Anti-CD38 antibodies for the treatment of autoimmune diseases

Abstract

Methods for treating patients with autoimmune diseases, such as myasthenia gravis (MG), by administering an isolated anti-CD38 antibody are disclosed. Also disclosed are unit dosage forms of anti-CD38 antibodies for use in treating patients with autoimmune diseases, such as myasthenia gravis (MG).

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63 / 478,884, filed January 6, 2023, and U.S. Provisional Application No. 63 / 515,285, filed July 24, 2023, the entire disclosures of which are incorporated herein by reference.

[0002] Incorporation by Reference of Electronically Submitted Materials This application contains a Sequence Listing that has been submitted electronically in XML file format, which is incorporated by reference in its entirety. The XML file was created on December 12, 2023, is named 101588-5017-WO Sequence Listing.xml, and is 16,384 bytes in size.

[0003] Field Methods for treating patients with autoimmune diseases, such as myasthenia gravis (MG), by administering an isolated anti-CD38 antibody are disclosed. Also disclosed are unit dosage forms of anti-CD38 antibodies for use in treating patients with autoimmune diseases, such as myasthenia gravis (MG). [Background technology]

[0004] Myasthenia gravis (MG) is a rare autoimmune disease in which autoantibodies target the neuromuscular junction (NMJ) and postsynaptic membrane, disrupting neuromuscular transmission and causing progressive skeletal muscle weakness. The prevalence of MG in the United States is approximately 77.7 cases per million, or 14–40 cases per 100,000 (Breiner et al. (2016) Neuromuscul. Disord. 26(1):41–6; Carr et al. (2010) BMC Neurol. 10:46; Heldal et al. (2012) Muscle Nerve 45(6):815–819; Santos et al. (2016) Muscle Nerve 54(3):413–21).

[0005] MG is characterized by skeletal muscle weakness and fatigue that worsens with physical activity and improves with rest (Ludwig et al. (2017) Front. Immunol. 8:603). In some cases, muscle weakness leads to respiratory and cardiac dysfunction (Phillips and Vincent (2016) F1000 Res. 5:F1000 Faculty Rev-1513). The disease can become life-threatening, with myasthenic crisis occurring when the muscles that control breathing become too weak, which can lead to death from respiratory failure.

[0006] MG is caused by pathogenic autoantibodies produced by plasma cells. Most MG patients (70%) produce immunoglobulin (Ig) G1 and IgG3 autoantibodies against the acetylcholine receptor (AChR), whereas the remaining patients produce IgG4 autoantibodies against muscle-specific tyrosine kinase (MuSK) (1–10% of MG patients), IgG1–3 antibodies against low-density lipoprotein receptor-related protein 4 (1–5% of MG patients), or no detectable autoantibodies (10% of MG patients). Binding of autoantibodies to proteins within the NMJ ultimately leads to damage of the postsynaptic membrane (Ludwig et al. (2017) Front. Immunol. 8:603).

[0007] Reducing the levels of pathogenic autoantibodies is difficult: autoantibody-producing plasma cells are not actively cycling and express relatively few surface antigens, making them resistant to many conventional pharmacological strategies.

[0008] The current standard of care for MG consists of a combination of symptomatic treatment (acetylcholinesterase inhibitors, which increase intrasynaptic acetylcholine levels) and immunosuppression. Immunosuppressive or immunomodulatory therapies (e.g., corticosteroids, azathioprine, methotrexate, cyclosporine, tacrolimus, cyclophosphamide, plasma exchange, and intravenous immunoglobulin [IVIg]) are administered to patients for whom symptomatic treatment alone does not produce satisfactory results. Nevertheless, approximately 10% of patients suffer from treatment-resistant disease, and up to 80% fail to achieve complete, stable remission (Mantegazza and Antozzi (2018) Ther. Adv. Neurol. Disord. 11:1756285617749134; Silvestri and Wolfe (2014) J. Clin. Neuromuscul. Dis. 15(4):167-178). Immunosuppressive drug therapy has several drawbacks, including limited efficacy and severe dose-limiting toxicities. Furthermore, these drugs do not directly affect the production of autoantibodies.

[0009] Targeting B-cell precursors of plasma cells can reduce autoantibody levels. Rituximab (an anti-CD20 antibody) targets these plasma cell precursors, thereby indirectly reducing autoantibody production by preventing the recruitment of autoreactive plasma cells. However, the efficacy of rituximab in MG is limited, possibly because the long-lived plasma cells thought to be primarily responsible for the production of anti-AChR antibodies do not express CD20 and are therefore not targeted by rituximab (Ludwig et al. (2017) Front. Immunol. 8:603).

[0010] Several therapeutic options are available to reduce autoantibody levels by increasing clearance of pathogenic autoantibodies (e.g., plasma exchange, administration of intravenous infusion (IVIg), or neonatal Fc receptor (FcRn) antagonists). Plasma exchange and IVIg are effective but short-lived, so they are mostly used (until other drug therapies become effective, before surgery, or in cases of myasthenic crisis). An alternative approach to enhance autoantibody clearance can be achieved by inhibiting FcRn. Several FcRn antagonists are currently in clinical development, and one therapy has recently been approved (Heo (2022) Drugs 82(3):341-348). These drugs reduce pathogenic IgG by inhibiting FcRn-mediated IgG recycling and thereby promoting clearance. However, these three treatments do not directly eliminate the source of pathogenic autoantibodies. Furthermore, the duration of efficacy is relatively short, as shown in preliminary published data (Heo (2022) Drugs 82 (3): 341-348). As a result, chronic administration is required to maintain low levels of pathogenic autoantibodies (Kiessling et al. (2017) Sci. Transl. Med. 9 (414): eaan1208).

[0011] Another therapeutic approach for MG that does not address the underlying cause is to reduce complement-mediated postsynaptic membrane damage at the NMJ. This can be achieved with eculizumab, a monoclonal antibody that targets the complement protein C5. Although it has shown moderate efficacy, eculizumab therapy is associated with an increased risk of meningococcal infection, thereby limiting risk assessment and mitigation strategies (Howard et al. (2017) Lancet. Neurol. 16(12):976-986). Other complement inhibitors are under development, but these drugs are expected to be effective only in AChR-positive patients. This is because AChR autoantibodies effectively activate complement, leading to postsynaptic membrane lysis, whereas MuSK autoantibodies do not bind complement (Yi et al. (2018) Muscle Nerve 57(2),172-84).

[0012] Therefore, novel therapies for treating MG that address the underlying cause of disease pathogenesis and result in more durable responses with a favorable safety profile are needed; such therapies may have the potential to reduce corticosteroid use and improve patients' quality of life. As described, available conventional pharmacological therapies do not target autoantibody-producing plasma cells, particularly long-lived plasma cells, which are the source of pathogenic autoantibodies in MG.

[0013] overview Provided herein are methods and unit dosage forms containing an anti-CD38 antibody or antigen-binding fragment thereof for use in treating patients with autoimmune diseases, such as myasthenia gravis (MG). AB79 (a component of the active pharmaceutical ingredient of mezagitamab) is a fully human recombinant monoclonal antibody (mAb) targeting CD38, an antigen highly expressed on plasma cells, plasmablasts, and natural killer (NK) cells and induced in activated T and B cells. AB79 specifically binds to CD38 with high affinity (Kd = 3.5 nM) (U.S. Patent No. 8,362,211, the contents of which are incorporated herein by reference in their entirety). Administration of AB79 results in the depletion of cells expressing high levels of CD38 through mechanisms involving apoptosis, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity (Smithson et al. (2017) J. Immunol. 198(1 Supplement):224.20). AB79 depletes cells that produce pathogenic autoantibodies (plasmablasts, plasma cells, particularly long-lived plasma cells). Reduction of plasmablasts and long-lived plasma cells by mezagitamab is expected to result in reduced levels of pathogenic autoantibodies, thereby ameliorating autoantibody-mediated pathology in MG, such as reducing NMJ damage and improving reversible neuromuscular disorders in these patients.

[0014] An object of the present invention is to provide a method for treating patients with autoimmune diseases, such as MG, by subcutaneous administration of mezagitamab.

[0015] In one aspect, the disclosure provides a method of treating myasthenia gravis in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0016] In a second aspect, the present disclosure provides a method for reducing levels of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0017] In a third aspect, the present disclosure provides a method of reducing levels of immunoglobulin(s) cells in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0018] In a fourth aspect, the present disclosure provides a method of reducing disease activity and / or progression of myasthenia gravis in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0019] In a fifth aspect, the present disclosure provides a unit dosage form comprising an isolated antibody or antigen-binding fragment thereof comprising a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the isolated antibody or antigen-binding fragment thereof at a dose of 100 milligrams to 800 milligrams in the treatment of myasthenia gravis.

[0020] The objects and features of the present invention will be better understood with reference to the following drawings. [Brief explanation of the drawings]

[0021] [Figure 1] An overview of patient accrual status in the safety analysis set is shown below. AE: adverse event; SAE: serious adverse event; W: week. *AEs that had not resolved as of week 16 and related AEs / SAEs that occurred after SFP were collected by LFP. [Figure 2] The mean observed change from baseline over time in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score is shown. Any assessments obtained after receiving rescue therapy or after early discontinuation of study medication are excluded from the descriptive statistics. Baseline represents a 2-point decrease in the MG-ADL total score from baseline. [Figure 3] The mean observed change from baseline in the Quantitative Myasthenia Gravis (QMG) total score over time is shown. Any assessments obtained after receiving rescue therapy or after early discontinuation of study medication are excluded from the descriptive statistics. Baseline represents a 3-point decrease in the QMG total score from baseline. [Figure 4]The mean observed change from baseline in the Quantitative Myasthenia Gravis Composite (MCG) total score over time is shown. Any assessments obtained after receiving rescue therapy or after early discontinuation of study medication are excluded from the descriptive statistics. Baseline represents a 3-point decrease in the MCG total score from baseline. [Figure 5] The mean observed change from baseline over time in the revised 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL15r) total score is shown. Any assessments obtained after receiving rescue therapy or prematurely discontinuing study medication are excluded from the descriptive statistics. [Figure 6] The proportion of subjects achieving a reduction of at least 2 points from baseline in the MG-ADL total score by week 16 (full analysis population). CI: confidence interval; MG-ADL: activities of daily living in myasthenia gravis; TAK-079: mezagitamab. Error bars represent the lower and upper limits of the 95% CI of the proportions. [Figure 7] The percentage of responders (subjects with a clinically meaningful reduction of 2 or more points from baseline in MG-ADL score) in the mezagitamab 300 mg group, the mezagitamab 600 mg group, and the placebo group is shown. Responders: The percentage of responders who achieved a reduction of at least 2 points from baseline in the MG-ADL total score. If a subject receives rescue therapy or prematurely discontinues study drug, the subject is subsequently considered a non-responder. MG-ADL: Activities of daily living in myasthenia gravis. TAK-079: Mezagitamab. [Figure 8] The proportion of subjects with at least a 3-point reduction in QMG total score from baseline to week 16 is shown (full analysis population). CI: confidence interval; QMG: quantitative myasthenia gravis; TAK-079: mezagitamab. Error bars are the lower and upper limits of the 95% CI of the proportions. [Figure 9]Figure 1 shows an ad hoc sensitivity analysis of the proportion of responders (subjects who demonstrated a clinically meaningful decrease from baseline in MG-ADL of ≥ 2 points and QMG score of ≥ 3 points) in the mezagitamab 300 mg group, mezagitamab 600 mg group, and placebo group. Responders: The proportion of responders who demonstrated a decrease from baseline in QMG of at least 3 points and a decrease in MG-ADL total score of at least 2 points. If a subject received rescue therapy or prematurely discontinued study medication, the subject was subsequently considered a non-responder. MG-ADL: Activities of daily living in myasthenia gravis. QMG: quantitative myasthenia gravis; TAK-079: mezagitamab. *Statistically significant difference from placebo. [Figure 10] The proportion of subjects achieving a reduction of at least 3 points in MGC total score from baseline to week 16 is shown (full analysis population). CI: confidence interval; MGC: myasthenia gravis composite; TAK-079: mezagitamab. Error bars are the lower and upper limits of the 95% CI of the proportions. [Figure 11] Figure 1 shows a mixed-model repeated-measures (MMRM) analysis of the percentage change from baseline in anti-AChR levels (nmol / L) over time. SEM: standard error of the mean; TAK-079: mezagitamab. Percent change from baseline was obtained from a mixed-effects model for repeated measures (MMRM) analysis at all post-baseline visits, adjusting for the percentage change from baseline for outcome, treatment group, visit, and treatment by visit interaction as factors, as well as the baseline value and baseline by visit interaction. An unstructured covariance matrix was used in the model. Any assessments obtained after receiving rescue therapy or prematurely discontinuing study drug were excluded from the MMRM analysis. Subjects 47503-512 in the TAK-079 (mezagitamab) 600 mg group on study Day 22 (Week 4) and Day 29 (Week 5) had percentage change values ​​≥ 1707 and were excluded from the calculation of the mixed-effects model estimates in this figure. [Figure 12] Figure 1 shows the observed anti-MuSK titer values ​​over individual time points in two subjects in the mezagitamab 300 mg group. MuSK: muscle-specific tyrosine kinase. The Week 1 visit refers to baseline. Titer values ​​are reported as the reciprocal of the observed titer. [Figure 13] The mean observed change from baseline in the Myasthenia Gravis Disability Index (MGII) total score over time is shown. Any assessments obtained after receiving rescue therapy or after early discontinuation of study medication are excluded from the descriptive statistics. Baseline represents an 8-point decrease from baseline in the MGII total score. [Figure 14] 1 shows a log-linear plot of mean / SD serum concentrations of mezagitamab versus time after multiple SC injections of 300 mg and 600 mg mezagitamab. [Figure 15] The percentage change in IgG from baseline over time is shown (pharmacodynamic analysis population). [Figure 16] The mean change from baseline observed over time in the MG-ADL total score is shown by domain. MG-ADL: Activities of daily living in myasthenia gravis; SEM: Standard error of the mean; TAK-079: Mezagitamab. [Figure 17] The mean change observed over time in QMG total score from baseline is shown by region. QMG: quantitative myasthenia gravis; SEM: standard error of the mean; TAK-079: mezagitamab. [Figure 18] Figure 1 shows the observed mean change from baseline over time in MG-ADL total score with the use of acetylcholinesterase inhibitors. AchE-i: acetylcholinesterase inhibitors; MG-ADL: activities of daily living in myasthenia gravis; SEM: standard error of the mean; TAK-079: mezagitamab. [Figure 19] Figure 1 shows the observed mean change from baseline in QMG total score over time with the use of acetylcholinesterase inhibitors. AchE-i: acetylcholinesterase inhibitors; QMG: quantitative myasthenia gravis; SEM: standard error of the mean; TAK-079: mezagitamab. [Figure 20] Pharmacodynamic effects: A moderate decrease in total IgG and a corresponding reduction in anti-AChR antibodies are shown. A shows the change from baseline in IgG levels. B shows the change from baseline in anti-AChR antibody levels. [Figure 21A]After 8 weeks of treatment, depletion of IgA and IgM is shown by week 32. IgA is shown. [Figure 21B] After 8 weeks of treatment, depletion of IgA and IgM is shown by week 32. IgM is shown. [Figure 22] PD response of mezagitamab compared to efgartigimod. [Figure 23-1] The 300 mg dose group demonstrates high consistency between QMG response and IgG depletion, but the placebo group demonstrates inconsistency. The dashed red line indicates a 3-point reduction in QMG score. [Figure 23-2] The 300 mg dose group demonstrates high consistency between QMG response and IgG depletion, but the placebo group demonstrates inconsistency. The dashed red line indicates a 3-point reduction in QMG score. [Figure 24] At 300 mg, there is a high consistency between QMG / ADL response and IgG reduction. The dashed red line indicates a 3-point reduction in QMG score. [Figure 25] Change from baseline in anti-MuSK antibody levels (secondary endpoint) is shown. [Figure 26] The MGII and MGQOL15-R show that the placebo response was less pronounced (based on investigator's treatment / no intervention patient assessment). [Figure 27-1] Individual MG-ADL and QMG responses at 16 weeks are shown. [Figure 27-2] Individual MG-ADL and QMG responses at 16 weeks are shown. [Figure 28] Figure 1 shows the placebo response of mezagitamab compared to the comparative study MG-ADL. [Figure 29] Mezagitamab compared with comparative study QMG is shown. [Figure 30] Figure 1 shows the placebo response of mezagitamab compared to the comparative study QMG. [Figure 31] The PK profile is consistent with MM, demonstrating mezagitamab exposure within the expected range. [Figure 32] 1 shows mezagitamab exposure parameters for responders and non-responders. [Figure 33] Exposure-response assessment of IgG (best % reduction in IgG) across MM and MG studies is shown. [Figure 34] Exposure-response assessment of MG-ADL is shown. The dashed orange line represents the clinically meaningful threshold of a 2-point reduction in MG-ADL. [Figure 35] Background therapy is indicated. [Figure 36] Mixed-model repeated measures analysis of change from baseline in MG-ADL scores is shown (full analysis set). [Figure 37] Mixed-model repeated measures analysis of change from baseline in QMG scores (full analysis set). DETAILED DESCRIPTION OF THE INVENTION

[0022] Increased expression of CD38 has been described in various diseases, including autoimmune diseases such as MG (Yilmaz et al. (2018) Ann. Clin. Transl. Neurol. 5(11):1408-1414). CD38 is a type II glycoprotein uniformly and highly expressed on antibody-producing plasmablasts and plasma cells (Sullivan et al. (2017) Blood 129(22):3033-7; incorporated herein by reference in its entirety), making it a potential target for the treatment of myasthenia gravis. A recent study found that the frequency of circulating CD38+ plasmablasts in MG patients was significantly higher than in healthy individuals (Yamamoto, et al. (2021) Neurol. Neuroimmunol. Neuroinflamm. 8(6):e1087; incorporated herein by reference in its entirety).

[0023] The significantly higher CD38 expression on plasma cells and plasmablasts compared with other immune cells suggests the possibility of selectively eliminating these cells using anti-CD38 antibodies. Daratumumab, a commercially available anti-CD38 antibody, resulted in substantial clinical improvement in patients with myasthenia gravis (measured by the quantitative myasthenia gravis score) (from 16 to 8, n=1) due to clinically relevant depletion of autoreactive, long-lived plasma cells (Scheibe et al. (2022) Eur. J. Neurol. 29(6):1847-1854; incorporated herein by reference in its entirety). Intravenous daratumumab has been approved for patients with multiple myeloma (relapsed and newly diagnosed). However, the most frequent adverse reactions (≥20%) observed with daratumumab monotherapy or in combination with standard antimyeloma therapy are infusion-related reactions (IRRs), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, fever, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection (Darzalex USPI). Daratumumab can cause severe and / or serious infusion reactions, including anaphylactic reactions, which have been reported in approximately half of all patients (Darzalex USPI). Importantly, attention must also be paid to daratumumab's interference with certain laboratory assays, which may complicate hemocompatibility testing (Darzalex USPI).

[0024] Other antibodies targeting CD38 are known (see, e.g., WO2006 / 125640, incorporated herein by reference in its entirety, which discloses four additional human antibodies (MOR03077, MOR03079, MOR03080, and MOR03100) and two murine antibodies (OKT10 and IB4)). These prior art antibodies are inferior to mezagitamab for various reasons. MOR03080 binds to human CD38 and cynomolgus monkey CD38, but with low affinity to human CD38 (Biacore KD=27.5 nm). OKT10 binds to human CD38 and cynomolgus monkey CD38, but with low / moderate affinity to human CD38 (Biacore KD=8.28 nm). MOR03079 binds to human CD38 with high affinity (Biacore KD=2.4 nm), but does not bind to cynomolgus monkey CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD=10 nm and 56 nm, respectively). In comparison, mezagitamab binds to human and cynomolgus monkey CD38 with high affinity (Biacore KD=5.4 nm to human CD38). Furthermore, prior art antibodies have poor ADCC and CDC activity.

[0025] The advantage of more efficient ADCC is the ability to deliver anti-CD38 therapeutics as a low-volume injection. A safety profile and PD-targeting efficacy were observed after subcutaneous administration of mezagitamab to healthy subjects at doses up to 0.6 mg / kg. A single subcutaneous dose of 0.6 mg / kg mezagitamab reduced peripheral blood PB levels by more than 90% and NK cell levels by more than 80%, without comparable reductions in monocytes, B cells, and T cells. On average, PB and NK cell levels recovered to 50% of baseline levels 21 days after administration. At this dose, there were no serious adverse events (SAEs), on-study deaths, or adverse events (AEs) leading to study discontinuation (WO2019 / 140410, incorporated herein by reference in its entirety). Further studies have shown that following subcutaneous administration of mezagitamab at doses of 45 mg, 135 mg, 300 mg, or 600 mg to patients with relapsed and / or refractory multiple myeloma (RRMM), no drug-related serious adverse events (SAEs), on-study deaths, or AEs leading to study discontinuation were reported. Administration of mezagitamab dose-dependently reduced plasmablast levels in blood and bone marrow aspirates, and plasma cell levels in bone marrow aspirates. In patients with advanced RRMM, mezagitamab also demonstrated early signs of antitumor activity, as evidenced by at least a 50% reduction in disease burden in some patients and prolonged disease stabilization in others ( WO 2019 / 186273 ; incorporated herein by reference in its entirety). However, the feasibility and efficacy of administering mezagitamab to treat patients with myasthenia gravis are unknown.

[0026] The methods and unit dosages of the present disclosure provide, for the first time, subcutaneous administration of a therapeutically effective dosage of an anti-CD38 antibody in the treatment of patients with myasthenia gravis.

[0027] The present invention provides methods and unit dosage forms for subcutaneously administering a therapeutically effective amount of an isolated anti-CD38 antibody or antigen-binding fragment to a patient with myasthenia gravis. In some embodiments, the antibody or antigen-binding fragment for subcutaneous administration comprises a variable heavy chain (VH) region comprising or consisting of SEQ ID NO: 9 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto), and a variable light chain (VL) region comprising or consisting of SEQ ID NO: 10 (or a sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity thereto). In some embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of 100 milligrams to 800 milligrams.

[0028] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by those skilled in the art. The meaning and scope of terms shall be clear. However, in the event of any potential ambiguity, the definitions provided herein shall take precedence over any dictionary or external definitions. Furthermore, unless otherwise required by context, singular terms shall include pluralities, and plural terms shall include the singular. The term "or" includes "and / or" unless otherwise specified. Furthermore, the use of the terms "including," "includes," or "comprising" is not limiting. Terms such as "element" and "component" encompass both elements and components that constitute a single unit and elements and components that constitute two or more subunits, unless otherwise specified.

[0029] The methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the specification, unless otherwise indicated. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients. Commercial enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein.

[0030] All heading and section names are used for purposes of clarification and reference only and should not be construed as limiting in any way. For example, those skilled in the art will understand the utility of combining various aspects of the disclosure from different headings and sections as appropriate, depending on the spirit and scope of the disclosure set forth herein.

[0031] So that this disclosure may be more readily understood, select terms are defined below.

[0032] The terms "human CD38" and "human CD38 antigen" refer to the amino acid sequence of SEQ ID NO: 1, or a functional fragment (e.g., epitope) thereof, as defined herein (Table 1). Generally, CD38 retains a short intracytoplasmic tail, a transmembrane domain, and an extracellular domain. The terms "cynomolgus CD38" and "cynomolgus CD38 antigen" refer to the amino acid sequence of SEQ ID NO: 2, which is 92% identical to the amino acid sequence of human CD38 (Table 1). Synonyms for CD38 include cyclic ADP-ribose hydrolase, cyclic ADP-ribose-hydrolase 1, ADP-ribosyl cyclase, ADP-ribosyl cyclase 1, cADPr hydrolase 1, CD38-rs1, I-19, NIM-R5 antigen, 2'-phospho-cyclic ADP-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, 2'-phospho-cyclic ADP-ribose transferase, 2'-phospho-ADP-ribosyl cyclase, and T10. [Table 1]

[0033] The terms "therapeutically effective amount" and "therapeutically effective dose" refer to an amount of a therapeutic agent that is sufficient to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof, prevent progression of a disorder, cause regression of a disorder, prevent the recurrence, occurrence, onset, or progression of one or more symptoms associated with a disorder, or enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., a prophylactic or therapeutic agent), at dosages and for periods of time necessary to achieve the desired therapeutic result. A therapeutically effective amount may vary depending on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the pharmaceutical agent to elicit a desired response in the individual. A therapeutically effective amount of an antibody or antigen-binding fragment thereof is one in which any toxic or adverse effects of the antibody or antigen-binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0034] The terms "patient" and "subject" include both humans and other animals. Thus, the compositions, dosages, and methods disclosed herein are applicable to both human and veterinary therapy. In one embodiment, the patient is a mammal, e.g., a human.

[0035] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigen specificities. For example, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind to antigens other than CD38. However, an isolated antibody that specifically binds to an epitope, isoform, or variant of human CD38 or cynomolgus monkey CD38 may have cross-reactivity to other related antigens, for example, from other species (e.g., CD38 species homologs). Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0036] The term "about" refers to a degree of approximation in number, degree, volume, time, etc., with minor variations in magnitude only up to 10%.

[0037] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle suitable for administering a compound of the present disclosure to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials that are involved in carrying or transporting the compound of interest from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration.

[0038] The term "pharmaceutical composition" refers to a preparation suitable for administration to a subject and treatment of a disease. When administered to a mammal (e.g., a human) as a pharmaceutical, the anti-CD38 antibody of the present disclosure may be administered "as is" or as a pharmaceutical composition containing the anti-CD38 antibody in combination with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The pharmaceutical composition may be in the form of a unit dosage form for administration of a specific dosage of the anti-CD38 antibody at a specific concentration, amount, or volume. Pharmaceutical compositions comprising an anti-CD38 antibody, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier, are provided. Preferably, the pharmaceutical composition may comprise a unit dosage form according to the present disclosure, alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition may comprise a human anti-CD38 antibody as described herein, either alone or in combination with a prophylactic agent, a therapeutic agent, and / or a pharmaceutically acceptable carrier.

[0039] The structural unit of a conventional antibody typically comprises a tetramer. Each tetramer typically consists of two identical pairs of polypeptide chains, each pair having one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). Human light chains (LC) are classified as kappa and lambda light chains. Heavy chains (HC) are classified as mu, delta, gamma, alpha, or epsilon, defining the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has multiple subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgM1 and IgM2. Thus, "isotype" refers to any of the immunoglobulin subclasses defined by the chemical and antigenic characteristics of their constant regions. The known human immunoglobulin isotypes are IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgM1, IgM2, IgD, and IgE. Therapeutic antibodies may also comprise hybrids of isotypes and / or subclasses.

[0040] Each VH and VL region (approximately 100-110 amino acids in length) is composed of three hypervariable regions called "complementarity-determining regions" (CDRs) and four framework regions (FRs) (approximately 15-30 amino acids in length), arranged from amino terminus to carboxy terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. "Variable" refers to the fact that the CDRs vary extensively in sequence among antibodies, thereby defining unique antigen-binding sites.

[0041] The hypervariable regions generally consist of amino acid residues from about amino acid residues 24-34 (LCDR1, "L" indicates a light chain), 50-56 (LCDR2), and 89-97 (LCDR3) of the VL region, and amino acid residues from about amino acid residues 31-35B (HCDR1, "H" indicates a heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) of the VL region (Kabat et al. (1991) Sequences Of Proteins Of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD; incorporated herein by reference in its entirety), and / or those residues that form the hypervariable loops (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) of the VL region, and 26-32 (HCDR1), 53-55 (HCDR2), and 96-101 (HCDR3) of the VH region (Chothia and Lesk (1987) J. Mol. Biol. 196:901-917; incorporated herein by reference in its entirety)).

[0042] The Kabat numbering system is typically used when referring to residues within the variable domains (approximately residues 1-107 for the VL region and residues 1-113 for the VH region) (e.g., Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD; incorporated herein by reference in its entirety), with the EU numbering system being used for the Fc region.

[0043] The term "immunoglobulin (Ig) domain" refers to a region of an immunoglobulin having a distinct tertiary structure. Ig domains include VH and VL regions, CDRs, framework regions, constant region domains, and hinge regions. The HC and LC each have constant region domains called the constant heavy (CH) domain and the constant light (CL) domain. In the context of IgG antibodies, IgG isotypes each have a constant region containing three CH domains. The carboxy-terminal portion of each HC and LC defines a constant region primarily responsible for effector function. Thus, "CH" domains in the context of IgG are as follows: "CH1" refers to positions 118-220 according to the EU index of Kabat; "CH2" refers to positions 237-340 according to the EU index of Kabat; and "CH3" refers to positions 341-447 according to the EU index of Kabat.

[0044] Another type of Ig domain of the HC is the hinge region. The term "hinge region" refers to a flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain begins at EU position 237. Thus, with respect to IgG, the antibody hinge is defined herein to include positions 221 (D221 in IgG1) to 236 (G236 in IgG1), where the numbering is according to the EU index as in Kabat. For example, in some embodiments relating to the Fc region, a lower hinge is included, and "lower hinge" generally refers to positions 226 or 230.

[0045] The term "Fc region" refers to the polypeptide comprising the constant region of an antibody, excluding the CH1 domain and, in some cases, a portion of the hinge. Thus, Fc refers to the last two constant region Ig domains (CH2 and CH3) of IgA, IgD, and IgG, the last three constant region Ig domains of IgE and IgM, and the flexible hinge N-terminal to these domains. For IgA and IgM, Fc may include the J chain. For IgG, the Fc domain includes Ig domains Cγ2 and Cγ3 (Cγ2 and Cγ3) and the lower hinge region between Cγ1 (Cγ1) and Cγ2 (Cγ2). Although the boundaries of the Fc region may vary, the human IgG HC Fc region is usually defined to include residues C226 or P230 at its carboxy terminus, with numbering here according to the EU index as in Kabat. In some embodiments, as described more fully below, amino acid modifications are made to the Fc region to, for example, alter binding to one or more FcγR or FcRn receptors.

[0046] CD38 antibody Accordingly, the present disclosure provides isolated anti-CD38 antibodies that specifically bind to human and primate CD38 proteins, which find use in subcutaneous administration and unit dosage forms in the treatment of patients with myasthenia gravis (MG). The antibodies or antigen-binding fragments thereof used in the present disclosure bind to both human and primate CD38 proteins, and in particular bind to primates used in clinical trials, such as cynomolgus monkeys (Macaca fascicularis, also referred to herein as "cyno").

[0047] "Mezagitamab" or "TAK-079" is a therapeutic protein comprising a fully human immunoglobulin IgG1 monoclonal antibody that specifically binds to CD38 with high affinity (Kd=3.5 nM), and is referred to herein as AB79 (U.S. Patent No. 8,362,211, the contents of which are incorporated herein by reference in their entirety). The amino acid sequence of mezagitamab is shown in Table 2. [Table 2]

[0048] Mezagitamab inhibits the growth of CD38-expressing tumor cells by cell depletion via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Mezagitamab also reduces the levels of plasma cells and plasmablasts in blood isolated from healthy subjects and patients with autoimmune diseases. The anti-human CD38 mAb daratumumab also dose-dependently depletes CD38-expressing plasmablasts and plasma cells in samples from patients with autoimmune diseases in vitro. For example, daratumumab resulted in clinically relevant depletion of autoreactive, long-lived plasma cells in patients with treatment-resistant autoantibody-mediated neurological disorders such as myasthenia gravis (Scheibe et al. (2022) Eur. J. Neurol. 29(6):1847-1854).

[0049] In contrast to daratumumab, mezagitamab cross-reacts with CD38 expressed by cynomolgus monkeys, providing a unique opportunity to determine whether reducing the levels of CD38-expressing cells affects inflammation and tissue damage in non-human primate models of autoimmune disease. In healthy cynomolgus monkeys, the efficiency of depletion of lymphocytes, B cells, T cells, and NK cells positively correlated with CD38 expression levels and AB79 dose levels (PCT Application No. PCT / US2017 / 042128; U.S. Patent No. US8,362,211, incorporated herein by reference in its entirety).

[0050] In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof of the present disclosure interact with CD38 at multiple amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294, based on the human SEQ ID NO: Preferably, the anti-CD38 antibodies or antigen-binding fragments thereof of the present disclosure may interact with CD38 at several amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 1, based on human SEQ ID NOs. Preferably, the anti-CD38 antibodies or antigen-binding fragments thereof of the present invention interact with CD38 at multiple amino acid residues, including K121, F135, Q139, D141, M142, E239, W241, F274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294 of SEQ ID NO: 2. It should be noted that these residues are identical in both humans and cynomolgus monkeys, except that in cynomolgus monkeys, S274 is actually F274. These residues may represent immunodominant epitopes and / or residues within the footprint of a particular antigen-binding peptide.

[0051] In some embodiments, the anti-CD38 antibodies used according to the invention comprise a heavy chain (HC) comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), or variants of those sequences with up to three amino acid changes. In some embodiments, the antibodies used according to the invention comprise a light chain (LC) comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab), or variants of those sequences with up to three amino acid changes. In some embodiments, an antibody used in accordance with the present disclosure comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes, and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes. In some embodiments, the anti-CD38 antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab). In some embodiments, the antibody comprises a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab).In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, and the remainder of the VH region sequence may have at least 80% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, and the remainder of the VH region sequence may have at least 85% sequence identity with SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 90% sequence identity to SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 95% sequence identity to SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 97% sequence identity to SEQ ID NO:9. Suitably, the VH region may comprise the CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the VH region sequence having at least 99% sequence identity to SEQ ID NO:9.

[0052] In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO:9.

[0053] In some embodiments, the antibody comprises a LC comprising a VL region amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 85% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 90% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the VL region sequence having at least 95% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, with the remainder of the VL region sequence having at least 97% sequence identity to SEQ ID NO:10. Suitably, the VL region may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7, and SEQ ID NO:8, with the remainder of the VL region sequence having at least 99% sequence identity to SEQ ID NO:10.

[0054] In some embodiments, the antibody comprises a LC comprising the VL region amino acid sequence of SEQ ID NO:10.

[0055] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein, and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0056] As will be appreciated by those skilled in the art, the VH and VL regions can be linked to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4.

[0057] In some embodiments, the antibody comprises a heavy chain (HC) comprising or consisting of an amino acid sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 80% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 85% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 90% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, with the remainder of the HC having at least 95% sequence identity to SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, and the remainder of the HC may have at least 97% sequence identity with SEQ ID NO:11. Suitably, the HC may comprise CDR sequences defined by SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5, and the remainder of the HC may have at least 99% sequence identity with SEQ ID NO:11.

[0058] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11. In some embodiments, the antibody comprises a light chain (LC) comprising or consisting of an amino acid sequence having at least 80%, 85%, 90%, 95%, 97%, or 99% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 85% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 90% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 95% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 97% sequence identity with SEQ ID NO:12. Suitably, the LC may comprise the CDR sequences defined by SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8, and the remainder of the LC may have at least 99% sequence identity with SEQ ID NO:12.

[0059] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO:12.

[0060] In some embodiments, the antibody comprises or consists of the HC amino acid sequence of SEQ ID NO: 11 or a variant thereof as described herein and the LC amino acid sequence of SEQ ID NO: 12 or a variant thereof as described herein.

[0061] The present invention encompasses antibodies that bind to both human and cynomolgus monkey CD38 and interact with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the following amino acid residues in SEQ ID NO: 1 and SEQ ID NO: 2, based on human numbering: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294. Preferably, the antibody can interact with at least 90% of these amino acid residues. Preferably, the antibody can interact with at least 95% of these amino acid residues. Preferably, the antibody can interact with at least 97% of these amino acid residues. Preferably, the antibody can interact with at least 98% of these amino acid residues. Preferably, the antibody can interact with at least 99% of these amino acid residues. Preferably, the antibody can interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids of SEQ ID NO:1 and SEQ ID NO:2 based on human numbering: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293, and S294.

[0062] In some embodiments, the antibody is full length. By "full length antibody" herein is meant the structure that constitutes the natural biological form of an antibody, including variable and constant regions, including one or more modifications as outlined herein.

[0063] Alternatively, antibodies may take on a variety of structures, including but not limited to antibody fragments, antigen-binding fragments, monoclonal antibodies, bispecific antibodies, minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), chimeric antibodies, humanized antibodies, antibody fusions (sometimes referred to as "antibody conjugates"), and fragments of each. Specific antibody fragments include (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) an Fd fragment consisting of the VH and CH1 domains, (iii) an Fv fragment consisting of the VL and VH domains of a single antibody, (iv) a dAb fragment consisting of a single variable region (Ward et al. (1989) Nature 341:544-546), (v) isolated CDR regions, (vi) an F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments, and (vii) a single-chain Fv molecule (scFv) in which the VH and VL domains are linked by a peptide linker that allows these two domains to associate to form an antigen-binding site (Bird et al. (1988) Science 242:423-426, Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883), (viii) bispecific single-chain Fvs (WO03 / 11161), and (ix) "diabodies" or "triabodies," which are multivalent or multispecific fragments constructed by gene fusion (Tomlinson et al. (2000) Methods Enzymol. 326:461-479, WO94 / 13804; Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448).

[0064] Preferably, the antibody may be a Fab fragment. Preferably, the antibody may be an Fv fragment. Preferably, the antibody may be an Fd fragment. Preferably, the antibody structure may be an isolated CDR region. Preferably, the antibody may be a F(ab')2 fragment. Preferably, the antibody may be an scFv fragment.

[0065] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure further comprises one or more engineered glycoforms. In some embodiments, the engineered glycoforms comprise one or more glycosylations of the polypeptide. In some embodiments, the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. In some embodiments, the glycosylation is O-linked glycosylation.

[0066] In some embodiments, the isolated antibody of the disclosure is mezagitamab.

[0067] antibody modification The present invention further provides variant anti-CD38 antibodies. Thus, there are numerous modifications that can be made to the antibodies of this disclosure, including, but not limited to, amino acid modifications in the CDRs (affinity maturation), amino acid modifications in the VH and / or VL regions, amino acid modifications in the HC and / or LC, amino acid modifications in the Fc region, glycosylation variants, and other types of covalent modifications.

[0068] The term "variant" refers to a polypeptide that differs from that of a parent polypeptide. Amino acid variants can include amino acid substitutions, insertions, and deletions. Generally, variants can include any number of modifications as long as the protein's function, as described herein, remains intact. That is, even in the case of amino acid variants generated using the CDRs of mezagitamab, for example, the antibody will still specifically bind to both human and cynomolgus CD38. The term "variant Fc region" refers to an Fc sequence that differs from that of the wild-type or parent Fc sequence by at least one amino acid modification. An Fc variant can refer to the Fc polypeptide itself, a composition comprising the Fc variant polypeptide, or an amino acid sequence. If amino acid variants are generated in the Fc region, for example, the variant antibody should maintain the functionality required for the antibody's particular application or indication. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, e.g., 1-10, 1-5, 1-4, 1-3, and 1-2 substitutions, can be utilized. Suitable modifications can be made at one or more positions, particularly for specific amino acid substitutions that increase binding to Fc receptors, as generally outlined in, for example, U.S. Patent Application Nos. 11 / 841,654, 12 / 341,769, U.S. Patent Publication Nos. 2004013210, 20050054832, 20060024298, 20060121032, 20060235208, 20070148170, and U.S. Patent Nos. 6,737,056, 7,670,600, and 6,086,875 (all of which patents are expressly incorporated by reference in their entirety).

[0069] Variants can be considered in terms of similarity (ie, amino acid residues having similar chemical properties / functions), and preferably variants are expressed in terms of sequence identity.

[0070] Sequence comparison can be accomplished with the aid of readily available sequence comparison programs, or usually by eye. These publicly and commercially available computer programs can calculate the percent sequence identity between two or more sequences.

[0071] It may be desirable to have one to five modifications in the Fc region of the wild-type or engineered protein, and, for example, one to five modifications in the Fv region. The variant polypeptide sequence preferably has at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to the parent sequence (e.g., the VH or VL region, constant region, and / or HC and LC sequences of mezagitamab). Preferably, the variant may have at least 80% sequence identity to the parent sequence. Preferably, the variant may have at least 85% sequence identity to the parent sequence. Preferably, the variant may have at least 90% sequence identity to the parent sequence. Preferably, the variant may have at least 92% sequence identity to the parent sequence. Preferably, the variant may have at least 95% sequence identity to the parent sequence. Preferably, the variant may have at least 97% sequence identity to the parent sequence. Preferably, the variant may have at least 98% sequence identity to the parent sequence. Preferably, the variant may have at least 99% sequence identity to the parent sequence.

[0072] In one embodiment, sequence identity is determined across the entire sequence. In one embodiment, sequence identity is determined across the entire candidate sequence being compared to a sequence listed herein.

[0073] The term "amino acid substitution" refers to the replacement of an amino acid at a specific position in a parent polypeptide sequence with another amino acid. For example, the substitution S100A refers to a variant polypeptide in which the serine at position 100 is replaced with alanine. Preferably, the amino acid substitution can be a conservative amino acid substitution. Preferably, the variant can contain one or more, for example, two or three, conservative amino acid substitutions. Amino acids with similar biochemical properties can be defined as amino acids that can be substituted through conservative substitution.

[0074] Unless otherwise expressly defined herein by reference to specific individual amino acids, amino acids may be substituted using conservative substitutions as listed below. An aliphatic polar uncharged amino acid may be a cysteine, serine, threonine, methionine, asparagine, or glutamine residue. An aliphatic polar charged amino acid may be an aspartic acid, glutamic acid, lysine, or arginine residue. An aromatic amino acid may be a histidine, phenylalanine, tryptophan, or tyrosine residue. Conservative substitutions may be made, for example, according to Table 3 below. Amino acids in the same block in the second column, preferably in the same line in the third column, may be substituted for each other. [Table 3]

[0075] The term "amino acid insertion" refers to the addition of an amino acid at a particular position in a parent polypeptide sequence.

[0076] The term "amino acid deletion" refers to the removal of an amino acid at a particular position in a parent polypeptide sequence.

[0077] The terms "parent antibody" and "precursor antibody" refer to an unmodified antibody that is subsequently modified to create a variant. In one embodiment, the parent antibody is mezagitamab. In one embodiment, the parent antibody herein comprises a VH region having the amino acid sequence of SEQ ID NO: 9 and a VL region having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the parent antibody herein comprises an HC amino acid sequence of SEQ ID NO: 11 and an LC amino acid sequence of SEQ ID NO: 12. The parent antibody may refer to the polypeptide itself, a composition comprising the parent antibody, or the amino acid sequence encoding it. Accordingly, the term "parent Fc polypeptide" refers to an Fc polypeptide that is modified to create a variant.

[0078] The terms "wild type," "wild-type (WT)," and "native" refer to an amino acid sequence or nucleotide sequence found in nature, including allelic variations. A wild-type protein, polypeptide, antibody, immunoglobulin, IgG, etc., has an amino acid sequence or nucleotide sequence that has not been intentionally modified.

[0079] In some embodiments, one or more amino acid modifications are made in one or more CDRs of an anti-CD38 antibody. Generally, no more than 1, 2, or 3 amino acid substitutions are made in any single CDR, and generally no more than 4, 5, 6, 7, 8, 9, or 10 amino acid changes are made in a set of CDRs. However, it should be understood that any combination of none, 1, 2, or 3 substitutions in any CDR can be independently and optionally combined with any other substitution.

[0080] In some instances, amino acid modifications in the CDRs are referred to as "affinity maturation." An "affinity matured" antibody is one with one or more alterations in one or more CDRs that result in improved affinity of the antibody for the antigen, compared to a parent antibody that does not have the alteration(s) that result in improved affinity of the antibody for its antigen. In some instances, it may be desirable to decrease the affinity of an antibody for its antigen.

[0081] Affinity maturation can be carried out to increase the binding affinity of an antibody for an antigen by at least about 10% to 50%, 100%, 150% or more, or 1 to 5 fold compared to the "parent" antibody. Preferred affinity-matured antibodies will have nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by known procedures (e.g., Marks et al. (1992) Biotechnol. 10:779-783, Barbas et al. (1994) Proc. Nat. Acad. Sci. USA 91:3809-3813, Shier et al. (1995) Gene 169:147-155, Yelton et al. (1995) J. Immunol. 155:1994-2004, Jackson et al. (1995) J. Immunol. 154(7):3310-9, and Hawkins et al. (1992) J. Mol. Biol. 226:889-896, which are incorporated herein by reference in their entireties.

[0082] Alternatively, amino acid modifications that are "silent" (e.g., that do not significantly alter the affinity of the antibody for antigen) can be made, for example, in one or more of the CDRs of an antibody of the disclosure. These can be made for a variety of reasons, including expression optimization (as can be done for nucleic acids encoding the antibodies of the disclosure).

[0083] Thus, variant CDRs and antibodies are included in the definition of the CDRs and antibodies of the present invention, i.e., the antibodies of the present invention may comprise amino acid modifications in one or more of the CDRs set forth in SEQ ID NOS: 3 to 8. Furthermore, as outlined below, amino acid modifications can be made independently and optionally in any region outside the CDRs, including framework and constant regions.

[0084] In some embodiments, a variant antibody of mezagitamab specific for human CD38 (SEQ ID NO: 1) and cynomolgus monkey CD38 (SEQ ID NO: 2) is described. This antibody is composed of six CDRs, each of which may differ from SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and / or SEQ ID NO: 8 by 0, 1, or 2 amino acid substitutions.

[0085] Glycosylation Another type of modification is altered glycosylation. In one embodiment, the antibodies disclosed herein can be modified to contain one or more engineered glycoforms. As used herein, "engineered glycoform" refers to a carbohydrate composition covalently attached to an antibody that is chemically distinct from the carbohydrate composition of the parent antibody. Engineered glycoforms can be useful for a variety of purposes, including, but not limited to, enhancing or reducing effector function. A preferred form of engineered glycoform is afucosylation, which has been shown to correlate with increased ADCC function, likely due to tighter binding to the FcγRIIIa receptor. In this context, "afucosylation" means that the majority of antibodies produced in host cells are substantially devoid of fucose; for example, 90-95-98% of produced antibodies lack appreciable fucose as a component of the antibody's carbohydrate moiety (typically attached to N297 within the Fc region). When defined functionally, afucosylated antibodies generally exhibit at least 50% or greater affinity for the FcγRIIIa receptor.

[0086] Engineered glycoforms can be produced by a variety of methods known in the art (U.S. Patent No. 8,362,211, incorporated herein by reference in its entirety). Engineered glycoforms typically refer to different carbohydrates or oligosaccharides, and thus, antibodies can include engineered glycoforms.

[0087] Alternatively, engineered glycoforms may refer to IgG variants that contain different carbohydrates or oligosaccharides. As is known in the art, glycosylation patterns can depend on both the protein sequence (e.g., the presence or absence of specific glycosylated amino acid residues, discussed below) or the host cell or organism in which the protein is produced. Specific expression systems are discussed below.

[0088] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

[0089] Addition of glycosylation sites to an antibody is conveniently accomplished by altering the amino acid sequence to contain one or more of the above-described tripeptide sequences (for N-linked glycosylation sites). The alteration may also be accomplished by adding or substituting one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). To facilitate this, the antibody amino acid sequence is preferably altered by changes at the DNA level, specifically by mutating the DNA encoding the target polypeptide at preselected bases to generate codons that translate into the desired amino acids.

[0090] Another method for increasing the number of carbohydrate moieties on an antibody is by chemically or enzymatically coupling glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell with glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling mode used, sugar(s) can be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups (e.g., cysteine), (d) free hydroxyl groups (e.g., serine, threonine, or hydroxyproline), (e) aromatic residues (e.g., those of phenylalanine, tyrosine, or tryptophan), or (f) the amide group of glutamine. These methods are described in WO 87 / 05330 and Aplin and Wriston (1981) CRC Crit. Rev. Biochem. 10(4):259-306, both of which are incorporated herein by reference in their entireties.

[0091] Removal of carbohydrate moieties present on the starting antibody (e.g., post-translationally) can be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the polypeptide intact. Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and Edge et al., 1981, Anal. Biochem. 118:131, both of which are incorporated herein by reference in their entireties. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of various endoglycosidases and exoglycosidases, as described by Thotakura et al., 1987, Meth. Enzymol. 138:350 (incorporated herein by reference in its entirety). Glycosylation at potential glycosylation sites can be prevented by the use of the compound tunicamycin, described in Duskin et al. (1982) J. Biol. Chem. 257:3105 (incorporated herein by reference in its entirety). Tunicamycin blocks the formation of protein-N-glycosidic bonds.

[0092] Another type of covalent modification of antibodies involves conjugating the antibody to various nonproteinaceous polymers, including, but not limited to, various polyols (e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylene), for example, by methods described in Nektar Therapeutics' 2005-2006 PEG Catalog (available on the Nektar website), U.S. Patent Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, or 4,179,337 (incorporated herein by reference in their entireties). In addition, as is known in the art, amino acid substitutions can be made at various positions within the antibody to facilitate the addition of polymers such as PEG. See, for example, U.S. Patent Publication No. 2005 / 0114037 A1 (incorporated herein by reference in their entireties).

[0093] In addition to the modifications outlined above, other modifications can be made. For example, the molecule can be stabilized by the incorporation of disulfide bridges linking the VH and VL domains (Reiter et al. (1996) Nature Biotech. 14:1239-1245, incorporated herein by reference in its entirety). Additionally, there are a variety of covalent modifications of antibodies that can be made, as outlined below.

[0094] Covalent modifications of antibodies are included within the scope of this disclosure and are typically (but not always) made post-translationally. For example, several types of covalent modifications of antibodies are introduced into the molecule by reacting specific amino acid residues of the antibody with organic derivatizing agents capable of reacting with selected side chains or the N- or C-terminal residues.

[0095] In some embodiments, the anti-CD38 antibodies of the present disclosure specifically bind to one or more residues or regions of CD38 but do not cross-react with other proteins that share homology with CD38 (e.g., BST-1 (bone marrow stromal cell antigen-1) and / or Mo5 (also known as CD157)).

[0096] Typically, lack of cross-reactivity means less than about 5% relative competitive inhibition between the molecules when assessed by ELISA and / or FACS analysis under suitable assay conditions and with sufficient amounts of the molecules.

[0097] Reduced side effects An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigational subject receiving a drug, but which does not necessarily have a causal relationship to this treatment. A treatment-emergent adverse event (TEAE) was defined as an AE that occurred after the first dose of study drug was received during the treatment period and through the end of safety follow-up. The terms "serious TEAE" and "treatment-emergent SAE" can be considered interchangeable herein. PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0. TEAEs are typically referred to as grades 1, 2, 3, 4, and 5, with grade 1 being the least severe TEAE and grade 5 being the most severe. Based on FDA and other guidelines for the Common Terminology Criteria for Adverse Events (CTCAE) standard for Oncology Drugs (see, e.g., U.S. Department of Health and Human Services, Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, 2010, and Nilsson and Koke (2001) Drug Inform. J. 35:1289-1299, incorporated herein by reference in their entireties), the following is how such grades are generally determined: Grade 1 is mild, with no or mild symptoms; clinical or diagnostic findings only; no intervention indicated. Grade 2 is moderate: minimal, local, or noninvasive intervention indicated; age-appropriate beneficial activities of daily living (ADLs) are limited. Grade 3 is severe or medically significant, but not immediately life-threatening, with hospitalization or prolonged hospitalization indicated; activity / incapacity; self-care activities of daily living are limited. Grade 4 is a life-threatening outcome and urgent intervention is indicated, and Grade 5 is death related to the AE.

[0098] The anti-CD38 antibodies of the present disclosure are capable of reducing side effects compared to prior art anti-CD38 antibodies. In some embodiments, the antibodies used in accordance with the present disclosure (e.g., mezagitamab) do not induce TEAEs. In some embodiments, the antibodies used in accordance with the present disclosure (e.g., mezagitamab) allow for a reduction in the incidence of TEAEs in a patient population compared to other anti-CD38 antibodies (e.g., MOR202). In some embodiments, the antibodies used in accordance with the present disclosure (e.g., mezagitamab) allow for a reduction in the grade of TEAEs in a patient population compared to other anti-CD38 antibodies (e.g., MOR202). In some embodiments, the antibodies used in accordance with the present disclosure (e.g., mezagitamab) allow for a reduction in the grade of TEAEs from Grade 5 to Grade 4 compared to other anti-CD38 antibodies. In some embodiments, the antibodies used in accordance with the present disclosure (e.g., mezagitamab) allow for a reduction in the grade of TEAEs from Grade 4 to Grade 3 compared to other anti-CD38 antibodies. In some embodiments, antibodies used in accordance with the present disclosure (e.g., mezagitamab) compared to other anti-CD38 antibodies enable the grade of TEAEs to be reduced from grade 3 to grade 2. In some embodiments, antibodies used in accordance with the present disclosure (e.g., mezagitamab) compared to other anti-CD38 antibodies enable the grade of TEAEs to be reduced from grade 2 to grade 1.

[0099] In some embodiments, an antibody (e.g., mezagitamab) used in accordance with the present disclosure allows for a reduction in the grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRR), leukopenia, lymphopenia, and nausea. In some embodiments, an antibody (e.g., mezagitamab) used in accordance with the present disclosure allows for a reduction in the occurrence of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRR), leukopenia, lymphopenia, and nausea.

[0100] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the present disclosure results in less than a 10% incidence of one or more Grade 3 or 4 TRAEs or TEAEs, optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infections, fever, shingles, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0101] In some embodiments, administration of an antibody or antigen-binding fragment thereof of the present disclosure results in one or more TRAEs or TEAEs with a maximal intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0102] Signs of disease The antibodies or antigen-binding fragments thereof, methods, and dosage units of the present disclosure find use in treating patients with myasthenia gravis (MG).

[0103] Myasthenia gravis (MG) Myasthenia gravis (MG) is a rare autoimmune disease in which autoantibodies target the neuromuscular junction (NMJ) and postsynaptic membrane, disrupting neuromuscular transmission and causing progressive skeletal muscle weakness. The prevalence of myasthenia gravis in the United States is approximately 14–40 cases per 100,000 people (Breiner et al. (2016) Neuromuscul. Disord. 26(1):41–6; Carr et al. (2010) BMC Neurol. 10:46; Heldal et al. (2012) Muscle Nerve 45(6):815–819; Santos et al. (2016) Muscle Nerve 54(3):413–21).

[0104] Myasthenia gravis is defined by the Myasthenia Gravis Foundation of America (MGFA) clinical classification, which divides MG into five major classes based on clinical features and disease severity (Jaretzki III et al. (2000) Neurology 55(1):16-23; Gilhus et al. (2011) Autoimmune Dis. 2011:847393; Trouth et al. (2012) Autoimmune Dis. 2012:874680, each of which is incorporated herein by reference in its entirety). Each class has a different prognosis or response to treatment.

[0105] Clinical classification of myasthenia gravis Class I: Weakness of any eye muscle; may have weakness in eye closure; all other muscle strength is normal.

[0106] Class II: Mild muscle weakness affecting parts of the body other than the eye muscles; may also have muscle weakness of any severity. Class IIa: Primarily affects limb muscles, trunk muscles, or both; may also have mild involvement of oropharyngeal muscles. Class IIb: Primarily affects oropharyngeal muscles, respiratory muscles, or both; may also have mild or equivalent involvement of limbs, trunk muscles, or both.

[0107] Class III: Moderate weakness affecting parts of the body other than the eyes; may also have eye weakness of any severity. Class IIIa: Primarily affecting the limbs, trunk muscles, or both; may also have mild involvement of the oropharyngeal muscles. Class IIIb: Primarily affecting the oropharyngeal muscles, respiratory muscles, or both; may also have mild or equivalent involvement of the limbs, trunk muscles, or both.

[0108] Class IV: Affects areas other than the eye muscles; may also have muscle weakness of any severity. Class IVa: Affects primarily the limb and / or trunk muscles; may also have mild involvement of the oropharyngeal muscles. Class IVb: Affects primarily the oropharyngeal muscles, respiratory muscles, or both; may also have mild or equivalent involvement of the limbs, trunk muscles, or both.

[0109] Class V: Defined by intubation with or without mechanical ventilation, except when used during routine postoperative care. Use of a feeding tube without intubation places the patient in Class IVb.

[0110] Subtypes of myasthenia gravis Subtypes of MG are broadly classified as follows: (1) early-onset MG: age at onset before 50 years; thymic hypertrophy, usually in women; (2) late-onset MG: age at onset after 50 years; thymic atrophy, mainly in men; (3) thymoma-associated MG (10%-15%); (4) MG associated with anti-MUSK antibodies; (5) ocular MG (oMG): symptoms affecting only the extraocular muscles; and (6) MG in which AChR and muscle-specific tyrosine kinase (MuSK) antibodies are not detectable.

[0111] To confirm the diagnosis of MG, necessary investigations include AChR antibodies, MuSK antibodies, and CT / MR of the anterior mediastinum for thymoma or thymic hyperplasia. Neurophysiological testing using repetitive nerve stimulation and jitter measurements is important in establishing the initial diagnosis, especially in patients without detectable antibodies.

[0112] In some embodiments, the present disclosure provides a method of treating myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating generalized myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class I myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class II myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IIa myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IIb myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class III myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IIIa myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IIIb myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IV myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IVa myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating Class IVb myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating class V myasthenia gravis in a subject.

[0113] In some embodiments, the present disclosure provides a method of treating early-onset myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating late-onset myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating thymoma-associated myasthenia gravis in a subject. In some embodiments, the present disclosure provides a method of treating myasthenia gravis with an anti-MUSK antibody in a subject. In some embodiments, the present disclosure provides a method of treating ocular myasthenia gravis antibodies in a subject. In some embodiments, the present disclosure provides a method of treating myasthenia gravis in a subject without detectable AChR and muscle-specific tyrosine kinase (MuSK) antibodies.

[0114] The therapeutic anti-CD38 antibodies of the present disclosure bind to CD38-positive cells and result in the depletion of these cells through multiple mechanisms of action, including both the CDC and ADCC pathways.

[0115] In some embodiments, the disclosure provides a method of treating myasthenia gravis in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dose of about 100 to about 800 milligrams.

[0116] In some embodiments, the disclosure provides a method of reducing levels of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0117] In some embodiments, the disclosure provides a method of reducing the level of immunoglobulin(s) in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, a CDR2 having the amino acid sequence of SEQ ID NO: 7, and a CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0118] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the immunoglobulin is IgA, IgG, and / or IgM. In some embodiments, the immunoglobulin is IgA. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is IgM.

[0119] In some embodiments, the disclosure provides a method of reducing the level of one or more autoantibodies in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0120] In some embodiments, the disclosure provides a method as disclosed herein, wherein the one or more autoantibodies are selected from the group consisting of anti-AChR and anti-MuSK.

[0121] In some embodiments, the disclosure provides a method of reducing disease activity and / or progression of myasthenia gravis in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

[0122] In some embodiments, the disclosure provides a method, as disclosed herein, wherein the myasthenia gravis disease activity is measured by a score selected from one or more of Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite (MGC), the revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r), and / or the Myasthenia Gravis Disability Index (MGII). In some embodiments, the myasthenia gravis disease activity is measured by Myasthenia Gravis Activities of Daily Living (MG-ADL). In some embodiments, the myasthenia gravis disease activity is measured by Quantitative Myasthenia Gravis (QMG). In some embodiments, the myasthenia gravis disease activity is measured by Myasthenia Gravis Composite (MGC). In some embodiments, the myasthenia gravis disease activity is measured by the revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r). In some embodiments, myasthenia gravis disease activity is measured by the Myasthenia Gravis Disability Index (MGII).

[0123] In some embodiments, the present disclosure provides a method, as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more modified glycoforms.

[0124] In some embodiments, the disclosure provides a method as disclosed herein, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, wherein the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0125] In some embodiments, the disclosure provides a method, as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0126] In some embodiments, the disclosure provides a method, as disclosed herein, wherein the glycosylation is O-linked glycosylation.

[0127] In some embodiments, the disclosure provides a method as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 10.

[0128] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9.

[0129] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10.

[0130] In some embodiments, the invention provides a method as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9.

[0131] In some embodiments, the invention provides a method as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10.

[0132] In some embodiments, the invention provides a method as disclosed herein, wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:11.

[0133] In some embodiments, the invention provides a method as disclosed herein, wherein the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:12.

[0134] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291, and E292 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human SEQ ID NOs.

[0135] In some embodiments, the invention provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO: 1) at a concentration of 10 or more. -8 The binding affinity is measured by standard Biacore assays.

[0136] In some embodiments, the disclosure provides a method as disclosed herein, wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10.

[0137] In some embodiments, the disclosure provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0138] In some embodiments, the present disclosure provides a method, as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises an Fc domain.

[0139] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0140] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0141] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the subject receives background myasthenia gravis medication(s).

[0142] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the background myasthenia gravis medication(s) is / are selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof. In some embodiments, the present disclosure provides a method as disclosed herein, wherein the background myasthenia gravis medication(s) is / are selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, azathioprine, and cyclosporine, and combinations thereof.

[0143] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the background myasthenia gravis medication(s) is administered in combination with an antibody or antigen-binding fragment thereof.

[0144] In some embodiments, the disclosure provides a method, as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered at a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage of about 300 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 600 mg.

[0145] In some embodiments, the disclosure provides a method as disclosed herein, wherein the dosage is administered once weekly, once every two weeks, once every two weeks, or once every four weeks.

[0146] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0147] In some embodiments, the present disclosure provides a method as disclosed herein, wherein the pharmaceutically acceptable composition comprises the isolated antibody or antibody fragment thereof and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0148] In some embodiments, the disclosure provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12; and the antibody or antigen-binding fragment thereof is administered subcutaneously once a week for 8 weeks. In some embodiments, the disclosure provides a method as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more modified glycoforms, wherein the modified glycoforms comprise glycosylation of one or more polypeptides, and wherein the glycosylation is N-linked glycosylation.

[0149] In some embodiments, the disclosure provides a method, as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

[0150] In some embodiments, the disclosure provides a method as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than a 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4. In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infections, fever, shingles, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0151] In some embodiments, the disclosure provides a method as disclosed herein, wherein administering the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs having a maximal intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0152] Antibody Compositions for In Vivo Administration Formulations of antibodies or antigen-binding fragments thereof used in accordance with the present disclosure are prepared for storage in the form of lyophilized formulations or aqueous solutions by mixing antibodies having the desired purity with any pharmaceutically acceptable carriers, excipients, or stabilizers (Remington's Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed; incorporated herein by reference in its entirety).

[0153] The formulations herein may contain two or more active compounds as needed for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to provide an antibody or antigen-binding fragment thereof with additional specificity. Alternatively, or in addition, the composition may include a cytotoxic agent, cytokine, growth inhibitory agent, and / or small molecule antagonist. Such molecules are preferably present in combination in amounts effective for the intended purpose.

[0154] In some embodiments, two mezagitamab pharmaceutical formulations have been developed, designated Process A and Process B, as disclosed herein.

[0155] In one embodiment, the Process A mezagitamab drug product is a clear to milky white, colorless solution containing AB79 (20 mg / mL) in water at about pH 6.5, arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection. The Process A placebo is a clear, colorless solution containing arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection in water at approximately pH 6.5. The Process A mezagitamab drug product and placebo are supplied in sterile-filled, clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0156] In another embodiment, Process B mezagitamab drug product is made in two concentrations: 5 mg / mL or 100 mg / mL. Each strength is a clear to opalescent, colorless to brownish-yellow solution containing mezagitamab in an aqueous solution (approximate pH 5.9) of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection. Process B placebo is a clear, colorless solution containing histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection in water (approximate pH 5.9). Process B mezagitamab drug product and placebo are supplied in aseptically filled, clear, single-use Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0157] Subcutaneous administration The anti-CD38 antibodies described herein, such as mezagitamab, can be administered at dosages sufficient to be therapeutically effective, thereby allowing for subcutaneous administration. Subcutaneous administration is the least invasive method of administration and is considered the most versatile and therefore desirable method of administration, which can be used for short-term and long-term treatment. In some embodiments, subcutaneous administration can be accomplished by injection. In some embodiments, if multiple injections or devices are required, the site of injection or device can be rotated.

[0158] Thus, subcutaneous formulations are much easier for patients to self-administer, especially since they may have to be taken periodically throughout the patient's life. Furthermore, the ease and speed of subcutaneous delivery allows for increased patient compliance and faster access to medication when needed. Thus, the subcutaneous formulations of anti-CD38 antibodies provided herein offer substantial advantages over the prior art and solve certain unmet needs.

[0159] In some embodiments, the antibody of the present disclosure is administered to a subject via a subcutaneous route according to known methods. In some embodiments, the antibody of the present disclosure can be administered by subcutaneous injection. In certain embodiments, the subcutaneous formulation is subcutaneously injected into the same site on the patient for repeated or sequential injections (e.g., into the upper arm, anterior thigh, lower abdomen, or upper back). In other embodiments, the subcutaneous formulation is subcutaneously injected into different or rotating sites on the patient. Single or multiple administrations of the formulation can be used.

[0160] In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat myasthenia gravis. In some embodiments, the subcutaneous unit dosage forms described herein can be used to treat generalized myasthenia gravis.

[0161] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure, after subcutaneous administration to a subject, results in depletion of plasmablasts, plasma cells, NK cells, B cells, and / or T cells. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure results in depletion of plasmablasts. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure results in depletion of plasma cells. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure allows increased depletion of NK cells compared to depletion of B cells or T cells. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure allows increased depletion of NK cells compared to B cells, and increased depletion of NK cells compared to T cells. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure allows increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure allows increased depletion of NK cells compared to B cells, and increased depletion of B cells compared to T cells. Suitably, an antibody or antigen-binding fragment thereof of the present disclosure binds to CD38 - CD38 compared to cells + This may allow for increased cell depletion.

[0162] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure results in a decrease in immunoglobulin levels after subcutaneous administration to a subject. In some embodiments, the immunoglobulin is IgA, IgG, and / or IgM. In some embodiments, the immunoglobulin is IgA. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is IgM.

[0163] In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure, after subcutaneous administration to a subject, results in a reduction of one or more autoantibodies, in some embodiments, the one or more autoantibodies are selected from the group consisting of anti-AChR and anti-MuSK.

[0164] In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 50% to at least 80% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 60% to at least 80% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 50% to 70% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 65% compared to intravenous administration normalized to the same dose. In certain embodiments, the bioavailability of an anti-CD38 antibody described herein after subcutaneous administration is at least 55% to 70% compared to intravenous administration normalized to the same dose.

[0165] In certain embodiments, the bioavailability of an anti-CD38 antibody described herein following subcutaneous administration is at least 40%, at least 45%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, or at least 85% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 50% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 60% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 70% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 80% compared to intravenous administration normalized to the same dose. Preferably, the bioavailability may be at least 90% compared to intravenous administration normalized to the same dose.

[0166] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the present disclosure following subcutaneous administration is 50% to 80% compared to intravenous administration standardized to the same dose.

[0167] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 50% compared to intravenous administration standardized to the same dose.

[0168] In some embodiments, the disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 55% compared to intravenous administration normalized to the same dose.

[0169] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 60% compared to intravenous administration standardized to the same dose.

[0170] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 65% compared to intravenous administration standardized to the same dose.

[0171] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 70% compared to intravenous administration standardized to the same dose.

[0172] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 75% compared to intravenous administration standardized to the same dose.

[0173] In some embodiments, the present disclosure provides methods wherein the bioavailability of an antibody of the disclosure after subcutaneous administration is at least 80% compared to intravenous administration standardized to the same dose.

[0174] In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously in a single bolus injection. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously monthly. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every two weeks. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously weekly. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously twice weekly. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously daily. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 12 hours. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 8 hours. In certain embodiments, the anti-CD38 antibodies or antigen-binding fragments described herein are administered subcutaneously every 6 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every 4 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every 2 hours. In certain embodiments, the anti-CD38 antibody or antigen-binding fragment thereof described herein is subcutaneously administered every hour. In some embodiments, the antibody or antigen-binding fragment thereof disclosed herein is subcutaneously administered once a week for 8 weeks.

[0175] In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof disclosed herein are administered subcutaneously at a dose of about 100 milligrams to about 800 milligrams. In some embodiments, the anti-CD38 antibodies or antigen-binding fragments thereof disclosed herein are administered subcutaneously at a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage of about 300 mg or about 600 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage of about 300 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage of about 600 mg.

[0176] Unit dosage form In some embodiments, the therapeutic anti-CD38 antibody or antigen-binding fragment thereof is formulated as a portion of a unit dosage form. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes. In some embodiments, the antibody or antigen-binding fragment thereof comprises a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6, LCDR1 mezagitamab), RDS (SEQ ID NO: 7, LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes. In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes, and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab), or variants of these sequences with up to three amino acid changes. In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab). In some embodiments, the antibody comprises a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab).In some embodiments, the antibody comprises a HC comprising the following CDR amino acid sequences: GFTFDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), and a LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO: 6; LCDR1 mezagitamab), RDS (SEQ ID NO: 7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8; LCDR3 mezagitamab). In some embodiments, the antibody or antigen-binding fragment thereof comprises a HC comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 9. Suitably, the HC may comprise the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO: 3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO: 4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO: 5; HCDR3 mezagitamab), and the remainder of the HC may have at least 80% sequence identity to SEQ ID NO: 9. In some embodiments, the antibody comprises a HC comprising the VH region amino acid sequence of SEQ ID NO: 9. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQGTLVTVSSASTKGPSVFPLA (SEQ ID NO: 9).

[0177] In some embodiments, the antibody comprises an LC comprising an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 10. Suitably, the LC may comprise the following CDR sequences: SSNIGDNY (SEQ ID NO: 6, LCDR1 mezagitamab), RDS (SEQ ID NO: 7, LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO: 8, LCDR3 mezagitamab), and the remainder of the LC may have at least 80% sequence identity to SEQ ID NO: 10. In some embodiments, the antibody comprises an LC comprising the VL region amino acid sequence of SEQ ID NO: 10. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEEL (SEQ ID NO: 10).

[0178] In some embodiments, the antibody comprises a HC comprising a VH region amino acid sequence of SEQ ID NO: 9 or a variant thereof as described herein, and a LC comprising a VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0179] As will be appreciated by those skilled in the art, the VH and VL regions can be bound to human IgG constant domain sequences, generally IgG1, IgG2, or IgG4. In some embodiments, the antibody comprises an HC having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise the CDR sequences defined by SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, with the remainder of the HC having at least 80% sequence identity to SEQ ID NO: 11. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11. EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGKTHYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0180] In some embodiments, the antibody comprises an LC having an amino acid sequence having at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise the CDR sequences defined by SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, with the remainder of the LC having at least 80% sequence identity to SEQ ID NO: 12. In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12. QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 12).

[0181] In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11, or a variant thereof as described herein, and the LC amino acid sequence of SEQ ID NO: 12, or a variant thereof as described herein.

[0182] In some embodiments, the formulation containing the anti-CD38 antibody is in a unit dosage form, which contains an amount sufficient to administer a dosage of about 100 mg to about 800 mg, e.g., about 100 mg to about 500 mg, about 150 mg to about 450 mg, about 200 mg to about 400 mg, about 400 mg to about 800 mg, about 450 mg to about 750 mg, or about 500 mg to about 700 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dosage of about 300 mg or about 600 mg.

[0183] In some embodiments, the unit dosage form contains an amount sufficient to administer about a 100 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 125 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 150 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 175 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 200 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 225 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 250 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 275 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 300 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 325 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 350 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 375 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 400 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 425 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 450 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 475 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 500 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 525 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 550 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 575 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 600 mg dose. In some embodiments, the unit dosage form contains an amount sufficient to administer about a 625 mg dose. In some embodiments, the unit dosage form contains sufficient to administer a dose of about 650 mg.In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 675 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 700 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 725 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 750 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 775 mg. In some embodiments, the unit dosage form contains an amount sufficient to administer a dose of about 800 mg.

[0184] In some embodiments, unit dosage forms of anti-CD38 antibodies provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents. In some embodiments, the anti-CD38 antibodies are provided as pharmaceutical compositions comprising unit dosage forms according to the present disclosure. Suitably, the pharmaceutical compositions may further comprise one or more pharmaceutically acceptable excipients, carriers, and / or diluents.

[0185] The dosage regimen is adjusted to provide the optimum desired response (e.g., therapeutic response). For example, a single bolus can be administered, multiple divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the requirements of the therapeutic situation. The composition can be formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers, in some embodiments, to physically discrete units suitable as a single dosage for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0186] The specifications for the dosage unit forms of the present disclosure are dictated by and directly depend upon: (a) the unique characteristics of the active compound(s) and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active compound(s) for the treatment of individuals.

[0187] The effective dosage and dosage regimen of the anti-CD38 antibodies or antigen-binding fragments thereof used in the present disclosure will depend on the severity of the disease or condition to be treated and can be determined by those skilled in the art.

[0188] In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 mg to about 800 mg once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 mg to about 800 mg once a week. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 mg to about 800 mg once every two weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 mg to about 800 mg once every three weeks. In some embodiments, the anti-CD38 antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 mg to about 800 mg once every four weeks.

[0189] Preferably, the weekly dosage may be about 100 mg. Preferably, the weekly dosage may be about 125 mg. Preferably, the weekly dosage may be about 150 mg. Preferably, the weekly dosage may be about 175 mg. Preferably, the weekly dosage may be about 200 mg. Preferably, the weekly dosage may be about 225 mg. Preferably, the weekly dosage may be about 250 mg. Preferably, the weekly dosage may be about 275 mg. Preferably, the weekly dosage may be about 300 mg. Preferably, the weekly dosage may be about 325 mg. Preferably, the weekly dosage may be about 350 mg. Preferably, the weekly dosage may be about 375 mg. Preferably, the weekly dosage may be about 400 mg. Preferably, the weekly dosage may be about 425 mg. Preferably, the weekly dosage may be about 450 mg. Preferably, the weekly dosage may be about 475 mg. Preferably, the weekly dosage may be about 500 mg. Preferably, the weekly dosage may be about 525 mg. Preferably, the weekly dosage may be about 550 mg. Preferably, the weekly dosage may be about 575 mg. Preferably, the weekly dosage may be about 600 mg. Preferably, the weekly dosage may be about 625 mg. Preferably, the weekly dosage may be about 650 mg. Preferably, the weekly dosage may be about 675 mg. Preferably, the weekly dosage may be about 700 mg. Preferably, the weekly dosage may be about 725 mg. Preferably, the weekly dosage may be about 750 mg. Preferably, the weekly dosage may be about 775 mg. Preferably, the weekly dosage may be about 800 mg. Administration as disclosed herein may be repeated, for example, 4 to 12 times. In some embodiments, administration as disclosed herein may be repeated 4 times, i.e., weekly for a total of 4 weeks. In some embodiments, administration as disclosed herein may be repeated 5 times, i.e., weekly for a total of 5 weeks. In some embodiments, administration as disclosed herein may be repeated 6 times, i.e., weekly for a total of 6 weeks. In some embodiments, administration as disclosed herein may be repeated 7 times, i.e., weekly for a total of 7 weeks.In some embodiments, administration as disclosed herein may be repeated 8 times, i.e., weekly for a total of 8 weeks. In some embodiments, administration as disclosed herein may be repeated 9 times, i.e., weekly for a total of 9 weeks. In some embodiments, administration as disclosed herein may be repeated 10 times, i.e., weekly for a total of 10 weeks. In some embodiments, administration as disclosed herein may be repeated 11 times, i.e., weekly for a total of 11 weeks. In some embodiments, administration as disclosed herein may be repeated 12 times, i.e., weekly for a total of 12 weeks.

[0190] In one embodiment, the anti-CD38 antibody or antigen-binding fragment thereof is administered at a weekly dosage of about 100 mg to about 800 mg. Suitably, the weekly dosage may be about 100 mg to about 500 mg. Suitably, the weekly dosage may be about 150 mg to about 450 mg. Suitably, the weekly dosage may be about 200 mg to about 400 mg. Suitably, the weekly dosage may be about 400 mg to about 800 mg. Suitably, the weekly dosage may be about 450 mg to about 750 mg. Suitably, the weekly dosage may be about 500 mg to about 700 mg. The dosage may be determined or adjusted by measuring the amount of the compound of the present invention in the blood at the time of administration, for example, by collecting a biological sample and using an anti-idiotypic antibody targeting the antigen-binding region of the anti-CD38 antibody.

[0191] In one embodiment, the therapeutic antibody is formulated at a concentration of about 5 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 20 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 50 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 100 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 120 mg / ml. In another embodiment, the therapeutic antibody is formulated at a concentration of about 150 mg / ml. In some embodiments, a volume of 0.8 mL, 0.9 mL, 1.8 mL, 2.7 mL, or 2.8 mL is injected into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at a concentration of about 75 mg / ml. In some embodiments, a volume of 0.53 mL, 0.6 mL, 1.2 mL, 1.8 mL, or 1.87 mL is injected into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at a concentration of about 90 mg / ml. In some embodiments, a volume of 0.44 mL, 0.5 mL, 1.0 mL, 1.5 mL, or 1.56 mL is injected into the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at a concentration of about 100 mg / ml. In some embodiments, a volume of 0.4 mL, 0.45 mL, 0.9 mL, 1.35 mL, or 1.4 mL is injected into the thigh, abdomen, or arm. In some embodiments, the dose is administered over 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, or 10 hours. In some embodiments, the dose is administered weekly. In some embodiments, the dose is administered every 2 weeks. In some embodiments, the dose is administered every 3 weeks. In some embodiments, the dose is administered every 4 weeks.

[0192] In some embodiments, the disclosure provides a unit dosage form comprising an isolated antibody or antigen-binding fragment thereof comprising a VH region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5, and a VL region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8, wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO: 1), and the unit dosage form is formulated for subcutaneous administration of the antibody or antigen-binding fragment thereof at a dosage of 100 milligrams to 800 milligrams in the treatment of myasthenia gravis.

[0193] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof further comprises one or more engineered glycoforms. In some embodiments, the engineered glycoforms comprise one or more polypeptide glycosylation, wherein the glycosylation is N-linked glycosylation or O-linked glycosylation. In some embodiments, the glycosylation is N-linked glycosylation. In some embodiments, the glycosylation is O-linked glycosylation.

[0194] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the VH region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 9, and / or the VL region of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 10.

[0195] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9.

[0196] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10.

[0197] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9.

[0198] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10.

[0199] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the HC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:11.

[0200] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the LC of the antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:12.

[0201] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291, and E292 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human SEQ ID NOs.

[0202] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO: 1) in an amount of 10 -8 The binding affinity is measured by standard Biacore assays.

[0203] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO:10.

[0204] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO:11 and an LC set forth in SEQ ID NO:12.

[0205] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain. In some embodiments, the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0206] In some embodiments, the invention provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment is a human IgG antibody. In some embodiments, the human IgG antibody is a human IgG1 antibody.

[0207] In some embodiments, the present disclosure provides a unit dosage form further comprising background myasthenia gravis medication(s) disclosed herein.

[0208] In some embodiments, the present invention provides a unit dosage form disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof is used in combination with one or more background myasthenia gravis medications. In some embodiments, the background myasthenia gravis medication(s) is / are selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof. In some embodiments, the background myasthenia gravis medication(s) is / are selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, and azathioprine and cyclosporine, and combinations thereof. In some embodiments, the unit dosage form disclosed herein comprises one or more background myasthenia gravis medications.

[0209] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the antibody or antigen-binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a 100 mg dosage. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 125 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 150 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 175 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 200 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 225 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 250 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 275 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 300 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 325 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 350 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 375 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 400 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 450 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 475 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 500 mg.In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 525 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 550 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 575 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 600 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 625 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 650 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 675 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 700 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 725 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 750 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 775 mg. In some embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of 800 mg.

[0210] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the dosage is administered once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0211] In some embodiments, the present invention provides a unit dosage form as disclosed herein, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

[0212] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein administration of the antibody or antigen-binding fragment thereof results in less than a 10% incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4. In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infections, fever, shingles, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea. In some embodiments, administration of the antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs having a maximum intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

[0213] In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof comprises an HC set forth in SEQ ID NO: 11 and an LC set forth in SEQ ID NO: 12; and the antibody or antigen-binding fragment thereof is administered subcutaneously once a week for 8 weeks. In some embodiments, the disclosure provides a unit dosage form as disclosed herein, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more modified glycoforms, wherein the modified glycoforms comprise one or more glycosylation of the polypeptide, and wherein the glycosylation is N-linked glycosylation.

[0214] treatment method In the methods of the disclosure, treatment is used to provide a positive therapeutic response with respect to a disease or condition. The term "positive therapeutic response" refers to an improvement in the disease or condition and / or an improvement in symptoms associated with the disease or condition.

[0215] A positive therapeutic response in any given disease or condition can be determined by standardized response criteria specific to that disease or condition. In addition to a positive therapeutic response, a subject receiving treatment can experience the beneficial effect of an improvement in symptoms associated with the disease.

[0216] Measurement of efficacy in treating myasthenia gravis can be assessed based on myasthenia gravis disease activity scales according to the SOE Study Activity Table (Table 8, Example 1). Myasthenia gravis disease assessments are based on scores including, but not limited to, Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite (MGC), Revised 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL15r), and / or Myasthenia Gravis Disability Index (MGII), as disclosed in Example 1.

[0217] Treatment according to the present disclosure includes the use of a "therapeutically effective amount" of an agent. The terms "therapeutically effective amount" and "therapeutically effective dosage" refer to an amount of a therapeutic agent that is sufficient, at dosages and for periods of time necessary to achieve the desired therapeutic result, to reduce or ameliorate the severity and / or duration of a disorder or one or more symptoms thereof, to prevent progression of a disorder, to cause regression of a disorder, to prevent the recurrence, occurrence, onset, or progression of one or more symptoms associated with a disorder, or to enhance or improve the prophylactic or therapeutic effect(s) of another therapy (e.g., a prophylactic or therapeutic agent). A therapeutically effective amount may vary according to factors such as the individual's disease state, age, sex, and weight, and the ability of the pharmaceutical agent to elicit a desired response in an individual. A therapeutically effective amount is also one in which any toxic or damaging effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

[0218] Anti-CD38 antibody kit In another aspect, kits for treating MG are provided. In some embodiments, kits for treating systemic MG are provided. In one embodiment, the kit includes a dose of an anti-CD38 antibody described herein, such as TAK-079. In one embodiment, the kit includes a volume of an anti-CD38 antibody described herein, such as mezagitamab. In some embodiments, the kits provided herein may include one or more doses of a liquid or lyophilized formulation provided herein. When the kit includes a lyophilized formulation of an anti-CD38 antibody described herein (e.g., mezagitamab), the kit will generally also contain a suitable liquid (e.g., sterile water or a pharmaceutically acceptable buffer) for reconstituting the liquid formulation. In some embodiments, the kit may include an anti-CD38 antibody formulation described herein prefilled into a syringe for subcutaneous administration by a healthcare professional or for home use.

[0219] In certain embodiments, the kit will be for a single dose or administration of an anti-CD38 antibody described herein, such as mezagitamab. In other embodiments, the kit may contain multiple doses of an anti-CD38 antibody described herein, such as mezagitamab, for subcutaneous administration. In one embodiment, the kit may include an anti-CD38 antibody formulation described herein prefilled into a syringe for subcutaneous administration by a healthcare professional or for home use.

[0220] product In another embodiment, an article of manufacture containing materials useful for treating the disorders described above is provided. The article of manufacture includes a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The container can be formed from a variety of materials (e.g., glass or plastic). The container holds a composition effective for treating a condition and can have a sterile access port (e.g., the container can be an intravenous solution bag or vial with a stopper pierceable by a hypodermic injection needle). The active agent in the composition is an antibody. A label on or associated with the container indicates that the composition is used for treating the selected condition. The article of manufacture may further include a second container containing a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer's solution, or dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. [Example]

[0221] Example 1: A Phase 2 Randomized, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of TAK-079 in Patients with Generalized Myasthenia Gravis Test objectives and research plan The primary objective of this study was to evaluate the safety and tolerability of mezagitamab in subjects receiving stable background therapy for generalized myasthenia gravis (MG).

[0222] A secondary objective of the study was to evaluate the effect of mezagitamab on MG disease activity using clinical rating scales and autoantibody levels.

[0223] The exploratory objectives of this study were: (1) to determine the pharmacokinetics (PK) of mezagitamab; (2) to determine the pharmacodynamic (PD) profile of mezagitamab; (3) to investigate the effect of repeated administration of mezagitamab on MG disease activity using novel clinical disease assessment scales; (4) to investigate the duration of clinically meaningful effects on MG disease severity (using at least one MG clinical assessment scale); (5) to investigate the frequency and proportion of subjects requiring rescue therapy; (6) to investigate vaccine-induced protective antibodies; and (7) to investigate the effect of repeated administration of mezagitamab on exploratory biomarkers of disease activity.

[0224] This was a phase 2, randomized, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, and efficacy of mezagitamab in subjects with systemic MG in combination with standard background therapy.

[0225] Approximately 36 subjects were randomized into the study. After a screening period of up to 28 days, eligible subjects were randomized in a 1:1:1 ratio to one of the following treatment groups: (a) mezagitamab 300 mg added to stable standard background therapy; (b) mezagitamab 600 mg added to stable standard background therapy; or (c) matching placebo added to stable standard background therapy.

[0226] The study was divided into three consecutive periods: an 8-week treatment period, an 8-week safety follow-up period (SFP), and a 16-week long-term follow-up period (LFP).

[0227] During the 8-week treatment period, mezagitamab / matching placebo was administered by subcutaneous (SC) injection once weekly for 8 weeks.

[0228] Safety assessments (e.g., safety laboratory tests) were performed weekly prior to subsequent dosing. Subjects may have had their study drug (mezagitamab / placebo) dose altered (e.g., withheld or postponed) for safety reasons.

[0229] After completing the 8-week treatment period, subjects entered an 8-week blinded SFP and completed safety and efficacy assessments every 2 weeks. After completing the 16-week SFP visit, subjects were unblinded before entering the 20-week LFP visit.

[0230] Subjects randomized to mezagitamab were followed for MG clinical activity scores and autoantibody levels every 4 weeks from week 20 to week 32 of LFP; an end-of-study visit was conducted at week 32 of LFP. For subjects randomized to placebo, an end-of-study visit was conducted at week 20 of LFP. A schematic diagram of the study is shown in Figure 1.

[0231] Adverse events (AEs) (e.g., unresolved clinical / laboratory parameters) that were ongoing at the SFP week 16 visit were monitored through the LFP until they resolved, returned to baseline, or were clearly determined to be due to the subject's stable or chronic condition or intercurrent illness(ies). Study drug-related AEs / serious AEs (SAEs) that occurred after the SFP were collected through the LFP.

[0232] Overall, the maximum follow-up period was approximately 24 weeks after the last dose of study medication. Subjects were permitted to receive rescue medications (e.g., IVIg, high-dose corticosteroids, or plasma exchange / plasmapheresis, or an increase in ongoing background medications) as determined by the investigator. Subjects would automatically enter SFP if they received rescue therapy. Rescue therapy was defined as the additional administration of concurrent medications, according to institutional practice or the physician's best medical judgment, to control and manage the underlying MG condition.

[0233] Selection of study population Selection criteria To be eligible for randomization to treatment, each subject must meet all of the following inclusion criteria: (a) the subject understood and agreed to study participation by providing a signed and dated informed consent document (ICF) and any necessary privacy authorizations prior to the start of any study procedures (where applicable, the subject's legally authorized representative may provide a written informed consent document in accordance with local and regional regulatory requirements), and was, in the investigator's opinion, competent to comply with the requirements of the protocol; (b) the subject was 18 years of age or older. (c) a diagnosis of MG supported by a positive serological test for anti-AChR or anti-MuSK antibodies at screening; (d) Myasthenia Gravis Foundation of America (MGFA) clinical classification II–IV at screening; (e) a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 6 or more at screening, with at least 4 points attributable to non-ophthalmologic components; (f) receiving immunosuppressive medications (i.e., mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, cyclophosphamide). (g) if receiving oral corticosteroids, treatment must have been ongoing for at least 6 months and at a stable dose for at least 3 months prior to screening; subjects receiving azathioprine were on a stable dose for at least 6 months prior to screening; (g) if receiving oral corticosteroids, treatment must have been ongoing for at least 3 months at a stable dose for at least 1 month prior to screening; corticosteroids, including dexamethasone, were administered as oral, daily, or alternate-day therapy, not as pulse therapy; (h) if receiving a cholinesterase inhibitor, treatment must have been on a stable dose for at least 2 weeks prior to screening; (i) the dose of concomitant standard background therapy was expected to remain stable throughout the study unless a dose reduction was required due to toxicity; acceptable background therapy was defined as a cholinesterase inhibitor ± corticosteroid ± one steroid-sparing immunosuppressant (limited to azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide);Subjects must have been taking at least one acceptable background medication; (j) female subjects of childbearing potential were required to have a negative pregnancy test; both male and female subjects had to be on an effective, reliable, and approved contraceptive regimen for 90 days or five half-lives (whichever is longer) during the study or after discontinuation of treatment; (k) subjects were able and willing to comply with study procedures;

[0234] Exclusion criteria Subjects who met any of the following exclusion criteria were not eligible for randomization to treatment: (a) presence of thymoma (history of a completely encapsulated thymoma resected ≥12 months before screening was permitted) or a history of invasive thymic malignancy unless deemed cured by adequate treatment without evidence of recurrence for ≥5 years prior to screening; (b) history of thymectomy within 12 months prior to screening; (c) MGFA class I or V; (d) receipt of IVIg, subcutaneous Ig, or plasma exchange / plasmapheresis within ≥4 weeks prior to screening, or any therapy other than the subject's standard background therapy (e.g., rescue therapy) expected to be used for the treatment of MG between screening and administration; (e) chronic obstructive pulmonary disease (COPD) or asthma with a pre-bronchodilator forced expiratory volume in 1 second (FEV1) <50% of predicted normal (FEV1 testing was required for patients suspected of having COPD or asthma). (f) Receipt of rituximab, belimumab, eculizumab, or any immunomodulatory monoclonal antibody within 6 months prior to the first dose (subjects previously exposed to rituximab must have CD19 counts within the normal range at screening); (g) Known autoimmune disease other than MG that may interfere with the course and conduct of the study; (h) Receipt of a live vaccine within 4 weeks prior to screening or any live vaccination planned during the study period; (i) Any medical condition (e.g., significant cardiovascular, pulmonary, hematologic, gastrointestinal, endocrine, hepatic, renal, neurological, malignant, or infectious disease) that, in the opinion of the investigator, may prevent the subject from participating in the study, pose additional risk to the patient, or confound the patient's evaluation; (j) Pregnancy or lactation during the screening period or on Day 1 prior to the first dose of study drug; (k) Participation in another investigational drug study or exposure to another investigational drug within 4 weeks or 5 half-lives (whichever is longer) prior to Day 1;(l) current treatment for an opportunistic infection within 12 weeks prior to the first study dose or a chronic opportunistic infection (e.g., tuberculosis (TB), Pneumocystis pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria) (mild, localized herpes simplex infection within 12 weeks prior to study dose was permitted as long as the lesions resolved without systemic therapy before Day 1); (m) inadequate organ and bone marrow function: (i) ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3 times the upper limit of normal (ULN); (ii) total bilirubin >1.5 times the ULN (subjects with a confirmed and documented diagnosis of Gilbert syndrome were not excluded based on this criterion); (iii) platelet count 75,000 / mm; 3 (iv) absolute neutrophil count less than 1500 / mm 3 (v) hemoglobin less than 8 g / dL; (vi) IgG less than 5 g / L (500 mg / dL); or (vii) lymphocyte count less than 500 / mm 3(n) A positive T-cell interferon-gamma release assay (TIGRA) (either by QuantiFERON-TB Gold test or T-Spot / Elispot) at the time of the screening visit, with the following caveats: (i) If a TIGRA test was not available, a purified protein derivative (PPD) skin test may have been used; (ii) Subjects with an indeterminate TIGRA result had to meet the following criteria: (1) a negative PPD skin test (defined as a duration of <5 mm); and (2) a chest x-ray within 6 months prior to the screening visit consistent with low risk of contracting TB (e.g., avoiding close contact with TB-positive person(s)) and / or no evidence of latent or active TB; (o) Within the investigator's option, Any serious medical or psychiatric illness that could potentially interfere with completing treatment according to the protocol; (p) a positive test result for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, or HIV antibody / antigen at screening (individuals with a confirmed negative hepatitis C virus RNA polymerase chain reaction test at screening and a known history of chronic hepatitis C who had been treated and completely cured of their disease were not excluded on the basis of a positive hepatitis C antibody alone); (q) a history of severe allergic or anaphylactic reaction to recombinant proteins or excipients used in the mezagitamab / placebo formulation.

[0235] Exclusion of subject from treatment or evaluation Study drug may be permanently discontinued for subjects who meet any of the following criteria: (a) withdrawal by the subject, and (b) pregnancy.

[0236] Treatment with the study drug may be discontinued for any of the following reasons: (a) AE / SAE, (b) protocol deviation, (c) symptomatic worsening, (d) inadequate treatment response, (e) sponsor terminated trial, or (f) loss to follow-up.

[0237] Collection of demographic and medical history data A complete medical history was collected for each subject during the screening period (i.e., within 28 days prior to Study Day 1) and included assessment and recording of medical history, comorbidities, and concomitant treatments. This included assessment of current MG signs, symptoms, and prevalence as assessed and scored with a disease activity tool, as well as assessment of past and current MG treatments.

[0238] Demographic data included age, sex, race, and ethnicity (optional in some countries).

[0239] treatment Treatment performed Premedication On each dosing day, subjects were premedicated with an antipyretic (e.g., acetaminophen) and an antihistamine (e.g., diphenhydramine) 1-3 hours prior to mezagitamab / placebo administration. The premedication regimen was consistent with, but not limited to, the following: (a) antipyretic: oral acetaminophen (650-1000 mg); (b) antihistamine: oral or intravenous diphenhydramine (25-50 mg, or equivalent).

[0240] Mezagitamab / placebo Subjects received mezagitamab 300 mg, mezagitamab 600 mg, or matching placebo by SC injection once weekly for 8 weeks, according to their assigned treatment. The administration of mezagitamab / placebo doses is outlined in Table 4. [Table 4]

[0241] Post-administration drug therapy Subjects were closely monitored in the clinic for at least 2 hours after the first and second doses of mezagitamab / placebo; possible signs and symptoms of anaphylactic reactions and cytokine release syndrome (CRS) were reviewed with the subject before discharge from the clinic.

[0242] After the first dose of study medication, subjects received low-dose methylprednisolone (≤20 mg) or equivalent for prophylaxis of delayed injection-related reactions. To account for the timing of maximal pharmacological effect of mezagitamab, post-dose medication was administered 2 hours (±15 minutes) after the first injection of the first dose and 1 day after the first morning dose of study medication.

[0243] Post-dose low-dose methylprednisolone (≤20 mg) after subsequent doses of mezagitamab / placebo (weeks 2–8) was not required but could be administered if clinically indicated and at the investigator's discretion.

[0244] Subjects at high risk for respiratory complications (e.g., subjects with a history of COPD, subjects with asthma) may have received (at the investigator's discretion) the following after each study dose: (a) an antihistamine (diphenhydramine or equivalent) on days 1 and 2 after study dose; (b) a short-acting beta-2 adrenergic receptor agonist (e.g., salbutamol (albuterol) aerosol); (c) pulmonary disease control medications, such as: (i) inhaled corticosteroids with or without long-acting beta-2 adrenergic receptor agonists for asthma patients; or (ii) long-acting bronchodilators (e.g., tiotropium or salmeterol) with or without inhaled corticosteroids for COPD disease.

[0245] Clinical trial sites were responsible for procuring the treatments administered before or after mezagitamab / placebo.

[0246] Based on emerging data, the physician / designated representative may administer intensified treatment before or after mezagitamab / placebo injection to ensure subject safety.

[0247] Identification of the test drug Mezagitamab is a full-length human IgG1 monoclonal antibody targeted to human CD38. The antibody is composed of two light chains of the λ (lambda) subclass and two heavy chains held together by two disulfide bonds.

[0248] The concentration of mezagitamab used SC in this study was 100 mg mezagitamab in 1 mL (100 mg / mL) (Table 5). [Table 5]

[0249] Packaging, Labeling, and Storage Mezagitamab and matching placebo were supplied in aseptically filled clear, single-use, Type I borosilicate glass vials with aluminum crimp seals having fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0250] Mezagitamab supplies will be labeled in accordance with current GCP (Good Clinical Practice) and International Conference on Harmonisation (ICH) guidelines on Good Manufacturing Practice, including any local requirements.

[0251] During transport, vials were protected from light and maintained within the temperature ranges provided in the dispensing manual. Each shipment of mezagitamab included a packing slip describing the contents of the shipment and all applicable forms. The investigator or designated representative must ensure that proper temperature conditions were maintained for all mezagitamab received and that any discrepancies were reported and resolved before use.

[0252] Upon receipt of the study drug, the investigator or designated representative was required to verify the contents of the shipment against the packing list. The verifier was required to confirm that the quantity was correct, that the drug was received within the storage conditions indicated on the label, and that it was in good condition. If the quantity and condition were within acceptable limits, the investigator or designated representative confirmed receipt of the shipment by signing the bottom half of the packing list and faxing it according to the instructions provided on the form. If there were any discrepancies between the packing list and the actual product received, Takeda was contacted to resolve the issue. The packing list was submitted in the investigator's required documentation file. The sponsor was immediately notified of all temperature excursions and shipping, handling, or storage discrepancies. All clinical trial materials were required to be stored in an appropriate, secure location with limited access until used, destroyed, or returned to the sponsor or designated representative. Mezagitamab was required to be stored according to the manufacturer's instructions as specified on the label (see the dispensing manual for additional information). Detailed dosage preparation instructions were provided in the instructions for use section of the dispensing manual. Complete records were to be kept of the receipt, inventory, control, reconciliation, and disposal of all used and unused study drug vials. Detailed instructions for these activities and related documentation were found in the Dispensing Manual. Drug supplies were counted and reconciled on-site before being returned to Takeda or its designated representative or destroyed.

[0253] The investigator or designated representative was required to ensure that the study drug was used in accordance with the approved protocol and distributed only to patients enrolled in the study. To document the appropriate use of the study drug (mezagitamab), the investigator was required to keep records of all study drug deliveries to the site, site inventory, use by each patient, and return to the sponsor or designated representative.

[0254] During the conduct of the study, the investigator was notified of any expiration date or retest date extension for clinical trial materials. Upon notification of an expiration date from the sponsor or its designated representative, the site must complete all instructions outlined in the notification, including segregating expired clinical trial materials for return to the sponsor or its designated representative.

[0255] Medication Management All clinical trial materials were stored in a secure location with appropriate restricted access until used, destroyed, or returned to the sponsor or its designated representative. Mezagitamab was stored according to the manufacturer's instructions as specified on the label. Detailed administration procedures are described in the instructions for use in the pharmacy manual. Complete records were kept of the receipt, inventory, control, reconciliation, and disposal of all used and unused study drug vials. Detailed instructions and related documentation for these activities were included in the dispensing manual. Drug supplies were counted and reconciled on-site before being returned to Takeda or its designated representative or destroyed.

[0256] The investigator or designated representative was required to ensure that the study drug was used in accordance with the approved protocol and distributed only to subjects enrolled in the study. To document the appropriate use of the study drug (mezagitamab), the investigator was required to keep records of all study drug deliveries to the site, site inventory, use by each subject, and return to the sponsor or its designated representative.

[0257] During the conduct of the study, the investigator was notified of any expiration date or retest date extension for clinical trial materials. Upon notification of an expiration date from the sponsor or its designated representative, the site was required to have completed all instructions outlined in the notification, including segregating expired clinical trial materials for return to the sponsor or its designated representative.

[0258] Overdose Overdose was defined as the known planned or accidental administration of an investigational drug to or by a study subject at a dose that exceeded the dose assigned to that particular subject according to the study protocol.

[0259] To date, there have been no cases of mezagitamab overdose.

[0260] If an overdose occurs, close monitoring and supportive care as medically indicated will be recommended.

[0261] placebo Matching placebo was supplied in sterile-filled clear, disposable Type I borosilicate glass vials with aluminum crimp seals with fluoropolymer-coated butyl rubber stoppers and flip-off caps.

[0262] How subjects were assigned to treatments Subjects were randomly assigned in a 1:1:1 ratio to one of three treatment groups outlined in Table 4 upon completion of study screening and prior to dosing on study day 1 according to a randomization schedule generated by the interactive voice / web response system (IXRS).

[0263] Dose selection for the study The criteria for selecting the mezagitamab dose and regimen for treating patients with MG were based on identifying a safe and well-tolerated dose that exhibited adequate pharmacodynamic (PD) activity.

[0264] Pretrial clinical experience demonstrated that mezagitamab was safe and well tolerated across a wide range of doses (up to 1200 mg), vascular concentrations, and exposures in three different populations (i.e., healthy subjects, subjects with relapsed and / or refractory multiple myeloma (RRMM), and subjects with systemic lupus erythematosus (SLE)).

[0265] In healthy subjects, mezagitamab was well tolerated at doses up to 0.06 mg / kg (intravenous) and 0.6 mg / kg (subcutaneous). The overall safety, tolerability, and PD profile of mezagitamab in dose-escalation studies in healthy, RRMM, and SLE subjects indicates that the optimal dose and schedule of mezagitamab for patients with MG consists of 8 weeks of administration of 300 mg or 600 mg.

[0266] Selection and timing of dose for each subject Prior to mezagitamab / placebo administration, subjects received premedication and underwent safety assessments.

[0267] Because the dose levels (300 and 600 mg) required multiple SC injections to administer the full dose, the Week 1 dose was administered by administering each SC injection 30 minutes apart (±10 minutes) until the full scheduled dose was administered. On all other drug administration days, SC injections would be administered simultaneously with no waiting period if the subject did not have a clinically significant infusion reaction, as determined by the investigator.

[0268] Investigators assessed subjects before each dose. For the first dose, laboratory assessments were evaluated using results obtained at screening. Otherwise, laboratory results were obtained the day before or the day of dosing. If clinical parameters did not meet the criteria for continued dosing, study drug administration was temporarily withheld or discontinued at the investigator's discretion until parameters met the dosing level. Otherwise, mezagitamab / placebo administration was not reduced or increased for a given subject.

[0269] If study dosing was withheld for two consecutive doses due to safety concerns or other circumstances outlined below, the subject was to discontinue study dosing and proceed to SFP. If two or more subjects discontinued the study, the clinician or designated representative was to review the available safety data to determine whether adjustments to the treatment plan should be made.

[0270] Subjects were required to continue a stable dose of standard background therapy throughout the study period unless a dose reduction was required due to toxicity. Acceptable background therapy was defined as cholinesterase inhibitors ± corticosteroids ± one steroid-sparing immunosuppressant (limited to azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide) or less. Subjects were on at least one permitted background medication.

[0271] Blinding Study subjects will remain assigned to one of the three study treatment groups through a blinded randomization schedule available to the investigator in the event of a medical emergency. Otherwise, site staff will remain blinded until Week 16 (SFP) of the study.

[0272] To maintain the integrity of the study, all study personnel (e.g., investigators, site personnel, contract research organization (CRO) medical monitors, study clinicians, and sponsor) were blinded to treatment assignment during the treatment period. Treatment assignment was captured through IXRS according to procedures outlined in the study manual or relevant training materials. Information regarding treatment assignment was securely stored by a designated representative per standard operating procedure.

[0273] Records of subject number, study drug administration dates, and treatment assignment were kept by the study site.

[0274] If necessary, emergency unblinding was performed via the IXRS. No emergency unblinding occurred during this study.

[0275] Prior and concomitant therapy Excluded concomitant medications and procedures Excluded concomitant medications are presented in Table 6. If a subject received an excluded medication, the dosing period was discontinued and the subject was automatically placed into SFP. [Table 6]

[0276] Permitted Concomitant Medications and Procedures Permitted concomitant medications are summarized in Table 7. [Table 7]

[0277] Rescue therapy Rescue therapy was defined as the additional administration of concomitant medications according to institutional practice or the physician's best medical judgment to control and manage the underlying MG condition. Rescue medications may include, but are not limited to, high-dose corticosteroids, IVIg, and plasma exchange / plasmapheresis.

[0278] Subjects were to continue receiving stable doses of immunosuppressant and corticosteroid therapy (per protocol requirements) throughout the study. Subjects would automatically enter SFP if they received rescue therapy.

[0279] Any increase, addition, or change in background immunosuppressive therapy, or addition of medication, as deemed necessary by the investigator to treat the symptoms of MG, but not otherwise within protocol limits, will result in the subject discontinuing study administration and proceeding to SFP.

[0280] treatment compliance Mezagitamab / placebo was administered or dispensed only to eligible subjects under the supervision of the investigator or designated subinvestigator(s). The appropriate investigator maintained records of receipt and dispensing of study medication.

[0281] Efficacy, pharmacokinetics (PK), pharmacodynamics (PD), biomarkers, immunogenicity, and safety variables Evaluation of measurement values ​​and flow chart A schedule of the test procedures is presented in Table 8. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0282] Safety follow-up evaluation completed End-of-SFP clinical parameters outlined in Table 9 were assessed at week 16 of the SFP (see below: SOE in Table 8). If clinical symptoms and parameters did not meet the end-of-SFP criteria and were deemed study-related by the investigator, then study-related parameters that did not meet the end-of-study criteria continued to be assessed with LFP until they normalized or returned to baseline levels. [Table 9]

[0283] Measuring effectiveness The study investigator or appropriately trained and delegated study site staff assessed each subject's disease activity according to the SOEs in Table 8 based on the following MG disease activity scales outlined in the following sections:

[0284] MG-ADL Score: The MG-ADL has been validated as an 8-question patient-reported outcome measure of MG symptoms (Muppidi et al. (2011) Muscle Nerve 44(5):727-31; Wolfe et al. (1999) Neurology 52(7):1487-9, both of which are incorporated herein by reference in their entireties). The MG-ADL assessed relevant MG symptoms and their functional impact on the subject. Subjects were assessed for impairment due to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items). Each item was rated separately, ranging from 0 (normal) to 3 (severe). The total MG-ADL score ranged from 0 to 24 points, with higher scores indicating greater impairment and disability. A 2-point reduction in the MG-ADL total score was considered a clinically meaningful improvement.

[0285] QMG Score for Disease Severity: The Quantitative Myasthenia Gravis (QMG) score is a physician-reported, validated 13-item disease severity assessment tool. The QMG score assesses muscle strength based on quantitative testing and clinician assessment of sentinel muscle groups: ocular muscles (2 items), facial muscles (1 item), bulbar muscles (2 items), gross motor muscles (6 items), axial muscles (1 item), and respiratory muscles (1 item). Each item is rated on a scale of 0 to 3, with 3 being the most severe. Total scores range from 0 to 39, with higher scores indicating greater disease burden (Barohn et al. (1998) Ann. NY Acad. Sci. 841:769-772; Katzberg et al. (2014) Muscle Nerve 49(5):661-665, both incorporated herein by reference in their entireties). A 3-point reduction in the QMG total score was considered a clinically meaningful improvement.

[0286] MGII Score: The Myasthenia Gravis Disability Index (MGII) is a novel, validated assessment scale of MG severity that has demonstrated feasibility, reliability, and construct validity (Barnett et al. (2016) Neurology 87(9):879-886; Barnett et al. (2017) Neurology 89(23):2357-2364, both incorporated herein by reference in their entireties). The MGII score was developed using patient information and consists of 6 physician-examination items and 22 patient-reported items. The MGII has a lower floor effect (i.e., a wider dynamic range at the lower end of the scale) than other commonly used metrics, and therefore is more sensitive in detecting change. Total scores range from 0 to 84 (higher scores indicate worse MG disease activity), and an 8-point reduction at the group level reflects a minimal clinically important difference (MCID). The MCID at the group level (estimating the trial sample size) was 8.1 points, and at the individual level (classifying subjects as responders) was 5.5 points.

[0287] MGC Score: The Myasthenia Gravis Composite Scale (MGC) is a validated 10-item assessment tool for assessing the signs and symptoms of MG, both subject- and physician-reported (Barnett et al. (2018) Neurol. Clin. 36(2):339-353, incorporated herein by reference in its entirety). Physician assessment includes assessment of ptosis (upward gaze), diplopia with lateral gaze, eye closure, neck flexion or extension, shoulder abduction, and hip flexion; subject assessment includes self-report of speech, chewing, swallowing, and breathing. Items are scored based on four potential levels of impact: normal, mild, moderate, or severe. The total score ranges from 0 to 50, with higher scores indicating a greater impact of MG on functional activity (Benatar et al. (2012) Muscle Nerve, 45(6), 909-917; Burns et al. (2012) Ann. NY Acad. Sci. 1274:99-106; Sadjadi et al. (2012) Muscle Nerve 45(6):820-825, each of which is incorporated herein by reference in its entirety). A 3-point reduction in the MGC total score was considered a clinically meaningful improvement.

[0288] MG-QoL15r: The revised 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL15r) is a validated tool containing 15 subject-reported items relating to the subject's perception of functional impairment and disability and the degree to which the subject tolerates disease symptoms (Burns et al. (2010) Muscle Nerve 41(2):219-226; Burns et al. (2011) Muscle Nerve 43(1):14-18; Burns et al. (2016) Muscle Nerve 54(6):1015-1022, each of which is incorporated herein by reference in its entirety). Total scores range from 0 to 30, with higher scores indicating worse MG disease activity. The MCID of this clinical outcome assessment (COA) tool has not been fully determined (Barnett et al. (2018) Neurol. Clin. 36(2):339-353, incorporated herein by reference in its entirety).

[0289] PGIC: The Patient Global Impression of Change (PGIC) is an anchor measure used to aid in the interpretation of the MG disease activity assessment tools mentioned above (MG-ADL, MGII, MGC, QMG, and MG-QoL15r). The PGIC can be used to analyze meaningful change and other psychometric and performance characteristics of these assessment tools.

[0290] PGIS: The Patient Global Impression of Severity (PGIS) is an anchor scale used to aid in the interpretation of the MG disease activity assessment tools mentioned above (MG-ADL, MGII, MGC, QMG, and MG-QoL15r). The PGIS can be used to analyze meaningful change and other psychometric and performance characteristics of these assessment tools.

[0291] Ig Quantitation: Serum samples for IgM, IgG, and IgA were obtained at screening and throughout the study at the time points specified in Table 8; testing was performed at a central laboratory.

[0292] PK, Pharmacodynamics / Biomarker Samples: Samples were collected by venipuncture or indwelling catheter for measurement of mezagitamab serum concentrations and biomarker evaluation as detailed in the SOE in Table 8. Samples were tested in a central laboratory.

[0293] PK Measurements: Serum samples for measurement of mezagitamab concentrations were collected at multiple time points as specified in the SOE in Table 8. Additional PK samples could be requested if deemed necessary by the medical monitor for specific events or AEs of clinical interest.

[0294] Pharmacodynamic / Biomarker Measurements: Several biomarkers were evaluated in this study to test for correlation with safety, PK, and, if possible, efficacy. These biomarkers were used to identify subjects likely to respond or have an adverse reaction to mezagitamab. Biomarker sample analysis was performed if or when necessary. Samples for pharmacodynamic measurements were collected as detailed in Table 8. If a subject exhibited signs or symptoms that could be assessed by the investigator as CRS, blood was drawn for central evaluation, which may include, but is not limited to, immune and cytokine markers.

[0295] autoantibodies Serum samples were collected and analyzed at a central laboratory to detect anti-AChR and anti-MuSK antibodies as outlined in Table 8.

[0296] Pharmacodynamics: Blood samples were collected before, during, and at the end of treatment to analyze CD38+ expression and monitor immune cell changes by flow cytometry. These assessments were performed in a central laboratory.

[0297] Circulating biomarkers: Serum samples for cytokines / chemokines were collected before, during, and at the end of treatment to help identify subjects likely to experience a response to or adverse reaction to mezagitamab.

[0298] Immune profiling: Blood samples for immune profiling were collected before, during, and at the end of treatment. These blood samples were analyzed for the presence and changes of immune cells by flow or mass cytometry.

[0299] Vaccine-induced protective antibodies: Serum samples for vaccine-induced protective antibodies (measles, mumps, rubella, tetanus, and diphtheria) were collected before, during, and at the end of treatment.

[0300] Immunogenicity Sample Collection: Serum samples for measurement of anti-medaxitamab antibodies (anti-drug antibodies and ADA are interchangeable terms in the protocol) were collected at multiple time points as specified in the SOE in Table 8. Samples were collected before each dose. Details regarding immunogenicity sample preparation, handling, and transport are provided in the laboratory manual. Positive ADA screening samples were further tested for true positive rate and titer at the study's central laboratory.

[0301] Safety Measures: Safety was assessed using the safety analysis set by frequency, severity, type of AE, and change from baseline in subject vital signs, body weight, and clinical laboratory results. Exposure to study drug and reasons for discontinuation were tabulated. Treatment-emergent adverse events (TEAEs) occurring after the first dose of study drug through the end of the SFP were tabulated. AEs were tabulated and data summarized using preferred terms (PTs) and major system organ classes (SOCs) according to the Medical Dictionary of Clinical Practice (MedDRA) version 25.0. All safety analyses were performed using the safety analysis set.

[0302] Physical Examination: A complete physical examination and symptom-directed physical examination, including assessment of signs and symptoms of MG, was completed according to standard of care at the times specified in the SOE in Table 8. Women of childbearing potential were asked about their menstrual history at each visit. A serum pregnancy test was performed due to delayed menstruation.

[0303] Height and Weight: Height was measured only during screening (within 28 days of the first dose of TAK079). Weight was measured during screening and at weeks 10, 16, and 32, as outlined in Table 8.

[0304] Vital Signs: Vital signs (temperature, respiratory rate, heart rate, and blood pressure) were assessed and recorded on both the source document and the eCRF at the visits specified in Table 8. Additionally, vital signs were assessed at any time clinically indicated; i.e., if the subject exhibited signs or symptoms of an injection site reaction (ISR), CRS, or hypersensitivity reaction. Vital signs were assessed before each study dose and 2 hours (± 10 minutes) after the first and second doses of mezagitamab / placebo, as shown in Table 8. Clinically significant values, as determined by the investigator, were recorded as AEs and closely monitored for follow-up.

[0305] 12-Lead ECG: One 12-lead electrocardiogram (ECG) was performed and read on-site at the screening visit (to assess eligibility), weeks 10 and 16 for SFP, and week 32 for LFP. Additional ECGs may have been performed per investigator discretion. Standard site practice was followed for each ECG recording. Any ECG result (except at the screening visit) deemed clinically significant by the investigator was considered an AE and was recorded and monitored on source documentation and in the eCRF.

[0306] Adverse Events (AEs): AEs (serious and non-serious) were monitored throughout the study as specified in Table 8.

[0307] Clinical Laboratory Evaluations: Hematology, serum chemistry, and serology evaluations were performed on-site with reference ranges provided in the electronic data capture (EDC) system. Throughout the study, clinical laboratory evaluations were performed in accordance with the SOEs in Table 8. Instructions for handling and delivery of clinical laboratory samples were provided in the study laboratory manual.

[0308] Clinical Chemistry and Hematology Blood samples for analysis of the clinical chemistry and hematology parameters shown in Table 10 were obtained as specified in the SOE in Table 8. [Table 10]

[0309] If two or more subjects discontinued study drug based on the discontinuation criteria listed in Table 11, the clinician / designated representative reviewed the available safety data to determine whether any adjustments to the treatment plan were necessary. [Table 11-1] [Table 11-2]

[0310] pregnancy Serum pregnancy (human chorionic gonadotropin [hCG]) testing was completed for all female subjects; tests were performed at screening and during the SFP and, if negative, were negative for the subject to be randomized and continue in the study.

[0311] A urine pregnancy test was performed for all female subjects before the first dose of mezagitamab / placebo and at week 5 of the treatment period. If the subject reported a delayed menstrual period, a serum pregnancy test was completed with a negative result before administration of study drug.

[0312] All study pregnancy tests were to be performed at a designated local laboratory determined and confirmed by the sponsor, and appropriate laboratory documentation was provided prior to study testing.

[0313] When to take a pregnancy test Women of childbearing potential were required to complete pregnancy testing according to the timing outlined below. (a) Prior to first study dose: (i) Screening Period: Negative serum pregnancy test (hCG <5 mIU / mL); and (ii) Baseline: Negative urine pregnancy test with a sensitivity of at least 50 mIU / mL (either 1 day prior to first study dose or 1 day prior to study dose). If the urine test was indeterminate, a serum pregnancy test was required. (b) During study enrollment: (i) Week 5, pre-dose (urine pregnancy test); (ii) During SFP and LFP (outlined in Table 8) (serum pregnancy test); (iii) If menstruation was late (serum pregnancy test); and (iv) Additional pregnancy tests were performed based on IRB requirements and / or local regulations.

[0314] Measuring relevance The safety and efficacy assessments used in this study were standard for the disease population and study phase.

[0315] Evaluation items Primary endpoint Proportion of patients with TEAEs, including grade ≥3 events, SAEs, and AEs leading to discontinuation of mezagitamab. Secondary endpoints

[0316] Secondary endpoints were: (a) change from baseline in the following scores: (i) MG Activities of Daily Living (MG-ADL) score; (ii) Quantitative Myasthenia Gravis (QMG) score; (iii) Myasthenia Gravis Composite score (MGC score); and (iv) Revised 15-item Myasthenia Gravis Quality of Life Scale (MG-QoL15r); (b) change from baseline in anti-AChR or anti-MuSK antibody levels; and (c) the proportion of patients meeting the MCID criteria for each MG clinical disability scale (MG-ADL, QMG, MGC).

[0317] Exploratory endpoints The exploratory endpoints were as follows: (a) Serum concentration-time profile PK parameters of mezagitamab were the concentration at the end of the dosing interval (C トラフ(b) Changes in serum Ig levels. (c) Pharmacodynamic analysis of the presence and changes in immune cells in peripheral blood before and during treatment. (d) Changes in MGII score from baseline. (e) Duration of clinically meaningful effect on MG disease severity (all clinical disease disability scales: MG-ADL, QMG, MGC, MGII). (f) Proportion of subjects meeting MCID criteria on the MGII scale. (g) Frequency and proportion of subjects requiring rescue therapy. (h) Immunogenicity assessment of mezagitamab in peripheral blood (including, for example, anti-drug antibodies (ADA)). (i) Biomarkers of disease activity (e.g., complement levels (C3, C4, complement split products)); specific markers of CD38 pathway regulation may also be assessed. (j) Changes in levels of the following vaccine-protective antibodies: measles, mumps, rubella, diphtheria, and tetanus.

[0318] Statistical methods and determination of case size Analysis population Full Analysis Set: All enrolled subjects. For efficacy analyses, only subjects with both a baseline value and at least one valid post-baseline value were included.

[0319] Safety analysis population: Subjects who received at least one dose of study drug.

[0320] PK analysis population: Subjects who received at least one dose and had at least one measurable serum concentration of mezagitamab.

[0321] Pharmacodynamic analysis population: Subjects who underwent baseline and at least one post-baseline PD sample assessment.

[0322] Immunogenicity Analysis Population: Subjects in the safety population who had baseline and at least one post-baseline immunogenicity sample assessment.

[0323] Efficacy analysis Efficacy was not the primary endpoint of this study. Secondary efficacy assessments included: (a) change from baseline in the following scores: (i) MG-ADL score, (ii) QMG score, (iii) MGC score, and (iv) MG-QoL15r; (b) change from baseline in anti-AChR antibody or anti-MuSK antibody levels; and (c) the proportion of subjects meeting the MCID criteria for each MG clinical disability scale (MG-ADL, QMG, MGC).

[0324] Exploratory efficacy assessments included: (a) score change from baseline in the MGII score; (b) duration of clinically meaningful effect on MG disease severity (all clinical disease and disability scales: MG-ADL, QMG, MGC, MGII); (c) proportion of subjects meeting MCID criteria on the MGII scale; and (d) frequency and proportion of subjects requiring rescue therapy.

[0325] Efficacy endpoints were summarized with descriptive statistics and presented by treatment group. When appropriate, efficacy endpoints were analyzed in the following ways: (a) dichotomous endpoints were analyzed using Fisher's exact test; (b) changes from baseline in endpoints measured repeatedly over time were analyzed using mixed-model repeated-measures analysis, which included treatment, visit, and the (treatment × visit) interaction term as factors, with baseline value as a covariate.

[0326] All tests of treatment effect were performed at a two-sided alpha level of 0.05 and provided 95% confidence intervals (CIs) for the differences in proportions and least-squares (LS) means. Because no inferential hypothesis tests were performed for these endpoints, the confidence intervals and p-values ​​were not adjusted for multiplicity.

[0327] All efficacy analyses were performed using the full analysis set.

[0328] PK analysis A descriptive overview of the serum mezagitamab concentration-time profile was provided. PK parameters were C トラフA population PK model could be developed. If developed, the population PK model would be reported separately. PK / PD analyses of selected PD and / or efficacy measures could be performed if data permitted. Any population PK / PD analyses, if performed, would be reported separately.

[0329] Immunogenicity analysis The immunogenicity status (ADA incidence) of mezagitamab was analyzed and summarized using descriptive statistics, where applicable, and using the immunogenicity analysis population. The impact of immunogenicity on PK, PD, safety, and efficacy could be investigated. The immunogenicity analysis was based on available data from subjects with a baseline assessment and at least one post-baseline immunogenicity assessment.

[0330] Safety analysis Safety was assessed using the safety analysis set by measuring the frequency, severity, and type of AEs, as well as changes from baseline in subjects' vital signs, body weight, and clinical laboratory results. Exposure to study drug and reasons for discontinuation were tabulated.

[0331] TEAEs occurring after the first dose of study drug through the end of the SFP were tabulated.

[0332] AEs were tabulated according to MedDRA and data were summarized using PTs and major SOCs. All safety analyses were performed using the safety analysis set.

[0333] This study began with the first 12 safety-evaluable subjects, and then monitored every 12 safety-evaluable subjects for Grade 2 or higher medication-related toxicity. If the discontinuation boundary was reached in 3 or more of 12 subjects or 5 or more of 24 subjects, study participation was paused to allow for blinded review of the safety profile. If necessary, a decision on whether participation could be resumed was made after review by the study team, including the safety and medical management team, particularly if unblinding of the case was required. AE grading limits were based on the International Consensus Guidelines for the Management of Myasthenia Gravis, with a target of Grade 1 or lower for CTCAE (Common Terminology Criteria for Adverse Events) adverse drug reactions. Statistical boundaries were based on a Bayesian strategy for monitoring clinical trial outcomes. When the stopping rule was met, there was an 80% probability that the true toxicity rate would exceed 10% based on a prior beta distribution with binomial toxicity rate parameters of 0.2 and 1.8.

[0334] Clinicians reviewed SAEs and related clinical parameters to ensure consistency with an acceptable benefit-risk ratio throughout the study. If more than two subjects experienced the same SAE, the study was paused to allow for a blinded review by the study team, including the safety management team described above, after which a decision was made whether participation could be resumed.

[0335] Determining sample size Approximately 36 subjects were planned to be randomized to treatment (mesagitamab 300 mg, mezagitamab 600 mg, or placebo) in a 1:1:1 ratio. The study was exploratory and not powered to address any predefined hypotheses.

[0336] Example 2: Test Subjects Target accumulation status Data on subject accrual are summarized for the full analysis set in Table 12 and for the dosing schedule in Figure 1. A total of 76 subjects were screened, of which 40 did not participate in the study. Reasons for ineligibility at screening were failure to meet inclusion criteria (38 subjects) and subject withdrawal (2 subjects).

[0337] Thirty-six subjects were randomized at five study sites in the United States, Poland, Serbia, Spain, and Canada. Four of the 36 subjects (two each in the 300 mg and 600 mg mezagitamab groups) discontinued the study due to subject withdrawal. [Table 12]

[0338] Protocol Deviation Significant protocol deviations are summarized in Table 13. In total, significant protocol deviations were reported for 13 subjects, with the most common reason for significant deviations being in the category of missing endpoint assessments (19.4%; 7 subjects), which typically involved missing either the MG-ADL, QMG, MGC, or MG-QoL15r assessments due to site staff shortages, subject quarantine requirements, missed consultations, or missing assessment tools. Other categories of significant protocol deviations reported in one or more subjects were administration of additional concomitant background medications, data privacy, study treatment administration / dispensing, and study treatment supply / control (2 subjects each; 5.6%). These deviations were unlikely to compromise the integrity of the study. [Table 13]

[0339] Example 3: Efficacy, PK, PD, biomarker, and immunological evaluation Analyzed dataset The analysis populations are summarized in Table 14. [Table 14]

[0340] Demographic characteristics Table 15 provides an overview of the demographic characteristics of the subjects enrolled in the study. Demographic characteristics were generally comparable across all groups. Overall, the majority of subjects were Caucasian (91.7%), particularly of European descent (72.2%). The median age for all study groups was 50.0 years, with the oldest age being 81 years. There was some age imbalance between study arms, with the median age for the mezagitamab 600 mg group being approximately 18 and 16 years older than the median ages for the placebo and mezagitamab 300 mg groups, respectively. Regarding the gender distribution in the overall study population, female subjects (n=22, 61.1%) outnumbered male subjects (n=14), but within each study group, the gender distribution was not well balanced: the placebo group was predominantly female (75%), the mezagitamab 300 mg group had an equal number of men and women, and the mezagitamab 600 mg group had a slight female predominance (58.3%). [Table 15-1] [Table 15-2]

[0341] Medical history and other baseline characteristics Of the 36 subjects enrolled in the study, 29 (80.6%) reported data on medical history.

[0342] Key baseline disease characteristics are summarized in Table 16. MG severity, based on the MGFA classification, was class IIIb in 12 subjects (33%), class IIa in 10 subjects (27.8%), and class IIb in 6 subjects (16.7%). MG IIIa and IVa were reported in less than 15% of subjects overall. The mean time since MG diagnosis was 8.8 years overall, with no significant differences between study groups. Most subjects (91.7%) had AChR+ antibodies, and 3 of 36 subjects had MuSK+ antibodies. Baseline scores on all assessed clinical disease disability scales were lower in the placebo group than in the mezagitamab-treated group, suggesting that subjects in the placebo group had less severe disease at baseline. Furthermore, based on mean clinical disease disability scale baseline scores, subjects in the mezagitamab 300 mg group appeared to have more severe disease at baseline compared with subjects in the other two study groups. With regard to previous MG pharmacotherapy, all study subjects had been treated with acetylcholinesterase inhibitors (100%), and the majority had also received a combination of corticosteroids (83.3%) and / or immunosuppressants (72.2%), consistent with refractory disease. [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4]

[0343] Medication history, ongoing background medications, and rescue therapy Ongoing background MG medication All subjects in the study were receiving background MG therapy (Table 17). These included an acetylcholinesterase inhibitor (pyridostigmine) administered to 32 subjects (88.9%); oral corticosteroids (primarily prednisone) administered to 27 subjects (75%); and immunosuppressants (most commonly azathioprine and cyclosporine) administered to 23 subjects (63.9%). These medications were already ongoing and stable at the time of subject enrollment and continued throughout the subjects' study participation. The background therapy administered to subjects in this study was consistent with the study inclusion criteria and the treatment algorithm used to treat subjects with systemic MG. No imbalances in MG background medications were evident at baseline. [Table 17]

[0344] Use of rescue therapy By week 16, 2 subjects (17%) in the placebo group and 1 subject (8%) in the mezagitamab 600 mg group required rescue therapy.

[0345] Five subjects required rescue therapy during the study: two each in the placebo and mezagitamab 600 mg groups and one in the mezagitamab 300 mg group. Table 18 provides a summary of subject levels of rescue therapy use in the study. [Table 18]

[0346] Efficacy, PK, PD, biomarker, and immunogenicity results Efficacy Results Analysis of secondary efficacy endpoints MG-ADL total score At baseline, the mean (SD) MG-ADL total score was lower in the placebo group compared with the mezagitamab-treated group (7.9 (1.78) for placebo; 9.3 (2.49) for mezagitamab 300 mg; and 8.4 (2.23) for mezagitamab 600 mg) (Table 19). At week 16, the mean (SD) change from baseline in MG-ADL response was -4.1 (3.21), -4.3 (2.79), and -3.1 (3.48) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively. Clinically meaningful improvements (≥2-point reduction in MG-ADL total score from baseline) were achieved in all three study groups, although with slight variations in timing and duration. The placebo and mezagitamab 300 mg groups achieved clinical response earlier (week 4), whereas a delay was observed in the mezagitamab 600 mg group. Clinically meaningful improvements achieved with mezagitamab 300 mg appeared to be the most durable across study groups, present from week 4 to the end of the study (week 32); however, comparisons with placebo were not possible after week 16 of the study because placebo data were not collected after week 16. In the MMRM analysis, there were no statistically significant differences between placebo, mezagitamab 300 mg, and mezagitamab 600 mg at any of the evaluation time points.

[0347] Table 19 shows summary statistics for the MG-ADL total score (baseline, week 16, and week 32). Figure 2a shows a plot of the observed mean change from baseline over time in the MG-ADL total score. [Table 19-1] [Table 19-2]

[0348] QMG Total Score At baseline, the mean (SD) QMG total scores were lower in the placebo group compared with the mezagitamab treatment groups (11.4 (5.21) for placebo; 12.9 (6.47) for mezagitamab 300 mg; and 12.8 (4.26) for mezagitamab 600 mg) (Table 20). The mean (SD) change from baseline in QMG scores at week 16 was -1.2 (3.22), -3.3 (3.43), and -0.3 (4.81) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively. In the mezagitamab 300 mg group, clinically meaningful improvements (≥3-point reduction from baseline in QMG total score) were observed from week 8 through week 16, with the greatest response observed at week 12 (mean [SD] change: 3.9 [2.55]). At week 16, no statistically significant differences in change from baseline QMG total score were observed among placebo, the mezagitamab 300 mg group (LS mean difference vs. placebo, -1.37), and the mezagitamab 600 mg group (LS mean difference vs. placebo, 1.20).

[0349] Table 20 shows summary statistics for QMG total score (baseline, week 16, and week 32). Figure 3 shows a plot of the observed mean change from baseline in QMG total score over time. [Table 20-1] [Table 20-2]

[0350] MGC Total Score At baseline, the mean (SD) MGC total scores were lower in the placebo group compared with the mezagitamab-treated group (14.7 (5.80) for placebo; 16.8 (6.58) for mezagitamab 300 mg; and 15.3 (6.00) for mezagitamab 600 mg) (Table 11). The mean (SD) change from baseline in MGC score at week 16 was 6.6 (4.95), −9.2 (5.18), and −2.9 (6.45) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively. Clinically meaningful responses (≥3-point reduction from baseline in MGC total score) were observed with placebo and mezagitamab 300 mg as early as week 4 of the study. This clinically meaningful response was sustained from week 4 to the end of the study (week 32) in the mezagitamab 300 mg group and until week 16 in the placebo group (placebo data were available only through week 16). In the mezagitamab 600 mg group, clinically meaningful improvements were observed only intermittently at weeks 6, 12, 24, and 28. MMRM analysis showed no statistically significant differences at week 16 between placebo, mezagitamab 300 mg (LS mean difference vs. placebo, -1.01), and mezagitamab 600 mg (LS mean difference vs. placebo, 4.81).

[0351] Table 21 shows summary statistics for the MGC total score. Figure 4 shows a plot of the observed mean change from baseline in the MGC total score over time. [Table 21-1] [Table 21-2]

[0352] MG-QoL15r total score The mean (SD) MG-QoL15r total scores at baseline were 11.5 (4.15) in the placebo group, 17.1 (6.76) in the mezagitamab 300 mg group, and 13.9 (4.72) in the mezagitamab 600 mg group (Table 22). The mean (SD) change from baseline in MG-QoL15r scores at week 16 was -3.8 (4.44), -5.8 (6.83), and -2.3 (6.43) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively. Although the MCID for MG-QoL15r has not been established, numerically greater score reductions were observed in the mezagitamab 300 mg group compared with placebo and mezagitamab 600 mg during the first 16 weeks of the study. Furthermore, the reduction in MG-QoL15r scores in the mezagitamab 300 mg group persisted from week 6 to the end of the study, indicating a potential trend toward a lasting impact of this dose of mezagitamab on subjects' quality of life. MMRM analysis showed no significant differences at week 16 between placebo, mezagitamab 300 mg (LS mean difference vs. placebo, 0.20), and mezagitamab 600 mg (LS mean difference vs. placebo, 2.48).

[0353] Table 22 shows summary statistics for MG-QoL15r total score. Figure 5 shows a plot of the observed mean change from baseline in MG-QoL15r total score over time. [Table 22-1] [Table 22-2]

[0354] Responder analysis of MG-ADL At week 16, the responder rates (i.e., subjects meeting the MCID criteria) were 66.67% (8 subjects) in both the placebo and mezagitamab 300 mg groups; the responder rates were 33.33% (4 subjects) in the mezagitamab 600 mg group. Both mezagitamab treatment dose levels demonstrated 41.67% responders (5 subjects) at week 32 (placebo was not evaluated after week 16).

[0355] FIG. 6 shows the proportion of responders in the study groups from week 4 to week 16.

[0356] Figure 7 shows the proportion of responders (subjects with a clinically meaningful reduction of 2 points or more from baseline in MG-ADL score) in the mezagitamab 300 mg group, the mezagitamab 600 mg group, and the placebo group.

[0357] QMG responder analysis At week 16, the proportion of responders (i.e., subjects meeting the MCID criteria) was 33.33% (4 subjects) in the placebo group, 58.33% (7 subjects) in the mezagitamab 300 mg group, and 33.33% (4 subjects) in the mezagitamab 600 mg group.

[0358] The mezagitamab 300 mg group had a response rate of over 40% from weeks 16 to 28 (41.67%, 5 subjects), whereas mezagitamab 600 mg had a lower proportion of responders at these time points (placebo: not assessed after week 16). At week 32, both the mezagitamab 300 mg and 600 mg groups had 16.67% responders (2 each).

[0359] FIG. 8 shows the proportion of responders in the study groups from week 4 to week 16.

[0360] Figure 9 shows an ad hoc sensitivity analysis of the proportion of responders (subjects with a clinically meaningful reduction from baseline in MG-ADL of ≥ 2 points and QMG score of ≥ 3 points) in the zagitamab 300 mg group, the zagitamab 600 mg group, and the placebo group. The ad hoc analysis used a composite endpoint that defined responders as subjects who simultaneously met clinically relevant thresholds for both MG-ADL and QMG.

[0361] MGC responder analysis At week 16, the responder rates were 66.67% (8 subjects) in the placebo group, 75.00% (9 subjects) in the mezagitamab 300 mg group, and 41.67% (5 subjects) in the mezagitamab 600 mg group. At week 32, the mezagitamab 300 mg group had 41.67% (5 subjects) responders compared with 25.00% (3 subjects) in the mezagitamab 600 mg group (placebo was not evaluated after week 16).

[0362] FIG. 10 shows the proportion of responders in the study group from week 4 to week 16.

[0363] Anti-AChR antibody levels At baseline, mean (SD) anti-AChR antibody levels (nmol / L) were higher in the placebo group (119.66 [207.98]) than in the mezagitamab 300 mg group (89.86 [110.93]) and mezagitamab 600 mg group (36.12 [74.80]) (Table 23).

[0364] Both mezagitamab groups demonstrated a reduction in anti-AChR antibodies at week 2, which persisted until the end of the study. In contrast, increases in anti-AChR antibody levels were observed at multiple time points in the placebo group. Significant differences in the change from baseline in anti-AChR antibody levels were observed between the mezagitamab 300 mg group and the placebo group at week 8, as well as at days 10, 14, and 16 (week 16: LS mean difference: -62.98, 95% CI: -100.64, -25.31; p=0.001). A significant difference in the change from baseline in anti-AChR antibody levels was also observed between the mezagitamab 600 mg group and the placebo group at week 14 (LS mean difference: -36.94, 95% CI: 71.39, -2.48; p=0.036).

[0365] At week 16, mean (SD) reductions from baseline of 35.74% (41.58) and 33.69% (37.73) were observed in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively, compared with a mean (SD) increase of 1.23% (18.26) in the placebo group. However, these differences were not statistically significant (LS mean difference vs. placebo: -13.18%, mezagitamab 300 mg; -21.39%, mezagitamab 600 mg), likely due to small sample size and high variability. Nevertheless, the difference between the placebo and mezagitamab 600 mg groups was statistically significant at week 7 (LS mean difference: 36.41, 95% CI: -69.53, -3.29; p=0.032) and week 8 (LS mean difference: -30.54, 95% CI: 55.68, -5.41; p=0.019) (Figure 11). At week 32, the mean (SD) percentage reduction from baseline in anti-AChR antibody levels was 35.77% (33.69) and 24.41% (69.13) in the 300 mg and 600 mg treatment groups, respectively.

[0366] Table 23 shows summary statistics for anti-AChR antibody levels (nmol / L). [Table 23-1] [Table 23-2]

[0367] Anti-MuSK antibody levels For the three MuSK-positive subjects, the placebo subject had a higher baseline anti-MuSK titer value (1:2560) than the two mezagitamab 300 mg subjects (1:160 and 1:640, respectively). No change in anti-MuSK titer values ​​was observed in the placebo subjects at any of the evaluation time points, but a gradual decrease was observed in one of the mezagitamab 300 mg subjects (see Figure 12 for a plot of individual observations over time in the mezagitamab 300 mg group). Due to the small number of cases, statistical analysis of these three cases was not appropriate.

[0368] Table 24 summarizes the percent change from baseline in anti-MuSK titer levels by visit and treatment group. [Table 24-1] [Table 24-2]

[0369] Analysis of exploratory efficacy endpoints MGII Total Score At baseline, the mean (SD) MGII total scores for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups were 30.0 (9.17), 38.3 (12.43), and 34.8 (10.07), respectively. At week 16, the mean (SD) changes from baseline in MGII total scores were -11.9 (9.76), -16.4 (12.29), and -6.6 (15.13) for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. A clinically meaningful reduction was observed in the mezagitamab 300 mg group at week 4, and this improvement was sustained through the end of the study. The placebo and mezagitamab 600 mg groups also intermittently achieved the MCID for this measure, but the magnitude of reduction in MGII total score was smaller and not sustained as long as the mezagitamab 300 mg group. The placebo and mezagitamab 600 mg groups also intermittently achieved the MCID for this measure, but the magnitude of reduction in MGII total score was smaller and not sustained as long as the mezagitamab 300 mg group. The difference in change from baseline in mean MGII total score between the mezagitamab 300 mg and placebo groups was statistically significant at week 6 (difference in LS mean change from baseline: -8.00; 95% CI: -14.17, -1.83; p=0.013).

[0370] FIG. 13 shows a plot of the observed mean change from baseline in MGII total score over time.

[0371] MGII eye subscore At baseline, the mean (SD) MGII ocular subscore between study groups was 6.9 (5.32) for placebo, 8.8 (4.37) for mezagitamab 300 mg, and 8.4 (4.89) for mezagitamab 600 mg. At week 16, the mean change from baseline in MGII ocular subscore was -3.9 (3.93), -2.9 (4.04), and -1.7 (6.24) for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. No significant differences were observed in the change from baseline in mean MGII ocular subscore between the placebo and mezagitamab groups at any of the evaluation time points.

[0372] MGII general symptoms subscore At baseline, mean (SD) MGII global symptom subscores between study groups were as follows: placebo, 8.4 (3.23), mezagitamab 300 mg, 9.7 (3.92), and mezagitamab 600 mg, 9.1 (3.37). At week 16, mean changes from baseline in MGII global symptom scores were -3.6 (3.63), -3.2 (4.61), and -1.3 (4.00) in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. Similar to the MGII total score, the largest difference in mean change from baseline in the MGII global symptoms subscore was observed between the placebo and mezagitamab 300 mg groups at week 6, and this difference was statistically significant (LS mean change difference from baseline: -2.84; 95% CI: 5.11, 0.57; p=0.016).

[0373] Responder-based analysis of MGII At week 16, the proportion of responders (i.e., subjects meeting the MCID criteria) was 66.67% (8 subjects) for placebo, 58.33% (7 subjects) for mezagitamab 300 mg, and 41.67% (5 subjects) for mezagitamab 600 mg. At the end of the open-label follow-up period (week 32), there were 6 responders (50.00%) in the mezagitamab 300 mg group and 4 responders (33.33%) in the mezagitamab 600 mg group (placebo patients not evaluated after week 16).

[0374] Duration of clinically meaningful effects on MG disease severity on the following clinical disease disability measures: MG-ADL By week 16, the proportion of subjects with a clinically meaningful improvement in MG-ADL total score, cumulative over at least 12 weeks, was 33.33% (n=4) for placebo, 66.67% (n=8) for mezagitamab 300 mg, and 25% (n=3) for mezagitamab 600 mg (Table 24). At week 16, the risk difference (95% CI) based on cumulative response data (over 12 weeks) for mezagitamab 300 mg versus placebo was 0.33 (-0.11, 0.69), and the risk difference for mezagitamab 600 mg versus placebo was -0.08 (-0.45, 0.30).

[0375] By week 32, the proportion of subjects whose response was sustained for a cumulative period of 12 weeks or more was 75% (9 subjects) in the mezagitamab 300 mg group and 50.00% (6 subjects) in the mezagitamab 600 mg group (placebo was not evaluated after week 16).

[0376] Table 25 shows the cumulative duration of clinically meaningful effects on MG disease severity as assessed by the MG-ADL in the study group at weeks 16 and 32. Table 26 shows the percentage of participants who achieved a 2-point reduction in the MG-ADL total score. [Table 25] [Table 26]

[0377] QMG By week 16, the proportion of subjects with a clinically meaningful improvement in QMG for at least 12 weeks was 8.33% (1 patient) for placebo, 25% (3 patients) for mezagitamab 300 mg, and 16.67% (2 patients) for mezagitamab 600 mg (Table 27). At week 16, the risk differences (95% CI) based on the number of subjects with a cumulative response of 8 weeks or more and 10 weeks or more were statistically significant for mezagitamab 300 mg versus placebo (8 weeks or more: 0.50 [0.08, 0.80]; 10 weeks or more: 0.42 [0.04, 0.73]), but not for the number of subjects with a cumulative response of 12 weeks or more. No statistically significant differences were observed between placebo and mezagitamab 600 mg for these cumulative responses.

[0378] By week 32, the proportion of subjects whose response was sustained for a cumulative period of 12 weeks or more was 66.67% (8 patients) in the mezagitamab 300 mg group and 33.33% (4 patients) in the mezagitamab 600 mg group (placebo was not evaluated after week 16). [Table 27]

[0379] Table 28 shows the percentage of participants who achieved a 3-point decrease in the QMG total score. [Table 28]

[0380] MGC By week 16, 33.33% (n=4) of patients in the placebo group, 66.67% (n=8) of patients in the mezagitamab 300 mg group, and 33.33% (n=4) of patients in the mezagitamab 600 mg group had a clinically meaningful improvement from baseline in MGC total score, cumulative for at least 12 weeks. At week 16, the risk difference (95% CI) based on cumulative data (≥12 weeks) for mezagitamab 300 mg versus placebo was 0.33 (-0.11, 0.69), and the risk difference for mezagitamab 600 mg versus placebo was 0 (-0.38, 0.38).

[0381] By week 32, the proportion of subjects who achieved a clinically meaningful improvement from baseline in MGC total score, cumulatively sustained for ≥12 weeks, was 83.33% (10 subjects) in the mezagitamab 300 mg group and 58.33% (7 subjects) in the mezagitamab 600 mg group (placebo was not assessed after week 16).

[0382] Table 29 shows the percentage of participants who achieved a 3-point reduction in the MCG total score. [Table 29]

[0383] MGII By week 16, 16.67% (2 patients) in the placebo group, 58.33% (7 patients) in the mezagitamab 300 mg group, and 16.67% (2 patients) in the mezagitamab 600 mg group had a clinically meaningful improvement from baseline in the MGII total score, cumulative for at least 12 weeks. At week 16, the risk difference (95% CI) based on cumulative data (≥12 weeks) for mezagitamab 300 mg versus placebo was statistically significant: 0.42 (0.01, 0.73).

[0384] By week 32, the proportion of subjects who achieved a clinically meaningful improvement from baseline in MGII total score, cumulatively sustained for ≥12 weeks, was 75% (n=9) in the mezagitamab 300 mg group and 33.33% (n=4) in the mezagitamab 600 mg group (placebo was not assessed after week 16).

[0385] PK result Serum concentrations of mezagitamab were detectable in all subjects at both dose levels (Figure 14). Mezagitamab concentrations were measurable in all subjects post-baseline, through weeks 12 and 16 in the 300 mg and 600 mg dose groups, respectively.

[0386] A two-fold increase in dose from 300 mg to 600 mg resulted in an approximately 2.5-fold increase in mean mezagitamab trough concentrations (collected predose) from 85,323 ng / mL to 216,741 ng / mL at Week 8. A greater than dose-proportional increase in drug concentration was observed at early time points. PK samples were not collected to capture peak mezagitamab concentrations.

[0387] Compared with data from the dosing period, large fluctuations in drug concentrations were observed after week 8. After the end of the treatment period, mean drug concentrations showed a decline over 24 weeks, with 100% and 50% of subjects in the 300 mg and 600 mg groups, respectively, achieving values ​​below the lower limit of quantitation (LLOQ) by week 32.

[0388] PD and biomarker results Biomarker validation Preliminary characterization and technical validation of a flow cytometry assay for assessing levels of CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, plasmablasts, and plasma cells in whole blood has been completed. Additionally, the assay has been validated to quantitatively determine CD38 receptor occupancy across each cell type.

[0389] PD and biomarker measurements Individual values ​​and percent change from baseline were calculated for the two mezagitamab doses tested (300 mg and 600 mg) from pre-dose week 1 to week 32. The total number of subjects (N) per study arm was listed in the corresponding table. For CD38+ NK cells and plasmablasts in whole blood, figures of mean receptor occupancy (receptor occupancy (%)) and cell depletion (change from baseline (%)) were generated.

[0390] Target engagement based on receptor occupancy flow cytometry analysis We developed a CD38 receptor occupancy assay to assess changes in CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, plasmablasts, and plasma cells in whole blood. Furthermore, we assessed CD38 expression and mezagitamab receptor occupancy on each cell type by comparing the CD38 fluorescence signal with two independent flow cytometry samples containing either labeled mezagitamab (for quantification of "free" CD38 receptor) or labeled TSF-19 (a non-competitive CD38 antibody for quantification of "total" CD38 receptor).

[0391] NK cells are the most abundant CD38-expressing cell population in peripheral blood, and receptor occupancy on this cell type can be used as a surrogate marker of CD38 engagement on target cells. Mezagitamab CD38 receptor occupancy on CD38+ NK cells reached a mean of 76.6% and 74.3% at 300 mg and 600 mg, respectively, at week 4. NK cell target engagement plateaued between weeks 4 and 12 in both treatment groups and recovered to near baseline by week 32.

[0392] Target engagement was accompanied by changes in absolute CD38+ NK cell counts. The maximum mean decrease in CD38+ NK cells was similar in both mezagitamab treatment groups, with changes from baseline (-83.3% and -80.3%) observed at 300 mg and 600 mg, respectively. NK cell counts decreased continuously throughout the 8-week treatment period, and depletion persisted throughout SFP and LFP, respectively, highlighting the durability of response. Subjects receiving placebo showed only modest changes from baseline in CD38+ NK cells throughout the study period.

[0393] Because these cells represent target cells for mezagitamab that can be quantified in peripheral blood, changes in plasmablast receptor occupancy and absolute numbers were examined. Maximum mean receptor occupancy on plasmablasts was 86.8% and 95.9% at the 300 mg and 600 mg treatment doses, respectively. Plasmablast receptor occupancy reached a plateau between weeks 4 and 16 in both treatment groups and returned to near baseline by week 32.

[0394] Absolute plasmablast count reductions were mostly similar between mezagitamab treatment groups. The greatest effect was observed at week 4, with mean changes from baseline of -84.5% and -57.7% in the 300 mg and 600 mg groups, respectively. Absolute plasmablast counts returned to near baseline by week 32.

[0395] Downstream pharmacology targeting CD38 Serum concentrations of total IgA, IgG, and IgM were assessed as surrogate biomarkers of the effect of mezagitamab on CD38-expressing, antibody-secreting target cells. Serum immunoglobulin depletion was similar between the two mezagitamab treatment groups.

[0396] At week 16, 8-week administration of mezagitamab doses of 300 mg and 600 mg resulted in a mean (SD) decrease from baseline in IgG of 28.3% (9.6) and 25.8% (12.7), respectively (Figure 15). IgG showed a sustained pattern of depletion, with a mean decrease of 24.4% observed in the combined treatment group at week 32, the last time point tested in the study.

[0397] Treatment with 300 mg and 600 mg mezagitamab induced maximum mean (SD) decreases from baseline in IgM of 36.4% (13.0) and 37.8% (15.4), respectively. Partial recovery to baseline was observed during the long-term follow-up period, which was more pronounced in the 300 mg group.

[0398] IgA depletion was greatest, with maximum mean (SD) decreases from baseline of 56.8% (9.4) and 52.6% (17.2) in the 300 mg and 600 mg dose groups, respectively. In all subjects treated with mezagitamab, IgA did not fully recover to baseline by week 32.

[0399] In the placebo group, the maximum mean (SD) reductions were 8.5% (6.1) for IgG, 8.5% (8.1) for IgA, and 15.4% (21.8) for IgM.

[0400] Changes in autoantibodies were evaluated for disease-specific PD effects. Anti-AChR antibodies and total IgG showed concordant longitudinal profiles. Reductions in anti-AChR concentrations did not appear to be dose-dependent, with maximum mean (SD) decreases from baseline of 49.6% (29.8%) and 42.7% (24.6%) at 300 mg and 600 mg, respectively. In the placebo group, anti-AChR reductions showed a maximum mean (SD) decrease from baseline of 17.4% (30.5%). Anti-AChR depletion showed substantial variability at the individual level. Data on depletion of anti-MuSK antibodies by mezagitamab were limited.

[0401] Immunogenicity results All 36 subjects in the immunogenicity set underwent baseline and at least one post-baseline ADA assessment.

[0402] Subjects who had a positive ADA response in both baseline and postbaseline samples (maximum postbaseline ADA titer less than four times the baseline titer value) were considered to have a pre-existing ADA. One subject in the placebo group had a pre-existing ADA, but there were no subjects with pre-existing ADA in either the mezagitamab 300 mg or 600 mg groups, for an overall pre-existing ADA incidence of 2.78%.

[0403] Subjects with a positive baseline ADA result and a post-baseline titer increase of 4-fold or greater than the baseline titer were considered to have treatment-emergent ADAs; however, no subjects in this study met these criteria. Subjects with a negative baseline ADA result and any post-dose positive ADA result were considered to have treatment-emergent ADAs. No subjects in the placebo group experienced treatment-emergent ADAs, and one subject in the mezagitamab 300 mg group and one subject in the mezagitamab 600 mg group experienced treatment-emergent ADAs. This represents an overall incidence of treatment-emergent ADAs of 5.56% (Table 30).

[0404] The overall ADA prevalence, including both pre-existing and treatment-emergent ADA at any time point, was 8.33% (3 of 36).

[0405] The minimum dilution or titer required for this study was 40, and titers were assessed only for ADA-positive samples. In all subjects with treatment-emergent ADA, the range was 40 to 1280 (Table 31). No correlation was observed between ADA titer and dosage.

[0406] ADA response was accompanied by a decrease in mezagitamab concentrations at the individual level. In the mezagitamab-treated group, ADA-positive subjects (one in each treatment group) had lower drug concentrations than ADA-negative subjects at the time of visit with ADA-positive samples. No clear association was observed between ADA response and PD or efficacy. No clinically significant AEs were observed in the two subjects with treatment-emergent ADA. [Table 30] [Table 31-1] [Table 31-2]

[0407] Statistical and analytical issues Covariate adjustment: No covariate adjustment was performed.

[0408] Treatment of Dropouts or Missing Data: Efficacy data were analyzed using only observed case data based on the "missing at random" assumption.

[0409] Interim Analysis and Data Monitoring: This study underwent interim analysis or data monitoring.

[0410] Multicenter Study: This was a multicenter study. No statistical adjustments were made to compensate for the multicenter nature of the study.

[0411] Multiple comparisons / multiplicity: Statistical adjustments were made for multiple comparisons.

[0412] Use of Efficacy Subset of Interest: Efficacy analyses were performed on the full analysis population consisting of all enrolled patients with a baseline value and at least one valid post-baseline value.

[0413] Active controlled trial intended to show equivalence: This was not an active controlled trial intended to show equivalence.

[0414] Subgroup Examination: Exploratory post-hoc subgroup analyses comparing clinical responses assessed by MG-ADL and QMG total scores in subjects based on region (North America vs. Europe). These post-hoc analyses demonstrated significantly greater placebo response in North American subjects compared with European subjects in both MG-ADL and QMG (Figures 16 and 17). Furthermore, subgroup analyses by timing of acetylcholinesterase inhibitor administration revealed that the lack of consistency in the timing of these symptomatic medications between and within patients prior to clinical evaluation contributed to significant variability in clinical responses assessed by MG-ADL and QMG (Figures 18 and 19).

[0415] Figure 20 shows the pharmacodynamic effect (moderate reduction in total IgG with a corresponding depletion in anti-AChR antibodies). A shows the change from baseline in IgG levels. B shows the change from baseline in anti-AChR antibody levels.

[0416] Figure 21 shows the depletion of IgA and IgM after 8 weeks of treatment by week 32. Figure 21A shows IgA and Figure 21B shows IgM.

[0417] FIG. 22 shows the PD response of mezagitamab compared to efgartigimod.

[0418] Figure 23 shows that there is a high consistency between QMG response and IgG depletion in the 300 mg dose group, but not in the placebo group. The dashed red line indicates a 3-point reduction in QMG score.

[0419] Figure 24 shows that at 300 mg, there is high consistency between QMG / ADL response and IgG reduction. The dashed red line indicates a 3-point reduction in QMG score.

[0420] Figure 25 shows the change from baseline in anti-MuSK antibody levels (secondary endpoint).

[0421] Figure 26 shows that the placebo response was less pronounced in MGII and MGQOL15-R (based on investigator's non-administration / non-intervention patient assessment).

[0422] FIG. 27 shows the individual MG-ADL and QMG responses at 16 weeks.

[0423] FIG. 28 shows the placebo response of mezagitamab compared to the comparative study MG-ADL.

[0424] Figure 29 shows mezagitamab compared to the comparative study QMG.

[0425] FIG. 30 shows the placebo response of mezagitamab compared to the comparative study QMG.

[0426] Figure 31 shows mezagitamab exposure within the expected range, with a PK profile consistent with MM. There was a dose-proportional increase in exposure from 300 mg to 600 mg. The PK profile of mezagitamab in MG is consistent with that expected from the MM study, with concentrations trending toward the upper limit of exposure prediction. The dashed black line and shaded area represent the median and 90% prediction interval based on simulations from a preliminary MM population PK model. One subject with an abnormal PK profile at 300 mg developed ADA at week 4 (potency 40), then at week 7 (potency 40) and week 8 (potency 20). Other visits were ADA-negative.

[0427] Figure 32 shows mezagitamab exposure parameters for responders and non-responders. A preliminary integrated population PK model was developed (based on the pooled SLE and MM final dataset and available MG data) to derive a complete concentration-time profile for each subject and used to calculate exposure metrics: (a) Cavg: average concentration (ng / mL) one week after the last (weekly) dose; (b) Cmax: maximum drug concentration (ng / mL) during the study; and (c) cumAUC: cumulative AUC (hxng / mL) up to one week after the last (weekly) dose. No clear differences in mezagitamab exposure were observed between responders and non-responders (based on MG-ADL response at Week 16).

[0428] FIG. 33 shows exposure-response assessment of IgG (best % reduction in IgG) across MM and MG studies.

[0429] Figure 34 shows the exposure-response assessment of MG-ADL. The orange dashed line represents the clinically meaningful threshold of a 2-point reduction in MG-ADL. Increasing exposure was not associated with improvements in MG-ADL scores. A similar pattern was observed for QMG.

[0430] Figure 35 shows background therapy.

[0431] Figure 36 shows a mixed-model repeated measures analysis of the change from baseline in MG-ADL scores (full analysis set).

[0432] Figure 37 shows a mixed-model repeated measures analysis of the change from baseline in QMG scores (Full Analysis Set).

[0433] PK, efficacy, PD, biomarker, and immunogenicity conclusions Penalty kick A two-fold increase in dose from 300 mg to 600 mg resulted in an approximately 2.5-fold increase in mean mezagitamab trough concentrations (collected pre-dose) at week 8 from 85323 ng / mL to 216741 ng / mL.

[0434] After the treatment period, mean drug concentrations showed a decline over 24 weeks, with 100% and 50% of subjects achieving values ​​below the lower limit of quantitation (LLOQ) by week 32 at 300 mg and 600 mg, respectively.

[0435] Effectiveness MG-ADL total score At week 16, the mean (SD) reduction from baseline in MG-ADL total score was -4.1 (3.21), -4.3 (2.79), and -3.1 (3.48) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively.

[0436] At week 16, the responder rate was 66.67% in both the placebo and mezagitamab 300 mg groups, compared with 33.33% in the mezagitamab 600 mg group.

[0437] By week 16, 33.33%, 66.67%, and 25% of subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had a clinically meaningful improvement from baseline for at least 12 weeks cumulatively. By week 32, these rates were 75% and 50% in the mezagitamab 300 mg and 600 mg groups, respectively.

[0438] QMG Total Score At week 16, the mean (SD) reductions from baseline in QMG scores were -1.2 (3.22), -3.3 (3.43), and -0.3 (4.81) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively. The largest change from baseline observed in the study occurred at week 12 in the mezagitamab 300 mg group (mean [SD] -3.9 [2.55]).

[0439] At week 16, the responder rates in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups were 33.33%, 58.33%, and 33.33%, respectively.

[0440] By week 16, 8.33%, 25%, and 16.67% of subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had a clinically meaningful improvement from baseline for at least 12 weeks cumulatively. By week 32, these rates were 66.67% and 33.33% in the mezagitamab 300 mg and 600 mg groups, respectively.

[0441] MGC Total Score At week 16, the mean (SD) reduction from baseline in MGC total score was -6.6 (4.95), -9.2 (5.18), and -2.9 (6.45) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively.

[0442] At week 16, the responder rates were 66.67%, 75%, and 41.67% in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively.

[0443] By week 16, 33.33%, 66.67%, and 33.33% of subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had a clinically meaningful improvement from baseline for at least 12 weeks cumulative; by week 32, these rates were 83.33% and 58.33% in the mezagitamab 300 mg and 600 mg groups, respectively.

[0444] MG-QoL15r total score At week 16, the mean (SD) change from baseline in MG-QoL15r scores was -3.8 (4.44), -5.8 (6.83), and -2.3 (6.43) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively.

[0445] MGII Total Score At week 16, the mean (SD) reduction from baseline in MGII total score was -11.9 (9.76), -16.4 (12.29), and -6.6 (15.13) in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. At week 6, the difference in change from baseline in mean MGII total score between the placebo and mezagitamab 300 mg groups was statistically significant and clinically meaningful (LS mean change difference at baseline: -8.00; 95% CI: -14.17, -1.83; p=0.013).

[0446] At week 16, the responder rates in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups were 66.67%, 58.33%, and 41.67%, respectively.

[0447] By week 16, 16.67%, 58.33%, and 16.67% of subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had at least 12 weeks of cumulative clinically meaningful improvement. By week 32, these rates were 75% and 33.33% for mezagitamab 300 mg and 600 mg, respectively.

[0448] Rescue therapy By week 16, 2 subjects (17%) in the placebo group and 1 subject (8%) in the mezagitamab 600 mg group required rescue therapy.

[0449] By week 32, five subjects required rescue therapy: two each in the placebo and mezagitamab 600 mg groups and one in the mezagitamab 300 mg group.

[0450] Anti-AChR antibody levels Reductions in anti-AChR antibodies were observed as early as week 2, were not dose-dependent, and persisted until the end of the study (week 32).

[0451] At week 16, mean (SD) reductions of 35.74% (41.58) and 33.69% (37.73) were observed in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively, compared with a mean (SD) increase of 1.23% (18.26) in the placebo group.

[0452] At week 32, the mean (SD) percentage reduction from baseline in anti-AChR antibody levels was 35.77% (33.69) in the mezagitamab 300 mg group and 24.41% (69.13) in the mezagitamab 600 mg group.

[0453] Anti-MuSK antibody levels Of the three MuSK-positive subjects, no change in anti-MuSK titer values ​​was observed in subjects in the placebo group at any of the evaluation time points, but a gradual decrease was observed in one of the two mezagitamab 300 mg subjects.

[0454] PD and biomarkers Mezagitamab mean CD38 receptor occupancy on CD38+ NK cells reached a near-maximum of approximately 75% at week 4 in both the 300 mg and 600 mg mezagitamab groups, remained stable through week 12, and returned to near baseline by week 32. CD38+ NK cells were depleted by up to approximately 80% at either 300 mg or 600 mg, with depletion kinetics closely resembling those of receptor occupancy in the same cell types. Placebo-treated subjects showed only modest changes from baseline in CD38+ NK cells throughout the study period.

[0455] The maximum mean (SD) receptor occupancy on plasmablasts was mostly similar between the mezagitamab 300 mg and mezagitamab 600 mg groups (86.8% (22.3) and 95.9% (3.6), respectively). The greatest plasmablast reduction was observed at week 4, with a mean (SD) reduction from baseline of 84.5% (17.7) and 57.7% (41.1) in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively.

[0456] Serum IgG depletion was similar between the two mezagitamab treatment groups, with a mean (SD) reduction at week 16 of 28.3% (9.6) and 25.8% (12.7) for the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively, and IgG depletion persisted in both mezagitamab groups through week 32. The placebo group did not experience a significant decrease in IgG, with a maximum mean (SD) reduction of 8.5% (6.1).

[0457] The maximum mean (SD) reductions from baseline in IgM were 15.4% (21.8), 36.4% (13.0), and 37.8% (15.4) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, with partial recovery to baseline being more pronounced in the 300 mg group.

[0458] The maximum mean (SD) reductions from baseline in IgA were 8.5% (8.1), 56.8% (9.4), and 52.6% (17.2) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, with no apparent recovery to baseline by week 32.

[0459] immunogenicity The overall ADA prevalence, including both pre-existing and treatment-emergent ADA at any time point, was 8.33% (3 of 36).

[0460] In all subjects with treatment-emergent ADA, the range was 40 to 1280. No correlation was observed between ADA titer and medication dose.

[0461] Although ADA responses were detected in parallel with reduced drug concentrations, data are too limited to conclusively determine the impact of ADA on PK. No clear association was observed between ADA responses and PD, efficacy, or safety.

[0462] Example 4: Evaluation of safety and safety biomarkers Extent of exposure A summary of study drug exposure and compliance is presented in Table 32. Twenty-four subjects received at least one dose of mezagitamab (12 in each treatment group), and 12 subjects received at least one dose of placebo. Mean compliance was 100% in the placebo group and 99.0% in the mezagitamab combination group. [Table 32]

[0463] Administration interruption Prior to receiving each study drug, subjects were assessed for dosing criteria based on laboratory assessments and clinical events defined in Table 11.

[0464] Dosing was withheld for two subjects: one in the mezagitamab 300 mg group and one in the mezagitamab 600 mg group; the decision was based on laboratory evaluation (decreasing lymphocyte count) and clinical event (positive COVID-19 test), respectively. The outcome of both events was recovery / resolution.

[0465] AE A pretreatment event (PTE) was defined as any untoward medical event in a subject who had signed informed consent for study participation but before administration of any study medication, but which did not necessarily have a causal relationship to study participation.

[0466] An AE is defined as any untoward medical occurrence in a subject receiving a drug, but not necessarily having a causal relationship to this treatment. A TEAE was defined as an AE that occurred after the first dose of study drug was received through the end of the treatment period and safety follow-up. Serious TEAEs are hereafter referred to as SAEs.

[0467] Verbatim terms of PTEs and AEs were coded by SOC and PT using MedDRA version 25.0.

[0468] A brief summary of adverse events A summary of TEAEs is presented in Table 33. Overall, mezagitamab was well tolerated in patients with MG. There was no substantial imbalance in AEs between treatment groups, and the majority were mild in severity. SAEs were balanced between study arms (two SAEs in the placebo group, one SAE each in the mezagitamab 300 mg and mezagitamab 600 mg groups). All reported SAEs were related to study drug. Additionally, there were no discontinuations of study treatment, and no on-study deaths were reported. Grade ≥ 3 TEAEs were balanced between study arms. Only one relevant TEAE was reported, which occurred in one subject in the mezagitamab 300 mg group and consisted of a decrease in lymphocyte count; the outcome of this event was recovery / resolution. Other clinically relevant AEs (e.g., injection- and infusion-related reactions (IRR), anemia, and lymphopenia) were balanced between study arms. No cases of thrombocytopenia were reported during the study. [Table 33]

[0469] Adverse Event Display The most frequent TEAEs (≥10% of all subjects) and TEAEs considered related to study drug are presented by SOC and PT in Table 34 and Table 35, respectively. [Table 34] [Table 35-1] [Table 35-2]

[0470] AE analysis Most common TEAEs The most frequently reported TEAEs (≥10% of all subjects) by preferred term in the safety analysis population are summarized in Table 34.

[0471] Overall, 15 subjects (41.7%) experienced 20 TEAEs regardless of causality, compared with 4 subjects (33.3%) in the placebo group, 3 subjects (25%) in the mezagitamab 300 mg group, and 8 subjects (66.7%) in the mezagitamab 600 mg group.

[0472] In the placebo group, one subject (8.3%) experienced fever and nasopharyngitis, respectively, and two subjects (16.7%) experienced gastroenteritis.

[0473] In the mezagitamab 300 mg group, 2 subjects (16.7%) experienced fever and 1 subject (8.3%) experienced fatigue. In the mezagitamab 600 mg group, 3 subjects (25%) experienced fever and chills, respectively, and 2 subjects (16.7%) experienced fatigue and nasopharyngitis, respectively.

[0474] All TEAEs were grade 1 or grade 2 toxicities, except for four TEAEs that were grade 3 toxicities (three unrelated to the study drug and one related to the study drug); two in the placebo group and one each in the mezagitamab 300 mg and mezagitamab 600 mg groups.

[0475] One subject tested positive for COVID-19, and there were no COVID-19-related TEAEs in the study.

[0476] Study drug-related TEAEs TEAEs assessed by the investigator as related to study drug are summarized in Table 35. In total, 15 subjects experienced 27 events: 2 subjects (16.7%) in the placebo group, 5 subjects (41.7%) in the mezagitamab 300 mg group, and 8 subjects (66.7%) in the mezagitamab 600 mg group. The most frequently reported treatment-related TEAEs were pyrexia in the mezagitamab 300 mg group and chills and pyrexia in the mezagitamab 600 mg group.

[0477] The outcomes of all relevant TEAEs were recovery / resolution, except for the grade 1 events of normocytic anemia and a decrease in serum immunoglobulin A in the mezagitamab 600 mg group, which did not resolve by the end of the study.

[0478] TEAEs by severity In this study, most TEAEs were grade 1 or 2 in severity. Four of the 98 TEAEs were grade 3 in severity. Of these four events, only one event (decreased lymphocyte count) was reported by the investigator as related to study treatment. The outcome of the event was recovery / dissolution.

[0479] Death, other AEs, and other serious AEs List of deaths, other SAEs, and other serious AEs death No deaths occurred during the study period.

[0480] Other serious adverse events A total of four SAEs were reported in three subjects (Table 36). One subject each in the mezagitamab 300 mg group and the mezagitamab 600 mg group experienced the SAEs of suicidal ideation and MG (worsening MG), respectively. One subject in the placebo group experienced two SAEs (enteritis and gastroenteritis). All SAEs were reported to be unrelated to study drug and had recovery / resolution outcomes. [Table 36]

[0481] Other serious AEs TEAEs leading to discontinuation of study drug No TEAEs led to discontinuation of study drug.

[0482] TEAEs leading to dose modification Dose modifications in this study consisted of either dose interruptions or drug withholding. Two subjects were withheld.

[0483] Infusion reaction TEAE local injection site reactions Local injection site reaction TEAEs are summarized in Table 37. In total, 3 subjects (1 in the placebo group and 2 in the mezagitamab 600 mg group) experienced Grade 1 injection site reactions. The outcomes of all events were recovery / resolution. [Table 37]

[0484] systemic IRR Investigator-determined systemic IRRs were reported in equal numbers of subjects in the mezagitamab 300 mg and 600 mg groups (3 subjects each). In the mezagitamab 300 mg group, 3 subjects experienced systemic IRR TEAEs of influenza-like illness, visual disturbances, and fever. In the mezagitamab 600 mg group, 3 subjects experienced systemic IRR TEAEs of chills and fever. Most events were grade 1 in severity; two subjects in the mezagitamab 600 mg group experienced grade 2 fever. All events were reported as related to mezagitamab. Most events resolved within 1 day (median time to recovery was 1 day), and all events had a resolved / dissolved outcome.

[0485] Analysis and discussion of deaths, other SAEs, and other serious AEs There were 3 subjects with treatment-emergent SAEs, all of which were considered life-threatening.SAEs were balanced between study arms.

[0486] Clinical Laboratory Evaluation serum chemistry AEs related to serum chemistry parameters were observed in both the placebo and mezagitamab treatment groups, with no apparent dose-dependence.

[0487] Fifteen subjects (five in the placebo group, six in the mezagitamab 300 mg group, and four in the mezagitamab 600 mg group) reported higher-than-normal lactate dehydrogenase levels at screening, which remained elevated throughout the study. Four subjects (one in the placebo group, one in the mezagitamab 300 mg group, and two in the mezagitamab 600 mg group) reported mild and transient increases in LDH during the study, all of which resolved and were within the normal range by the end of the study. One subject in the mezagitamab 600 mg group experienced a threefold increase above the ULN in ALT and AST at week 16. This event occurred after administration of rescue medication and was reported by the investigator as a non-study drug-related TEAE because it was believed to be caused by the administration of IVIG used in this subject at that time in the study to treat disease progression.

[0488] hematology Overall, three subjects (one in each of the three study groups) had abnormal values ​​for the combined total lymphocyte count. Only one TEAE of lymphocyte count decrease was observed in this study, which occurred in one subject in the mezagitamab 300 mg group; it was reported as related to the study drug, and the event outcome was recovery / resolution. Three TEAEs of anemia were reported (one in the mezagitamab 300 mg group and two in the mezagitamab 600 mg group). Of these, one TEAE of anemia in the mezagitamab 600 mg group was related to the study drug and did not resolve. The remaining two anemia events in the mezagitamab 300 mg and 600 mg groups were not related to the study drug and resolved and improved, respectively. Furthermore, anemia reported in one subject in the 300 mg group was already present at the start of the study and therefore was not considered related to the study drug. A subset of subjects had lower than normal hemoglobin / hematocrit levels at the start of the study, which may be due to ongoing immunosuppressant treatment; several of these experienced a slight downward trend in both hemoglobin and hematocrit over the course of the study. Because the number of affected subjects was balanced between the placebo and mezagitamab-treated groups, no dose-dependence was apparent regarding this downward trend. No subjects in the study group experienced a decrease in hemoglobin levels of less than 8 g / dL at any time during the study.

[0489] Vital signs and ECG Vital signs No trends were observed in the means or changes from baseline of vital sign-related parameters. In the placebo group, abnormal vital signs were reported in one subject for heart rate >120 bpm, systolic blood pressure >180 mmHg, and temperature <35.6°C. Similarly, in the 600 mg group, abnormal vital parameters were reported in one subject for systolic blood pressure >180 mmHg and diastolic blood pressure <50 mmHg.

[0490] Vital sign-related AEs included fever in six subjects (one in the placebo group, two in the mezagitamab 300 mg group, and three in the mezagitamab 600 mg group). Fever in subjects in the mezagitamab 300 mg and 600 mg groups was reported as related to study drug. Event outcomes were resolved / dissolved in all six subjects, with most events resolving within 1 day.

[0491] electro-cardiogram No trends were observed in electrocardiogram (ECG) mean values ​​or changes from baseline. At baseline, all subjects had normal or no clinically significant abnormal ECG results. No subjects had a shift to clinically significant abnormal results post-baseline at any time point.

[0492] Safety Biomarkers Vaccine-induced antibodies (e.g., measles, mumps, rubella, diphtheria, and tetanus) were assessed to determine the impact of mezagitamab on protective immunity. The maximum mean reduction in these antibodies was comparable to the mezagitamab treatment group, with all showing less than a 25% change from baseline. The placebo group showed minimal reductions, except for diphtheria antibodies, which showed a mean maximum reduction of 13.0%. All vaccine-induced antibodies recovered to near baseline or showed an increase by week 32.

[0493] In each mezagitamab dose group, three subjects were below the LLOQ of the diphtheria assay at any point during the study. Additionally, one subject in the 300 mg dose group had a value below the LLOQ for rubella. In the placebo group, two subjects (one subject each for rubella and tetanus) had observations below the LLOQ. All of these subjects had baseline values ​​near the LLOQ for their respective antibodies.

[0494] pregnancy No pregnancies were reported during the study period.

[0495] Safety Conclusions Overall, mezagitamab was well tolerated in subjects with generalized myasthenia gravis in this study. There was no substantial imbalance in AEs between treatment arms, and no dose-dependent AEs or new safety concerns were identified.

[0496] Overall, 24 subjects received at least one dose of mezagitamab (12 in each treatment group) and 12 subjects received at least one dose of placebo.

[0497] TEAEs reported in ≥10% of subjects were gastroenteritis in the placebo group and fever in the mezagitamab 300 mg group, but fever and chills were the most common in the mezagitamab 600 mg group.

[0498] The majority of TEAEs were grade 1 or grade 2 in severity. Grade 3 TEAEs were reported in only four subjects and were balanced between study arms. In this study, three subjects reported treatment-emergent SAEs: one in each study arm; two SAEs of enterocolitis and gastroenteritis reported by one subject in the placebo group; one SAE of suicidal ideation in the mezagitamab 300 mg group; and one SAE of MG (worsening MG) in the mezagitamab 600 mg group. None of these SAEs were related to study treatment, and all SAE outcomes were recovery / resolution.

[0499] IRRs were reported only in mezagitamab-treated subjects and were observed in 25% of subjects in each of the mezagitamab 300 mg and 600 mg groups. Clinical events of interest (e.g., lymphopenia and anemia) were balanced between study arms.

[0500] There were no clinically significant findings on laboratory evaluation, vital signs, or ECG.

[0501] The decrease in vaccine-induced antibodies was not dose-dependent, with changes from baseline (<25%) observed in the mezagitamab-treated groups. All vaccine-induced antibodies recovered to near baseline or showed an increase by week 32. In the mezagitamab 300 mg and mezagitamab 600 mg groups, only three subjects who already had baseline antibodies near the LLOQ fell below the LLOQ for diphtheria and rubella antibodies.

[0502] Example 5: Discussion and Overall Conclusions Business plan overview Demographic and baseline characteristics: No significant differences were identified between baseline characteristics.

[0503] Safety: Mezagitamab TAK was well tolerated at doses up to 600 mg, with no new safety concerns identified. SAEs and grade ≥ 3 TEAEs were uncommon and balanced between study arms. Infections, anemia, and lymphopenia were uncommon and not clearly dose-related.

[0504] Efficacy: The 300 mg dose of mezagitamab demonstrated clinically relevant reductions in both MG-ADL and QMG, both in response magnitude / amplitude and proportion of responders. The 600 mg dose of mezagitamab demonstrated mixed efficacy signals despite biochemical responses. A higher-than-expected placebo response.

[0505] Pharmacodynamics: Mezagitamab induced moderate PD responses, with maximum mean depletion of approximately 30% for IgG antibodies and approximately 50% for anti-AChR antibodies.

[0506] Durability: Mezagitamab at both dose levels was sustained beyond treatment week 32 in most subjects with IgG / AChR antibody data. Clinical responses were sustained at the 300 mg dose in both MG-ADL and QMG.

[0507] Pharmacokinetics / Immunogenicity: Exposure within the expected range with a PK profile consistent with MM, trending towards the upper end of predicted exposure. Only one subject treated with mezagitamab (300 mg group) developed a low-titer ADA response.

[0508] Consideration The primary objective of this study was to evaluate the safety and tolerability of mezagitamab in patients with systemic MG. This was the second study to administer mezagitamab to an autoimmune patient population, following the systemic lupus erythematosus (SLE) study (TAK-079-2001). In the SLE study (TAK-079-2001), the highest dose level was 135 mg, and mezagitamab was administered every 3 weeks for a total of 12 weeks. MG subjects in this study received a maximum of 600 mg weekly for 8 weeks. Overall, the safety data collected in this study suggest that mezagitamab is well tolerated, with a favorable safety profile, at doses significantly higher than those evaluated in SLE patients, resulting in higher exposure. The mezagitamab AEs reported in this study were consistent with those observed in first-in-human studies in healthy volunteers (TAK-079-101) and SLE patients. No new safety events were identified in patients with myasthenia gravis.

[0509] The clinically significant events based on mezagitamab's mechanism of action were hypersensitivity reactions, CRS, and systemic infections. There were no cases of CRS, and the observed cases of IRR were mild and reported in 25% of subjects in each mezagitamab treatment group. These IRRs primarily occurred during the first administration event and resolved within a few days. Regarding infections, nasopharyngitis (one event in one placebo subject and two events in two 600 mg subjects) and gastroenteritis (two events in the same placebo subject) were reported in the study. All of these infections were considered related to the study drug and did not appear to be dose-related. All cases of nasopharyngitis were mild (less than grade 1). Additional clinical events closely monitored during the study included anemia and thrombocytopenia due to CD38 expression on red blood cells and platelets. Only one case of drug-related anemia (grade 1) was reported in the mezagitamab 600 mg group. No cases of thrombocytopenia were reported, providing preliminary evidence that high-dose mezagitamab is not expected to increase the risk of anemia or thrombocytopenia. Regarding the other clinically relevant event, dose dependency was unclear; only one event of lymphopenia was reported in the mezagitamab 300 mg group. This event was grade 3 and was considered related to the study drug; however, the subject was also receiving moderately high doses of concomitant systemic corticosteroids, which may have contributed to the lymphopenia.

[0510] Although mezagitamab substantially reduced immunoglobulins at both doses evaluated, the effect on pre-existing vaccine-induced antibodies did not appear to be clinically significant in this study and patient population, providing preliminary evidence that administration of mezagitamab may not adversely affect pre-existing vaccine-induced immunity.

[0511] The low incidence of treatment-emergent ADAs (5.56%) observed in this study is consistent with previous findings suggesting a low immunogenicity risk for mezagitamab. Limited ADA data preclude a definitive determination of the effect on ADA exposure. ADA responses did not appear to be dose-dependent, and no clear association between ADA responses and safety or efficacy was observed.

[0512] From a PK perspective, a dose-proportional increase in drug concentration was observed from 300 mg to 600 mg. This suggests that mezagitamab exhibits linear PK behavior at these doses. Mezagitamab has been reported to have nonlinear PK due to CD38-mediated elimination in the low dose range tested in healthy subjects (TAK-079-101) and subjects with systemic lupus erythematosus (TAK-079-2001). This appears to saturate at doses above 300 mg in this patient population.

[0513] A secondary objective of the study was to evaluate the effect of mezagitamab on MG disease severity. While the mezagitamab 300 mg group, but not the mezagitamab 600 mg group, met the clinically relevant thresholds for the following clinical measures evaluated in this study (MG-ADL, QMG, MGC, and MGII), this potential signal of preliminary clinical benefit was worse than the expected placebo response observed within the study (Bril et al. (2021) Neurology 96(6):e853-e865; Howard et al. (2019) Neurology 92(23),e2661-e2673; Howard et al. (2020) Neurology 77(5):582-592). The elevated placebo response was particularly pronounced for MG-ADL and less pronounced for other clinical measures. When stratified by region, MG-ADL placebo responses within European subjects were found to be comparable to those observed in other MG trials, whereas placebo responses within North American subjects were found to be significantly elevated. Numerous factors in this study may explain the elevated placebo response (including, but not limited to, elevated baseline scores) due to enrollment of only MG-ADL (patients with reported outcomes) and the predominance of female and younger subjects with less severe disease within the placebo group (Katz (2021) Pain Rep. 6(1):e845; Landin et al. (2000) Biometrics 56(1):271-278). Additionally, the MG-ADL has inherent limitations as an assessment tool that accurately and relevantly captures subject symptoms.

[0514] Additional confounding factors in the study include the nonstandardized withholding of acetylcholinesterase inhibitors before clinical evaluation and the extension of additional prophylactic corticosteroid use beyond week 1 in some subjects. Discrepancies in the timing of when subjects received acetylcholinesterase inhibitors with respect to clinical evaluation (particularly QMG) may confound the actual treatment effect and / or inflate placebo responses. While the use of prophylactic CS at the time of initial administration was necessary to mitigate potential IRRs, the additional use of CS after initial treatment is thought to have resulted in a disproportionate treatment effect in subjects who received additional CS for up to 4 weeks after the start of the study.

[0515] From a PD perspective, mezagitamab demonstrated a reduction in CD38+ target cells and immunoglobulins (including depletion of anti-AChR antibodies). No dose-dependent trends were observed in immunoglobulin responses or any other evaluated PD parameters. This indicates a clear saturation of biochemical responses at the 300 mg weekly dose and no additional benefit at the 600 mg dose. Moderate depletion of IgG and autoantibodies was observed in certain subjects in the 600 mg cohort. Changes in all Ig isotypes were significantly greater in the mezagitamab-treated group compared with the placebo group, providing evidence for this disease mechanism. Notably, Ig depletion was maintained up to 6 months after the end of treatment. In line with observations in other studies using mezagitamab, the greatest changes were observed in the IgA class.

[0516] In this study, subjects were primarily positive for anti-AChR antibodies, reflecting the high prevalence of this autoantibody type in the MG patient population. The therapeutic hypothesis that targeting CD38-expressing plasma cells and plasmablasts would result in a reduction of pathogenic antibodies involved in MG was confirmed by the reduction in anti-AChR concentrations. The attenuation of pathophysiology was similar between the two tested doses, but was accompanied by an efficacy signal only in the 300 mg dose group.

[0517] conclusion The results of this phase 2 study demonstrate that weekly administration of mezagitamab at doses up to 600 mg had a favorable safety profile in patients with systemic MG receiving stable concomitant background therapy. No new safety events specific to MG subjects were identified, and the study did not reveal a dose-dependent pattern of clinically relevant AEs.

[0518] Improvements in the severity of MG symptoms, as assessed by various MG assessment scales (i.e., MG-ADL, QMG, MGC, MG-QoL15r, and MGII), were present in all three placebo-treated cohorts throughout the 16-week blinded study period, albeit with different degrees and durations of response.

[0519] A durable and sustained reduction in both IgG and anti-AChR antibody levels was seen in both mezagitamab-treated groups, confirming that anti-CD38 mechanisms are relevant for modulating this autoantibody-driven disease.

[0520] In conclusion, this study established a favorable safety profile and provided proof of mechanism of action for mezagitamab in subjects with generalized myasthenia gravis.

[0521] Incorporation by Reference The contents of all cited references (including literature references, patents, patent applications, and websites) that may be cited throughout this application, as well as the references cited therein, are expressly incorporated herein by reference in their entirety for any purpose to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety for any purpose.

[0522] equivalent The present disclosure may be embodied in other specific forms without departing from its spirit or essential characteristics. Accordingly, the above-described embodiments should be considered in all respects as illustrative and not limiting of the present disclosure. The scope of the present disclosure is therefore indicated by the appended claims, rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein. Modifications for carrying out the present disclosure that are obvious to those skilled in the art are intended to be within the scope of the appended claims.

Claims

1. 1. A method of treating myasthenia gravis in a subject, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

2. 1. A method for reducing the level of plasmablasts, plasma cells, and / or NK cells in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO:3, CDR2 having the amino acid sequence of SEQ ID NO:4, and CDR3 having the amino acid sequence of SEQ ID NO:5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO:6, CDR2 having the amino acid sequence of SEQ ID NO:7, and CDR3 having the amino acid sequence of SEQ ID NO:8; wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

3. 1. A method of reducing the level of immunoglobulin cells(s) in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

4. 4. The method of claim 3, wherein the immunoglobulin is IgA, IgG, and / or IgM.

5. 1. A method for reducing the level of one or more autoantibodies in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

6. 6. The method of claim 5, wherein the one or more autoantibodies are selected from the group consisting of anti-AChR and anti-MuSK.

7. 1. A method for reducing disease activity and / or progression of myasthenia gravis in a subject diagnosed with myasthenia gravis, the method comprising administering to the subject an isolated human anti-CD38 antibody or antigen-binding fragment thereof, wherein the isolated antibody or antigen-binding fragment thereof comprises a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO: 6, CDR2 having the amino acid sequence of SEQ ID NO: 7, and CDR3 having the amino acid sequence of SEQ ID NO: 8; wherein the isolated antibody or antigen-binding fragment thereof is administered subcutaneously at a dosage of about 100 to about 800 milligrams.

8. 8. The method of claim 7, wherein the myasthenia gravis disease activity is measured by a score selected from one or more of Myasthenia Gravis Activities of Daily Living (MG-ADL), Quantitative Myasthenia Gravis (QMG), Myasthenia Gravis Composite (MGC), Myasthenia Gravis Quality of Life Scale Revised 15-item (MG-QoL15r), and / or Myasthenia Gravis Disability Index (MGII).

9. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more modified glycoforms, wherein the modified glycoforms comprise one or more polypeptide glycosylations, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

10. the variable heavy chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO:9, and / or the variable light chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO:10; Optionally, the variable heavy chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9, and / or the variable light chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10; Optionally, the variable heavy chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9, and / or the variable light chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10; Optionally, the heavy chain of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 11; and / or the light chain of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 12; Optionally, the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291, and E292 of SEQ ID NO:1 and SEQ ID NO:2, based on human SEQ ID NOs; Optionally, the isolated antibody or antigen-binding fragment thereof is －８ binds to human CD38 (SEQ ID NO: 1) with a K of 1 M or greater, as measured by a standard Biacore® assay; Optionally, the variable heavy chain region comprises SEQ ID NO:9 and the variable light chain region comprises SEQ ID NO:10; and Optionally, the isolated antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO:11 and a light chain set forth in SEQ ID NO:

12.

11. the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain; Optionally, the Fc domain is a human Fc domain or a variant Fc domain; and 2. The method of any one of the preceding claims, optionally wherein the isolated antibody or antigen-binding fragment is a human IgG antibody, and optionally wherein the human IgG antibody is a human IgG1 antibody.

12. 10. The method of any one of the preceding claims, wherein the subject is administered a background myasthenia gravis medication(s), and optionally the background myasthenia gravis medication(s) is / are selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof; and optionally the background myasthenia gravis medication(s) is / are selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, azathioprine, and cyclosporine, and combinations thereof.

13. 13. The method of claim 12, wherein the background myasthenia gravis therapeutic agent(s) is administered in combination with the isolated antibody or antigen-binding fragment thereof.

14. Administration of the isolated antibody or antigen-binding fragment thereof results in an incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4 less than 10%; optionally, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, parasitic infections, fever, shingles, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea; and Optionally, the method of any one of the preceding claims, wherein administration of the isolated antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs with a maximal intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

15. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof is administered at a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg; and optionally, the isolated antibody or antigen-binding fragment thereof is administered at a dosage of about 300 mg or about 600 mg.

16. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

17. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof is administered in the form of a pharmaceutically acceptable composition, and optionally, the pharmaceutically acceptable composition comprises the isolated antibody or antigen-binding fragment thereof and at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

18. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 11 and a light chain set forth in SEQ ID NO: 12; and the antibody or antigen-binding fragment thereof is administered subcutaneously once a week for eight weeks.

19. 10. The method of any one of the preceding claims, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

20. 1. A unit dosage form comprising an isolated antibody or antigen-binding fragment thereof, the unit dosage form comprising: a variable heavy chain (VH) region comprising CDR1 having the amino acid sequence of SEQ ID NO:3, CDR2 having the amino acid sequence of SEQ ID NO:4, and CDR3 having the amino acid sequence of SEQ ID NO:5; and a variable light chain (VL) region comprising CDR1 having the amino acid sequence of SEQ ID NO:6, CDR2 having the amino acid sequence of SEQ ID NO:7, and CDR3 having the amino acid sequence of SEQ ID NO:8, wherein the isolated antibody or antigen-binding fragment thereof binds to human CD38 (SEQ ID NO:1), and the unit dosage form is formulated for subcutaneous administration of the isolated antibody or antigen-binding fragment thereof at a dose of 100 milligrams to 800 milligrams in the treatment of myasthenia gravis.

21. 21. The unit dosage form of claim 20, wherein the isolated antibody or antigen-binding fragment thereof further comprises one or more modified glycoforms, wherein the modified glycoforms comprise one or more polypeptide glycosylations, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

22. the variable heavy chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO:9, and / or the variable light chain region of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 90% identity to SEQ ID NO:10; Optionally, the variable heavy chain region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:9, and / or the variable light chain region comprises an amino acid sequence having at least 95% identity to SEQ ID NO:10; Optionally, the variable heavy chain region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:9, and / or the variable light chain region comprises an amino acid sequence having at least 99% identity to SEQ ID NO:10; Optionally, the heavy chain of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 11, and / or the light chain of the isolated antibody or antigen-binding fragment thereof comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 12; Optionally, the isolated antibody or antigen-binding fragment thereof interacts with at least K121, F135, Q139, D141, E239, W241, C275, K276, F284, P291, and E292 of SEQ ID NO:1 and SEQ ID NO:2, based on human SEQ ID NOs; Optionally, the isolated antibody or antigen-binding fragment thereof has an affinity of 10 －８ binds to human CD38 (SEQ ID NO: 1) with a K of equal to or greater than M, said affinity being measured by a standard Biacore® assay; Optionally, the variable heavy chain region comprises SEQ ID NO:9 and the variable light chain region comprises SEQ ID NO:10; and 22. The unit dosage form of claim 20 or 21, optionally wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO:11 and a light chain set forth in SEQ ID NO:

12.

23. the isolated antibody or antigen-binding fragment thereof further comprises an Fc domain, optionally wherein the Fc domain is a human Fc domain or a variant Fc domain; and Optionally, the isolated antibody or antigen-binding fragment is a human IgG antibody; 23. The unit dosage form of any one of claims 20 to 22, optionally wherein the human IgG antibody is a human IgG1 antibody.

24. 24. The unit dosage form of any one of claims 20-23, wherein the isolated antibody or antigen-binding fragment thereof is used in combination with one or more background myasthenia gravis treatment medication(s), optionally wherein the background myasthenia gravis treatment medication(s) is / are selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof; and optionally wherein the background myasthenia gravis treatment medication is selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, azathioprine, and cyclosporine, and combinations thereof.

25. administration of the isolated antibody or antigen-binding fragment thereof results in an incidence of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs) of Grade 3 or 4 of less than 10%; Optionally, the TRAE or TEAE is selected from the group consisting of gastrointestinal disorders, nausea, parasitic infections, fever, shingles, urinary tract infections, skin and skin tissue disorders, headache, fever, chills / rigors, vomiting, diarrhea, joint pain, muscle pain, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea; and 25. The unit dosage form of any one of claims 20-24, optionally wherein administration of the isolated antibody or antigen-binding fragment thereof results in one or more TRAEs or TEAEs with a maximal intensity of Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or Grade 2.

26. 26. The unit dosage form of any one of claims 20-25, wherein the isolated antibody or antigen-binding fragment thereof is administered in a dosage selected from the group consisting of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, or about 800 mg; and optionally, the isolated antibody or antigen-binding fragment thereof is administered in a dosage of about 300 mg or about 600 mg.

27. 27. The unit dosage form of any one of claims 20 to 26, wherein the dosage is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

28. 28. The unit dosage form of any one of claims 20 to 27, further comprising at least one pharmaceutically acceptable carrier, excipient, or stabilizer.

29. 29. The unit dosage form of any one of claims 20-28, wherein the isolated antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO:11 and a light chain set forth in SEQ ID NO:12; and the isolated antibody or antigen-binding fragment thereof is administered subcutaneously once weekly for eight weeks.

30. 30. The unit dosage form of any one of claims 20-29, wherein the isolated antibody or antigen-binding fragment thereof is mezagitamab.

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