mg was well tolerated in patients not receiving ozorlizumab. Therefore, all SC doses in the study described in Example 3 were administered as a single SC injection. SC is absorbed slowly after injection (based on currently available data (data not shown), Cmax between day 2 and day 10. Injection of the total dose of SC on day 1 helps achieve onset of action at a rate similar to that of an IV infusion, for which the total dose is systemically available by day 14.

[0313] Treatment Administration Satisfaction Questionnaire (TASQ) data indicate high satisfaction with OCR SC; most patients receiving OCR SC 1,200 mg or 920 mg reported satisfaction with SC administration. Specifically, most patients were satisfied or very satisfied with the SC procedure (n=92, 93.9%). Most patients found the SC procedure convenient or very convenient (n=86, 87.8%). Most patients felt the time taken to receive the injection was just right (n=92, 93.9%).

[0314] Example 3: III This phased study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, radiological and clinical effects of subcutaneous ozetilumab versus intravenous ozetilumab in patients with multiple sclerosis.

[0315] Objectives and Endpoints

[0316] This study evaluated the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiological and clinical effects of subcutaneous (SC) administration of ozetilumab compared to intravenous (IV) infusion in patients with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The specific objectives and corresponding endpoints of the study are as follows and are summarized below. Specifically, the primary endpoint was the non-inferiority of the area under the curve (AUC) of serum serum from day 1 to week 12 after subcutaneous injection compared to IV infusion. Secondary endpoints included the maximum serum concentration (Cmax) of ozetilumab, the total number of active gadolinium-enhancing T1 lesions at weeks 8 and 12, and the number of active gadolinium-enhancing T1 lesions at weeks 12 and 24. The total number of new or enlarged T2 lesions per week, as well as safety, immunogenicity, and biomarker results.Instructions for Use, Pages 50 / 58, CN 121843712 A

[0317] Primary Pharmacokinetic Objective

[0318] The primary PK objective of this study was to demonstrate the non-inferiority of the SC formulation of olarelizumab in patients with multiple sclerosis (MS) based on the following endpoint: the area under the serum olarelizumab concentration-time curve (AUCW1-12) after SC administration compared to IV infusion from day 1 to week 12.

[0319] Secondary Pharmacokinetic Objective

[0320] The secondary PK objective of this study was to determine the maximum serum concentration (Cmax) of olarelizumab SC in patients with MS.

[0321] Secondary Radiological Objectives

[0322] The secondary radiological objectives of this study were to evaluate the radiological efficacy of ozretrimumab SC compared to ozretrimumab IV in patients with MS based on the following endpoints:

[0323] 1. The total number of T1Gd+ lesions detected by brain MRI at weeks 8 and 24.

[0324] 2. The total number of new or enlarged T2 lesions detected by brain MRI at weeks 12 and 24, respectively (relative to previous scans).

[0325] Safety Objectives

[0326] The safety profile following administration of OCR SC versus OCR IV was assessed and compared, and the safety of the selected dose of OCR SC in patients with MS was determined based on the following endpoints during the study:

[0327] 1. The incidence and severity of adverse events, wherein severity was determined according to NCI CTCAE version 5.0.

[0328] 2. Changes in target vital signs relative to baseline.

[0329] 3. Changes in target clinical laboratory test results relative to baseline.

[0330] Immunogenicity Targets

[0331] The immune response to OCR SC and IV and rHuPH20 was assessed based on the following endpoints:

[0332] 1. The incidence and / or formation of ADA during treatment with OCR SC and OCR IV relative to baseline.

[0333] 2. The relationship between ADA status of OCR and PK, PD and safety.

[0334] 3. The incidence of antibodies during treatment with rHuPH20 after SC administration relative to baseline, and the relationship between rHuPH20 antibodies and safety.

[0335] Pharmacokinetic Targets

[0336] The effect of OCR SC on PD markers of the mechanism of action of OCR (i.e., B cell depletion) compared to OCR IV was evaluated based on the endpoint of the proportion of patients achieving CD19+ B cell levels ≤ 5 cells / µL at weeks 12, 24, 48 and / or 96.

[0337] Biomarker Targets

[0338] Biomarkers that predict response to OCR (i.e., predictive biomarkers), are early alternatives to efficacy, are associated with progression to a more severe disease state (i.e., prognostic biomarkers), provide evidence of OCR activity (i.e., PD markers), or can increase knowledge and understanding of the biology of the disease were evaluated based on the following endpoints: biomarkers (including, but not limited to, serum NfL) levels compared between dosing groups at weeks 12, 24, 48 and / or 96 compared to baseline.

[0339] Patient Population and Inclusion Criteria

[0340] Number of Patients: Approximately 232 patients with different types of MS (RMS and PPMS) were enrolled.

[0341] Inclusion Criteria: Instructions for Use, pages 51 / 58, CN 121843712 A

[0342] Diagnosis of PPMS or RMS was based on the revised McDonald 2017 criteria (Thompson et al. 2018).

[0343] Informed consent was obtained.

[0344] Age at the time of obtaining informed consent was 18 to 65 years (inclusive).

[0345] Patients were able to adhere to the study protocol and protocol evaluation plan at the investigator's discretion.

[0346] EDSS scores at screening were 0 to 6.5 (inclusive).

[0347] Neurological stability was ≥ 30 days prior to both screening and baseline.

[0348] For patients with an EDSS score < 2.0 at screening, the duration of disease from the onset of MS symptoms is less than 15 years.

[0349] For women of fertility: consent to abstinence (avoidance of heterosexual intercourse) or use of appropriate contraception during treatment cycles and for 6 to 12 months after the last dose of OCR (if applicable, according to the local label of OCR IV [Ocrevus®]. If more stringent, local requirements must be followed.

[0350] Women are considered fertile if they are postmenopausal and have not reached postmenopausal status (absence of menstruation for ≥ 12 consecutive months without other causes other than menopause), and are not permanently infertile due to surgery (i.e., removal of the ovaries, fallopian tubes, and / or uterus) or other causes determined by the investigator (e.g., Müller duct dysplasia).According to this definition, women who have undergone tubal ligation are considered fertile. The definition of fertility potential may be adapted to local guidelines or requirements.

[0351] As defined in the guidelines, the following methods of contraception are considered acceptable (failure rate > 1%): (1) progesterone-only contraception where the primary mode of action is not ovulation suppression; (2) male or female condoms with or without spermicide; (3) caps, septa, or sponges with spermicide; (4) combinations of male condoms with spermicide and caps, septa, or sponges (double-barrier method).

[0352] Highly effective contraceptive methods (failure rate < 1%) may also be used, but are not necessary, and include: (1) oral, intravaginal, or transdermal combination hormonal contraceptives associated with ovulation suppression; (2) oral, injectable, or implantable pure progesterone contraceptives associated with ovulation suppression; (3) intrauterine contraceptive devices; (4) intrauterine hormone-releasing systems; (5) bilateral tubal occlusion; (6) partner vasectomy; (7) sexual abstinence.

[0353] The reliability of sexual abstinence should be assessed based on the duration of the clinical trial and the patient’s preferred and habitual lifestyle. Regular abstinence (e.g., calendar, ovulation, symptom-temperature contraception, or post-ovulation methods) and withdrawal are unacceptable contraceptive methods. Locally recognized appropriate contraceptive methods and information on the reliability of abstinence should be stated in the local informed consent form if required by local guidelines or regulations.

[0354] For female patients who are infertile: If the female patient is postmenopausal (i.e., with follicle-stimulating hormone levels > 40 mIU / mL) Patients with confirmed spontaneous amenorrhea over the past year are eligible for enrollment unless they are currently receiving hormone therapy for their amenorrhea or undergoing aseptic surgery (i.e., hysterectomy, total bilateral oophorectomy).

[0355] Exclusion criteria:

[0356] Any known or suspected active infection (excluding nail bed infection) at screening or baseline, or any major infection requiring hospitalization or treatment with IV antibiotics within 8 weeks prior to screening and during screening, or any major infection requiring treatment with oral antibiotics within 2 weeks prior to screening and during screening.

[0357] History of confirmed or suspected PML.

[0358] History of cancer within 10 years prior to screening, including hematologic malignancies and solid tumors.

[0359] Basal cell carcinoma or squamous cell carcinoma of the skin that has been excised and is considered cured, and cervical carcinoma in situ with significant success in curative therapy within 1 year prior to screening.

[0360] Immunocompromised status is defined as one or more of the following: CD4 count < 250 / µL; absolute neutrophil count < 1.5 × 10³ / µL; serum IgG < 4.6 g / L.

[0361] Received a live attenuated vaccine within 6 weeks prior to randomization.

[0362] Influenza vaccination is permitted if an inactivated vaccine formulation is administered.

[0363] Contraindications to MRI (e.g., due to pacemakers, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entering the study, coronary artery stenting within 8 weeks prior to the scheduled MRI time) or gadolinium administration.

[0364] Contraindications to mandatory pre-treatment (i.e., corticosteroids and antihistamines), including angle-closure glaucoma due to antihistamines.

[0365] Other known neurological conditions that may interfere with the diagnosis or efficacy and / or safety assessment of MS during the study, including but not limited to: 1. A history of hemorrhagic or ischemic stroke of the brain or spinal cord. 2. A history of or known presence of CNS or spinal cord tumors (e.g., meningioma, glioma). 3. A history of or known presence of myelopathy with underlying metabolic causes (e.g., untreated vitamin B12 deficiency). 4. A history of or known presence of myelopathy with infectious causes (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy). 5. A history of genetically inherited progressive CNS degenerative disorders (e.g., hereditary paraplegia, mitochondrial myopathy, encephalopathy, lactic acidosis, stroke [MELAS] syndrome). 6. Neuromyelitis optica. 7. A history of or known presence of systemic autoimmune disorders that may lead to progressive neurological disease (e.g., lupus, antiphospholipid syndrome, Shugrange syndrome, Becette's disease). 8. A history of or known presence of sarcomatoid diseases. 9. A history of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression).

[0366] Any comorbidity that may require long-term treatment with systemic corticosteroids (e.g., mineralocorticoids and glucocorticoids) or immunosuppressants during the study period.

[0367] Significant, uncontrolled disease, such as cardiovascular (including arrhythmias), pulmonary (including obstructive pulmonary disease), kidney, liver, endocrine, or gastrointestinal disease, or any other significant disease that may prevent a patient from participating in the study.

[0368] A history of primary or secondary (non-drug-related) immunodeficiency or currently active immunodeficiency.

[0369] Pregnancy or breastfeeding, or planning to become pregnant, during the study period and 6 or 12 months after the last administration of the study drug (if applicable, according to the OCR [Ocrevus®] local label). Women of childbearing age must have negative serum and urine pregnancy test results (negative serum β-CG measured at screening and negative urine β-CG measured at baseline) before initiating administration of the study drug.

[0370] Lack of peripheral intravenous access.

[0371] History of alcohol or other drug abuse within 12 months prior to screening.

[0372] Treatment with any investigational agent or any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency) within 24 weeks prior to screening or 5 half-lives of the investigational drug (whichever is longer).

[0373] Patients who have previously received anti-CD20 (including OCR) treatment in the following circumstances: the last treatment was less than 2 years prior to screening, and / or the B-cell count was below the lower limit of normal and / or treatment was discontinued for safety reasons or lack of efficacy.

[0374] Prior treatment with cladribine, acecept, and alemtuzumab.

[0375] Prior treatment with fingolimod, sinimod, pernemod, or ozagimide within 6 weeks after baseline.

[0376] Prior treatment with interferon beta (1a or 1b) or glatiramer acetate within 2 weeks after baseline.

[0377] Prior treatment with nastatinumab within 4.5 months after baseline.

[0378] Treatment with mitoxantrone within 2 years prior to baseline visit, or evidence of cardiotoxicity following mitoxantrone use, see product information 53 / 58, page 57, CN 121843712 A, or a cumulative lifetime dose greater than 60 mg / m2. Prior treatment with any other immunomodulatory or immunosuppressive drug not listed above without proper washing as described on the applicable local label. If the washing requirement is not described on the applicable local label (washing must be completed before baseline), the washing period must be 5 times the half-life of the drug. The PD effect of the prior drug must also be considered when determining the expected time for washing. Patients selected for this study should not withdraw from treatment solely to meet eligibility requirements for the trial.

[0379] Any prior treatment concomitant with bone marrow transplantation or hematopoietic stem cell transplantation.

[0380] Any history of prior transplantation or anti-rejection treatment.

[0381] Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization.

[0382] Systemic corticosteroid therapy should be administered within 4 weeks prior to screening. For patients already using systemic corticosteroids for MS prior to screening, the screening period may be extended. Systemic corticosteroids should not be administered between screening and baseline to ensure patient eligibility.

[0383] For active, latent, or improperly treated hepatitis B, a positive screening test (as demonstrated by any of the following): 1. Positive hepatitis B surface antigen. 2. Positive hepatitis B core antibody (total HBcAb) and detectable hepatitis B virus DNA.

[0384] Sensitivity or intolerance to any component of the OCR (including excipients).

[0385] Any additional exclusion criteria according to the OCR (Ocrevus®) label (if more stringent than those above).

[0386] Pre-baseline retesting

[0387] In the rare cases where screening laboratory samples are rejected by the central laboratory (e.g., hemolyzed samples) or the results are unevaluable (e.g., indeterminate) or abnormal, retesting is required as soon as possible or within the permitted screening period. Any clinically relevant abnormal screening laboratory values ​​should be retested to exclude any progressive or uncontrolled underlying conditions. The last value before randomization must meet the study criteria.

[0388] Study design

[0389] Study drug: OCR comprises an IV formulation and an SC formulation co-formulated with rHuPH20.

[0390] Test product (study drug): OCR SC is provided as a sterile single-dose liquid formulation at a concentration of 40 mg / mL, which is preservative-free. The formulation described in Example 1 is used as the OCR SC in this example.

[0391] Comparative: OCR IV is provided as a sterile single-dose liquid formulation at a concentration of 30 mg / mL, which is preservative-free. The liquid solution also contains glacial acetic acid (0.25 mg / mL), polysorbate 20 (0.2 mg / mL), sodium acetate trihydrate (2.14 mg / mL), and trehalose dihydrate (40 mg / mL), with a pH of 5.3.

[0392] Non-investigation drugs

[0393] Specific pre-treatments required before ozoleizumab infusion or injection, including mandatory methylprednisolone or dexamethasone, mandatory diphenhydramine or desloratadine, and optional oral analgesics as needed.

[0394] Statistical methods

[0395] Preliminary analysis

[0396] The primary objective of this study was to confirm the non-inferiority of ozoleizumab SC compared to ozoleizumab IV based on the area under the serum ozoleizumab concentration-time curve (AUC) up to week 12 (AUCW1-12). The geometric mean ratio (GMR) of AUC SC versus AUC IV is given, along with a two-sided 90% confidence interval. Non-inferiority is confirmed if the lower end of the two-sided 90% CI of the GMR for AUC is >0.8. For SC administration versus IV, a non-inferiority limit of 0.8 corresponds to a maximum loss of 20% in AUC. All available results from PK samples obtained within the first 12 weeks are included in the PK analysis. The primary comparison between osrelizumab administered via SC and IV is based on AUCW1–12 (i.e., the period prior to the 3 months of the 6-month dosing interval following a single dose, as absorption is expected to be completed by week 12.

[0397] Treatment Phase

[0398] Patients are recruited globally.All patients received five OCR doses during the treatment phase (day 1, week 24, week 48, week 72, and week 96). See, for example, Figure 1. Eligible patients were randomly assigned to one of two treatment groups: OCR SC or OCR IV. Randomization was performed at a 1:1 ratio via an interactive voice or web-based response system (1xRS).

[0399] The first administration of the study drug should be performed within 24 hours of randomization (in exceptional circumstances, within 48 hours of randomization, provided that the investigator ensures that all inclusion and exclusion criteria are still met on the day of administration).

[0400] During the control period (i.e., up to the week 24 dose of OCR SC), the first dose of OCR SC was administered as a single SC injection at a dose of 920 mg. The first dose of OCR IV was administered as two 300 mg IV infusions at 2-week intervals. During the control period prior to administration of the second dose (e.g., MRI), all necessary assessments were performed to the best of our ability. For all patients, including those initially randomized to the OCR IV (OCR SC treatment cycle), subsequent doses of the study drug were administered via SC injection.

[0401] For patients randomized to the OCR IV group, there was at least 20 weeks between the last OCR IV infusion and the first OCR SC dose (i.e., between the IV infusion at week 2 / day 14 of the study and the first SC dose during week 24). There was at least 22 weeks between all SC doses.

[0402] To enable home administration at participating sites, starting with the third OCR dose (i.e., starting week 48), the OCR dose could be administered by a healthcare professional at the patient's home or another suitable location.

[0403] Two hundred and thirty-six patients across 37 sites were randomized to OCR SC (n=118) and IV (n=118). At baseline (BL), the mean (standard deviation [SD]) age was 39.9 (11.4) / 40.0 (11.9) years, the median weight was 75 kg / 72 kg, and 65.3% / 59.3% of patients in the SC and IV cohorts were female, respectively. The majority of participants had RMS (90.7%, 89.8%), and the remaining participants had PPMS (9.3%, 10.2%).In patients receiving OCR SC and IV, the mean (SD) duration since the onset of MS symptoms was 7.7 (8.3) and 6.8 (7.1) years, respectively, and the mean (SD) duration since the diagnosis of MS was 5.7 (6.8) and 4.8 (5.8) years, respectively. In BL, the mean (SD) number of Gd+ T1 lesions was 0.5 (1.7) in patients treated with OCR SC and 1.0 (2.5) in patients treated with OCR IV. BL data for patients enrolled in OCARINA II reflect the typical MS population currently eligible for OCR IV. The new administration route has the potential to deliver the clinical benefit of OCR while providing treatment flexibility and additional treatment options.

[0404] The Phase III OCARINA II trial, which evaluated OCREVUS® (ozolizumab) as twice-yearly 10-minute subcutaneous injections, achieved its primary and secondary endpoints (or targets). As measured by pharmacokinetics (blood levels), subcutaneous ozonalizumab was demonstrated to be non-inferior to intravenous (IV) administration of ozonalizumab over 12 weeks. Subcutaneous ozonalizumab was also comparable to IV in controlling MRI-recorded brain lesion activity over 12 weeks. Subcutaneous ozonalizumab resulted in rapid, complete, and sustained B-cell depletion, similar to IV administration. The safety profile of subcutaneous ozonalizumab was consistent with that of IV administration. No new safety signals were identified. No antidrug antibodies (ADAs) were observed during treatment. Secondary targets included Cmax, MRI lesions during control periods (e.g., 24 weeks prior to treatment), B-cell depletion, and immune responses to subcutaneous and IV formulations of ozonalizumab and rHuPH20.

[0405] The 10-minute injection of ozretrimumab is designed for administration without an IV infrastructure, thus facilitating its use in MS centers without an IV infrastructure or in centers with IV capacity limitations. It also retains the twice-yearly dosing regimen of ozretrimumab IV, which has demonstrated high durability and adherence since becoming a standard of care for MS treatment. This provides additional delivery options so that ozretrimumab administration can be tailored to the individual needs of patients and healthcare professionals.

[0406] The study combined ozretrimumab with Halozyme Therapeutics’ Enhanceze® drug delivery technology using a subcutaneous formulation.

[0407] Results:

[0408] A. Pharmacokinetics

[0409] As shown in Figures 2A-2B, the primary objective (pharmacokinetics) was achieved. Administration of OCR SC 920 mg and OCR IV 600 mg produced similar overall exposure to OCR during the 12 weeks prior to the OCARINA II study (primary endpoint).

[0410] B. Radiographic Targets (MRI)

[0411] As shown in Figures 3A-3C, secondary radiographic targets were achieved. Orelizumab (OCR) SC was similar to ozretrimumab IV in controlling MRI lesion activity in the brain during the control period. Of the 107 patients treated with ozretrimumab SC, 106 were relapse-free within the first 24 weeks. Of the 106 patients treated with ozretrimumab IV, 105 were relapse-free within the first 24 weeks. Overall: OCR SC 920 mg administration produced near-complete suppression of MRI lesion activity, and most patients remained relapse-free until week 24.

[0412] C. Pharmacodynamics

[0413] As shown in Figure 4, ozretrimumab SC produced rapid, complete, and sustained B-cell depletion. Baseline: Last assessment prior to first exposure.

[0414] D. Safety

[0415] The safety profile of ozretrimumab SC was similar to that of ozretrimumab IV. No new safety signals were identified from the known risks associated with ozretrimumab and the route of administration.

[0416] E. Immunogenicity

[0417] In patients who completed the 24-week control cycle, no ADA was observed during treatment in either treatment group (63 / 118 patients in both groups). No ozoleizumab antidrug antibody (ADA) was observed during treatment in either group (IV and SC). No antibodies against the anti-rHuPH20 antibody were observed during treatment in either group (IV and SC).

[0418] Summary and Conclusion

[0419] These data suggest that ozoleizumab SC delivers similar clinical benefits to ozoleizumab IV, while providing patients and healthcare providers with treatment flexibility and additional treatment options.

[0420] This study achieves its primary objective of demonstrating non-inferiority of ozoleizumab SC 920 mg to ozoleizumab IV 600 mg in AUCW1-12.

[0421] The selected dose of ozretrimumab SC 920 mg was well tolerated and achieved levels of B-cell depletion similar to those seen with ozretrimumab IV 600 mg, without the ADA observed with ozretrimumab treatment.

[0422] Similar to ozretrimumab IV 600 mg, administration of ozretrimumab SC 920 mg produced near-complete suppression of radiographic (MRI) and clinical (relapsed) disease activity, as measured up to week 24.

[0423] The safety profile of IR is consistent with the characteristics identified in OCARINA I and does not limit treatment. Specification page 56 / 58 60 CN 121843712 A

[0424] V. Serial List

[0425] Specification page 57 / 58 61 CN 121843712 A

[0426] Specification page 58 / 58 62 CN 121843712 A Figure 1 Specification Figure 1 / 8 page 63 CN 121843712 A Figure 2A Specification Figure 2 / 8 page 64 CN 121843712 A Figure 2B Specification Figure 3 / 8 page 65 CN 121843712 A Figure 3A Specification Figure 4 / 8 page 66 CN 121843712 A Figure 3B Specification Figure 5 / 8 page 67 CN 121843712 A Figure 3C Specification Figure 6 / 8 page 68 CN 121843712 A Figure 4 Specification Figure 7 / 8 page 69 CN 121843712 A Figure 5 Instruction Manual Appendix 8 / 8 Page 70 CN 121843712 A.

Claims

1. A method of treating a patient with multiple sclerosis, the method comprising subcutaneously administering an anti-CD20 antibody to the patient at a dose of about 920 mg, wherein the anti-CD20 antibody comprises: V H A structural domain containing the amino acid sequence shown in SEQ ID NO: 8; V L The structural domain contains the amino acid sequence shown in SEQ ID NO: 7; and the human IgG1 constant region.

2. The method of claim 1, wherein the patient has not previously received an intravenous administration of the anti-CD20 antibody at a dose of about 600 mg.

3. The method of claim 1 or claim 2, wherein the patient has not previously received intravenous administration of the anti-CD20 antibody.

4. The method according to any one of claims 1 to 3, wherein the patient has not previously received subcutaneous administration of the anti-CD20 antibody at a dose of less than about 900 mg.

5. The method of claim 1, wherein the patient has received prior treatment with an anti-CD20 antibody, optionally wherein the prior treatment includes intravenous administration of the anti-CD20 antibody, optionally wherein the prior treatment includes intravenous administration of the anti-CD20 antibody at a dose of about 300 mg or about 600 mg.

6. The method according to any one of claims 1 to 5, wherein the method comprises subcutaneously administering more than one dose of the anti-CD20 antibody, wherein each dose comprises about 920 mg of the anti-CD20 antibody.

7. The method of claim 6, wherein the method comprises administering at least two, three, or four doses of the antibody against CD20.

8. The method according to any one of claims 1 to 7, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 24 weeks or about once every 24 weeks.

9. The method according to any one of claims 1 to 7, wherein the anti-CD20 antibody is administered at a frequency not exceeding once every 6 months or about once every 6 months.

10. The method according to any one of claims 1 to 9, wherein the anti-CD20 antibody is the only drug administered to the patient for the treatment of multiple sclerosis.

11. The method according to any one of claims 1 to 10, wherein the anti-CD20 antibody is in a pharmaceutical formulation, wherein the pharmaceutical formulation comprises: a. Approximately 40 mg / ml anti-CD20 antibody; b. Approximately 20 mM sodium acetate, which provides a pH of approximately 5.3; c. Approximately 240 mM trehalose; d. Approximately 10 mM methionine; e. Approximately 0.06% (w / v) of polysorbate 20; and f. Approximately 1000 U / ml hyaluronidase.

12. The method according to any one of claims 1 to 11, wherein the patient has received oral dexamethasone and an antihistamine shortly before the subcutaneous administration of the antiCD20 antibody, optionally, the oral dexamethasone and antihistamine are administered within 30 minutes, 20 minutes, or 15 minutes before the subcutaneous administration.

13. The method according to any one of claims 1 to 12, wherein the anti-CD20 antibody comprises: a light chain comprising the amino acid sequence of SEQ ID NO: 9; and a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 or 11.

14. The method according to any one of claims 1 to 13, wherein the anti-CD20 antibody is ozoleizumab.

15. The method according to any one of claims 1 to 14, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS).

16. The method of claim 15, wherein the patient has clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), or active secondary progressive multiple sclerosis (SPMS).

17. The method according to any one of claims 1 to 14, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS).

18. The method according to any one of claims 1 to 17, wherein the treatment achieves at least one of the following: a) Results measured by pharmacokinetics (levels in blood, e.g., area under the curve (AUC)) over 12 weeks, showing no inferiority to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); b) Magnetic resonance imaging (MRI) findings of lesion activity in the brain of the patient within 12 weeks equivalent to intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg); and c) A safety profile consistent with that of intravenous infusion of the anti-CD20 antibody (e.g., at a dose of 600 mg).

19. The method according to any one of claims 1 to 18, wherein the anti-CD20 antibody is contained in a liquid formulation and the subcutaneous administration takes no more than about 10 minutes.

20. A liquid formulation comprising: a. Approximately 35 to approximately 45 mg / mL (e.g., 40 mg / mL) of anti-CD20 antibody; b. Approximately 20 mM sodium acetate, which provides a pH of approximately 5.0 to approximately 5.6 (e.g., pH 5.3). c. Trehalose, approximately 190 to approximately 290 mM (e.g., 240 mM); d. Approximately 5 to approximately 15 mM (e.g., 10 mM) of methionine; e. about 0.04% to 0.08% (w / v) (e.g., 0.06% (w / v)) of polysorbate 20; and f. Approximately 1000 U / ml hyaluronidase The anti-CD20 antibody comprises: V H A structural domain containing the amino acid sequence shown in SEQ ID NO: 8; V L The structural domain contains the amino acid sequence shown in SEQ ID NO: 7; and the human IgG1 constant region.

21. The liquid formulation according to claim 20, wherein the anti-CD20 antibody is olizumab.

22. The liquid formulation of claim 20 or claim 21, wherein the formulation is for subcutaneous administration.

23. A unit dosage form of an anti-CD20 antibody, said unit dosage form comprising a sealed vial containing a measured amount of anti-CD20 antibody suitable for subcutaneous administration to a patient, said amount being sufficient to deliver a dose of approximately 920 mg, said anti-CD20 antibody comprising: V H A structural domain containing the amino acid sequence shown in SEQ ID NO: 8; V L The structural domain contains the amino acid sequence shown in SEQ ID NO: 7; and the human IgG1 constant region.

24. The unit dosage form according to claim 23, wherein the anti-CD20 antibody is contained in the liquid formulation at a concentration of about 40 mg / ml.

25. The unit dosage form according to claim 23 or claim 24, wherein the formulation further comprises a buffer, a stabilizer and a surfactant, and optionally, wherein the formulation further comprises hyaluronidase.

26. The unit dosage form of claim 25, wherein the buffer comprises sodium acetate, and optionally, wherein the formulation comprises about 20 mM sodium acetate providing a pH of about 5.

3.

27. The unit dosage form according to claim 25 or 26, wherein the stabilizer comprises trehalose and / or methionine, optionally, wherein the formulation comprises a) about 240 mM trehalose and b) about 10 mM methionine.

28. The unit dosage form according to any one of claims 25 to 27, wherein the surfactant comprises polysorbate 20, and optionally, wherein the formulation comprises about 0.06% (w / v) polysorbate 20.

29. The unit dosage form according to any one of claims 25 to 28, wherein the hyaluronidase comprises recombinant human hyaluronidase, optionally, the recombinant human hyaluronidase is rHuPH20, and further optionally, the formulation comprises about 1000 U / ml hyaluronidase.

30. An article comprising a single fixed dose of anti-CD20 antibody, said anti-CD20 antibody comprising: V H A structural domain containing the amino acid sequence shown in SEQ ID NO: 8; V L The domain contains the amino acid sequence shown in SEQ ID NO: 7; and the human IgG1 constant region, wherein the fixed dose is about 920 mg.

31. The article of claim 30, comprising a single-use vial.

32. The article of claim 30 or 31, comprising a syringe or a device comprising a needle, optionally wherein said device is a body device.

33. The article of any one of claims 30 to 32, wherein the anti-CD20 antibody is ozoleizumab.

34. The article of manufacture according to any one of claims 30 to 33, further comprising a packaging insert instructing a user to subcutaneously administer the fixed dose of the anti-CD20 antibody to a patient suffering from multiple sclerosis, optionally wherein the user is the patient.

35. A single-use vial containing a measured amount of anti-CD20 antibody suitable for subcutaneous administration to a patient, said amount being sufficient to deliver a dose of about 920 mg, said anti-CD20 antibody comprising: V H A structural domain containing the amino acid sequence shown in SEQ ID NO: 8; V L The structural domain contains the amino acid sequence shown in SEQ ID NO: 7; and the human IgG1 constant region.

36. The single-use vial according to claim 35, wherein the anti-CD20 antibody is ozoleizumab.

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