EP4646435A1 - Anti-cd38 antibodies for the treatment of autoimmune diseases - Google Patents

Abstract

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

Description

ANTI-CD38 ANTIBODIES FOR THE TREATMENT

OF AUTOIMMUNE DISEASES

Cross Reference to Related Applications

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application Serial No. 63/478,884 filed on January 6, 2023, and U.S. Provisional Application Serial No.

63/515,285 filed on July 24, 2023, the entire disclosures of which are incorporated herein by reference.

Incorporation By Reference Of Material Submitted Electronically

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML file format and is hereby incorporated by reference in its entirety. Said XML file, created on December 12, 2023, is named 101588-5017-WO Sequence Listing.xml and is 16,384 bytes in size.

Field

[0003] Methods for treating patients with autoimmune diseases such as myasthenia gravis (MG) by administering isolated anti-CD38 antibodies are disclosed. Also disclosed are unit dosage forms for the anti-CD38 antibodies used in treating patients with autoimmune diseases such as myasthenia gravis (MG).

Background

[0004] Myasthenia gravis (MG) is a rare autoimmune disorder in which autoantibodies target the neuromuscular junction (NMJ) and postsynaptic membrane and interfere with neuromuscular transmission which leads to progressive weakness of skeletal muscles. The prevalence of MG is approximately 77.7 per million 14 to 40 per 100,000 individuals in the US (Breiner etal. (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] Characteristically for MG, the skeletal muscle weakness and fatigability worsen with physical activity and improve with rest (Ludwig et al. (2017) Front. Immunol. 8: 603). In some cases, muscle weakness can lead to respiratory and cardiac dysfunction (Phillips and Vincent (2016) FlOOORes. 5: F1000 Faculty Rev-1513). The disease may be life-threatening; in a myasthenic crisis, the muscles that control breathing become too weak, which can result in death due to respiratory failure.

[0006] MG is caused by pathogenic autoantibodies that are produced by plasma cells. Most patients (70%) with MG produce immunoglobulin (Ig)Gl and IgG3 autoantibodies against the acetylcholine receptor (AChR), while the remaining patients either produce IgG4 autoantibodies against muscle-specific tyrosine kinase (MuSK; 1-10% of MG patients), IgGl-3 antibodies against the low-density lipoprotein receptor-related protein 4 (1-5% of MG patients) or produce no detectable autoantibodies (10% of MG patients). The binding of autoantibodies to proteins in 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 challenging. Autoantibodyproducing plasma cells are resistant to many conventional pharmacologic strategies because they are not actively cycling and express relatively few surface antigens.

[0008] The current standard of care for MG consists of a combination of symptomatic therapy (acetylcholinesterase inhibitors to increase the levels of acetylcholine in the synapse) and immunosuppression. Immunosuppressive or immunomodulatory therapies (such as corticosteroids, azathioprine, methotrexate, cyclosporine, tacrolimus, cyclophosphamide, plasmapheresis/plasma exchange, and intravenous immunoglobulin [IVIg]) are given to patients who do not have satisfactory results with symptomatic therapy alone. Nevertheless, approximately 10% of patients have treatment-refractory disease, and up to 80% of patients fail to reach a 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 medications have several drawbacks, including limited efficacy and severe dose-limiting toxicities. Furthermore, these drugs do not directly affect autoantibody production. [0009] Autoantibody levels can be lowered by targeting the B-cell progenitors of plasma cells. Rituximab (an anti-CD20 antibody) targets these plasma cell progenitors, thereby indirectly decreasing autoantibody production by preventing the replenishment of autoreactive plasma cells. However, rituximab’s efficacy in MG has been limited, likely because the long-lived plasma cells that are thought to be primarily responsible for anti-AChR antibody production do not express CD20 and are therefore not targeted by rituximab (Ludwig et al. (2017) Front. Immunol. 8: 603).

[0010] There are some therapeutic options available to lower autoantibody levels by increasing the clearance of pathogenic autoantibodies, e.g.. plasmapheresis/plasma exchange, administration of IVIg, or neonatal Fc receptor (FcRn) antagonists. Plasmapheresis and IVIg are mostly used until other medications take effect, before surgery, or for myasthenic crisis because of their fast but short-lived impact. An alternative approach to increase the clearance of autoantibodies may be achieved by blocking the FcRn; several FcRn antagonists are currently in clinical development and one therapy has been recently approved (Heo (2022) Drugs 82(3): 341- 348). These drugs decrease pathogenic IgG by inhibiting FcRn-mediated IgG recycling, thereby by accelerating their clearance. However, these three treatment methods do not directly eliminate the source of pathogenic autoantibodies. Furthermore, the duration of effect is relatively short, as shown by preliminary published data (Heo (2022) Drugs 82(3): 341-348). Consequently, chronic administration is required to maintain low levels of pathogenic autoantibodies (Kiessling et al. (2017) Sci. Transl. Med. 9(414): eaanl208).

[0011] Another therapeutic strategy in MG that does not eliminate the root cause of the disease is to reduce the complement-mediated damage of the postsynaptic membrane at the NMJ. This can be achieved with eculizumab, a monoclonal antibody that targets complement protein C5. While showing moderate efficacy, eculizumab therapy is related to increased risks of meningococcal infections and thereby is restricted by risk evaluation and mitigation strategies (Howard et al. (2017) Lancet. Neurol. 16(12): 976-986). Other complement inhibitors are in development; however, these agents are expected to benefit only AChR-positive patients because AChR autoantibodies effectively activate complement and lead to postsynaptic membrane lysis whereas MuSK autoantibodies do not bind complement (Yi et al. (2018) Muscle Nerve 57(2), 172-84). [0012] Thus, there is a need for novel therapies to treat MG that act at the source of the disease pathogenesis and provide a more sustained response with a favorable safety profile; treatments such as these may have the potential to decrease the use of corticosteroids and improve patients’ quality of life. As described, available conventional pharmacological therapies do not target autoantibody-producing plasma cells, especially long-lived plasma cells, which are the source of pathogenic autoantibody formation in MG.

Summary

[0013] Provided herein are methods and unit dosage forms comprising anti-CD38 antibodies or antigen binding fragments thereof used in treating patients with autoimmune diseases such as myasthenia gravis (MG). AB79 (the drug substance component of mezagitamab) is a fully human recombinant monoclonal antibody (mAb) directed against CD38, an antigen that is highly expressed on plasma cells, plasmablasts, and natural killer (NK) cells and is induced on activated T cells and B cells. AB79 binds specifically to CD38 with high affinity (Kd = 3.5 nM) (US Patent No. US 8,362,211, the contents of which is hereby incorporated by reference in its entirety). AB79 administration results in depletion of cells expressing high levels of CD38 through a mechanism that involves apoptosis, antibody-dependent cell-mediated cytotoxicity, and complement-dependent cytotoxicity (Smithson et al. (2017) J. Immunol. 198(1 Supplement): 224.20). AB79 depletes the cells that produce the pathogenic autoantibodies (plasmablasts, plasma cells, and especially long-lived plasma cells). A reduction in plasmablasts and long-lived plasma cells by mezagitamab is expected to result in a reduction in the levels of pathogenic autoantibodies, thereby improving the autoantibody -mediated pathology in MG, e.g., reducing damage at the NMJ and improving the reversible neuromuscular deficits in these patients.

[0014] It is an objective of the present invention to provide methods of 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0016] In a second aspect, the disclosure provides a method of 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0017] In a third aspect, the disclosure provides a method of reducing the level 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0018] In a fourth aspect, the disclosure provides a method of reducing myasthenia gravis disease activity and/or progression 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0019] In a fifth aspect, the disclosure provides a unit dosage form comprising an isolated antibody or antigen binding fragment thereof that comprises a variable heavy (VH) chain region comprising a 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 (VL) chain region comprising a 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 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 dosage of from 100 milligrams to 800 milligrams in the treatment myasthenia gravis.

Brief Description of the Drawings

[0020] The objects and features of the invention may be better understood by reference to the drawings described below.

[0021] Figure 1 shows a summary of patient disposition for the safety analysis set. AE: adverse event; SAE: serious adverse event; W: week. *Unresolved AEs as of Week 16 and related AEs/SAEs with onset after the SFP were collected throughout the LFP.

[0022] Figure 2 shows the observed mean change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) total score over time. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from descriptive statistics. Reference line indicates 2-point reduction in MG-ADL total score from baseline.

[0023] Figure 3 shows the observed mean change from baseline in the Quantitative Myasthenia Gravis (QMG) total score over time. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from descriptive statistics. Reference line indicates 3-point reduction in QMG total score from baseline.

[0024] Figure 4 shows the observed mean change from baseline in the Quantitative Myasthenia Gravis Composite (MCG) total score over time. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from descriptive statistics. Reference line indicates 3-point reduction in MGC total score from baseline.

[0025] Figure 5 shows the observed mean change from baseline in the revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r) total score over time. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from descriptive statistics.

[0026] Figure 6 shows the proportion of subjects with at least a 2-point reduction in MG-ADL total score from baseline up to Week 16 (full analysis set). CL confidence interval; MG-ADL: Myasthenia Gravis Activities of Daily Living; TAK-079: mezagitamab. The error bars are lower and upper limit of the 95% CI in the proportion.

[0027] Figure 7 shows the proportion of responders (subjects with clinically meaningful reduction from baseline in MG-ADL score >2 points) for 300 mg mezagitamab, 600 mg mezagitamab, and placebo groups. Responder: The proportion of responders with at least a two- point reduction in MG-ADL total score from baseline. If a subject receives rescue therapy or prematurely discontinues from study drug, the subject is considered not a responder thereafter. MG-ADL: Myasthenia Gravis Activities of Daily Living. TAK-079: mezagitamab.

[0028] Figure 8 shows the proportion of subjects with at least a 3-point reduction in QMG total score from baseline up to Week 16 (full analysis set). CL confidence interval; QMG: Quantitative Myasthenia Gravis; TAK-079: mezagitamab. The error bars are lower and upper limit of the 95% CI in the proportion. [0029] Figure 9 shows an ad-hoc sensitivity analysis of the proportion of responders (subjects with clinically meaningful reduction from baseline in MG-ADL >2 points and QMG score >3 points) for 300 mg mezagitamab, 600 mg mezagitamab, and placebo groups. Responder: The proportion of responders with at least a three-point reduction in QMG and at least a two-point reduction in MG-ADL total score from baseline. If a subject receives rescue therapy or prematurely discontinues from study drug, the subject is considered not a responder thereafter. MG-ADL: Myasthenia Gravis Activities of Daily Living. QMG: Quantitative Myasthenia Gravis; TAK-079: mezagitamab. * Statistically significant difference from placebo.

[0030] Figure 10 shows the proportion of subjects with at least a 3-point reduction in MGC total score from baseline up to Week 16 (full analysis set). CI: confidence interval; MGC: Myasthenia Gravis Composite; TAK-079: mezagitamab. The error bars are lower and upper limit of the 95% CI in the proportion.

[0031] Figure 11 shows a Mixed-model Repeated Measures (MMRM) Analysis of Percent Change from Baseline in Anti-AChR Values (nmol/L) over time. SEM: standard error of the mean; TAK-079: mezagitamab. Percent change from baseline is from a mixed-effects model for repeated measures (MMRM) analysis over all post baseline visits, with the percent change from baseline as the outcome, treatment group, visit, and treatment by visit interaction as factors, and adjusted by baseline value and baseline-by-visit interaction. The unstructured covariance matrix was used for the model. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from MMRM analysis. Subject 47503-512 in the group TAK-079 (mezagitamab) 600 mg at study Day 22 (Week 4) and 29 (Week 5) had a percent change value >1707, excluded from calculation of mixed-effects model estimates in this figure.

[0032] Figure 12 shows individual observed anti-MuSK titer values over time for two subjects in the 300 mg mezagitamab group. MuSK: muscle specific tyrosine kinase. Week 1 Visit refers to baseline. The titer values are reported as reciprocal of the observed titers.

[0033] Figure 13 shows the observed mean change from baseline in Myasthenia Gravis

Impairment Index (MGII) total score over time. Any assessments obtained after receiving rescue therapy or prematurely discontinued from study drug are excluded from descriptive statistics. Reference line indicates 8-point reduction in MGII total score from baseline.

[0034] Figure 14 shows log-linear plot of mean/SD serum concentrations of mezagitamab versus time following multiple dose administration of mezagitamab with SC injection at 300 mg and 600 mg.

[0035] Figure 15 shows the percent change from baseline in IgG over time (pharmacodynamic analysis set).

[0036] Figure 16 shows the observed mean change from baseline in MG-ADL total score over time by region. MG-ADL: Myasthenia Gravis Activities of Daily Living; SEM: standard error of the mean; TAK-079: mezagitamab.

[0037] Figure 17 shows the observed mean change from baseline in QMG total score over time by region. QMG: Quantitative Myasthenia Gravis; SEM: standard error of the mean; TAK-079: mezagitamab.

[0038] Figure 18 shows the observed mean change from baseline in MG-ADL total score over time by acetylcholinesterase inhibitor use. AchE-i: acetylcholinesterase inhibitor; MG-ADL: Myasthenia Gravis Activities of Daily Living; SEM: standard error of the mean; TAK-079: mezagitamab.

[0039] Figure 19 shows the observed mean change from baseline in QMG total score over time by acetylcholinesterase inhibitor use. AchE-i: acetylcholinesterase inhibitor; QMG: Quantitative Myasthenia Gravis; SEM: standard error of the mean; TAK-079: mezagitamab.

[0040] Figure 20 shows pharmacodynamic effects: moderate total IgG reduction with concordant depletion in anti-AChR antibody. Figure 20A shows the change from baseline in IgG levels. Figure 20B shows the change from baseline in anti-AChR antibody levels.

[0041] Figure 21 shows IgA and IgM depletion after 8 weeks of dosing to Week 32. Figure 21A shows IgA and Figure 21B shows IgM.

[0042] Figure 22 shows the PD response of mezagitamab compared to efgartigimod. [0043] Figure 23 shows high consistency between QMG response and IgG depletion for 300 mg dose group but not for placebo. Red dashed line indicates 3-point reduction in QMG score.

[0044] Figure 24 shows high consistency between QMG/ADL response and IgG depletion for 300 mg. The red dashed line indicates 3-point reduction in QMG score.

[0045] Figure 25 shows the change from baseline in anti-MuSK antibody levels (secondary endpoint).

[0046] Figure 26 shows the placebo response was less pronounced in MGII and MGQOL15-R (based on patient assessment without investigator admini strati on/interventi on).

[0047] Figure 27 shows individual MG-ADL and QMG response at Week 16.

[0048] Figure 28 shows the placebo response for mezagitamab compared to comparator’s studies: MG-ADL.

[0049] Figure 29 shows mezagitamab compared to comparator’s studies: QMG.

[0050] Figure 30 shows the placebo response of mezagitamab compared to comparator’s studies: QMG.

[0051] Figure 31 shows mezagitamab exposures in expected range with PK profde consistent with MM.

[0052] Figure 32 shows mezagitamab exposure parameters in responders versus non-responders.

[0053] Figure 33 shows exposure-response assessment for IgG (best %reduction in IgG) across MM and MG studies.

[0054] Figure 34 shows exposure response assessment for MG-ADL. Orange dashed line represents clinically meaningful threshold of 2-point reduction in MG-ADL.

[0055] Figure 35 shows background therapies.

[0056] Figure 36 shows a mixed-model repeated measures analysis of change from baseline in MG-ADL score (full analysis set). [0057] Figure 37 shows a mixed-model repeated measures analysis of change from baseline in QMG score (full analysis set).

Detailed Description

[0058] Increased expression of CD38 has been documented in a variety of 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 that is highly and uniformly expressed on antibodyproducing 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 treatment of myasthenia gravis. A recent study found that the frequency of circulating CD38+ plasmablasts was significantly higher in patients with MG than healthy subjects (Yamamoto, etal. (2021) Neurol. Neuroimmunol. Neuroinflamm. 8(6): el087, herein incorporated by reference in its entirety).

[0059] The significantly higher CD38 expression on plasma cells and plasmablasts compared with other immune cells suggests the potential for selectively depleting these cells with an anti- CD38 antibody. Daratumumab, a commercially available anti-CD38 antibody, provided a substantial clinical improvement in a myasthenia gravis patient as measured by the Quantitative Myasthenia Gravis score (from 16 to 8 points, n = 1) by the 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%) with daratumumab monotherapy or in combination with standard antimyeloma regimens are infusion-related reactions (IRRs), neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infections (Darzalex USPI). Daratumumab can cause severe and/or serious infusion reactions including anaphylactic reactions and have been reported in approximately half of all patients (Darzalex USPI). Attention must also be paid to daratumumab interference with certain laboratory assays, which importantly may complicate blood compatibility testing. (Darzalex USPI). [0060] Other antibodies targeting CD38 are known (see, e.g., WO 2006/125640 incorporated herein by reference in its entirety, which discloses four human antibodies: MOR03077, MOR03079, MOR03080, and MOR03100 and two murine antibodies: OKT10 and IB4). These prior art antibodies are inferior to mezagitamab for a variety of reasons. MOR03080 binds to human CD38 and cynomolgus CD38 but with a low affinity to human CD38 (Biacore KD = 27.5 nm). OKT10 binds to human CD38 and cynomolgus CD38 but with a low/moderate affinity to human CD38 (Biacore KD = 8.28 nm). MOR03079 binds to human CD38 with a high affinity (Biacore KD = 2.4 nm) but does not bind to cynomolgus CD38. MOR03100 and MOR03077 bind to human CD38 with moderate or low affinity (Biacore KD = 10 nm and 56 nm, respectively). By comparison, mezagitamab binds to human and cynomolgus CD38 with a high affinity (to human CD38 with Biacore KD = 5.4 nm). Moreover, the prior art antibodies have poor ADCC as well as CDC activity.

[0061] An advantage of more efficient ADCC is the ability to deliver an anti-CD38 therapeutic as a low volume injection. A safety profile and PD target effect was observed after mezagitamab, at a dose up to 0.6 mg/kg dose was subcutaneously administered to healthy subjects. A single subcutaneous dose of 0.6 mg/kg mezagitamab reduced the level of PBs in peripheral blood >90% and NK cells >80% without comparable reductions in monocytes and B and T cells. Levels of PBs and NK cells recovered to 50% of baseline levels 21 days after administration, on average. At this dose, there were no Serious Adverse Events (SAEs), on- study deaths, or Adverse Events (AEs) that led to study discontinuation (WO 2019/140410, incorporated herein by reference in its entirety). Further studies showed that after mezagitamab was subcutaneously administered at a dosage of 45mg, 135mg, 300mg, or 600mg to patients with relapsed and/or refractory multiple myeloma (RRMM), no drug-related SAEs, on-study deaths, or AEs that led to study discontinuation were reported. Administration of mezagitamab reduced levels of plasmablasts in blood and bone marrow aspirates as well as plasma cells in bone marrow aspirates in a dose dependent manner. In patients with advanced RRMM, mezagitamab also showed early signs of anti-tumor activity as evidenced by at least 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 in treating patients with myasthenia gravis is unknown. [0062] The methods and unit dosages of the present disclosure provide, for the first time, subcutaneous administration of therapeutically effective dosages of anti-CD38 antibodies in treating patients with myasthenia gravis.

[0063] The present disclosure provides methods and unit dosage forms for subcutaneous administration of 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 with 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 with at least 80%, 85%, 90%, 95%, 97% or 99% sequence identity thereto). In some embodiment, the antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from 100 milligrams to 800 milligrams.

[0064] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear. However, in the event of any latent ambiguity, definitions provided herein take precedence over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The term “or” includes “and/or” unless stated otherwise. Furthermore, the use of the term “including,” “includes,” or “included” is not limiting. Terms such as “element” and “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise.

[0065] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present 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. [0066] All headings and section designations are used for clarity and reference purposes only and are not to be considered limiting in any way. For example, those of skill in the art will appreciate the usefulness of combining various aspects of the disclosure from different headings and sections as appropriate according to the spirit and scope of the disclosure described herein.

[0067] Select terms are defined below in order for the present disclosure to be more readily understood.

[0068] The terms “human CD38” and “human CD38 antigen” refer to the amino acid sequence of SEQ ID NO: 1, or a functional fraction thereof, such as an epitope, as defined herein (Table 1). In general, CD38 possesses 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-rsl; 1-19; 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. Amino Acid Sequence of Human and Cynomolgus Monkey CD38

[0069] The terms “therapeutically effective amount” and “therapeutically effective dosage” refer to an amount of a therapy that is sufficient to reduce or ameliorate the severity and/or duration of a disorder or one or more symptoms thereof; prevent the advancement of a disorder; cause regression of a disorder; prevent the recurrence, development, 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., prophylactic or therapeutic agent), at dosages and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments 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 detrimental effects of the antibody or antigen binding fragment thereof are outweighed by the therapeutically beneficial effects.

[0070] 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 therapies. In one embodiment, the patient is a mammal, for example, a human.

[0071] The term “isolated antibody” refers to an antibody that is substantially free of other antibodies having different antigenic specificities. For instance, an isolated antibody that specifically binds to CD38 is substantially free of antibodies that specifically bind antigens other than CD38. An isolated antibody that specifically binds to an epitope, isoform or variant of human CD38 or cynomolgus CD38 may, however, have cross-reactivity to other related antigens, for instance from other species, such as CD38 species homologs. Moreover, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0072] The term “about” refers to an extent near in number, degree, volume, time, etc., with only minor variations in dimension of up to 10%.

[0073] The term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable material, composition, or vehicle, suitable for administering compounds of the present disclosure to mammals. The carriers include liquid or solid fdler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. In one embodiment, the pharmaceutically acceptable carrier is suitable for subcutaneous administration.

[0074] The term “pharmaceutical composition” refers to preparations suitable for administration to a subject and treatment of disease. When the anti-CD38 antibodies of the present disclosure are administered as pharmaceuticals to mammals, e.g., humans, they can 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 can be in the form of a unit dosage form for administration of a particular dosage of the anti-CD38 antibody at a particular concentration, a particular amount, or a particular volume. Pharmaceutical compositions comprising the anti-CD38 antibodies, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers are provided. Suitably, the pharmaceutical composition may comprise a unit dosage form according to the present disclosure either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers. Suitably, the pharmaceutical composition may comprise a human anti-CD38 antibody as described herein either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers.

[0075] Traditional antibody structural units typically comprise a tetramer. Each tetramer is typically composed 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, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to IgGl, IgG2, IgG3, and IgG4. IgM has subclasses, including, but not limited to, IgMl and IgM2. Thus, “isotype” refers to any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions. The known human immunoglobulin isotypes are IgGl, IgG2, IgG3, IgG4, IgAl, IgA2, IgMl, IgM2, IgD, and IgE. Therapeutic antibodies can also comprise hybrids of isotypes and/or subclasses.

[0076] Each VH and VL region (about 100 to 110 amino acids in length) is composed of three hypervariable regions called “complementarity determining regions” (CDRs) and four framework regions (FRs) (about 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 differ extensively in sequence among antibodies and thereby determines a unique antigen binding site.

[0077] The hypervariable region generally encompasses amino acid residues from about amino acid residues 24-34 (LCDR1; “L” denotes light chain), 50-56 (LCDR2) and 89-97 (LCDR3) in the VL region and around about 31-35B (HCDR1; “H” denotes heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in 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 forming a hypervariable loop (e.g, residues 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3) in the VL region and 26-32 (HCDR1), 53-55 (HCDR2) and 96-101 (HCDR3) in the VH region (Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917; incorporated herein by reference in its entirety)

[0078] The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately, residues 1-107 of the VL region and residues 1-113 of 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 number system used for the Fc region.

[0079] 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. Each HC and LC has constant region domains referred to as constant heavy (CH) domains and constant light (CL) domains. In the context of IgG antibodies, the IgG isotypes each have a constant region comprising three CH domains. The carboxy-terminal portion of each HC and LC defines a constant region primarily responsible for effector function. Accordingly, “CH” domains in the context of IgG are as follows: “CHI” refers to positions 118-220 according to the EU index as in Kabat. “CH2” refers to positions 237-340 according to the EU index as in Kabat, and “CH3” refers to positions 341-447 according to the EU index as in Kabat.

[0080] Another type of Ig domain of the HC is the hinge region. The term “hinge region” refers to the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CHI domain ends at EU position 220, and the IgG CH2 domain begins at residue EU position 237. Thus, for IgG the antibody hinge is herein defined to include positions 221 (D221 in IgGl) to 236 (G236 in IgGl), wherein the numbering is according to the EU index as in Kabat. In some embodiments, for example in the context of an Fc region, the lower hinge is included, with the “lower hinge” generally referring to positions 226 or 230.

[0081] The term “Fc region” refers to the polypeptide comprising the constant region of an antibody excluding the CHI domain and in some cases, part 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 comprises Ig domains Cy2 and Cy3 (Cy2 and Cy3) and the lower hinge region between Cyl (Cyl) and Cy2 (Cy2). Although the boundaries of the Fc region may vary, the human IgG HC Fc region is usually defined to include residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index as in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcyR receptors or to the FcRn receptor.

CD38 Antibodies

[0082] Accordingly, the present disclosure provides isolated anti-CD38 antibodies that specifically bind human and primate CD38 protein that find use in subcutaneous administration methods and unit dosage forms in treating patients with myasthenia gravis (MG). The antibodies or antigen binding fragments thereof used in the present disclosure bind to both the human and primate CD38 proteins, particularly primates used in clinical testing, such as cynomolgus monkeys (Macaca fascicularis, Crab eating macaque, also referred to herein as “cyno”).

[0083] “Mezagitamab” or “TAK-079” is a therapeutic protein comprising a fully human immunoglobulin IgGl monoclonal antibody that binds specifically to CD38 with high affinity (Kd = 3.5 nM) referred to herein as AB79 (US Patent No. US 8,362,211, the contents of which is hereby incorporated by reference in its entirety). The amino acid sequences of mezagitamab are shown in Table 2.

Table 2: Amino Acid Sequences of Mezagitamab

[0084] Mezagitamab inhibits the growth of tumor cells expressing CD38 by cell depletion via antibody dependent cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). Mezagitamab also reduces the level of plasma cells and plasmablasts in blood isolated from healthy subjects and patients with autoimmune diseases. The anti-human CD38 mAb daratumumab also depletes CD38-expressing plasmablasts and plasma cells in samples from patients with autoimmune diseases in a dose-dependent manner in vitro. For example, daratumumab provided a clinically relevant depletion of autoreactive long-lived plasma cells in patients with treatment-refractory autoantibody-mediated neurological diseases such as myasthenia gravis (Scheibe et al. (2022) Eur. J. Neurol. 29(6): 1847-1854).

[0085] In contrast to daratumumab, mezagitamab cross-reacts with CD38 expressed by cynomolgus monkeys providing a unique opportunity to determine if reducing the level of cells expressing CD38 would affect inflammation and tissue damage in a non-human primate model of autoimmune disease. In healthy cynomolgus monkeys, the efficiency of depletion for lymphocytes, and B, T and NK cells correlated positively with level of CD38 expression and AB79 dose level (PCT Application No. PCT/US2017/042128; US Patent No. US 8,362,211; incorporated herein by reference in their entirety).

[0086] In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure interact with CD38 at a number of 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 human sequence numbering. Suitably, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure may interact with CD38 at a number of 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 sequence numbering. Suitably, the anti-CD38 antibodies or antigen binding fragments thereof of the disclosure interact with CD38 at a number of 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 human and cynomolgus monkeys, with the exception that S274 is actually F274 in cynomolgus monkeys. These residues may represent the immunodominant epitope and/or residues within the footprint of the specific antigen binding peptide.

[0087] In some embodiments, the anti-CD38 antibody for use according to the disclosure comprises a heavy chain (HC) comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NON; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the disclosure comprises a light chain (LC) comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody for use according to the disclosure comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID N0:3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NON; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the anti-CD38 antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NON; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NON; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 mezagitamab). In some embodiments, the antibody comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NON; LCDR3 mezagitamab). In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NO:3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NON; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 mezagitamab) and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID N0:7; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID N0:8; LCDR3 mezagitamab). In some embodiments, the antibody comprises an 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 the CDR sequences as 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 as 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 to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as 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 90% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as 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 95% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as 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 97% sequence identity to SEQ ID NO: 9. Suitably, the VH region may comprise the CDR sequences as 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 99% sequence identity to SEQ ID NO: 9.

[0088] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NOV.

[0089] In some embodiments, the antibody comprises an 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 as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 80% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 85% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 90% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 95% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 97% sequence identity to SEQ ID NO: 10. Suitably, the VL region may comprise the CDR sequences as defined by SEQ ID NO: 6, SEQ ID NO: 7 and SEQ ID NO: 8 and the remainder of the VL region sequence may have at least 99% sequence identity to SEQ ID NO: 10.

[0090] In some embodiments, the antibody comprises an LC comprising the VL region amino acid sequence of SEQ ID NO: 10.

[0091] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NOV or a variant thereof as described herein and an LC comprising the VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein.

[0092] As will be appreciated by those in the art, the VH and VL regions can be joined to human IgG constant domain sequences, generally IgGl, IgG2 or IgG4.

[0093] 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 the CDR sequences as 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 80% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as 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 85% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as 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 90% sequence identity to SEQ ID NO 11.

Suitably, the HC may comprise the CDR sequences as 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 95% sequence identity to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as 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 to SEQ ID NO 11. Suitably, the HC may comprise the CDR sequences as 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 to SEQ ID NO 11 .

[0094] 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 the CDR sequences as 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 80% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as 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 85% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as 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 90% sequence identity to SEQ ID NO 12.

Suitably, the LC may comprise the CDR sequences as 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 95% sequence identity to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as 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 to SEQ ID NO 12. Suitably, the LC may comprise the CDR sequences as 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 to SEQ ID NO 12.

[0095] In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12.

[0096] 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.

[0097] The present disclosure encompasses antibodies that bind to both human and cynomolgus 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: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human numbering. Suitably, the antibody may interact with at least 90% of these amino acid residues. Suitably, the antibody may interact with at least 95% of these amino acid residues. Suitably, the antibody may interact with at least 97% of these amino acid residues. Suitably, the antibody may interact with at least 98% of these amino acid residues. Suitably, the antibody may interact with at least 99% of these amino acid residues. Suitably, the antibody may interact with at least 14 (e.g., at least 15 or at least 16) of the following amino acids: K121, F135, Q139, D141, M142, E239, W241, S274, C275, K276, F284, V288, K289, N290, P291, E292, D293 and S294 of SEQ ID NO: 1 and SEQ ID NO: 2, based on human numbering.

[0098] In some embodiments, the antibodies are 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.

[0099] Alternatively, the antibodies can be a variety of structures, including, but not limited to, antibody fragments, antigen binding fragment, 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, respectively. Specific antibody fragments include, but are not limited to, (i) the Fab fragment consisting of VL, VH, CL and CHI domains, (ii) the Fd fragment consisting of the VH and CHI domains, (iii) the Fv fragment consisting of the VL and VH domains of a single antibody; (iv) the dAb fragment (Ward et al. (1989) Nature 341 : 544-546) which consists of a single variable, (v) isolated CDR regions, (vi) F(ab’)2 fragments, a bivalent fragment comprising two linked Fab fragments (vii) single chain Fv molecules (scFv), wherein a VH domain and a VL domain are linked by a peptide linker which allows the 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 Fv (WO 03/11161) and (ix) “diabodies” or “triabodies”, 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).

[0100] Suitably, the antibody may be a Fab fragment. Suitably, the antibody may be an Fv fragment. Suitably, the antibody may be an Fd fragment. Suitably, the antibody structure may be isolated CDR regions. Suitably, the antibody may be a F(ab’)2 fragment. Suitably, the antibody may be an scFv fragment. [0101] In some embodiments, the antibody or antigen binding fragment thereof of the present disclosure further comprises one or more engineered glycoforms. In some embodiments, the engineered glycoform comprises glycosylation of one or more polypeptides. 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.

[0102] In some embodiments, the isolated antibody of the present disclosure is mezagitamab.

Antibody Modifications

[0103] The present disclosure further provides variant anti-CD38 antibodies. That is, there are a number of modifications that can be made to the antibodies of the disclosure, including, but not limited to, amino acid modifications in the CDRs (affinity maturation), amino acid modifications in the VH region and/or VL region, amino acid modifications in the HC and/or LC, amino acid modifications in the Fc region, glycosylation variants, covalent modifications of other types, etc.

[0104] The term “variant” means a polypeptide that differs from that of a parent polypeptide. Amino acid variants can include substitutions, insertions, and deletions of amino acids. In general, variants can include any number of modifications, as long as the function of the protein is still present, as described herein. That is, in the case of amino acid variants generated with the CDRs of mezagitamab, for example, the antibody should still specifically bind to both human and cynomolgus CD38. The term “variant Fc region” means an Fc sequence that differs from that of a wild-type or parental Fc sequence by virtue of at least one amino acid modification. Fc variant may refer to the Fc polypeptide itself, compositions comprising the Fc variant polypeptide, or the amino acid sequence. If amino acid variants are generated with the Fc region, for example, the variant antibodies should maintain the required functions for the particular application or indication of the antibody. For example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions can be utilized, for example, 1-10, 1-5, 1-4, 1-3, and 1-2 substitutions. Suitable modifications can be made at one or more positions as is generally outlined, for example in US Patent Application Serial Nos. 11/841,654; 12/341,769; US Patent Publication Nos. 2004013210; 20050054832; 20060024298; 20060121032; 20060235208; 20070148170; and US Patent Nos. 6,737,056; 7,670,600; and 6,086,875, all of which are expressly incorporated by reference in their entirety, and in particular for specific amino acid substitutions that increase binding to Fc receptors.

[0105] A variant can be considered in terms of similarity (i.e., amino acid residues having similar chemical properties/functions), preferably a variant is expressed in terms of sequence identity.

[0106] Sequence comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These publicly and commercially available computer programs can calculate sequence identity between two or more sequences.

[0107] It may be desirable to have from 1-5 modifications in the Fc region of wild-type or engineered proteins, as well as from 1 to 5 modifications in the Fv region, for example. A variant polypeptide sequence will preferably possess at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the parent sequences (e.g, the VH or VL regions, the constant regions, and/or the HC and LC sequences for mezagitamab). Suitably, the variant may have at least 80% sequence identity to the parent sequence. Suitably, the variant may have at least 85% sequence identity to the parent sequence. Suitably, the variant may have at least 90% sequence identity to the parent sequence. Suitably, the variant may have at least 92% sequence identity to the parent sequence. Suitably, the variant may have at least 95% sequence identity to the parent sequence. Suitably, the variant may have at least 97% sequence identity to the parent sequence. Suitably, the variant may have at least 98% sequence identity to the parent sequence. Suitably, the variant may have at least 99% sequence identity to the parent sequence.

[0108] In one embodiment, the sequence identity is determined across the entirety of the sequence. In one embodiment, the sequence identity is determined across the entirety of the candidate sequence being compared to a sequence recited herein.

[0109] The term “amino acid substitution” means the replacement of an amino acid at a particular 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. Suitably the amino acid substitution may be a conservative amino acid substitution. Suitably a variant may comprise one or more, e.g., two or three conservative amino acid substitutions. Amino acids with similar biochemical properties may be defined as amino acids which can be substituted via a conservative substitution.

[0110] Unless otherwise explicitly stated herein by way of reference to a specific, individual amino acid, amino acids may be substituted using conservative substitutions as recited below. An aliphatic, polar uncharged amino 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 and preferably in the same line in the third column may be substituted for each other:

Table 3. Conservative Substitutions

[0111] The term “amino acid insertion” means the addition of an amino acid at a particular position in a parent polypeptide sequence.

[0112] The term “amino acid deletion” means the removal of an amino acid at a particular position in a parent polypeptide sequence.

[0113] The terms “parent antibody” and “precursor antibody” mean an unmodified antibody that is subsequently modified to generate a variant. In an embodiment, the parent antibody herein is mezagitamab. In an embodiment, the parent antibody herein comprises a VH region having the amino acid sequence of SEQ ID NO: 9 and the VL region having the amino acid sequence of SEQ ID NO: 10. In an embodiment, 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. Parent antibody may refer to the polypeptide itself, compositions that comprise the parent antibody, or the amino acid sequence that encodes it. Accordingly, the term “parent Fc polypeptide” means an Fc polypeptide that is modified to generate a variant.

[0114] The terms “wild type,” “WT,” and “native” mean an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A WT protein, polypeptide, antibody, immunoglobulin, IgG, e/c., has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0115] In some embodiments, one or more amino acid modifications are made in one or more of the CDRs of the anti-CD38 antibody. In general, only 1, 2, or 3 amino acids are substituted in any single CDR, and generally no more than from 4, 5, 6, 7, 8 9 or 10 changes are made within a set of CDRs. However, it should be appreciated that any combination of no substitutions, 1, 2 or 3 substitutions in any CDR can be independently and optionally combined with any other substitution.

[0116] In some cases, amino acid modifications in the CDRs are referred to as “affinity maturation”. An “affinity matured” antibody is one having one or more alteration(s) in one or more CDRs which results in an improvement in the affinity of the antibody for antigen, compared to a parent antibody which does not possess those alteration(s). In some cases, it may be desirable to decrease the affinity of an antibody to its antigen.

[0117] Affinity maturation can be done to increase the binding affinity of the antibody for the antigen by at least about 10% to 50%, 100%, 150% or more, or from 1- to 5-fold as compared to the “parent” antibody. Preferred affinity matured antibodies will have nanomolar or even picomolar affinities 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; incorporated herein by reference in their entirety).

[0118] Alternatively, amino acid modifications can be made, e.g., in one or more of the CDRs of the antibodies of the disclosure that are “silent”, e.g., that do not significantly alter the affinity of the antibody for the antigen. These can be made for a number of reasons, including optimizing expression (as can be done for the nucleic acids encoding the antibodies of the disclosure). [0119] Thus, included within the definition of the CDRs and antibodies of the disclosure are variant CDRs and antibodies; that is, the antibodies of the disclosure can include amino acid modifications in one or more of the CDRs set forth in SEQ ID NO: 3 to 8. In addition, as outlined below, amino acid modifications can also independently and optionally be made in any region outside the CDRs, including framework and constant regions.

[0120] In some embodiments, variant antibodies of mezagitamab that are specific for human CD38 (SEQ ID NO: 1) and cynomolgus CD38 (SEQ ID NO:2) is described. This antibody is composed of six CDRs, wherein each CDR of this antibody can differ from SEQ ID NO:3, SEQ ID NON, 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.

Glycosylation

[0121] Another type of modification is alterations in glycosylation. In one embodiment, the antibodies disclosed herein can be modified to include one or more engineered glycoforms. By “engineered glycoform” as used herein is meant a carbohydrate composition that is covalently attached to the antibody, wherein said carbohydrate composition differs chemically from that of a parent antibody. Engineered glycoforms may 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 be correlated to an increase in ADCC function, presumably through tighter binding to the FcyRIIIa receptor. In this context, “afucosylation” means that the majority of the antibody produced in the host cells is substantially devoid of fucose, e.g., 90-95-98% of the generated antibodies do not have appreciable fucose as a component of the carbohydrate moiety of the antibody (generally attached at N297 in the Fc region). Defined functionally, afucosylated antibodies generally exhibit at least a 50% or higher affinity to the FcyRIIIa receptor.

[0122] Engineered glycoforms may be generated by a variety of methods known in the art (US Patent No. US 8,362,211; incorporated herein by reference in its entirety). Engineered glycoform typically refers to the different carbohydrate or oligosaccharide; thus, an antibody can include an engineered glycoform. [0123] Alternatively, engineered glycoform may refer to the IgG variant that comprises the different carbohydrate or oligosaccharide. As is known in the art, glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Particular expression systems are discussed below.

[0124] 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 the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tri-peptide 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 may also be used.

[0125] Addition of glycosylation sites to the antibody is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tri-peptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). For ease, the antibody amino acid sequence is preferably altered through changes at the DNA level, particularly by mutating the DNA encoding the target polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

[0126] Another means of increasing the number of carbohydrate moieties on the antibody is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. These methods are described in W087/05330 and in Aplin and Wriston (1981) CRC Crit. Rev. Biochem. 10(4): 259-306, both entirely incorporated by reference.

[0127] Removal of carbohydrate moi eties present on the starting antibody (e.g., post- translationally) may 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 by Edge et al., 1981, Anal. Biochem. 118: 131, both entirely incorporated by reference. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol. 138:350, entirely incorporated by reference. Glycosylation at potential glycosylation sites may be prevented by the use of the compound tunicamycin as described by Duskin et al. (1982) J. Biol. Chem. 257: 3105, entirely incorporated by reference. Tunicamycin blocks the formation of protein-Nglycoside linkages.

[0128] Another type of covalent modification of the antibody comprises linking the antibody to various nonproteinaceous polymers, including, but not limited to, various polycols such as polyethylene glycol, polypropylene glycol or polyoxyalkylenes, in the manner set forth in, for example, 2005-2006 PEG Catalog from Nektar Therapeutics (available at the Nektar website) US Patents 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337, all entirely incorporated by reference. In addition, as is known in the art, amino acid substitutions may be made in various positions within the antibody to facilitate the addition of polymers such as PEG. See for example, U.S. Publication No. 2005/0114037A1, entirely incorporated by reference.

[0129] In addition to the modifications outlined above, other modifications can be made. For example, the molecules may be stabilized by the incorporation of disulphide bridges linking the VH and VL domains (Reiter et al. (1996) Nature Biotech. 14: 1239-1245; incorporated herein by reference in its entirety). In addition, there are a variety of covalent modifications of antibodies that can be made as outlined below. [0130] Covalent modifications of antibodies are included within the scope of this disclosure, and are generally, but not always, done post-translationally. For example, several types of covalent modifications of the antibody are introduced into the molecule by reacting specific amino acid residues of the antibody with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.

[0131] In some embodiments, the anti-CD38 antibody of the present disclosure specifically binds to one or more residues or regions in CD38 but also does not cross-react with other proteins with homology to CD38, such as BST-1 (bone marrow stromal cell antigen-1) and/or Mo5, also called CD 157.

[0132] Typically, a lack of cross-reactivity means less than about 5% relative competitive inhibition between the molecules when assessed by ELISA and/or FACS analysis using sufficient amounts of the molecules under suitable assay conditions.

Side Effect Reduction

[0133] An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it did not necessarily have to have a causal relationship with this treatment. Treatment-emergent adverse events (TEAEs) were defined as AEs that occurred after the first dose of study drug received in the treatment period and until the end of safety follow-up. The terms “serious TEAEs” and “treatment-emergent SAEs” and can be considered interchangeable in this document. PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 24.0. TEAEs are typically referred to by grades 1, 2, 3, 4, and 5, grade 1 being the least severe and grade 5 being the most severe TEAE. Based on FDA and other guidelines for Common Terminology Criteria for Adverse Events (CTCAE) standards 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 its entirety) the following is how such grades are generally determined. Grade 1 is mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated. Grade 2 is moderate: minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (“ADL”). Grade 3 is severe or medically significant but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 is life-threatening consequence: urgent intervention indicated. Grade 5 is death related to AE.

[0134] The anti-CD38 antibodies of the present disclosure allow for reduced side effects compared to prior art anti-CD38 antibodies. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab does not induce TEAEs. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the incidence of TEAEs in a patient population as compared to other anti- CD38 antibodies, such as MOR202. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the grade of the TEAEs in a patient population as compared to other anti-CD38 antibodies, such as MOR202. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade 5 to grade 4. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the grade of the TEAEs as compared to other anti- CD38 antibodies from grade 4 to grade 3. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade 3 to grade 2. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in the grade of the TEAEs as compared to other anti-CD38 antibodies from grade 2 to grade 1.

[0135] In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab allows for a reduction in grade of one or more TEAEs selected from the group consisting of anemia (including hemolytic anemia), thrombocytopenia, fatigue, infusion-related reactions (IRRs), leukopenia, lymphopenia, and nausea. In some embodiments, the antibody for use according to the present disclosure, e.g., mezagitamab 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 (IRRs), leukopenia, lymphopenia, and nausea.

[0136] In some embodiments, administering the antibody or antigen binding fragment thereof of the present disclosure results in less than 10% incidence of grade 3 or 4 of one or more TRAEs or TEAEs; optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, pyrexia, Herpes Zoster, urinary tract infection, skin and cutaneous tissue disorders, headache, fever, chills/rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0137] In some embodiments, administering the antibody or antigen binding fragment thereof of the present disclosure 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.

Disease Indication

[0138] The antibodies or antigen binding fragment thereof, methods, and dosage units of the disclosure find use in treating patients with myasthenia gravis (MG).

Myasthenia Gravis (MG)

[0139] Myasthenia gravis (MG) is a rare autoimmune disorder in which autoantibodies target the neuromuscular junction (NMJ) and postsynaptic membrane and interfere with neuromuscular transmission, which leads to progressive weakness of skeletal muscles. The prevalence of myasthenia gravis is approximately 14 to 40 per 100,000 individuals in the US (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).

[0140] Myasthenia gravis is defined by the Myasthenia Gravis Foundation of America (MGFA) clinical classification which divides MG into 5 main classes based on the clinical features and the 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 herein incorporated by reference in their entirety). Each class carries different prognoses or responses to therapy.

Clinical Classification of Myasthenia Gravis

[0141] Class I: Any ocular muscle weakness; may have weakness of eye closure; all other muscle strength is normal. [0142] Class II: Mild weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity. Class Ila: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles. Class lib: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both.

[0143] Class III: Moderate weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity. Class Illa: Predominantly affecting limb, axial muscles, or both; may also have lesser involvement of oropharyngeal muscles. Class Illb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both.

[0144] Class IV: Severe weakness affecting other than ocular muscles; may also have ocular muscle weakness of any severity. Class IVa: Predominantly affecting limb and/or axial muscles; may also have lesser involvement of oropharyngeal muscles. Class IVb: Predominantly affecting oropharyngeal, respiratory muscles, or both; may also have lesser or equal involvement of limb, axial muscles, or both.

[0145] Class V: Defined by intubation, with or without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb.

Myasthenia Gravis Subtypes

[0146] Subtypes of MG are broadly classified as follows: (1) early-onset MG: age at onset <50 years; thymic hyperplasia, usually females; (2) late-onset MG: age at onset >50 years; thymic atrophy, mainly males; (3) thymoma-associated MG (10%— 15%); (4) MG with anti-MUSK antibodies; (5) Ocular MG (oMG): symptoms only affecting extraocular muscles; and (6) MG with no detectable AChR and muscle-specific tyrosine kinase (MuSK) antibodies.

[0147] To establish the diagnosis of MG, necessary investigations include: AChR antibodies, MuSK antibodies, and CT/MR of anterior mediastinum for thymoma or thymic hyperplasia. Neurophysiological examination with repetitive nerve stimulation and jitter measurements are important in establishing the initial diagnosis, especially in patients without detectable antibodies. [0148] In some embodiments, the disclosure provides methods of treating myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating generalized myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class I myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class II myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class Ila myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class lib myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class III myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class Illa myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class Illb myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class IV myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class IVa myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class IVb myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating class V myasthenia gravis in a subject.

[0149] In some embodiments, the disclosure provides methods of treating early-onset myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating late-onset myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating thymoma-associated myasthenia gravis in a subject. In some embodiments, the disclosure provides methods of treating myasthenia gravis with anti -MUSK antibodies in a subject. In some embodiments, the disclosure provides methods of treating ocular myasthenia gravis antibodies in a subject. In some embodiments, the disclosure provides methods of treating myasthenia gravis with no detectable AChR and muscle-specific tyrosine kinase (MuSK) antibodies in a subject.

[0150] The therapeutic anti-CD38 antibodies of the present disclosure bind to CD38 positive cells, resulting in depletion of these cells through multiple mechanisms of action, including both CDC and ADCC pathways.

[0151] In some embodiments, the disclosure provides methods 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0152] In some embodiments, the disclosure provides methods of 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0153] In some embodiments, the disclosure provides methods 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams. [0154] In some embodiments, the disclosure provides the methods 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.

[0155] In some embodiments, the disclosure provides methods 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

[0156] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the one or more autoantibodies is selected from the group consisting of anti-AChR and anti- MuSK.

[0157] In some embodiments, the disclosure provides methods of reducing myasthenia gravis disease activity and/or progression 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams. [0158] In some embodiments, the disclosure provides the methods 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), revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r), and/or Myasthenia Gravis Impairment Index (MGII). In some embodiments, myasthenia gravis disease activity is measured by Myasthenia Gravis Activities of Daily Living (MG-ADL). In some embodiments, myasthenia gravis disease activity is measured by Quantitative Myasthenia Gravis (QMG). In some embodiments, myasthenia gravis disease activity is measured by Myasthenia Gravis Composite (MGC). In some embodiments, myasthenia gravis disease activity is measured by revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r). In some embodiments, myasthenia gravis disease activity is measured by Myasthenia Gravis Impairment Index (MGII).

[0159] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms.

[0160] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, and wherein the glycosylation is N-linked glycosylation or O-linked glycosylation.

[0161] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is N-linked glycosylation.

[0162] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the glycosylation is O-linked glycosylation.

[0163] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO:9, and/or the VL region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10. [0164] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NOV.

[0165] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO:10.

[0166] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NOV.

[0167] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO:10.

[0168] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the HC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11.

[0169] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the LC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0170] In some embodiments, the disclosure provides the methods 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 sequence numbering.

[0171] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10’⁸ M or a greater affinity, and wherein the affinity is measured by a standard Biacore assay.

[0172] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the VH region comprises SEQ ID NOV and the VL region comprises SEQ ID NO: 10. [0173] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO:11 and an LC as set forth in SEQ ID NO: 12.

[0174] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof further comprises an Fc domain

[0175] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the Fc domain is a human Fc domain. In some embodiments, the Fc domain is a variant Fc domain.

[0176] In some embodiments, the disclosure provides the methods 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 IgGl antibody.

[0177] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the subject receives background myasthenia gravis medication(s).

[0178] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background myasthenia gravis medication(s) is selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background myasthenia gravis medication(s) is selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, azathioprine and cyclosporine, and combinations thereof.

[0179] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the background myasthenia gravis medication(s) is administered in combination with the antibody or antigen binding fragment thereof.

[0180] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof is administered in a dosage selected from the group consisting 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 dosage of about 300 mg. In some embodiments, wherein the antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

[0181] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the dosage is a dosage administered once every week, once every two weeks, once every three weeks or once every four weeks.

[0182] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the antibody or antigen binding fragment thereof is administered in the form of a pharmaceutically acceptable composition.

[0183] In some embodiments, the disclosure provides the methods 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.

[0184] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 11 and an LC as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once weekly for 8 weeks. In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

[0185] In some embodiments, the disclosure provides the methods as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof is mezagitamab.

[0186] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering the antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment- emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, pyrexia, Herpes Zoster, urinary tract infection, skin and cutaneous tissue disorders, headache, fever, chill s/rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea.

[0187] In some embodiments, the disclosure provides the methods as disclosed herein, wherein administering 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.

Antibody Compositions for In Vivo Administration

[0188] Formulations of the antibodies or antigen binding fragments thereof used in accordance with the present disclosure are prepared for storage by mixing an antibody having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington’s Pharmaceutical Sciences 16th edition (1980) Osol, A. Ed.; incorporated herein by reference in its entirety), in the form of lyophilized formulations or aqueous solutions.

[0189] The formulations herein may also contain more than one active compound as necessary 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 antibodies or antigen binding fragments thereof with other specificities. Alternatively, or in addition, the composition may comprise a cytotoxic agent, cytokine, growth inhibitory agent and/or small molecule antagonist. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0190] In some embodiments, two mezagitamab drug product formulations have been developed, referred to Process A and Process B as disclosed herein.

[0191] In one embodiment, the Process A mezagitamab drug product is a clear-to-opalescent, colorless solution containing AB79 (20 mg/mL) aqueous solution of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at approximately pH 6.5. The Process A placebo is a clear, colorless solution containing an aqueous solution of arginine hydrochloride, anhydrous citric acid, sodium citrate, polysorbate 80, and water for injection at approximately pH 6.5. The Process A mezagitamab drug product and placebo are supplied in aseptically filled, single-use, clear, type I borosilicate glass vials with fluoropolymer coated butyl rubber stoppers and aluminum crimp seals with flip-off caps.

[0192] In another embodiment, the Process B mezagitamab drug product is made in 2 strengths, 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 of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at approximately pH 5.9. The Process B placebo is a clear, colorless solution containing an aqueous solution of histidine, histidine hydrochloride monohydrate, sucrose, polysorbate 20, and water for injection at approximately pH 5.9. The Process B mezagitamab drug product and placebo are supplied in aseptically filled, single use, clear, type I, borosilicate glass vials with fluoropolymer coated butyl rubber stoppers and aluminum crimp seals with flip-off caps.

Subcutaneous Administration

[0193] The anti-CD38 antibodies described herein, such as mezagitamab, can be administered at sufficiently dosages that are therapeutically effective, thereby allowing for subcutaneous administration. Subcutaneous administration is a minimally invasive mode of administration and is considered the most versatile and therefore desirable mode of administration that can be used for short-term and long-term therapies. In some embodiments, subcutaneous administration can be performed by injection. In some embodiments, the site of the injection or device can be rotated when multiple injections or devices are needed.

[0194] Accordingly, subcutaneous formulations are much easier for a patient to self-administer, especially since the formulation may have to be taken regularly during the patient’s entire life. Furthermore, the ease and speed of subcutaneous delivery allows increased patient compliance and quicker access to medication when needed. Thus, the subcutaneous formulations of the anti- CD38 antibodies provided herein provide a substantial benefit over the prior art and solve certain unmet needs.

[0195] In some embodiments, the antibodies of the disclosure are administered to a subject in accordance with known methods via a subcutaneous route. In some embodiments, antibodies of the present disclosure can be administered by subcutaneous injection. In specific embodiments, the subcutaneous formulation is subcutaneously injected into the same site of a patient (e.g., administered to the upper arm, anterior surface of the thigh, lower portion of the abdomen, or upper back) for repeat or continuous injections. In other embodiments, the subcutaneous formulation is subcutaneously injected into a different or rotating site of a patient. Single or multiple administrations of the formulations may be employed.

[0196] In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of myasthenia gravis. In some embodiments, the subcutaneous unit dosage forms described herein can be used for the treatment of generalized myasthenia gravis.

[0197] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasmablasts, plasma cells, NK cells, B cells and/or T cells after subcutaneous administration to a subject. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasmablasts. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to depletion of plasma cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to the depletion of B cells or T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells, as well as increased depletion of NK cells as compared to T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells, as well as increased depletion of B cells as compared to T cells. In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure allow for increased depletion of NK cells as compared to B cells and increased depletion of B cells as compared to T cells. Suitably, the antibodies or antigen binding fragments thereof of the disclosure may allow for increased depletion of CD38⁺ cells as compared to CD38' cells.

[0198] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to a decrease in the level of immunoglobulin(s) 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. [0199] In some embodiments, the antibodies or antigen binding fragments thereof of the disclosure lead to a decrease in one or more autoantibodies after subcutaneous administration to a subject. In some embodiments, the one or more autoantibodies is selected from the group consisting anti-AChR and anti-MuSK.

[0200] In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 50% and at least 80% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 60% and at least 80% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 50% and 70% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 55% and 65% as compared to intravenous administration normalized for the same dose. In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after subcutaneous administration is between at least 55% and 70% as compared to intravenous administration normalized for the same dose.

[0201] In certain embodiments, the bioavailability of the anti-CD38 antibodies described herein after 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% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least 50% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least 60% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least 70% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least 80% as compared to intravenous administration normalized for the same dose. Suitably the bioavailability may be at least 90% as compared to intravenous administration normalized for the same dose.

[0202] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is 50%-80% as compared to intravenous administration normalized for the same dose.

[0203] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 50% as compared to intravenous administration normalized for the same dose.

[0204] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 55% as compared to intravenous administration normalized for the same dose.

[0205] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 60% as compared to intravenous administration normalized for the same dose.

[0206] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 65% as compared to intravenous administration normalized for the same dose.

[0207] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 70% as compared to intravenous administration normalized for the same dose.

[0208] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 75% as compared to intravenous administration normalized for the same dose.

[0209] In some embodiments, the present disclosure provides a method wherein the bioavailability of the antibodies of the disclosure after subcutaneous administration is at least 80% as compared to intravenous administration normalized for the same dose. [0210] In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered in a single bolus injection. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered monthly. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every two weeks. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered weekly. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered twice a week. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered daily. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 12 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 8 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 6 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 4 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every 2 hours. In certain embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as described herein are subcutaneously administered every hour. In some embodiments, the antibodies or antigen binding fragments thereof as disclosed herein is subcutaneously administered once weekly for 8 weeks.

[0211] In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as disclosed herein are subcutaneously administered at a dosage of from about 100 milligrams to about 800 milligrams. In some embodiments, the anti-CD38 antibodies or antigen binding fragments thereof as disclosed herein are subcutaneously 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 in a dosage of about 300 mg or about 600 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of about 600 mg.

Unit Dosage Forms

[0212] In some embodiments, the therapeutic anti-CD38 antibodies or antigen binding fragments thereof are formulated as part of a unit dosage form. In some embodiments, the anti-CD38 antibody or antigen binding fragment thereof comprises an 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 having up to three amino acid changes. In some embodiments, the antibody or antigen binding fragment thereof comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NOY; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO:4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID NO:5; HCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes and an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NO:6; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NO:8; LCDR3 mezagitamab) or variants of those sequences having up to three amino acid changes. In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID NOY; HCDR1 mezagitamab), ISWNGGKT (SEQ ID NO:4; HCDR2 mezagitamab), and ARGSLFHDSSGFYFGH (SEQ ID NOY; HCDR3 mezagitamab). In some embodiments, the antibody comprises an LC comprising the following CDR amino acid sequences: SSNIGDNY (SEQ ID NOY; LCDR1 mezagitamab), RDS (SEQ ID NOY; LCDR2 mezagitamab), and QSYDSSLSGS (SEQ ID NOY; LCDR3 mezagitamab). In some embodiments, the antibody comprises an HC comprising the following CDR amino acid sequences: GFTFDDYG (SEQ ID N0:3; HCDR1 mezagitamab), ISWNGGKT (SEQ ID N0:4; HCDR2 mezagitamab), ARGSLFHDSSGFYFGH (SEQ ID N0:5; HCDR3 mezagitamab) and an 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 an 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 an HC comprising the VH region amino acid sequence of SEQ ID NO:9.

EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGK THYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLA (SEQ ID NO:9).

[0213] 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.

QSVLTQPPSASGTPGQRVTISCSGSSSNIGDNYVSWYQQLPGTAPKLLIYRDSQRPSGVP DRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVT LFPPSSEEL (SEQ ID NO: 10).

[0214] In some embodiments, the antibody comprises an HC comprising the VH region amino acid sequence of SEQ ID NO:9 or a variant thereof as described herein and an LC comprising the VL region amino acid sequence of SEQ ID NO: 10 or a variant thereof as described herein. [0215] As will be appreciated by those in the art, the VH region and VL region can be joined to human IgG constant domain sequences, generally IgGl, IgG2 or IgG4. In some embodiments, the antibody comprises an HC having amino acid sequence with at least 80% sequence identity to SEQ ID NO: 11. Suitably, the HC may comprise the CDR sequences as 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 80% sequence identity to SEQ ID NO 11. In some embodiments, the antibody comprises the HC amino acid sequence of SEQ ID NO: 11.

EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSDISWNGGK THYVDSVKGQFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGSLFHDSSGFYFGHWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPA VLQ S SGL YSLS S VVTVP S S SLGTQTYICNVNHKPSNTK VDKRVEPK SCDKTHTCPPC PAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAK TKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQ VYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFL YSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11).

[0216] In some embodiments, the antibody comprises an LC having amino acid sequence with at least 80% sequence identity to SEQ ID NO: 12. Suitably, the LC may comprise the CDR sequences as 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 80% sequence identity to SEQ ID NO 12. In some embodiments, the antibody comprises the LC amino acid sequence of SEQ ID NO: 12.

Q S VLTQPP S ASGTPGQRVTISC SGS S SNIGDNYVS W YQQLPGTAPKLLIYRD SQRPSGVP DRFSGSKSGTSASLAISGLRSEDEADYYCQSYDSSLSGSVFGGGTKLTVLGQPKANPTVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 12).

[0217] 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.

[0218] In some embodiments, the formulation comprising the anti-CD38 antibody is a unit dosage form. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg to about 800 mg, for example, 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 comprises 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 in a dosage of about 300 mg or about 600 mg.

[0219] In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 100 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 125 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 150 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 175 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 200 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 225 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 250 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 275 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 300 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 325 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 350 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 375 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 400 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 425 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 450 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 475 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 500 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 525 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 550 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 575 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 600 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 625 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 650 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 675 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 700 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 725 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 750 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 775 mg. In some embodiments, the unit dosage form comprises an amount sufficient to administer a dosage of about 800 mg.

[0220] In some embodiments, the anti-CD38 antibody unit dosage forms provided herein may further comprise one or more pharmaceutically acceptable excipients, carriers, and/or diluents. In some embodiments, the anti-CD38 antibody is provided as a pharmaceutical composition which comprises a unit dosage form according to the present disclosure. Suitably, the pharmaceutical composition may further comprise one or more pharmaceutically acceptable excipients, carriers, and/or diluents.

[0221] Dosage regimens are adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Compositions may be formulated in dosage unit form for ease of administration and uniformity of dosage. Dosage unit forms as used herein can, in some embodiments, refer to physically discrete units suited as unitary dosages for the subjects to be treated, each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0222] The specification for the dosage unit forms of the present disclosure is dictated by and is directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of an individual.

[0223] The efficient dosages and the dosage regimens for the anti-CD38 antibodies or antigen binding fragments thereof used in the present disclosure depend on the severity of the disease or condition to be treated and may be determined by persons skilled in the art.

[0224] In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every week, once every two weeks, once every three weeks or once every four weeks in a dosage of about 100 mg to about 800 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every week in a dosage of about 100 mg to about 800 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every two weeks in a dosage of about 100 mg to about 800 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every three weeks in a dosage of about 100 mg to about 800 mg. In some embodiments, the anti-CD38 antibody or antigen binding fragments thereof is administered by subcutaneous administration once every four weeks in a dosage of about 100 mg to about 800 mg.

[0225] Suitably, the weekly dosage may be about 100 mg. Suitably, the weekly dosage may be about 125 mg. Suitably, the weekly dosage may be about 150 mg. Suitably, the weekly dosage may be about 175 mg. Suitably, the weekly dosage may be about 200 mg. Suitably, the weekly dosage may be about 225 mg. Suitably, the weekly dosage may be about 250 mg. Suitably, the weekly dosage may be about 275 mg. Suitably, the weekly dosage may be about 300 mg. Suitably, the weekly dosage may be about 325 mg. Suitably, the weekly dosage may be about 350 mg. Suitably, the weekly dosage may be about 375 mg. Suitably, the weekly dosage may be about 400 mg. Suitably, the weekly dosage may be about 425 mg. Suitably, the weekly dosage may be about 450 mg. Suitably, the weekly dosage may be about 475 mg. Suitably, the weekly dosage may be about 500 mg. Suitably, the weekly dosage may be about 525 mg. Suitably, the weekly dosage may be about 550 mg. Suitably, the weekly dosage may be about 575 mg. Suitably, the weekly dosage may be about 600 mg. Suitably, the weekly dosage may be about 625 mg. Suitably, the weekly dosage may be about 650 mg. Suitably, the weekly dosage may be about 675 mg. Suitably, the weekly dosage may be about 700 mg. Suitably, the weekly dosage may be about 725 mg. Suitably, the weekly dosage may be about 750 mg. Suitably, the weekly dosage may be about 775 mg. Suitably, the weekly dosage may be about 800 mg. Such administration as disclosed herein may be repeated, e.g., 4 to 12 times. In some embodiments, such administration as disclosed herein may be repeated 4 times, i.e., weekly for a total of 4 weeks. In some embodiments, such administration as disclosed herein may be repeated 5 times, i.e., weekly for a total of 5 weeks. In some embodiments, such administration as disclosed herein may be repeated 6 times, i.e., weekly for a total of 6 weeks. In some embodiments, such administration as disclosed herein may be repeated 7 times, i.e., weekly for a total of 7 weeks. In some embodiments, such administration as disclosed herein may be repeated 8 times, i.e., weekly for a total of 8 weeks. In some embodiments, such administration as disclosed herein may be repeated 9 times, i.e., weekly for a total of 9 weeks. In some embodiments, such administration as disclosed herein may be repeated 10 times, i.e., weekly for a total of 10 weeks. In some embodiments, such administration as disclosed herein may be repeated 11 times, i.e., weekly for a total of 11 weeks. In some embodiments, such administration as disclosed herein may be repeated 12 times, i.e., weekly for a total of 12 weeks.

[0226] In one embodiment, the anti-CD38 antibody or antigen binding fragment thereof is administered in 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 compound of the present disclosure in the blood upon administration, for instance, by taking a biological sample and using anti -idiotypic antibodies that target the antigen binding region of the anti-CD38 antibody.

[0227] In one embodiment, the therapeutic antibody is formulated at about 5 mg/ml concentration. In another embodiment, the therapeutic antibody is formulated at about 20 mg/ml concentration. In another embodiment, the therapeutic antibody is formulated at about 50 mg/ml concentration. In another embodiment, the therapeutic antibody is formulated at about 100 mg/ml concentration. In another embodiment, the therapeutic antibody is formulated at about 120 mg/ml concentration. In another embodiment, the therapeutic antibody is formulated at about 150 mg/ml concentration. In some embodiments, 0.8 mL, 0.9 mb, 1.8 m , 2.7 mb or 2.8 mb volume is injected in the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at about 75 mg/ml concentration. In some embodiments, 0.53 mL, 0.6 mL, 1.2 mL, 1.8 mL or 1.87 mL volume is injected in the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at about 90 mg/ml concentration. In some embodiments, 0.44 mL, 0.5 mL, 1.0 mL, 1.5 mL or 1.56 mL volume is injected in the thigh, abdomen, or arm. In another embodiment, the therapeutic antibody is formulated at about 100 mg/ml concentration. In some embodiments, 0.4 mL, 0.45 mL, 0.9 mL, 1.35 mL or 1.4 mL volume is injected in the thigh, abdomen, or arm. In some embodiments, the dose is administered over a l-, 2-, 4-, 6-, 8-, or 10- hour period of time. In some embodiments, the doses are administered every week. In some embodiments, the doses are administered every 2 weeks. In some embodiments, the doses are administered every 3 weeks. In some embodiments, the doses are administered every 4 weeks.

[0228] In some embodiments, the disclosure provides a unit dosage form comprising an isolated antibody or antigen binding fragment thereof that comprises a VH region comprising a 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 VL region comprising a 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 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 from 100 milligrams to 800 milligrams in the treatment of myasthenia gravis.

[0229] In some embodiments, the disclosure provides the 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 glycoform comprises glycosylation of one or more polypeptides, and 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.

[0230] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VH region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO:9, and/or the VL region of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10.

[0231] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NOV.

[0232] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 10.

[0233] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VH region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NOV.

[0234] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VL region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10.

[0235] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the HC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 11. [0236] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the LC of the antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO: 12.

[0237] In some embodiments, the disclosure provides the 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 sequence numbering.

[0238] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10'⁸ M or a greater affinity, and wherein the affinity is measured by a standard Biacore assay.

[0239] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the VH region comprises SEQ ID NO:9 and the VL region comprises SEQ ID NO: 10.

[0240] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 11 and a LC as set forth in SEQ ID NO: 12.

[0241] In some embodiments, the disclosure provides the 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.

[0242] In some embodiments, the disclosure provides the 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 IgGl antibody.

[0243] In some embodiments, the disclosure provides the unit dosage form as disclosed herein further comprising background myasthenia gravis medication(s).

[0244] In some embodiments, the disclosure provides the unit dosage form as 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 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 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 as disclosed herein comprises the one or more background myasthenia gravis medications.

[0245] In some embodiments, the disclosure provides the 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 dosage of 100 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 125 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 150 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 175 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 200 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 225 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 250 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 275 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 300 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 325 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 350 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 375 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 400 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 450 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 475 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 500 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 525 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 550 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 575 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 600 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 625 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 650 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 675 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 700 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 725 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 750 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 775 mg. In some embodiments, the antibody or antigen binding fragment thereof is administered in a dosage of 800 mg.

[0246] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the dosage is a dosage administered once every week, once every two weeks, once every three weeks or once every four weeks.

[0247] In some embodiments, the disclosure provides the unit dosage form as disclosed herein further comprising at least one pharmaceutically acceptable carrier, excipient or stabilizer.

[0248] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein administering the antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment- emergent adverse events (TEAEs). In some embodiments, the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, pyrexia, Herpes Zoster, urinary tract infection, skin and cutaneous tissue disorders, headache, fever, chill s/rigors, vomiting, diarrhea, arthralgia, myalgia, hypotension, respiratory, thoracic and mediastinal disorders, thrombocytopenia, leukopenia, lymphopenia, cardiac disorders, palpitations, and dyspnea. In some embodiments, the 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.

[0249] In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof comprises an HC as set forth in SEQ ID NO: 11 and an LC as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once weekly for 8 weeks. In some embodiments, the disclosure provides the unit dosage form as disclosed herein, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides and the glycosylation is N-linked glycosylation.

Treatment Modalities

[0250] In the methods of the disclosure, therapy 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 a disease or condition, and/or an improvement in the symptoms associated with the disease or condition.

[0251] Positive therapeutic responses in any given disease or condition can be determined by standardized response criteria specific to that disease or condition. In addition to the positive therapeutic responses, the subject undergoing therapy may experience the beneficial effect of an improvement in the symptoms associated with the disease.

[0252] Measurements of efficacy in treating myasthenia gravis can be assessed based on myasthenia gravis disease activity scales in accordance with the SOE study activity table (Table 8, Example 1). The 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 Impairment Index (MGII) as disclosed in Example 1.

[0253] Treatment according to the present disclosure includes a “therapeutically effective amount” of the medicaments used. The terms “therapeutically effective amount” and “therapeutically effective dosage” refer to an amount of a therapy that is sufficient to reduce or ameliorate the severity and/or duration of a disorder or one or more symptoms thereof; prevent the advancement of a disorder; cause regression of a disorder; prevent the recurrence, development, 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., prophylactic or therapeutic agent), at dosages and for periods of time necessary to achieve a desired therapeutic result. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the medicaments to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.

Anti-CD38 Antibody Kits

[0254] In another aspect, kits are provided for the treatment of MG. In some embodiments, kits are provided for the treatment of generalized MG. In one embodiment, the kit comprises a dose of an anti-CD38 antibody described herein, such as TAK-079. In one embodiment, the kit comprises a dose of an anti-CD38 antibody described herein, such as mezagitamab. In some embodiments, the kits provided herein may contain one or more doses of a liquid or lyophilized formulation as provided herein. When the kits comprise a lyophilized formulation of an anti- CD38 antibody described herein such as mezagitamab, generally the kits will also contain a suitable liquid for reconstitution of the liquid formulation, for example, sterile water or a pharmaceutically acceptable buffer. In some embodiments, the kits may comprise an anti-CD38 antibody formulation described herein prepackaged in a syringe for subcutaneous administration by a health care professional or for home use.

[0255] In certain embodiments, the kit will be for a single administration or dose 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 comprise an anti-CD38 antibody formulation described herein prepackaged in a syringe for subcutaneous administration by a health care professional or for home use. Articles Of Manufacture

[0256] In other embodiments, an article of manufacture containing materials useful for the treatment of the disorders described above is provided. The article of manufacture comprises a container and a label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers may be formed from a variety of materials such as glass or plastic. The container holds a composition which is effective for treating the condition and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agent in the composition is the antibody. The label on, or associated with, the container indicates that the composition is used for treating the condition of choice. The article of manufacture may further comprise a second container comprising a pharmaceutically acceptable buffer, such as phosphate-buffered saline, Ringer’s solution or dextrose solution. It 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.

EXAMPLES

EXAMPLE 1: A PHASE 2, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE SAFETY, TOLERABILITY, AND EFFICACY OF TAK-079 IN PATIENTS WITH GENERALIZED MYASTHENIA GRAVIS

Study Objectives And Investigational Plan

[0257] The primary objective of the study was to evaluate the safety and tolerability of mezagitamab in subjects with generalized myasthenia gravis (MG) who are receiving stable background therapy for MG.

[0258] The secondary objective of the study was to assess the effects of mezagitamab on MG disease activity using clinical rating scales and autoantibody levels.

[0259] The exploratory objectives of the study were as follows: (1) to determine the pharmacokinetics (PK) of mezagitamab; (2) to determine the pharmacodynamic (PD) profile of mezagitamab; (3) to explore the effects of repeated administration of mezagitamab on MG disease activity using a novel clinical disease assessment scale; (4) to explore the duration of a clinically meaningful effect on MG disease severity (using at least 1 MG clinical rating scale); (5) to explore the frequency and proportion of subjects requiring rescue therapy; (6) to explore vaccine-induced protective antibodies; and (7) to explore the effects of repeated administration of mezagitamab on exploratory biomarkers of disease activity.

[0260] This was a phase 2, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and efficacy of mezagitamab in subjects with generalized MG in combination with standard background therapy.

[0261] 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; and (c) matching placebo added to stable standard background therapy.

[0262] The study was divided into 3 sequential periods: an 8-week dosing period, an 8-week safety follow-up period (SFP), and a 16-week long-term follow-up period (LFP).

[0263] During the 8-week dosing period, mezagitamab/matching placebo was administered via subcutaneous (SC) injection once weekly for 8 weeks.

[0264] Safety assessments, including safety laboratory tests, were performed each week before subsequent dosing. Subjects may have had study drug (mezagitamab/placebo) doses modified (e.g., withheld or delayed) for safety reasons.

[0265] After completing the 8-week dosing period, subjects entered an 8-week blinded SFP, completing safety and efficacy assessments every 2 weeks. After completion of the Week 16 visit in the SFP, subjects were unblinded before entering the LFP visit at Week 20.

[0266] Subjects randomized to mezagitamab were followed every 4 weeks from week 20 through week 32 of the LFP for MG clinical activity scores and autoantibody levels; the end of study visit took place at Week 32 of the LFP. For subjects randomized to placebo, the end-of- study visit took place at Week 20 of the LFP. The study schematic diagram is outlined in Figure 1 [0267] Adverse events (AEs) that were ongoing at the Week 16 visit of the SFP (including unresolved clinical/laboratory parameters were monitored through the LFP until they were resolved, returned to baseline, or were clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). Study drug-related AEs/serious AEs (SAEs) with onset after the SFP were collected throughout the LFP.

[0268] Overall, the maximum follow-up period was approximately 24 weeks after the last dose of the study drug.

Subjects were permitted to receive rescue medication (e.g.. IVIg, high dose corticosteroids, or plasmapheresis/plasma exchange, or increases in the ongoing background medications) as determined by the investigator. If the subject received rescue therapy, they would automatically enter the SFP. Rescue therapy was defined as additional dosing of concomitant medications in accordance with institutional practices or the physician’s best medical judgment to control and manage underlying MG conditions.

SELECTION OF STUDY POPULATION

Inclusion Criteria

[0269] Each subject must have met all the following inclusion criteria to be randomized to treatment: (a) the subject understood and agreed to study participation by providing a signed and dated written informed consent form (ICF) and any required privacy authorization before the initiation of any study procedures (as applicable, the subject’s legally acceptable representative could provide written informed consent in accordance with local and regional regulatory requirements) and, in the opinion of the investigator, was capable of complying with protocol requirements; (b) the subject was aged 18 years or older; (c) diagnosis of MG supported by a positive serologic test for anti-AChR or anti-MuSK antibodies at screening; (d) Myasthenia Gravis Foundation of America (MGFA) clinical classification II to IV at screening; (e) Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 6 or greater at screening, with at least 4 points attributed to non-ocular items; (f) if receiving immunosuppressive drugs (i.e., my cophenolate mofetil, methotrexate, cyclosporine, tacrolimus, cyclophosphamide), therapy was ongoing for at least 6 months, with stable dosing ongoing for at least 3 months before screening; subjects receiving azathioprine were on a stable dose for at least 6 months before screening; (g) if receiving oral corticosteroids, therapy was ongoing for at least 3 months, with a stable dose at least 1 month before screening; corticosteroids, including dexamethasone, were given as oral, daily or every-other-day therapy, as opposed to pulse therapy; (h) if receiving cholinesterase inhibitors, therapy with a stable dose was required at least 2 weeks before screening; (i) the doses of concomitant standard background therapy were expected to remain stable throughout the study unless dose reduction was required due to toxicities; allowed background therapy was defined as no more than a cholinesterase inhibitor ± corticosteroid ± 1 steroid-sparing immunosuppressive drug (limited to azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide); subjects must have been on at least one allowed background medication; (j) female subjects of childbearing potential were required to have a negative pregnancy test; both male and female subjects had to practice an effective, reliable, and approved contraceptive regimen during the study and for up to 90 days or 5 half-lives, whichever was longer, after discontinuation of treatment; and (k) subjects had been able and willing to comply with the study procedures.

Exclusion Criteria

[0270] Subjects meeting any of the following exclusion criteria were not randomized to treatment: (a) presence of a thymoma (previous history of a fully encapsulated thymoma removed >12 months before screening was allowed) or history of invasive thymic malignancy unless deemed cured by adequate treatment with no evidence of recurrence for >5 years before screening; (b) history of thymectomy within 12 months before screening; (c) MGFA class I or V; (d) received IVIg, subcutaneous Ig, or plasmapheresis/plasma exchange within 4 weeks before screening, or an expectation that any therapy besides the subject’s standard background therapies may be used for treatment of MG (e.g., a rescue therapy) between screening and dosing; (e) chronic obstructive pulmonary disease (COPD) or asthma with a pre bronchodilatory forced expiratory volume in 1 second (FEV1) <50% of predicted normal; FEV1 testing was required for patients suspected of having COPD or asthma; (f) received rituximab, belimumab, eculizumab, or any monoclonal antibody for immunomodulation within 6 months before first dosing; subjects with prior exposure to rituximab must had CD 19 counts within the normal range at screening; (g) known autoimmune disease other than MG that could interfere with the course and conduct of the study; (h) received a live vaccine within 4 weeks before screening or had any live vaccination planned during the study; (i) any medical condition that, in the opinion of the investigator, that could interfere with the subject’s participation in the study (such as significant cardiovascular, pulmonary, hematologic, gastrointestinal, endocrinologic, hepatic, renal, neurologic, malignant, or infectious disease), posed added risk for the patient, or could confound the assessment of the patient; (j) pregnancy or lactation during the screening period or on Day 1 before first dose of study drug; (k) participation in any other investigational drug study or exposure to other investigational agent within 4 weeks or 5 half-lives, whichever was longer, before Day 1; (1) an opportunistic infection <12 weeks before initial study dosing or currently receiving treatment for a chronic opportunistic infection, such as tuberculosis (TB), pneumocystis pneumonia, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria; a mild, localized herpes simplex infection within 12 weeks of study dosing was allowed, as long as the lesion has 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 ULN (subjects with a confirmed and documented diagnosis of Gilbert syndrome were not excluded based on this criterion); (iii) platelets <75,000/mm³; (iv) absolute neutrophil count <1500/mm³; (v) hemoglobin <8 g/dL; (vi) IgG < 5 g/L (500 mg/dL); or (vii) lymphocyte count <500/mm³; (n) a positive T-cell interferon-y release assay (TIGRA) (result through QuantiFERON-TB Gold test or T-Spot/Elispot) at the screening visit, noting the following: (i) a purified protein derivative (PPD) skin test may have been used if TIGRA testing was not available; (ii) subjects with an indeterminate TIGRA result had to meet the following criteria: (1) negative PPD skin test (defined as <5 mm in duration); and (2) at low risk of acquiring TB (e.g., avoided close contact with TB-positive individuals]) and/or chest X-ray <6 months before the screening visit that was consistent with no evidence of latent or active TB; (o) any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially interfere with the completion of 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; however, an individual who had a known history of chronic hepatitis C and had been treated and fully cured of the disease, confirmed with a negative hepatitis C virus RNA polymerase chain reaction test at screening, was not excluded on the basis of the positive hepatitis C antibody alone; or (q) a history of severe allergic or anaphylactic reactions to recombinant proteins or excipients used in the mezagitamab/placebo formulation.

Removal of Subjects from Therapy or Assessment

[0271] Study drug could be permanently discontinued for subjects meeting any of the following criteria: (a) withdrawal by subject; and (b) pregnancy.

[0272] Treatment with study drug could also discontinued for any of the following reasons: (a) AE/SAE; (b) protocol deviation; (c) symptomatic deterioration; (d) unsatisfactory therapeutic response; (e) study terminated by sponsor; or (f) lost to follow-up.

Collection of Demographic and Medical History Data

[0273] A complete medical history was compiled for each subject during the screening period (i.e., <28 days before study Day 1) and included assessment and documentation of prior medical history, comorbidities, and concomitant treatments. This included assessments of current MG signs, symptoms, morbidities, as evaluated and scored by disease activity tools, and previous and current MG therapies.

[0274] Demographics included the age, sex, race, and ethnicity (optional depending on country).

TREATMENTS

Treatments Administered

Premedication

[0275] On each dosing day, 1 to 3 hours before mezagitamab/placebo administration, subjects were premedicated with an antipyretic (such as acetaminophen) and an antihistamine (such as diphenhydramine). The premedication regimen was consistent with, but not limited to, the following: (a) antipyretic: oral acetaminophen (650-1000 mg); and (b) antihistamine: oral or intravenous diphenhydramine (25-50 mg, or equivalent).

Mezagitamab/Placebo [0276] Subjects received mezagitamab 300 mg, mezagitamab 600 mg, or matching placebo in accordance with their assigned treatment via SC injection once per week for 8 weeks. A summary of mezagitamab/placebo dose administration is outlined in Table 4.

Table 4. Summary of Mezagitamab/Placebo Dose Administration a Subjects were to receive mezagitamab or matching placebo via subcutaneous administration once weekly over the course of 8 weeks, i.e., for 8 total doses.

Postdose Medication

[0277] Subjects were closely monitored in the clinic for at least 2 hours after the first and second mezagitamab/placebo dose; before discharge from the clinic, the possible signs and symptoms of anaphylactic reactions and cytokine release syndrome (CRS) were reviewed with subjects.

[0278] After the first dose of study drug, subjects received low-dose methylprednisolone (<20 mg), or an equivalent, for the prevention of delayed injection-related reaction. Considering the timing of the greatest pharmacologic effect of mezagitamab, postdose medication was given 2 hours (±15 minutes) after the first injection of the first dose and 1 day after the first dose of study drug in the morning.

[0279] Postdose low-dose methylprednisolone (<20 mg) was not mandated after subsequent doses of mezagitamab/placebo (Weeks 2-8); however, it may have been given if clinically indicated and under the discretion of the principal investigator.

[0280] Subjects with a higher risk of respiratory complications (e.g, subjects with a history of COPD and those with asthma) may have been administered the following, after each study dose (at the investigator’s discretion): (a) an antihistamine (diphenhydramine or equivalent) on the first and second days after study dosing; (b) a short-acting 02-adrenergic receptor agonist, such as salbutamol (albuterol) aerosol; (c) control medications for lung disease, such as the following: (i) inhaled corticosteroids with or without long-acting 02 adrenergic receptor agonists for subjects with asthma; or (ii) long-acting bronchodilators, such as tiotropium or salmeterol, with or without inhaled corticosteroids, for subjects with COPD.

[0281] The clinical site was responsible for sourcing treatments administered pre- or post- mezagitamab/placebo administration.

[0282] On the basis of emerging data, the physician/designee may have enhanced treatments administered pre- or post-mezagitamab/placebo injection to ensure subject’s safety.

Identity of Study Drugs

[0283] Mezagitamab is a full-length, human IgGl monoclonal antibody directed against human CD38. The antibody is composed of 2 light chains of the (lambda) subclass and 2 heavy chains linked together by 2 disulfide bridges.

[0284] The strength of the mezagitamab for SC use in this study was 100 mg mezagitamab in 1 mL (100 mg/mL) (Table 5).

Table 5. Identity of Study Drugs

Packaging, Labeling, and Storage

[0285] Mezagitamab and matching placebo were supplied in aseptically filled, single-use, clear, type I, borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip-off caps.

[0286] Supplies of mezagitamab were labeled according to the current International Council for Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practices and include any locally required statements.

[0287] During shipping, vials were protected from light and maintained within temperatures provided in the pharmacy manual. Each mezagitamab shipment included a packing slip listing the contents of the shipment and any applicable forms. The investigator or designee must have confirmed that appropriate temperature conditions were maintained for all mezagitamab received and that any discrepancies were reported and resolved before use.

[0288] Upon receipt of study medication, the investigator or designee had to verify the contents of the shipments against the packing list. The verifier had to ensure that the quantity was correct, the medication was received within the labeled storage conditions, and was in good condition. If quantity and conditions were acceptable, the investigator or designee acknowledged the receipt of the shipment by signing the bottom half of the packing list and faxing per 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 filed in the investigator’s essential document file. The sponsor was notified immediately of any temperature excursions and shipping and handling or storage discrepancies. All clinical study material had to be kept in an appropriate, limited access, secure location until used, destroyed, or returned to the sponsor or designee. Mezagitamab had to be stored according to the manufacturer’s stipulation, as specified on the label (see the pharmacy manual for additional information). Detailed dosage preparation instructions were provided in the Directions for Use section of the pharmacy manual. Complete receipt, inventory, accountability, reconciliation, and destruction records had to be maintained for all used and unused study drug vials. Detailed instructions and the associated forms for these activities were in the pharmacy manual. Drug supplies were counted and reconciled at the site before being returned to Takeda or designee or being destroyed.

[0289] The investigator or designee had to ensure that the study medication was used in accordance with the approved protocol and was dispensed only to patients enrolled in the study. To document appropriate use of study medication (mezagitamab), the investigator had to maintain records of all study medication delivery to the site, site inventory, use by each patient, and return to the sponsor or designee.

[0290] The investigator was notified of any expiry date or retest date extension of clinical study material during the study conduct. On expiry date notification from the sponsor or designee, the site must complete all instructions outlined in the notification, including segregation of expired clinical study material for return to the sponsor or its designee.

Drug Accountability [0291] All clinical study material was kept in an appropriate, limited access, secure location until used, destroyed, or returned to the sponsor or designee. Mezagitamab was stored according to the manufacturer’s stipulation, as specified on the label. Detailed dosage preparation instructions were provided in the Directions for Use section of the pharmacy manual. Complete receipt, inventory, accountability, reconciliation, and destruction of records were maintained for all used and unused study drug vials. Detailed instructions and the associated forms for these activities were included in the pharmacy manual. Drug supplies were counted and reconciled at the site before being returned to Takeda or its designee or being destroyed.

[0292] The investigator or a designee had to ensure that the study medication was used in accordance with the approved protocol and was dispensed only to the subjects enrolled in the study. To document appropriate use of study medication (mezagitamab), the investigator had to maintain records of all study medication delivery to the site, site inventory, use by each subject, and return to the sponsor or its designee.

[0293] The investigator was notified of any expiry date or retest date extension of clinical study material during the study conduct. On expiry date notification from the sponsor or designee, the site must have completed all instructions outlined in the notification, including segregation of expired clinical study material for return to the sponsor or its designee.

Overdose

[0294] An overdose was defined as a known deliberate or accidental administration of the investigational drug to or by a study subject, at a dose that was above the dose assigned to that particular subject according to the study protocol.

[0295] To date, there was no experience with overdose of mezagitamab.

[0296] If an overdose occurred, close monitoring and supportive treatment, as medically required, would be recommended.

Placebo

[0297] Matching placebo was supplied in aseptically filled, single-use, clear, type I, borosilicate glass vials with fluoropolymer-coated butyl rubber stoppers and aluminum crimp seals with flip- off caps. Method of Assigning Subjects to Treatment

[0298] Subjects were randomly assigned in a 1 :1 : 1 ratio to 1 of the 3 treatment arms as outlined in Table 4 upon completion of study screening and before dosing on study Day 1, in accordance with the randomization schedule as generated by the interactive voice/web response system (IXRS).

Selection of Doses in the Study

[0299] The criteria for selecting doses and a regimen of mezagitamab for treating patients with MG was based upon identifying safe and well-tolerated doses that demonstrate pertinent pharmacodynamic (PD) activity.

[0300] The clinical experience prior to the start of the study had demonstrated that mezagitamab was safe and well-tolerated in 3 different populations (i.e., healthy subjects, subjects with relapsed and/or refractory multiple myeloma (RRMM), and subjects with systemic lupus erythematosus [SLE]) and across a broad range of doses (<1200 mg), vascular concentrations, and exposures.

[0301] In healthy subjects, single doses of mezagitamab up to 0.06 mg/kg intravenous and 0.6 mg/kg SC were well tolerated. The collective safety, tolerability, and PD profiles of mezagitamab in dose-escalation studies in healthy subjects, subjects with RRMM, and subjects with SLE indicate that the optimal doses and schedule of mezagitamab for patients with MG consisted of 8 weekly doses of 300 or 600 mg.

Selection and Timing of Dose for Each Subject

[0302] Before mezagitamab/placebo administration, subjects received premedication and underwent safety assessments.

[0303] As dose levels (300 and 600 mg) required multiple SC injections to administer the full dose, the Week 1 dose was administered by giving each SC injection 30 minutes apart (±10 minutes) until the full scheduled dose was administered. On all other drug administration days, if the subject did not have a clinically significant infusion reaction per the investigator, the SC injections were to be given at the same time without a waiting period. [0304] Investigators evaluated the subjects before each dose. For the first dose, laboratory assessments were evaluated using the results obtained at screening. Otherwise, laboratory results were obtained on the day before or the day of dosing. In instances where clinical parameters did not meet the criteria for continued dosing, the study drug was temporarily withheld until the parameters met dosing levels or was discontinued in accordance with the principal investigator’s judgment. Dosing of mezagitamab/placebo was not otherwise to be reduced or escalated for any given subject.

[0305] If study dosing was withheld for 2 consecutive doses because of safety concerns or other conditions outlined below, the subject was to be discontinued from study dosing and advanced to the SFP. If 2 or more subjects discontinued study, the clinician or designee was to review the available safety data to determine if adjustments to the treatment plan was made.

[0306] Subjects had to remain on their stable dose of standard background therapy, throughout the study unless dose reduction was required due to toxicities. Allowed background therapy was defined as no more than a cholinesterase inhibitor ± corticosteroid ± 1 steroid-sparing immunosuppressive drug (limited to azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide). Subjects were on at least one allowed background medication.

Blinding

[0307] The assignment of study subjects to 1 of 3 study arms were maintained through a blinded randomization schedule which was available in instances of medical emergencies to the principal investigator. Otherwise, site staff was blinded through Week 16 of the study (SFP).

[0308] To maintain the integrity of the study, all study personnel, including the investigators, site personnel, the contract research organization (CRO) medical monitor, study clinicians, and the sponsor were blinded to the treatment assignments during the treatment period. Treatment assignments were obtained through the IXRS according to the procedures outlined in the study manual or relevant training materials. Information regarding the treatment assignments were kept securely at designee, per its standard operating procedures.

[0309] Records of the subject number, the date the study drug was dispensed, and the treatment assignment was maintained by the study site. [0310] Emergency unblinding, if necessary, was conducted via the IXRS. There were no incidences of emergency unblinding during this study.

Prior and Concomitant Therapy

Excluded Concomitant Medications and Procedures

[0311] Excluded concomitant medications are presented in Table 6. If subjects received excluded medication, they were discontinued from the dosing period and automatically entered the SFP.

Table 6. Excluded Concomitant Medications

AE: adverse event; MG: myasthenia gravis.

“Exceptions to excluded medications were allowed for treatment of AEs, after discussion and agreement between the sponsor and principal investigator. bSubjects for whom any therapy (besides the allowed standard background therapies for MG) was reasonably expected between screening and dosing were excluded from study participation.

Permitted Concomitant Medications and Procedures

[0312] Permitted concomitant medications are summarized in Table 7. Table 7. Permitted Concomitant Medications aAzathioprine dosing must have been stable for at least 6 months before the screening visit.

Rescue Therapy

[0313] Rescue therapy was defined as additional dosing of concomitant medications in accordance with institutional practices or the physician’s best medical judgment to control and manage underlying MG conditions. Rescue medications may have included, but were not limited to, high-dose corticosteroids, IVIg, and plasmapheresis/plasma exchange.

[0314] Subjects were to remain on their stable dose of immunosuppressive and corticosteroid therapies throughout the study (as aligned with protocol requirements). If the subjects received rescue therapy, they would automatically enter the SFP.

[0315] Increasing, adding, or changing background immunosuppressive therapies, or adding a medication not otherwise within protocol limits, as deemed necessary by the principal investigator to treat manifestations of MG, resulted in discontinuation of the subject from study dosing and advancement to SFP.

Treatment Compliance

[0316] Mezagitamab/placebo was administered or dispensed only to eligible subjects under the supervision of the investigator or identified subinvestigator(s). The appropriate study personnel maintained the records of study drug receipt and dispensing. EFFICACY, PHARMACOKINETIC (PK), PHARMACODYNAMIC (PD), BIOMARKERS, IMMUNOGENICITY, AND SAFETY VARIABLES

Measurements Assessed and Flow Chart

[0317] A schedule of study procedures is presented in Table 8.

Table 8. Schedule of Study Procedures Table 8. Schedule o Procedures AChR: acetylcholine receptor; ADA: anti drug antibodies; AE: adverse event; CRS: cytokine release syndrome; COVID-19: coronavirus disease 2019; ECG: electrocardiogram; eCRF: electronic case report form; HBV: hepatitis B virus; HCV: hepatitis C virus; ICF: informed consent form; Ig: Immunoglobulin; IRB: institutional review board; IVIg: intravenous immunoglobulin; LFP: long-term follow-up period; MG: myasthenia gravis; MG-ADL: Myasthenia Gravis- Activities of Daily Living; MGC: Myasthenia Gravis Composite; MGII: Myasthenia Gravis Impairment Index; MG-QoL15r; Myasthenia Gravis Quality of Life Scale; MuSK: muscle-specific tyrosine kinase; PGIC: Patient Global Impression of Change; PGIS: Patient Global Impression of Severity; PK: pharmacokinetic; QMG: Quantitative Myasthenia Gravis; SAE: serious adverse event; SC: subcutaneous; SFP: safety follow-up period; TEAE: treatment-emergent adverse event. ^aSubjects could undergo additional laboratory assessments and observations as necessary based on the principal investigator’s best medical judgment, and as warranted by exhibited clinical signs or symptoms at each study clinic visit. ^bSubject visits at screening, Weeks 1-4, 8, 12, 16, 20, and 32 were done with the subject present at the investigative site. Other visits could be conducted at the clinic or by optional home healthcare visits (or a hybrid of Telehealth/Telemedicine with home healthcare) to extend flexibility to patients during COVID- 19 public health emergency. Home healthcare visits were documented in the study records and eCRF.

Subjects were unblinded after Week 16. Clinical parameters below the levels in Table 11 for continued dosing, including ongoing drug-related AEs, at Week 16 were monitored until the param eters/AEs are resolved, return to baseline, or are clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). ^dThe Week 20 visit of the LFP was the end-of-study visit for subjects randomized to placebo. Subjects randomized to placebo required only a symptom-directed physical examination at this visit. informed consent was documented before initiating any screening procedures associated with the study.

Screening period was 28 days (z.e., Day -28 to Day -1). Confirmation of subject eligibility by a project clinician or designee was required before enrollment and before receiving study drug. ^gPhysical examinations were to be symptom- and MG disease-directed with significant clinical findings noted as AEs. In LFP, needed only if there were ongoing drug-related AEs at the Week 16 assessment. Women of childbearing potential were asked about their menstrual history at each visit. A serum pregnancy test was conducted for delayed menses.

'’Assessments could be performed on the day before or the day of the indicated visit before dosing. ‘Vital signs (temperature, blood pressure, respiratory rate, and heart rate) were measured before all mezagitamab administrations and 2 hours (±10 minutes) postdose after the first and second mezagitamab/placebo dose. In addition, vital signs were assessed at any time it is clinically warranted. As per the investigator’s judgment, if there were no concerns raised by the symptom- directed physical, vital signs measurements were not required to be collected at the Weekl4 visit during the COVID-19 pandemic.

Hhe results of urine pregnancy tests were available and negative before mezagitamab was administered. A serum pregnancy test was completed if the subject's menstrual period was delayed, or if the IRB requests, and a negative result was obtained before dosing with the study drug. Serum pregnancy testing could be used in place of urine pregnancy testing with prior permission from the sponsor. ^kHematology and chemistry laboratory samples were collected locally. Local laboratory evaluations could be done more frequently at the investigator’s discretion (e.g., for acute management of TEAEs) and could be used for dosing decisions.

'Clinical laboratory evaluations for disease assessments (anti-AChR and anti-MuSK antibodies) were tested centrally.

‘"Samples collected before mezagitamab administration.

“CD 19 evaluation was performed only in patients with prior exposure to rituximab; CD 19 counts were within the normal range at screening to be eligible.

“Circulating biomarkers could include assessment of complement C3 and C4 levels. Sample was also drawn for cytokine markers. Additional samples of cytokine markers were drawn if CRS was suspected. ^pAdditional PK and biomarker sampling could be requested. ^qQuantitative immunoglobulins were tested at a central laboratory; thus, results were not available before each weekly dose. However, per standard medical practice, investigators had to review the results once available and take appropriate clinical action, which might include but was not limited to withholding study drug and treatment with IVIg, for example, in the setting of a severe infection.

■physician examination portion of this assessment could be omitted if performing a remote visit.

"Procedure could be omitted if performing a remote visit. The assessment of forced vital capacity for QMG test could be omitted for COVID-19-related reasons.

'Premedication and postdose medication before and after mezagitamab administration.

“Time and anatomical site were recorded for each injection. Subjects were closely monitored in the clinic for at least 2 hours after the first and second mezagitamab dose; before discharge from the clinic, the possible signs and symptoms of anaphylactic reactions and CRS had to be reviewed with subjects. ^vPostdose medication was given 2 hours (±15 minutes) after the first injection of the first dose and 1 day after the first dose of study drug in the morning. Postdose medication could be given with subsequent doses if clinically indicated and under the discretion of the principal investigator.

" Assessments for AEs were to include a symptomatic examination per standard medical practice.

End of Safety Follow-up Assessments

[0318] End of SFP clinical parameters, as outlined in Table 9, were assessed at Week 16 of the SFP (see SOE in Table 8). If clinical presentation and parameters did not meet the end of SFP criteria and were deemed by the principal investigator as study related, then the study-related parameters not meeting end-of-study criteria were continued to be assessed in the LFP until they were normalized or returned to baseline levels.

CRS: cytokine release syndrome; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; Hgb: hemoglobin; Ig: immunoglobulin; IRR: infusion-related reaction; LLN: lower limit of normal.

“Laboratory and infection grading are based on NCI CTCAE v4.03. Efficacy Measurements

[0319] The study principal investigator or appropriately trained, delegated, study site staff assessed each subject for disease activity based on the following MG disease activity scales outlined in the following sections and in accordance with the SOE in Table 8.

[0320] MG-ADL Score: The MG-ADL is a validated, 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 herein incorporated by reference in their entirety). The MG-ADL assessed relevant MG symptoms and their functional impact on the subject. The subject assessed functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb impairment (2 items). Each item was individually graded from 0 (normal) to 3 (severe). The total MG-ADL score ranged from 0 to 24 points, with higher scores indicating greater functional impairment and disability. A 2-point reduction in the MG- ADL total score was considered a clinically meaningful improvement.

[0321] 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 evaluates muscle strength based on quantitative testing and clinician assessment of sentinel muscle groups: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item is graded on a scale of 0 to 3, with 3 being the most severe. The total score ranges from 0 to 39, with higher scores representing a greater disease burden (Barohn etal. (1998) Ann. NY Acad. Sci. 841 : 769-772; Katzberg et al. (2014) Muscle Nerve 49(5): 661-665, both herein incorporated by reference in their entirety). A 3-point reduction in the QMG total score is considered a clinically meaningful improvement.

[0322] MGII Score: The Myasthenia Gravis Impairment Index (MGII) is a novel and validated measure of MG severity, with 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 herein incorporated by reference in their entirety). The MGII score was developed using patient input and consists of 6 physician-examination and 22 patient-reported items. The MGII has less floor effect (i.e., more dynamic range at the lower end of the scale) than other commonly used measures and is therefore more sensitive to detect change. The total score ranges from 0 to 84 (with higher scores indicating worse MG disease activity), and a group-level reduction by 8 points reflects the minimal clinically important difference (MCTD). The MCID at a group level — to estimate sample size for a trial — was 8.1 points, and at the individual level — to classify a subject as responder — was 5.5 points.

[0323] MGC Score: The Myasthenia Gravis Composite (MGC) scale is a validated subject- and physician-reported 10-item assessment tool for evaluating the signs and symptoms of MG (Barnett et al. (2018) Neurol. Clin. 36(2): 339-353, herein incorporated by reference in its entirety). Physician assessment includes assessment for ptosis (upward gaze), double vision on lateral gaze, eye closure, neck flexion or extension, shoulder abduction, and hip flexion; subject assessment includes self-report of talking, chewing, swallowing, and breathing. Items are scored based on 4 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 activities (Benatar etal. (2012) Muscle Nerve, 45(6), 909-917; Bums et al. (2012) Ann. NY Acad. Sci. 1274: 99-106; Sadjadi et al. (2012) Muscle Nerve 45(6): 820-825, each herein incorporated by reference in their entirety). A 3-point reduction in the MGC total score is considered a clinically meaningful improvement.

[0324] MG-QoL15r: The revised 15-item Myasthenia Gravis Quality of Life scale (MG- QoL15r) is a validated tool containing 15 subject-reported items about the subject’s perception of impairment and disability and the degree to which the subject tolerates disease manifestations (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 herein incorporated by reference in their entirety). The total score ranges from 0 to 30, with higher scores indicating worse MG disease activity. The MCID for this clinical outcome assessment (COA) tool has not been fully determined (Barnett et al. (2018) Neurol. Clin. 36(2): 339-353, herein incorporated by reference in its entirety).

[0325] PGIC: The Patient Global Impression of Change (PGIC) is an anchor scale used to aid the interpretation of the aforementioned MG disease activity instruments mentioned above (MG- ADL, MGII, MGC, QMG, and MG-QoL15r). The PGIC may be used in the analyses of meaningful change and other psychometric properties and performance characteristics of these instruments. [0326] PGIS: The Patient Global Impression of Severity (PGIS) is an anchor scale used to aid the interpretation of the aforementioned MG disease activity instruments (MG-ADL, MGII, MGC, QMG and MG-QoL15r). The PGIS may be used in the analyses of meaningful change and other psychometric properties and performance characteristics of these instruments.

[0327] Quantification of Ig: 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 the central laboratory.

[0328] PK, Pharmacodynamic/Biomaker Samples: Samples were collected by venipuncture or indwelling catheter at the time points detailed in the SOE Table 8 for the measurement of serum concentrations of mezagitamab and biomarker assessments. The samples were tested at a central laboratory.

[0329] PK Measurements: Serum samples for the measurement of concentrations of mezagitamab 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 of clinical interest or AEs.

[0330] Pharmacodynamic/Biomarker Measurements: In this study, several biomarkers were assessed to test for correlation with safety, PK, and, if possible, with efficacy. These biomarkers were used to identify subjects who had a higher probability of response or adverse reactions to mezagitamab. The biomarker sample analysis was performed if or when required. Samples for pharmacodynamic measurements were collected as detailed in Table 8. If a subject exhibited signs or symptoms possibly assessed as CRS by the investigator, a blood draw was performed for central evaluation that could include, but was not limited to, immune markers and cytokine markers.

Autoantibodies

[0331] Serum samples were collected to detect anti-AChR and anti-MuSK antibodies as outlined in Table 8 and were analyzed by a central laboratory. [0332] Pharmacodynamics: Blood samples were collected to analyze CD38+ expression and monitor changes in immune cells by flow cytometry before, during, and at the end of treatment. These evaluations were performed at a central laboratory.

[0333] Circulating Biomarkers: Serum samples for cytokines/chemokines were collected before, during, and at the end of treatment to help identify subject who had a higher probability of response or of experiencing adverse reactions to mezagitamab.

[0334] Immunoprofiling: Blood samples for immunoprofiling were collected for the profiling of immune cells 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.

[0335] 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.

[0336] Immunogenicity Sample Collection: Serum samples for the measurement of anti- mezagitamab antibody (antidrug antibody and ADA are exchangeable terms in the protocol) were collected at multiple time points as specified in the SOE in Table 8. The samples were taken before each dosing. Details regarding the preparation, handling, and shipping of the immunogenicity samples were provided in the laboratory manual. Positive ADA screening samples were further tested for true positivity and titer by the study central laboratory.

[0337] Safety Measurements: Safety was evaluated by the frequency of AEs, severity, and types of AEs, and by changes from baseline in subjects’ vital signs, weight, and clinical laboratory results using the safety analysis set. Exposure to study drug and reasons for discontinuation was tabulated. Treatment-emergent adverse events (TEAEs) that occurred after administration of the first dose of study drug and through the end of the SFP were tabulated. AEs were tabulated according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 25.0, and data were summarized using Preferred Term (PT) and primary System Organ Class (SOC). All safety analyses were performed using the safety analysis population.

[0338] Physical Examination: A complete physical examination as well as a symptom-directed physical examination with assessments for MG signs and symptoms was completed in accordance with standard of care at the times specified in the SOE Table 8. Women of childbearing potential were asked about their menstrual history at each visit. A serum pregnancy test was conducted for delayed menses.

[0339] Height and Weight: Height was measured during screening only (within 28 days before the first dose of TAK 079). Weight was measured during screening and at Weeks 10, 16, and 32 as outlined in Table 8.

[0340] Vital Signs: Vital signs (body temperature, respiratory rate, heart rate, and blood pressure) were evaluated at visits specified in Table 8 and was recorded both on the source documentation and in the eCRF. In addition, vital signs were assessed at any time it was clinically warranted, i.e., subject exhibited signs or symptoms of injection site reaction (ISR), CRS, or hypersensitivity reactions. As indicated in Table 8, vital signs were assessed before each study dose and 2 hours (±10 minutes) postdose after the first and second mezagitamab/placebo dose. Clinically significant values, as determined by the principal investigator, were documented as an AE and closely monitored for follow-up.

[0341] 12-Lead ECG: A single 12-lead electrocardiogram (ECG) was performed at the screening visit (for assessment of eligibility) and at Weeks 10 and 16 of the SFP, and Week 32 of the LFP and were read locally. Additional ECGs may have been done per investigator discretion. Each ECG recording was performed according to standard institutional practice. Any ECG finding that was judged by the investigator as clinically significant (except at the screening visit) was considered an AE and was recorded on the source documentation and in the eCRF and monitored.

[0342] Adverse Events: Monitoring of AEs, serious and nonserious, was conducted throughout the study as specified in Table 8.

[0343] Clinical Laboratory Evaluations: Hematology, serum chemistry, and serology assessments were performed locally, with reference ranges provided in the electronic data capture (EDC) system. Clinical laboratory evaluations were performed according to the SOE in Table 8 throughout the study. Instructions for handling and shipping clinical laboratory samples were provided in the study laboratory manual. Clinical Chemistry and Hematology

[0344] Blood samples for analysis of the clinical chemistry and hematology parameters shown in Table 10 were obtained as specified in the SOE Table 8.

Table 10. Clinical Chemistry and Hematology Tests

ANC: absolute neutrophil count.

[0345] If 2 or more subjects discontinued the study drug dosing on the basis of the dose discontinuation criteria mentioned in Table 11, the clinician/designee reviewed available safety data to determine if adjustments to the treatment plan had to be made.

Table 11. Summary of Subsequent Dosing Criteria

ANC: absolute neutrophil count; CRS: cytokine release syndrome; CTCAE: Common Terminology Criteria for Adverse Events; Hgb: hemoglobin; IRR: infusion-related reaction; MG: myasthenia gravis; NCI: National Cancer Institute; SFP: safety follow-up period. aSubjects whose clinical parameters meet dose-hold criteria will not receive the scheduled dose of mezagitamab; subjects instead return for reassessment and evaluation at next planned visit. bSubjects whose clinical parameters meet dose discontinuation criteria are to be permanently discontinued from study dosing; subjects will advance to the SFP, completing all associated assessments. Standard background therapy for MG will be managed according to the principal investigator’s discretion. cLaboratory, IRR, allergic reactions, anaphylaxis, and infection grading are based on NCI CTCAE v4.03. dAfull cytokine panel is to be obtained for any suspected events, at any grade, of CRS. eAnaphylaxis is diagnosed according to Sampson et al. (2006) J. Allergy Clin. Immunol.

117(2): 391-397, herein incorporated by reference in its entirety. fCRS is classified according to Lee et al. (2014) Blood 124(2): 188-195, herein incorporated by reference in its entirety. gSymptomatic treatment allowed in accordance with Lee et al. (2014) Blood 124(2): 188-195.

Pregnancy

[0346] A serum pregnancy (human chorionic gonadotropin [hCG]) test was completed for all female subjects; the test was performed at screening and during the SFP and were negative for the subject to be randomized and to continue in the study.

[0347] A urine pregnancy test was completed for all female subjects before the first dose of mezagitamab/placebo and at Week 5 of the dosing period. If the subject reported delayed menses a serum pregnancy test was completed, and a negative result was obtained before dosing with the study drug. [0348] All study pregnancy testing was to be conducted at a designated local laboratory as determined and confirmed by the sponsor, with appropriate laboratory documentation provided in advance of study testing.

Timins of Pregnancy Testing

[0349] Women of childbearing potential had to have a pregnancy testing completed in accordance with the timing outlined as follows, (a) Before initial study dosing: (i) screening period: a negative serum pregnancy test (hCG <5 mIU/mL); and (ii) baseline: (either Day 1 prior to initial study dosing, or 1 day before study dosing) a negative urine pregnancy test with a sensitivity of at least 50 mIU/mL. If the urine test was indeterminate, a serum pregnancy test was mandatory, (b) During study enrollment: (i) at Week 5, before dosing (urine pregnancy test); (ii) during SFP, and LFP as outlined in Table 8 (serum pregnancy test); (iii) if a menstrual period is delayed (serum pregnancy test); and (iv) additional pregnancy tests were conducted as requested by the IRB and/or as required by local regulations.

Appropriateness Measurements

[0350] The safety and efficacy assessments used in the study were standard for the disease population and phase of research.

Endpoints

Primary Endpoints

[0351] Percentage of patients with TEAEs, including Grade 3 or higher events, SAEs, and AEs leading to mezagitamab discontinuation.

Secondary Endpoints

[0352] Secondary endpoints are as follows, (a) Score change from baseline in the following: (i) MG Activities of Daily Living (MG-ADL) score; (ii) Quantitative Myasthenia Gravis (QMG) score; (iii) Myasthenia Gravis Composite (MGC) score; and (iv) Revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r). (b) Change from baseline in anti-AChR antibody or anti-MuSK antibody levels, (c) The percentage of patients meeting MCID criteria in the respective MG clinical impairment scales (MG-ADL, QMG, MGC). Exploratory Endpoints

[0353] Exploratory endpoints are as follows, (a) Serum concentration-time profile of mezagitamab PK parameters included but are not limited to observed concentration at the end of a dosing interval (Ctrough) over time, (b) Change in serum Ig levels, (c) Pharmacodynamic analysis of the presence and changes of immune cells in peripheral blood before and during therapy, (d) Score change from baseline in MGII scores, (e) Duration of a clinically meaningful effect on MG disease severity (in all of the clinical disease impairment scales: MG-ADL, QMG, MGC, MGII). (f) Percentage of subjects meeting MCID criteria in the MGII scale, (g) Frequency and proportion of subjects requiring rescue therapy, (h) Immunogenicity assessment of mezagitamab in peripheral blood, including antidrug antibody (ADA), (i) Biomarkers of disease activity such as complement levels (C3, C4, complement split products); specific markers of CD38 pathway modulation may also be evaluated, (j) Change in levels of the following vaccine-protective antibodies: measles, mumps, rubella, diphtheria, and tetanus.

STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE

Analysis Sets

[0354] Full analysis set: All enrolled subjects. In efficacy analyses, only subjects with both baseline and at least 1 valid postbaseline value were included.

[0355] Safety analysis set: Subjects who had received at least 1 dose of study drug.

[0356] PK analysis set: Subjects who had received at least 1 dose and had at least 1 measurable mezagitamab serum concentration.

[0357] Pharmacodynamic analysis set: Subjects who had a baseline and at least 1 postbaseline PD sample assessment.

[0358] Immunogenicity analysis set: Subjects from the safety population who had a baseline and at least 1 postbaseline immunogenicity sample assessment.

Efficacy Analysis

[0359] Efficacy was not the primary endpoint for this study. Secondary efficacy measures included: (a) score change from baseline for the following: (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) percentage of subjects meeting MCTD criteria in the respective MG clinical impairment scales (MG-ADL, QMG, MGC).

[0360] Exploratory efficacy measures included: (a) score change from baseline in the MGII score; (b) duration of a clinically meaningful effect on MG disease severity (in all the clinical disease impairment scales: MG-ADL, QMG, MGC, MGII); (c) percentage of subjects meeting MCID criteria in the MGII scale; and (d) frequency and proportion of subjects requiring rescue therapy.

[0361] Efficacy endpoints were summarized by descriptive statistics and presented by treatment group. Where appropriate, efficacy endpoints were analyzed with the following methods: (a) binary endpoints were analyzed using a Fisher’s exact test; and (b) change from baseline endpoints measured repeatedly over time were analyzed using a mixed model repeated-measures analysis, which included treatment, visit, and (treatment x visit) interaction terms as the factors, with baseline values as covariates.

[0362] All tests of treatment effects were conducted at a 2-sided a level of 0.05, and 95% Cis for the differences in proportions and least squares (LS) means were provided. No inferential hypothesis was tested with these endpoints; thus, Cis and p-values were not adjusted for multiplicity.

[0363] All efficacy analyses were performed using the full analysis set.

PK Analysis

[0364] Descriptive summary of the concentration-time profile of serum mezagitamab was provided. PK parameters included Ctrough. A population PK model could be developed. If developed, the population PK model was to be reported separately. PK/PD analyses of selected PD and/or efficacy measures could be conducted as data permitted. Any population PK/PD analysis if conducted was to be reported separately.

Immunogenicity Analysis

[0365] Mezagitamab immunogenicity status (ADA incidence) was analyzed and summarized using descriptive statistics, as applicable, and using the immunogenicity analysis set. The effect of immunogenicity on PK, PD, safety, and efficacy could be explored. Immunogenicity analyses were based on available data from subjects with a baseline assessment and at least 1 postbaseline immunogenicity assessment.

Safety Analysis

[0366] Safety was evaluated by the frequency of AEs, severity, and types of AEs, and by changes from baseline in subjects’ vital signs, weight, and clinical laboratory results using the safety analysis set. Exposure to study drug and reasons for discontinuation were tabulated.

[0367] TEAEs that occurred after administration of the first dose of study drug and through the end of the SFP were tabulated.

[0368] AEs were tabulated according to the MedDRA, and data were summarized using PT and primary SOC. All safety analyses were performed using the safety analysis population.

[0369] In this study, Grade 2 or greater medication related toxicities were monitored starting from the first 12 safety-evaluable subjects and then every 12 safety -evaluable subjects. If the stopping bounds of >3 of 12, and >5 of 24 have been achieved, accrual to the study were suspended to allow for a blinded investigation of the safety profile. After consideration by the study team, which could include the safety management team as appropriate, especially if case unblinding is necessary, a decision was made as to whether accrual can be resumed. The AE grading limits were based on the International Consensus Guidelines for the Management of Myasthenia Gravis where the aim was no more than grade 1 CTCAE (Common Terminology Criteria for Adverse Events) medication side effects. The statistical bounds were based on a Bayesian strategy to monitor outcomes in clinical trials. If the stopping rule was met, there was 80% probability that the true toxicity rate was greater than 10% with a prior beta distribution with parameters 0.2 and 1.8 for the binomially distributed toxicity rate.

[0370] Clinicians conducted reviews of SAEs and related clinical parameters to ensure consistency with an acceptable benefit-risk ratio throughout the study. If >2 subjects experienced the same SAE, the study was suspended to allow for a blinded investigation by the study team which could include the safety management team as noted above; after which a decision was made to whether accrual can be resumed. Determination of Sample Size

[0371] Approximately 36 subjects were planned to be randomized to treatment in a ratio of 1 : 1 : 1 (mezagitamab 300 mg, mezagitamab 600 mg, or placebo). This study was exploratory and not powered to address any predefined hypothesis.

EXAMPLE 2: STUDY SUBJECTS

Disposition of Subjects

[0372] Subject disposition data are summarized for the full analysis set in Table 12 and the dosing regimen in Figure 1. In total, 76 subjects were screened; however, 40 did not enter the study. The reasons for screen failure were not meeting the entrance criteria (38 subjects) and withdrawal by subject (2 subjects).

[0373] Thirty-six subjects were randomized at 5 study sites in USA, Poland, Serbia, Spain, and Canada. Among the 36 subjects, 4 (2 each in mezagitamab 300 mg and 600 mg groups) discontinued the study and the reason for discontinuation was withdrawal by subject. Table 12. Disposition of Patients (Full Analysis Set)

SFP: safety follow-up period.

Percentages are based on all subjects in Full Analysis Set within each column.

PROTOCOL DEVIATIONS

[0374] Significant protocol deviations are summarized in Table 13. In total, significant protocol deviations were reported for 13 subjects; the most common reason for significant deviations was under the category of missing endpoint assessments (19.4%; 7 subjects), which usually pertained to missing either MG-ADL, QMG, MGC, or MG-QoL15r assessment because of site staff shortages, subject's quarantine requirement, missing visits, or missing instruments. Other categories for significant protocol deviation that were reported in more than 1 subject were administration of additional concomitant background medication, data privacy, study treatment administration/dispensing, and study treatment supplies/control (2 subjects each; 5.6%). These deviations are unlikely to compromise the integrity of the study.

Table 13. Significant Protocol Deviations (Safety Analysis Set) Table 13. Significant Protocol Deviations (Safety Analysis Set)

GCP: Good Clinical Practice; ICF : informed consent form.

Percentages are based on all subjects in the Safety Analysis Set within each column. “Subjects with multiple protocol deviations are counted once in each deviation category.

EXAMPLE 3: EFFICACY, PK, PD, BIOMARKER, AND IMMUNOLOGY

EVALUATIONS

DATA SETS ANALYZED

[0375] The analysis populations are summarized in Table 14.

Table 14. Analysis Sets (All Randomized Subjects)

Percentages are based on all subjects randomized within each column.

“Full analysis set consists of all randomized subjects who had baseline and at least 1 postbaseline efficacy assessment. ^bSafety Analysis Set consists of subjects who received at least 1 dose of study drug. immunogenicity Analysis Set consists of subjects from the safety population who had a baseline and at least 1 postbaseline immunogenicity sample assessment. ^dPK Analysis Set consists of subjects who received at least 1 dose of study drug and at least 1 measurable mezagitamab serum concentration. ^ePD Analysis Set consists of subjects who received at least 1 dose of study drug and at least 1 postbaseline PD sample assessment. Demographic Characteristics

[0376] Table 15 provides a summary of demographic characteristics of the subjects enrolled in the study. Demographic characteristics were generally comparable between all the groups. Overall, the majority of the subjects were white (91.7%), particularly of European origin (72.2%). The median age across all the study groups was 50.0 years with a maximum age of 81 years. There were some age imbalances between the groups in the study, with the median age in the mezagitamab 600 mg group being approximately 18 and 16 years older than that in the placebo and mezagitamab 300 mg groups, respectively. Regarding sex distribution in the total study population, female subjects (n=22, 61.1%) were numerically more than male subjects (n=14); however, within each study group, sex distribution was not well balanced as the placebo group had a strong female predominance (75%), the 300 mg mezagitamab group presented with equal numbers of males and females, and the 600 mg mezagitamab group presented with a slightly larger number of females (58.3%).

Table 15. Demographics (Safety Analysis Set) Table 15. Demographics (Safety Analysis Set)

Medical History and Other Baseline Characteristics

[0377] Among 36 subjects enrolled in the study, 29 (80.6%) subjects had reported data pertaining to their medical history.

[0378] Key baseline disease characteristics are summarized in Table 16. MG severity based on MGFA classification was class IHb in 12 subjects (33%), Ila in 10 subjects (27.8%), and Hb in 6 subjects (16.7%). MG Illa and IVa were reported in less than 15% of the overall subjects.

Median time since MG diagnosis overall was 8.8 years, with no significant differences across the study groups. Most of the subjects (91.7%) had AChR+ antibodies, and 3 subjects out of 36 had MuSK+ antibodies. Baseline scores in all evaluated clinical disease impairment scales were lower in the placebo group than in the mezagitamab-treated groups, suggesting that subjects in the placebo group had less severe disease at baseline. Additionally, based on the mean clinical disease impairment scales baseline scores, the subjects in the mezagitamab 300 mg group appeared to have more severe disease at baseline when compared with those in the other 2 study groups. With regard to prior MG medications, all subjects in the study had been treated with acetylcholinesterase inhibitors (100%), and a majority of them also had received a combination of corticosteroids (83.3%) and/or immunosuppressants (72.2%), consistent with refractory disease.

Table 16. Baseline Characteristics by Treatment Group (Safety Analysis Set) Table 16. Baseline Characteristics by Treatment Group (Safety Analysis Set) Table 16. Baseline Characteristics by Treatment Group (Safety Analysis Set)

Percentages are based on all subjects in the Safety Anal sis Set within each column.

ECG = Electrocardiogram. MG = Myasthenia Gravis, MG-ADL = Myasthenia Gravis-Activities of Daily Living, QMG = Quantitative Myasthenia Gravis, MGC = Myasthenia Gravis Composite, MG-QoL15r = Revised 15-item Myasthenia Gravis Quality of Life Scale, MGII = Myasthenia Gravis Impairment Index.

BMI = Body Mass Index; calculated as [weight (kg)/height (m)^A2],

“Time since MG diagnosis (years) is calculated as (date of informed consent - date of diagnosis)/365.25. If date of diagnosis is a partial date with missing day, impute it to 1st day of month if month known; if only year is known, impute tire day and month to July 1.

*Brand name Calcort was used which is replaced with generic name deflazacort.

Medication History, Ongoing Background Medications, and Rescue Therapy

Ongoing Background MG Medications [0379] All subjects in the study received background MG therapy (Table 17). These included acetylcholinesterase inhibitors (pyridostigmine) administered to 32 subjects (88.9%); oral corticosteroids (primarily prednisone) which were given to 27 subjects (75%); and immunosuppressants, of which the most commonly used were azathioprine and cyclosporine, given to 23 subjects (63.9%). These medications had been ongoing and stable at the time of subjects' enrollment and continued to be administered during the subjects' participation in the study. 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 generalized MG. No imbalances in MG background medications were apparent at baseline.

Table 17. Ongoing Background MG Medications by Category and Medication Name and

Treatment Group (Safety Analysis Set)

MG medications are defined as medications with start dates within 28 days before the first dose of study treatment and are on-going at the subject’s enrollment and either ended during the study or administered through the end of the subject’s participation in the study as recorded in the eCRF.

Subjects were counted once per category and once per medication name per treatment group. Rescue Therapy Use

[0380] By Week 16, 2 subjects in the placebo group (17%) and 1 subject in the mezagitamab 600 mg group (8%) required rescue therapy.

[0381] Over the course of the study, 5 subjects in total required rescue therapy, 2 each in the placebo and mezagitamab 600 mg groups and 1 in the mezagitamab 300 mg group. Table 18 provides a subject-level summary of rescue therapy use in the study.

Table 18. Subjects Requiring Rescue Therapy During the Study

IVIg = Intravenous immunoglobulin, NR = Not reported

EFFICACY, PK, PD, BIOMARKER AND IMMUNOGENICITY RESULTS

Efficacy Results

Secondary Efficacy Endpoint Analysis

MG-ADL Total Score

[0382] At baseline, the mean (SD) MG-ADL total scores were lower in the placebo group when compared with the mezagitamab-treated groups: placebo, 7.9 (1.78); mezagitamab 300 mg, 9.3 (2.49); and mezagitamab 600 mg, 8.4 (2.23) (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 improvement (>2-point reduction in the MG-ADL total score from baseline) was achieved by all 3 study groups, albeit with slightly different timing and duration. The placebo and mezagitamab 300 mg group achieved clinical response earlier (Week 4), while the mezagitamab 600 mg group lagged behind. The clinically meaningful improvement achieved by mezagitamab 300 mg appeared to be the most durable across the study groups, being present from Week 4 until the end of the study (Week 32); however, comparison with placebo was not available after Week 16 as placebo data was not collected after Week 16 of the study. In the MMRM analyses, no statistically significant difference was present between placebo, mezagitamab 300 mg, and mezagitamab 600 mg at any of the assessment timepoints.

[0383] Table 19 shows the summary statistics for MG-ADL total scores (at baseline, Week 16, and Week 32). Figure 2 a shows a plot of the observed mean change from baseline in the MG- ADL total score over time.

Table 19. Summary and Analysis of Change from Baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score by Visit and Treatment Group (Full Analysis Set) Table 19. Summary and Analysis of Change from Baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score by Visit and Treatment Group (Full Analysis Set)

N/A: not applicable; SD: standard deviation

Baseline value is defined as the last observed value before the first dose of study drug. *Placebo data not collected after Week 16 of the study per protocol design.

QMG Total Score

[0384] At baseline, the mean (SD) QMG total scores were lower in the placebo group compared to the mezagitamab treated groups: placebo, 11.4 (5.21); mezagitamab 300 mg, 12.9 (6.47); and mezagitamab 600 mg, 12.8 (4.26) (Table 20). 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. Clinically meaningful improvement (>3-point reduction in the QMG total score from baseline) was observed in the mezagitamab 300 mg group from Week 8 until Week 16, with the peak response observed at Week 12 (mean [SD] change: 3.9 [2.55]). No statistically significant difference in the change from baseline QMG total scores was observed between placebo, mezagitamab 300 mg group (LS mean difference vs placebo, -1.37), and mezagitamab 600 mg group (LS mean difference vs placebo, 1.20) at Week 16.

[0385] Table 20 shows the summary statistics for QMG total scores (at baseline, Week 16, and Week 32). Figure 3 shows a plot of the observed mean change from baseline in the QMG total score over time.

Table 20. Summary and Analysis of Change from Baseline in QMG Total Score by Visit and Treatment Group (Full Analysis Set) Table 20. Summary and Analysis of Change from Baseline in QMG Total Score by Visit and Treatment Group (Full Analysis Set)

N/A: not applicable; SD: standard deviation

Baseline value is defined as the last observed value before the first dose of study drug.

If the baseline assessment of the Forced Vital Capacity (FVC) item in the QMG scale for a subject is missing and no other items in the QMG scale are missing for that subject, the missing FVC item score is imputed as the mean of all non-missing baseline FVC values from the set of randomized subjects. If the FVC item on any post baseline QMG assessment is missing, this missing item is imputed using last observation carried forward (LOCF) for that subject for that item only.

*Placebo data not collected after Week 16 per protocol design.

MGC Total Score [0386] At baseline, the mean (SD) MGC total scores were lower in the placebo group when compared with the mezagitamab-treated groups: placebo, 14.7 (5.80); mezagitamab 300 mg, 16.8 (6.58); and mezagitamab 600 mg, 15.3 (6.00) (Table 1 l.j). Mean (SD) change from baseline in MGC scores 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 response (>3-point reduction from baseline in the MGC total score) was observed in the placebo and mezagitamab 300 mg as early as the Week 4 of the study. This clinically meaningful response was sustained from Week 4 until the end of the study (Week 32) in the mezagitamab 300 mg group and until Week 16 in the placebo group (placebo data only available until Week 16). In the mezagitamab 600 mg group, clinically meaningful improvement was observed only intermittently at Weeks 6, 12, 24, and 28. In the MMRM analyses, no statistically significant difference was seen between placebo, mezagitamab 300 mg (LS mean difference vs placebo, -1.01), and the mezagitamab 600 mg group (LS mean difference vs placebo, 4.81) at Week 16.

[0387] Table 21 shows the summary statistics for MGC total scores. Figure 4 shows a plot of the observed mean change from baseline in the MGC total score over time.

Table 21. Summary and Analysis of Change from Baseline in MGC Total Score by Visit and Treatment Group (Full Analysis Set) Table 21. Summary and Analysis of Change from Baseline in MGC Total Score by Visit and Treatment Group (Full Analysis Set)

Baseline value is defined as the last observed value before the first dose of the study drug. *Placebo data not collected after Week 16 per protocol design. MG-QoL15r Total Score

[0388] 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). 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. While an MCID for MG-QoL15r has not been established, a numerically larger reduction in scores was observed for the mezagitamab 300 mg group compared to the placebo and mezagitamab 600 mg during the first 16 weeks of the study. Additionally, the reduction in MG-QoL15r scores for the mezagitamab 300 mg group persisted from Week 6 until the end of the study, suggesting a potential trend towards durable effect of this dose of mezagitamab on the subjects’ quality of life. In the MMRM analyses, no significant difference was seen between placebo, mezagitamab 300 mg (LS mean difference vs placebo, 0.20), and mezagitamab 600 mg (LS mean difference vs placebo, 2.48) at Week 16.

[0389] Table 22 shows the summary statistics for MG-QoL15r total scores. Figure 5 shows a plot of the observed mean change from baseline in the MG-QoL15r total score over time.

Table 22. Summary and Analysis of Change from Baseline in Revised 15-item MG-QoL15r Total Score by Visit and Treatment Group (Full Analysis Set) Table 22. Summary and Analysis of Change from Baseline in Revised 15-item MG-QoL15r Total Score by Visit and Treatment Group (Full Analysis Set)

N/A: not applicable; SD: standard deviation

Baseline value is defined as the last observed value before the first dose of study drug.

*Placebo data not collected after Week 16 per protocol study design Responder Analysis for MG-ADL

[0390] At Week 16, the percentage of responders (i.e., subjects meeting the MCID criteria) was 66.67% (8 subjects) in both the placebo and mezagitamab 300 mg groups; the mezagitamab 600 mg group had 33.33% (4 subjects) of responders. Both of the mezagitamab treated dose levels exhibited 41.67% of responders (5 subjects) at Week 32 (placebo not assessed after Week 16).

[0391] Figure 6 shows the proportion of responders in the study groups at Weeks 4 through 16.

[0392] Figure 7 shows the proportion of responders (subjects with clinically meaningful reduction from baseline in MG-ADL score >2 pts) for 300 mg mezagitamab, 600 mg mezagitamab, and placebo groups.

Responder Analysis for QMG

[0393] At Week 16, the percentage 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.

[0394] Responder rates were above 40% in the mezagitamab 300 mg group from Week 16 until Week 28 (41.67%; 5 subjects), while mezagitamab 600 mg had a lower percentage of responders at these timepoints (placebo: not assessed after Week 16). At Week 32, both mezagitamab 300 mg and 600 mg groups had 16.67% responders (2 subjects each).

[0395] Figure 8 shows the proportion of responders in the study groups at Weeks 4 through 16.

[0396] Figure 9 shows an ad-hoc sensitivity analysis of the proportion of responders (subjects with clinically meaningful reduction from baseline in MG-ADL >2 pts and QMG Score >3 pts) for 300 mg mezagitamab, 600 mg mezagitamab, and placebo groups. Ad-hoc analysis used a composite endpoint defining a responder as a subject who met both the MG-ADL and QMG clinically relevant thresholds at the same time.

Responder Analysis from MGC

[0397] At Week 16, the percentage of responders was 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, mezagitamab 300 mg group exhibited 41.67% of responders (5 subjects) compared to 25.00% (3 subjects) in the mezagitamab 600 mg group (placebo not assessed after Week 16).

[0398] Figure 10 shows the proportion of responders in the study groups at Weeks 4 through 16.

Anti-AChR Antibody Levels

[0399] At baseline, the mean (SD) anti-AChR antibody levels (nmol/L) were higher in the placebo group (119.66 [207.98]) than in the mezagitamab 300 mg (89.86 [110.93]) and mezagitamab 600 mg (36.12 [74.80]) groups (Table 23).

[0400] A reduction in anti-AChR antibodies was seen in both the mezagitamab groups as soon as Week 2, which persisted until the study end. In contrast, an increase in the anti-AChR antibody level was seen in the placebo group at multiple timepoints. A significant difference between the mezagitamab 300 mg and placebo groups in the change from baseline in anti-AChR antibody level was seen at Week 8 as well as at Weeks 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 level was also observed between the mezagitamab 600 mg and placebo groups at Week 14 (LS mean difference: -36.94; 95% CI: 71.39, -2.48; p=0.036).

[0401] In terms of percent change from baseline, at Week 16, a mean (SD) increase of 1.23% (18.26) was observed in the placebo group in contrast to mean (SD) reductions of 35.74% (41.58) and 33.69% (37.73) in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively. However, these differences were not statistically significant, presumably due to the low sample sizes and large variability (LS mean difference vs placebo: -13.18%, mezagitamab 300 mg; -21.39%, mezagitamab 600 mg). The difference between the placebo and the mezagitamab 600 mg groups was nevertheless statistically significant at Week 7 (difference in LS means: 36.41; 95% CI: -69.53, -3.29; p=0.032) and Week 8 (difference in LS means: -30.54; 95% CI: 55.68, -5.41; p=0.019) (Figure 11). At Week 32, the mean (SD) percent reduction from baseline in the anti-AChR antibody levels was 35.77% (33.69) and 24.41% (69.13) in the 300 mg and 600 mg dose groups, respectively.

[0402] Table 23 shows the summary statistics for anti-AChR antibody levels (nmol/L). Table 23. Summary and Analysis of Percent Change from Baseline in Anti-AChR Values (nmol/L) by Visit and Treatment Group (Full Analysis Set) Table 23. Summary and Analysis of Percent Change from Baseline in Anti-AChR Values (nmol/L) by Visit and Treatment Group (Full Analysis Set)

Baseline value is defined as the last observed value before the first dose of study drug. NA: Not Applicable; SD: standard deviation.

*Placebo data not collected after Week 16 per protocol study design. Anti-MuSK Antibody Levels

[0403] With regard to the 3 MuSK-positive subjects, the baseline anti-MuSK titer value for the subject in the placebo group was higher (1 :2560) than for the 2 subjects in the mezagitamab 300 mg group (1 : 160 and 1 :640, respectively). No change in the anti-MuSK titer value of the subject in the placebo group was observed at any of the assessment timepoints while a gradual reduction was observed in one of the mezagitamab 300 mg subjects (see Figure 12 for plot of individual observed values over time in the mezagitamab 300 mg group). Due to the low case numbers, statistical analysis of these 3 cases was not appropriate.

[0404] Table 24 shows the summary of percent change from baseline in anti-MuSK titer levels by visit and treatment group.

Table 24. Summary of Percent Change from Baseline in Anti-MuSK Titer Levels by Visit and Treatment Group (Full Analysis Set) Table 24. Summary of Percent Change from Baseline in Anti-MuSK Titer Levels by Visit and Treatment Group (Full Analysis Set)

Exploratory efficacy endpoint analysis

MGII Total Score

[0405] At baseline, the mean (SD) MGII total scores were 30.0 (9.17); 38.3 (12.43); and 34.8 (10.07) for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. At Week 16, the mean (SD) change from baseline in MGII total score was -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 as early as Week 4 in the mezagitamab 300 mg group; this improvement was sustained until the study end. The placebo and mezagitamab 600 mg group also intermittently achieved the MCID for this scale; however, the magnitude of the MGII total score decrease was less and not sustained as long as that of mezagitamab 300 mg. The placebo and mezagitamab 600 mg group also intermittently achieved the MCID for this scale; however, the magnitude of the MGII total score decrease was less and not sustained for as long as that of mezagitamab 300 mg. The difference in change from baseline in mean MGII total scores between the mezagitamab 300 mg and placebo groups was statistically significant at Week 6 (difference in LS mean change in baseline: -8.00; 95% CI: - 14.17, -1.83; p=0.013).

[0406] Figure 13 shows a plot of the observed mean change from baseline in the MGII total score over time.

MGII Ocular Subscore

[0407] At baseline, the mean (SD) MGII ocular subscores among the study groups were: placebo, 6.9 (5.32); mezagitamab 300 mg, 8.8 (4.37); and mezagitamab 600 mg, 8.4 (4.89). At Week 16, the mean change from baseline in the 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 difference in change from baseline in mean MGII ocular subscores between placebo and either of the mezagitamab groups was observed at any of the assessment timepoints.

MGII Generalized Symptoms Subscore

[0408] At baseline, the mean (SD) MGII generalized symptoms subscores among the 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, the mean change from baseline in MGII generalized symptoms score was -3.6 (3.63), -3.2 (4.61), and -1.3 (4.00) for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. Similar to the MGII total score, the largest difference in change from baseline in mean MGII generalized symptoms subscores was observed between the placebo and mezagitamab 300 mg groups at Week 6; this difference was statistically significant (difference in LS mean change from baseline: -2.84; 95% CI: 5.11, 0.57; p=0.016).

Responder -Based Analysis for MGII [0409] At Week 16, the percentage of responders (z.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 (33.33%) in the mezagitamab 600 mg group (placebo not assessed after Week 16).

Duration of a Clinically Meaningful Effect on MG Disease Severity in the Following Clinical Disease Impairment Scales

MG-ADL

[0410] By Week 16, the percentage of subjects with a clinically meaningful improvement in MG-ADL total score for at least 12 cumulative weeks was 33.33% (4 subjects) for placebo, 66.67% (8 subjects) for mezagitamab 300 mg, and 25% (3 subjects) for mezagitamab 600 mg (Table 24). At Week 16, the risk difference (95% CI) based on cumulative response data (>12 weeks) between mezagitamab 300 mg and placebo was 0.33 (-0.11, 0.69); the risk difference between mezagitamab 600 mg and placebo was -0.08 (-0.45, 0.30).

[0411] By Week 32, the percentage of subjects with response sustained for 12 or more cumulative weeks was 75% (9 subjects) in the mezagitamab 300 mg group and 50.00% (6 subjects) in the mezagitamab 600 mg group (placebo not assessed after Week 16).

[0412] Table 25 shows the cumulative duration of clinically meaningful effect on MG disease severity as assessed by MG-ADL in the study groups at Week 16 and Week 32. Table 26 shows the percentage of participants with 2-point reduction in MG-ADL total score.

Table 25. Cumulative Duration of Clinically Meaningful Effect on Myasthenia Gravis Disease Severity for MG-ADL by Treatment Group by Week 16 and Week 32 (Full Analysis Set)

N/A: not applicable.

Clinically meaningful effect is minimal clinically important difference in MG-ADL. It is defined as 2-point reduction in MG-ADL total score from baseline.

Cumulative duration is defined as the sum of all time periods during which the minimal clinically important difference from baseline is attained. The maximum possible cumulative duration at 16 weeks is 13 weeks and the maximum possible cumulative duration at 32 weeks is 29 weeks since the first efficacy assessment starts at Week 4.

*Placebo data not collected after Week 16 per protocol study design

Table 26. Percentage of Participants With 2-point

N/A: not applicable.

Clinically meaningful effect is minimal clinically important difference in MG-ADL. It is defined as 2- point reduction in MG-ADL total score from baseline.

*Placebo data not collected after Week 16 per protocol study design

OMG

[0413] By Week 16, the percentage of subjects with a clinically meaningful improvement in QMG for at least 12 cumulative weeks was 8.33% (1 subject) for placebo, 25% (3 subjects) for mezagitamab 300 mg, and 16.67% (2 subjects) for mezagitamab 600 mg (Table 27). At Week 16, the risk difference (95% CI) based on the number of subjects who exhibited cumulative response for >8 weeks and >10 weeks was statistically significant for mezagitamab 300 mg versus placebo (>8 weeks: 0.50 [0.08, 0.80]; >10 weeks: 0.42 [0.04, 0.73]), but not for the number of subjects who exhibited cumulative response for >12 weeks. No statistically significant difference was observed between placebo and mezagitamab 600 mg for these cumulative responses.

[0414] By Week 32, the percentage of subjects with response sustained for 12 or more cumulative weeks was 66.67% (8 subjects) in the mezagitamab 300 mg group and 33.33% (4 subjects) in the mezagitamab 600 mg group (placebo not assessed after Week 16). Table 27. Cumulative Duration of Clinically Meaningful Effect on Myasthenia Gravis

N/A: not applicable.

Clinically Meaningful Effect is minimal clinically important difference in QMG. It is defined as 3- point reduction in QMG total score from baseline.

Cumulative duration is defined as the sum of all time periods during which the minimal clinically important difference from baseline is attained. The maximum cumulative duration at 16 weeks is 13 weeks and the maximum cumulative duration at 32 weeks is 29 weeks since the first efficacy assessment starts at Week 4.

*Placebo data not collected after Week 16 per protocol study design

[0415] Table 28 shows the percentage of participants with 3-point reduction in QMG total score.

Table 28. Percentage of Participants With 3-point Reduction in QMG Total Score (Full

Analysis Set)

N/A: not applicable.

Clinically meaningful effect is minimal clinically important difference in QMG. It is defined as 3-point reduction in QMG total score from baseline.

*Placebo data not collected after Week 16 per protocol study design

MGC

[0416] By Week 16, 33.33% (4 subjects) in the placebo group, 66.67% (8 subjects) in the mezagitamab 300 mg group, and 33.33% (4 subjects) in the mezagitamab 600 mg group had clinically meaningful improvement from baseline in MGC total score for at least 12 cumulative weeks. At Week 16, the risk difference (95% CI) based on cumulative data (>12 weeks) between mezagitamab 300 mg and placebo was 0.33 (-0.11, 0.69); the risk difference between mezagitamab 600 mg and placebo was 0 (-0.38, 0.38).

[0417] By Week 32, the percentage of subjects with clinically meaningful improvement in MGC total score from baseline sustained for 12 or more cumulative weeks was 83.33% (10 subjects) in the mezagitamab 300 mg group and 58.33% (7 subjects) in the mezagitamab 600 mg group (placebo not assessed after Week 16).

[0418] Table 29 shows the percentage of participants with 3-point reduction in MCG total score. Table 29. Percentage of Participants With 3-point Reduction in MGC Total Score (Full

Analysis Set)

N/A: not applicable.

Clinically meaningful effect is minimal clinically important difference in MGC. It is defined as 3- point reduction in MGC total score from baseline.

*Placebo data not collected after Week 16 per protocol study design

MGIJ

[0419] By Week 16, 16.67% (2 subjects) in the placebo group, 58.33% (7 subjects) in the mezagitamab 300 mg group, and 16.67% (2 subjects) in the mezagitamab 600 mg group had clinically meaningful improvement from baseline in MGII total score for at least 12 cumulative weeks. At Week 16, the risk difference (95% CI) based on cumulative data (>12 weeks) between mezagitamab 300 mg and placebo was statistically significant: 0.42 (0.01, 0.73).

[0420] By Week 32, the percentage of subjects with clinically meaningful improvement in MGII total score from baseline sustained for 12 or more cumulative weeks was 75% (9 subjects) in the mezagitamab 300 mg group and 33.33% (4 subjects) in the mezagitamab 600 mg group (placebo not assessed after Week 16). PK Results

[0421] Serum concentrations of mezagitamab were detectable in all subjects at both dose levels (Figure 14). Mezagitamab concentrations were measurable postbaseline in all subjects up to Week 12 and Week 16 in 300 mg and 600 mg dose groups, respectively.

[0422] A 2-fold increase in dose from 300 mg to 600 mg resulted in an approximately 2.5-fold increase in mean mezagitamab trough concentration (collected predose) at Week 8 from 85323 ng/mL to 216741 ng/mL. Greater than dose-proportional increase in drug concentrations was observed at earlier time points. No PK samples were collected to capture mezagitamab peak concentrations.

[0423] Greater variability in drug concentrations was observed after Week 8, compared to data during the dosing period. Following the end of treatment period, mean drug concentrations showed decline over the course of 24 weeks, with 100% and 50% of subjects reaching values below lower limit of quantification (LLOQ) by Week 32 in the 300 mg and 600 mg groups, respectively.

PD and Biomarker Results

Biomarker Validation

[0424] Prevalidation characterization and technical validation were completed for flow cytometric assays to evaluate levels of CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, plasmablasts, and plasma cells in whole blood. Additionally, this assay was validated to quantitatively determine CD38 receptor occupancy across the respective cell types.

PD and Biomarker Measurements

[0425] Individual values and percent change from baseline were calculated for the two mezagitamab doses tested (300 mg and 600 mg) from predose Week 1 through Week 32. Total subject number (N) per study group was listed in the corresponding tables. Figures of mean receptor occupancy (percentage receptor occupancy) and cell depletion (percentage change from baseline) were generated for CD38+ NK cells and plasmablasts in whole blood. Target Engagement Based on Receptor Occupancy Flow Cytometric Analyses

[0426] The CD38 receptor occupancy assay was developed to evaluate changes in CD45+ lymphocytes, T cells, B cells, NK cells, monocytes, granulocytes, plasmablasts and plasma cells in whole blood. Additionally, CD38 expression and mezagitamab receptor occupancy were evaluated on respective cell types by comparing CD38 fluorescence signal for two independent flow cytometry samples containing either labeled mezagitamab (for quantification of “free” CD38 receptor) or labeled TSF-19 (non-competitive CD38 antibody for quantification of “total” CD38 receptor).

[0427] 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 for CD38 engagement on target cells. CD38 receptor occupancy of mezagitamab on CD38+ NK cells reached mean values of 76.6% and 74.3% for 300 mg and 600 mg, respectively, at Week 4. NK cell target engagement was at approximate plateau between Week 4 and Week 12 for both dose groups and returned to near baseline by Week 32.

[0428] Target engagement was accompanied by changes in absolute cell counts of CD38+ NK cells. Maximum mean reductions in CD38+ NK cells were comparable for both mezagitamab dose groups, with a -83.3% and -80.3% change from baseline observed for 300 mg and 600 mg, respectively. NK cell counts continuously decreased during the 8-week dosing period and their depletion persisted throughout the SFP and LFP, respectively, highlighting the durability of response. Subjects who received placebo showed only minor changes from baseline in CD38+ NK cells throughout the study.

[0429] Changes in plasmablast receptor occupancy and absolute counts were examined because these cells represent the target cells for mezagitamab that can be quantified in peripheral blood. Maximum mean receptor occupancies on plasmablasts were 86.8% and 95.9% at 300 mg and 600 mg treatment doses, respectively. Plasmablast receptor occupancy reached a plateau between Week 4 and Week 16 dosing for both dose groups and returned to near baseline by Week 32.

[0430] Reductions in absolute plasmablast counts were generally similar across mezagitamab- treated groups. The maximum effect was observed at Week 4 with a -84.5% and -57.7% mean change from baseline for 300 mg and 600 mg dose groups, respectively. Plasmablast absolute counts returned to near baseline by Week 32.

Downstream Pharmacology of Targeting CD38

[0431] Concentrations of total IgA, IgG, and IgM in serum were evaluated as surrogate biomarkers for mezagitamab effects on CD38-expressing antibody-secreting target cells. Depletion of serum immunoglobulins showed similar magnitude between two mezagitamab- treated groups.

[0432] Eight weekly administrations of 300 mg and 600 mg dose of mezagitamab resulted in 28.3% (9.6) and 25.8% (12.7) mean (SD) decrease from baseline in IgG, respectively, at Week 16 (Figure 15). IgG showed a sustained pattern of depletion, with 24.4% mean reduction observed at Week 32, the last time point examined in the study, for combined dose groups.

[0433] Mezagitamab treatment at 300 mg and 600 mg elicited 36.4% (13.0) and 37.8% (15.4) maximum mean (SD) decrease from baseline in IgM, respectively. Partial return to baseline was observed during the long-term follow up period, which was more prominent in the 300 mg dose group.

[0434] Depletion of IgA showed the greatest magnitude, with 56.8% (9.4) and 52.6% (17.2) maximum mean (SD) decrease from baseline in 300 mg and 600 mg dose groups, respectively. IgA did not show complete return to baseline by Week 32 in all subjects treated with mezagitamab.

[0435] In the placebo group, maximum mean (SD) reduction was 8.5% (6.1) for IgG and 8.5% (8.1) for IgA and 15.4% (21.8) for IgM.

[0436] Changes in autoantibodies were evaluated for disease-specific PD effects. Anti-AChR antibody and total IgG demonstrated concordant longitudinal profiles. Reductions in anti-AChR concentrations did not appear to be dose-dependent, with maximum mean (SD) decrease from baseline of 49.6% (29.8) and 42.7% (24.6) for 300 mg and 600 mg, respectively. In the placebo group, anti-AChR reduction showed maximum mean (SD) decrease from baseline of 17.4% (30.5). Depletion of anti-AChR showed substantial variability on individual level. Data for anti- MuSK antibody depletion with mezagitamab were limited. Immunogenicity Results

[0437] A baseline and at least 1 postbaseline ADA assessment was performed for all 36 subjects in the immunogenicity set.

[0438] Subjects who had positive ADA response in both baseline and postbaseline samples, with the maximum titer of the postbaseline ADA less than 4 times the baseline titer value were considered as pre-existing AD As positive subjects. One subject in the placebo group had preexisting ADA and no subjects in each of the mezagitamab 300 mg and 600 mg groups had preexisting AD As, giving an overall pre-existing ADA incidence rate of 2.78%.

[0439] Subjects with a baseline positive ADA result and with >4-fold postbaseline increase in titer versus baseline titer were considered to have treatment-boosted ADA; however, no subjects met these criteria in this study. Subjects with a baseline negative ADA result and any postdose positive ADA result were considered to have treatment-emergent AD As. No subjects in the placebo group, 1 subject in the mezagitamab 300 mg group, and 1 subject in the mezagitamab 600 mg group had treatment-emergent AD As, giving an overall treatment-emergent ADA incidence rate of 5.56% (Table 30).

[0440] The overall ADA prevalence, including both pre-existing and treatment-emergent ADA at any point in time, was 8.33% (3 out of 36 subjects).

[0441] The minimum required dilution or the minimum titer in this study was 40 and titer was only assessed for ADA positive samples. Among all subjects with treatment-emergent AD As, the range was 40 to 1280 (Table 31). No correlation between ADA titer and the dose of drug administered was observed.

[0442] ADA response was accompanied by decrease in mezagitamab concentrations on an individual level. In mezagitamab-treated groups, ADA positive subjects (1 in each dose group) had lower drug concentrations than ADA negative subjects at visits with ADA positive samples. No apparent associations were observed between ADA response and PD or efficacy. No clinically significant AEs were observed for the 2 subjects with treatment-emergent ADA. Table 30. Immunogenicity Status (Immunogenicity Analysis Set)

ADA: antidrug antibody. aADA Negative includes subjects who do not have positive ADA response at baseline and in all postbaseline assessments. bPre-existing ADA Positive includes subjects who have positive ADA response in the baseline sample and none of the postbaseline samples or subjects who have positive ADA response in both baseline and postbaseline samples but the maximum titer of the postbaseline ADA is <4 times the baseline titer value. cTreatment-boosted ADA Positive includes subjects who have positive ADA response in both baseline and postbaseline samples and the titer of the maximum postbaseline ADA is >=4 times that of the baseline titer value. dTreatment-emergent ADA Positive includes subjects negative ADA in baseline sample, and subjects who have positive ADA response in any postbaseline assessment. eTransiently ADA Positive includes subjects who have positive ADA response in 3 or less than 3 postbaseline assessments.

Persistently ADA Positive includes subjects who have positive ADA response in more than 3 postbaseline assessments.

⁸High ADA titer includes subjects who have at least one postbaseline ADA titer >320. hLow ADA titer includes subjects who have at least one postbaseline ADA titer <=320.

Table 31. Summary of Immunogenicity by Visit and Treatment Group (Immunogenicity

Analysis Set) Table 31. Summary of Immunogenicity by Visit and Treatment Group (Immunogenicity

Analysis Set)

ADA: antidrug antibody; SD: standard deviation; NA: not applicable.

Percentages are based on subjects with measurement in the Immunogenicity Analysis Set at given visit within each column.

Subjects with measurement represent the number of subjects with a nonmissing result at a given visit.

Baseline value is defined as the last observed value before the first dose of study drug.

Statistical and Analytical Issues

[0443] Adjustments for Covariates: Adjustments for covariates were not performed.

[0444] Handling of Dropouts or Missing Data: Efficacy data were analyzed using observed case data only based on a “missing at random” assumption.

[0445] Interim Analyses and Data Monitoring: No interim analyses or data monitoring were performed for this study.

[0446] Multicenter Studies: This was a multicenter study. No statistical adjustments were made to compensate for the multicenter nature of the study.

[0447] Multiple Comparisons/Multiplicity: No statistical adjustments were made for multiple comparisons.

[0448] Use of an Efficacy Subset of Subjects: Efficacy analyses were conducted on the full analysis set, which consisted of all enrolled patients with both baseline and at least 1 valid postbaseline value. [0449] Active-Control Studies Intended to Show Equivalence: This was not an active-control study intended to show equivalence.

[0450] Examination of Subgroups: Exploratory post-hoc subgroup analyses comparing subjects’ clinical response assessed by MG-ADL and QMG total scores based on region (North America vs Europe). These post-hoc analyses have shown that placebo response was substantially more pronounced in North American subjects compared to European subjects for both MG-ADL and QMG (Figures 16 and 17). Additionally, subgroup analysis by the timing of acetylcholinesterase inhibitor administration made it evident that non-consistent timing of use of these symptomatic medications both between and within patients prior to clinical assessments has added significant variability to clinical response assessed by MG-ADL and QMG (Figures 18 and 19)

[0451] Figure 20 shows pharmacodynamic effects: moderate total IgG reduction with concordant depletion in anti-AChR antibody. Figure 20A shows the change from baseline in IgG levels. Figure 20B shows the change from baseline in anti-AChR antibody levels.

[0452] Figure 21 shows IgA and IgM depletion after 8 weeks of dosing to Week 32. Figure 21A shows IgA and Figure 21B shows IgM.

[0453] Figure 22 shows the PD response of mezagitamab compared to efgartigimod.

[0454] Figure 23 shows high consistency between QMG response and IgG depletion for 300 mg dose group but not for placebo. Red dashed line indicates 3 -point reduction in QMG score.

[0455] Figure 24 shows high consistency between QMG/ADL response and IgG depletion for 300 mg. The red dashed line indicates 3 -point reduction in QMG score.

[0456] Figure 25 shows the change from baseline in anti-MuSK antibody levels (secondary endpoint).

[0457] Figure 26 shows the placebo response was less pronounced in MGII and MGQ0L15-R (based on patient assessment without investigator administration/intervention).

[0458] Figure 27 shows individual MG-ADL and QMG response at Week 16. [0459] Figure 28 shows the placebo response for mezagitamab compared to comparator’s studies: MG-ADL.

[0460] Figure 29 shows mezagitamab compared to comparator’s studies: QMG.

[0461] Figure 30 shows the placebo response of mezagitamab compared to comparator’s studies: QMG.

[0462] Figure 31 shows mezagitamab exposures in expected range with PK profile consistent with MM. There was a dose-proportional increase in exposure between 300 mg and 600 mg. Mezagitamab PK profile in MG is in line with expectations from MM study, with concentrations trending towards higher end of exposure predictions. Dashed black line and shaded region represent median and 90% prediction interval based on simulations from preliminary MM population PK model. One subject in 300 mg with an unusual PK profile developed ADA at Week 4 (titer: 40), and then Weeks 7 (titer: 40) and 8 (titer 20). Other visits were ADA negative.

[0463] Figure 32 shows mezagitamab exposure parameters in responders versus non-responders. Preliminary integrated population PK model was developed (based on pooled SLE and MM final datasets and available MG data) and used to derive full concentration-time profile for each subject and calculate exposure metrics: (a) Cavg: average concentration during one week after the last (weekly) dose in ng/mL; (b) Cmax: maximum drug concentration during the study in ng/mL; and (c) cumAUC: cumulative AUC up to one week after the last (weekly) dose in h x ng/mL. There were no apparent differences in exposure of mezagitamab between responders and non-responders (based on Week 16 MG-ADL response).

[0464] Figure 33 shows exposure-response assessment for IgG (best %reduction in IgG) across MM and MG studies.

[0465] Figure 34 shows exposure response assessment for MG-ADL. Orange dashed line represents clinically meaningful threshold of 2-point reduction in MG-ADL. Increase in exposure was not associated with improvement in MG-ADL score. Similar patterns were observed for QMG.

[0466] Figure 35 shows background therapies. [0467] Figure 36 shows a mixed-model repeated measures analysis of change from baseline in MG-ADL score (full analysis set).

[0468] Figure 37 shows a mixed-model repeated measures analysis of change from baseline in QMG score (full analysis set).

PK, Efficacy, PD, Biomarker, and Immunogenicity Conclusions

PK

[0469] A two-fold increase in dose from 300 mg to 600 mg resulted in an approximately 2.5-fold increase in mean mezagitamab trough concentration (collected pre-dose) at Week 8 from 85323 ng/mL to 216741 ng/mL.

[0470] Following the end of treatment period, mean drug concentrations showed a decline over the course of 24 weeks, with 100% and 50% of the subjects reaching values below lower limit of quantification (LLOQ) by Week 32 in 300 mg and 600 mg, respectively.

Efficacy

MG-ADL Total Score

[0471] 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.

[0472] At Week 16, the percentage of responders was 66.67% in both the placebo and mezagitamab 300 mg groups while it was 33.33% in the mezagitamab 600 mg group.

[0473] By Week 16, 33.33%, 66.67%, and 25% of the subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had clinically meaningful improvement from baseline for at least 12 cumulative weeks. By Week 32, these percentages were 75% and 50% for the mezagitamab 300 mg and 600 mg groups, respectively.

QMG Total Scores

[0474] At Week 16, the mean (SD) reduction from baseline in QMG scores was -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 was in the mezagitamab 300 mg group at Week 12 (mean [SD] of -3.9 [2.55]).

[0475] At Week 16, the percentage of responders was 33.33%, 58.33%, and 33.33% in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively.

[0476] By Week 16, 8.33%, 25%, and 16.67% of the subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had clinically meaningful improvement from baseline for at least 12 cumulative weeks. By Week 32, these percentages were 66.67% and 33.33% for the mezagitamab 300 mg and 600 mg groups, respectively.

MGC Total Scores

[0477] At Week 16, the mean (SD) reduction from baseline in MGC total scores was -6.6 (4.95), -9.2 (5.18), and -2.9 (6.45) for placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively.

[0478] At Week 16, the percentage of responders was 66.67%, 75%, and 41.67% in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively.

[0479] By Week 16, 33.33%, 66.67%, and 33.33% of the subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had clinically meaningful improvement from baseline for at least 12 cumulative weeks; by Week 32, these percentages were 83.33% and 58.33% for the mezagitamab 300 mg and 600 mg groups, respectively.

MG-QoL15r Total Scores

[0480] 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.

MGII Total Scores

[0481] 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) for the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively. At Week 6, the difference in change from baseline in mean MGII total scores between placebo and mezagitamab 300 mg groups was statistically significant and clinically meaningful (difference in LS mean change in baseline: -8.00; 95% CI: -14.17, -1.83; p=0.013).

[0482] At Week 16, the percentage of responders was 66.67%, 8.33% and 41.67% in the placebo, mezagitamab 300 mg, and mezagitamab 600 mg groups, respectively.

[0483] By Week 16, 16.67%, 58.33%, and 16.67% of the subjects receiving placebo, mezagitamab 300 mg, and mezagitamab 600 mg, respectively, had clinically meaningful improvement for at least 12 cumulative weeks. By Week 32, these percentages were 75% and 33.33% for mezagitamab 300 mg and 600 mg, respectively.

Rescue Therapy

[0484] By Week 16, 2 subjects in the placebo group (17%) and 1 subject in the mezagitamab 600 mg group (8%) required rescue therapy.

[0485] By Week 32, 5 subjects required rescue therapy, 2 each in the placebo and mezagitamab 600 mg groups and 1 in the mezagitamab 300 mg group.

Anti-AChR Antibody Levels

[0486] A reduction in anti-AChR antibodies was observed as early as Week 2, which was not dose-dependent and persisted until study end (Week 32).

[0487] At Week 16, a mean (SD) increase of 1.23% (18.26) was observed in the placebo group in contrast to mean (SD) reductions of 35.74% (41.58) and 33.69% (37.73) in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively.

[0488] At Week 32, the mean (SD) percent reduction from baseline in the anti-AChR antibody levels was 35.77% (33.69) and 24.41% (69.13) in mezagitamab 300 mg and mezagitamab 600 mg groups, respectively.

Anti-MuSK Antibody Levels

[0489] Among the 3 MuSK-positive subjects, no change in the anti-MuSK titer value of the subject in the placebo group was observed at any of the assessment timepoints while a gradual reduction was observed in 1 of the 2 mezagitamab 300 mg subjects. PD and Biomarkers

[0490] Mean CD38 receptor occupancy of mezagitamab on CD38+ NK cells reached near maximal values of approximately 75% at Week 4 in both mezagitamab 300 mg and mezagitamab 600 mg groups, remained stable through Week 12 and returned to near baseline by Week 32.

CD38+ NK cells were maximally depleted by approximately 80% with either 300 mg or 600 mg, and depletion kinetics mirrored that of receptor occupancy on the same cell type. Placebo- treated subjects showed only minor changes from baseline in CD38+ NK cells throughout the study.

[0491] Maximum mean (SD) receptor occupancies on plasmablasts were generally comparable between mezagitamab 300 mg and mezagitamab 600 mg groups (86.8% (22.3) and 95.9% (3.6), respectively). The maximum plasmablast depletion was observed at Week 4 with a 84.5% (17.7) and 57.7% (41.1) mean (SD) reduction from baseline for the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively.

[0492] Depletion of serum IgG showed similar magnitude between the two mezagitamab-treated groups, with mean (SD) reduction of 28.3% (9.6) and 25.8% (12.7) mean (SD) at Week 16 for mezagitamab 300 mg and mezagitamab 600 mg groups, respectively; IgG depletion was sustained until Week 32 in both mezagitamab groups. The placebo group did not show substantial decrease in IgG, with maximum mean (SD) reduction of 8.5% (6.1).

[0493] Maximum mean (SD) decrease from baseline in IgM was 15.4% (21.8), 36.4% (13.0) and 37.8% (15.4) for placebo, mezagitamab 300 mg and mezagitamab 600 mg, respectively, with a partial return to baseline being more prominent in the 300 mg dose group.

[0494] Maximum mean (SD) decrease from baseline in IgA was 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 return to baseline by Week 32.

Immunogenicity

[0495] The overall ADA prevalence, including both pre-existing and treatment-emergent ADA at any point in time, was 8.33% (3 out of 36 subjects). [0496] Among all subjects with treatment-emergent ADAs, the range was 40 to 1280. No correlation between ADA titer and the dose of drug administered was observed.

[0497] ADA response was detected in parallel with reduced drug concentrations, but data is too limited to determine conclusively the impact of ADA on PK. No apparent associations were observed between ADA response and PD, efficacy, or safety.

EXAMPLE 4: SAFETY AND SAFETY BIOMARKER EVALUATION

EXTENT OF EXPOSURE

[0498] A summary of study drug exposure and compliance is provided in Table 32. Twenty- four subjects received at least one dose of mezagitamab (12 in each dose 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 combined group.

Table 32. Investigational Product Exposure and Compliance by Treatment Group (Safety

Analysis Set)

Percentages are based on all subjects in the Safety Analysis Set within each column.

‘^Compliance is defined as (total number of doses taken/planned number of doses taken) x 100%.

Dose Interruptions

[0499] Before receiving each study drug dose, subjects were evaluated for dosing criteria based on laboratory evaluations and events of clinical interest as defined in Table 11.

[0500] Dosing was withheld in 2 subjects. One subject was in the mezagitamab 300 mg group and another in the mezagitamab 600 mg group; the decisions were based on laboratory evaluations (low lymphocyte count) and an event of clinical interest (COVID-19 test positive) respectively. The outcome of both the events was recovered/resolved. AEs

[0501] A pretreatment event (PTE) was defined as any untoward medical occurrence in a subject who had signed informed consent to participate in a study, but prior to administration of any study medication; it did not necessarily have to have a causal relationship with study participation.

[0502] An AE was defined as any untoward medical occurrence in a subject administered a drug; it did not necessarily have to have a causal relationship with this treatment. TEAEs were defined as AEs that occurred after the first dose of study drug received in the treatment period and until the end of safety follow-up. Serious TEAEs are hereafter referred to as SAEs.

[0503] PTE and AE verbatim terms were coded by SOC and PT using MedDRA version 25.0.

Brief Summary of Adverse Events

[0504] An overview of TEAEs is presented in Table 33. Overall, mezagitamab was well tolerated in subjects with MG. There were no substantial imbalances in AEs between the treatment groups and the majority of them were of mild severity. SAEs were balanced across study groups (2 SAEs in the placebo group, 1 SAE each in mezagitamab 300 mg and mezagitamab 600 mg groups respectively). None of the reported SAEs were related to study drug. Furthermore, there were no discontinuations of study treatment and no on-study deaths were reported. Grade 3 or higher TEAEs were balanced across study groups. Only 1 related TEAE was reported, which occurred in 1 subject in the mezagitamab 300 mg group and consisted of lymphocyte count decrease; the outcome of this event was recovered/resolved. Other clinically relevant AEs such as injection-related and infusion-related reactions (IRRs), anemia and lymphopenia were balanced across study groups. No cases of thrombocytopenia were reported during the study. Table 33. Overall TEAEs by Treatment Group - Dosing and SFP (Safety Analysis Set)

Percentages are based on all subjects in the Safety Analysis Set within each column.

IRR: infusion-related reaction; ISR: injection site reaction; m: number of events; n: number of subjects experiencing the event; SFP: safety follow-up period; TEAE: treatment-emergent adverse event.

A TEAE is defined as an adverse event having a start date and time equal to or later than the start date and time of the first dose of study drug.

TEAEs occurring during dosing and SFP are defined as TEAEs with a start date on or before the date of Week 16 visit date.

Subjects were counted once per category per treatment group.

Missing toxicity grade was imputed to grade 3.

A TEAE with missing causal relationship was classified as related to study drug.

*TEAE grading was based on NCI CTCAE v4.03. Display of Adverse Events

[0505] 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. Most Frequent (>10%) TEAEs by SOC, PT, and Treatment Group - Dosing and SFP (Safety Analysis Set)

Percentages are based on all subjects in the Safety Analysis Set within each column. n: number of subjects experiencing the event, m: number of events; SFP: safety follow-up period; MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SOC: system organ class; TEAE: treatment-emergent adverse event.

A TEAE is defined as an adverse event having a start date and time equal to or later than the start date and time of the first dose of study drug.

TEAEs occurring during dosing and SFP are defined as TEAEs with a start date on or before the date of Week 16 visit date.

Adverse events were classified into system organ class and preferred term using MedDRA version 25.0.

Subjects were counted once per SOC and once per PT per treatment group.

Adverse events with a frequency of >10% by PT in any treatment are included in this table. Table 35. TEAEs Considered Related to Study Drug by SOC, PT, and Treatment Group - Dosing and SFP (Safety Analysis Set)

Percentages are based on all subjects in the Safety Analysis Set within each column. m: number of events; MedDRA: Medical Dictionary for Regulatory Activities; n: number of subjects experiencing the event; PT: preferred term; SFP: safety follow-up period; SOC: system organ class; TEAE: treatment-emergent adverse event.

A TEAE is defined as an adverse event having a start date and time equal to or later than the start date and time of the first dose of study drug.

TEAEs occurring during Dosing and SFP are defined as TEAEs with a start date on or before the date of Week 16 visit date.

Adverse events were classified into SOC and PT using MedDRA version 25.0.

Subjects were counted once per SOC and once per PT per treatment group.

Adverse events with a frequency of >10% by PT in any treatment are included in this table.

TEAEs with a missing causal relationship was classified as related to study drug.

Relatedness was assessed by the study investigator.

Analysis of AEs

Most Frequent TEAEs

[0506] The most frequently reported (>10% of all subjects) TEAEs by Preferred Term in the safety analysis set are summarized in Table 34.

[0507] Overall, 15 subjects (41.7%) experienced 20 TEAEs regardless of causality, including 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.

[0508] In the placebo group, 1 subject each (8.3%) experienced pyrexia and nasopharyngitis and

2 subjects experienced gastroenteritis (16.7%).

[0509] In the mezagitamab 300 mg group, 2 subjects (16.7%) experienced pyrexia and 1 subject

(8.3%) experienced fatigue. In the mezagitamab 600 mg group, 3 subjects each (25%) experienced pyrexia and chills, and 2 subjects each (16.7%) each experienced fatigue and nasopharyngitis.

[0510] All TEAEs had a toxicity Grade 1 or Grade 2 except 4 TEAEs with Grade 3 toxicity (3 unrelated to study drug and 1 related to study drug); 2 were in the placebo group and 1 each in the mezagitamab 300 mg and mezagitamab 600 mg groups, respectively.

[0511] Although 1 subject tested positive for COVID-19, there were no COVID-19-related TEAEs in this study.

TEAEs by Relationship to Study Drug

[0512] TEAEs assessed as being related to study drug by the investigator 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 mezagitamab 300 mg group, and 8 subjects (66.7%) in the mezagitamab 600 mg group. The most frequently reported treatment related TEAE was pyrexia in the mezagitamab 300 mg group, chills and pyrexia in mezagitamab 600 mg group.

[0513] The outcome for all related TEAEs was recovered/resolved except grade 1 events of normocytic anaemia and blood immunoglobulin A decreased in mezagitamab 600 mg group which were not resolved by end of study.

TEAEs by Severity

[0514] In this study, most of the TEAEs were Grade 1 or 2 in severity. Four of the 98 TEAEs were of Grade 3 severity. Of these 4 events, only 1 event (lymphocyte count decreased) was reported as related to study treatment by the investigator. The outcome of the event was recovered/resolved.

DEATHS, OTHER SAEs, AND OTHER SIGNIFICANT AEs

Listing of Deaths, Other SAEs, and Other Significant AEs

Deaths

[0515] No deaths occurred during the study. Other Serious Adverse Events

[0516] A total 4 SAEs were reported in 3 subjects (Table 36). One subject each in the mezagitamab 300 mg and mezagitamab 600 mg groups experienced SAEs of suicidal ideation and MG (worsening of MG), respectively. One subject in the placebo group experienced two SAEs, enteritis and gastroenteritis. All the SAEs were reported as not related to the study drug and had an outcome of recovered/resolved.

Table 36. Serious TEAEs by SOC, PT, and Treatment Group - Dosing and SFP (Safety

Analysis Set)

Percentages are based on all subjects in the Safety Analysis Set within each column. m: number of events; MedDRA: Medical Dictionary for Regulatory Activities; n: number of subjects experiencing the event; PT: preferred term; SFP: safety follow-up period; SOC: system organ class; TEAE: treatment-emergent adverse event.

A TEAE is defined as an adverse event having a start date and time equal to or later than the start date and time of the first dose of study drug.

TEAEs occurring during Dosing and SFP are defined as TEAEs with a start date on or before the date of Week 16 visit date.

Adverse events were classified into SOC and PT using MedDRA version 25.0.

Subjects were counted once per SOC and once per PT per treatment group. ^Verbatim text from the CIOMS. Other Significant AEs

TEAEs Leading to Study Drug Discontinuation

[0517] There were no TEAEs that led to study drug discontinuation.

TEAEs Leading to Dose Modification

[0518] Dose modification in this study consisted of either dose interrupted or drug withdrawn. Dosing was withheld in two subjects.

Injection Reactions TEAEs

Local Injection Site Reactions

[0519] 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 reaction. The outcome for all the events was recovered/resolved.

Table 37. Local Inj ection Site Reaction TEAEs (Safety Analysis Set)

ID: identification; MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; SFP: safety follow-up period; TEAE: treatment-emergent adverse event.

A TEAE is defined as an adverse event having a start date and time equal to or later than the start date and time of the first dose of study drug.

TEAEs occurring during Dosing and SFP are defined as TEAEs with a start date on or before the date of Week 16 visit date. Adverse events were classified into system organ class and preferred term using MedDRA version 25.0.

*TEAE grading was based on NCI CTCAE v4.03.

Systemic IRRs

[0520] Systemic IRRs, as determined by the investigator, was reported in an equal number of subjects in the mezagitamab 300 mg and 600 mg groups (3 subjects each). In the mezagitamab 300 mg group, the 3 subjects experienced systemic IRR TEAEs of influenza-like illness, visual impairment, and pyrexia. In the mezagitamab 600 mg group, 3 subjects experienced systemic IRR TEAEs of chills and pyrexia. Most of the events were Grade 1 in severity; Grade 2 pyrexia occurred in 2 subjects in the mezagitamab 600 mg group. All the events were reported as related to mezagitamab. Most of the events were resolved within 1 day (median duration of recovery was 1 day) and outcome of all the events was recovered/resolved.

Analysis and Discussion of Deaths, Other SAEs, and Other Significant AEs

[0521] There were 3 subjects with treatment-emergent SAEs, none of which were considered life-threatening. SAEs were balanced across study groups.

CLINICAL LABORATORY EVALUATIONS

Serum Chemistry

[0522] AEs pertaining to serum chemistry parameters were observed in both placebo and mezagitamab-treated groups with no apparent dose dependencies.

[0523] Fifteen subjects (5 subjects in placebo group, 6 subjects in mezagitamab 300 mg group and 4 subjects in mezagitamab 600 mg group) reported higher than normal lactate dehydrogenase levels already at screening which remained high over the course of the study. Four subjects (1 subject in placebo group, 1 subject in mezagitamab 300 mg group, and 2 subjects in mezagitamab 600 mg group) reported a mild and transient increase in LDH on study; all of these were resolved and within normal range at study end. One subject in mezagitamab 600 mg group experienced increases in ALT and AST of 3xULN at Week 16. This event occurred after administration of rescue medication and was reported as a non-study drug related TEAE by the investigator because it was believed to be caused by the administration of IVIGs used in this subject at that time point of the study to treat exacerbation of the disease.

Hematology

[0524] Overall, 3 subjects, 1 each in the 3 study groups had abnormal values in total lymphocyte count. Only 1 TEAE of lymphocyte count decrease was observed in the study, which occurred in 1 subject in the mezagitamab 300 mg group; this was reported as related to the study drug and the outcome of the event was recovered/resolved. Three TEAEs of anemia was reported (1 in mezagitamab 300 mg group and 2 in mezagitamab 600 mg group). Among them, one TEAE of anemia in mezagitamab 600 mg group was related to study drug and was not recovered.

Remaining two events of anemia in mezagitamab 300 mg and 600 mg groups were not related to study drug and was recovered and recovering, respectively. Additionally, the anemia reported in one subject in the 300 mg group was already present at study start hence why it was not considered related to study drug. A subset of subjects had lower than normal hemoglobin/hematocrit levels at study start, likely due to the on-going immunosuppressant treatments; of these, a few experienced a slightly decreasing trend over the course of the study for both hemoglobin and hematocrit. No dose dependency was apparent with regard to this decreasing trend as the number of subjects impacted was balanced between placebo and the mezagitamab-treated groups. No subjects in the study group experienced any hemoglobin decreases below 8 g/dL at any time in the study.

VITAL SIGNS AND ECG

Vital Signs

[0525] There were no trends observed in the mean values or change from baseline in vital signs- related parameters. In placebo group, abnormal values in vital signs were heart rate >120 bpm, systolic blood pressure >180 mmHg and temperature <35.6 deg Celsius were reported in one subject. Similarly, in the 600 mg group, abnormal values in vital parameters were systolic blood pressure >180 mmHg and diastolic pressure <50 mmHg was reported in one subject.

[0526] AEs pertaining to vital signs included pyrexia in 6 subjects (1 subject in placebo group, 2 subjects in mezagitamab 300 mg group, and 3 subjects in mezagitamab 600 mg group). Pyrexia which presented in subjects from the mezagitamab 300 mg and 600 mg groups was reported as related to study drug. The outcome of the events was recovered/resolved in all the 6 subjects and most of the events were resolved within 1 day.

Electrocardiograms

[0527] There were no trends observed in the mean values or change from baseline in electrocardiograms (ECGs). At baseline, all subjects had normal or not clinically significant abnormal ECG results. No subjects had shifts to clinically significant abnormal postbaseline results at any timepoint.

Safety Biomarkers

[0528] Vaccine-induced antibodies, such as measles, mumps, rubella, diphtheria, and tetanus were evaluated to determine the impact of mezagitamab on protective immunity. Maximum mean reduction in any of these antibodies was less than 25% change from baseline and was comparable in mezagitamab-treated groups. Placebo group showed minimal decrease, with exception of diphtheria antibody that demonstrated maximum mean reduction of 13.0%. All vaccine-induced antibodies returned near baseline or showed an increase by Week 32.

[0529] There were 3 subjects in each mezagitamab dose group who dropped below LLOQ of assay for diphtheria at any point during the study. In addition, one subject in 300 mg dose group had values below LLOQ for rubella. In placebo group, 2 subjects had <LLOQ observations, 1 subject each for rubella and tetanus. All of these subjects had a baseline value near LLOQ for the respective antibody.

Pregnancy

[0530] No pregnancies were reported during the study.

SAFETY CONCLUSIONS

[0531] Overall, mezagitamab was well-tolerated in subjects with generalized myasthenia gravis in this study. There were no substantial imbalances in AEs between the treatment groups and no dose-dependent AEs or new safety concerns were identified.

[0532] Overall, 24 subjects received at least one dose of mezagitamab (12 in each dose group), and 12 subjects received at least one dose of placebo. [0533] TEAEs reported in >10% of subjects were gastroenteritis in the placebo group, pyrexia in the mezagitamab 300 mg group while pyrexia and chills were most common in the mezagitamab 600 mg group.

[0534] The majority of the TEAEs were Grade 1 or Grade 2 in severity. Grade 3 TEAEs were reported in only 4 subjects, and these were well-balanced between the study groups. Three subjects reported treatment-emergent SAEs in the study, 1 in each study group: 2 SAEs of enteritis and gastroenteritis reported by 1 subject in the placebo group; 1 SAE of suicidal ideation in the mezagitamab 300 mg group; and 1 SAE of MG (worsening of MG) in the mezagitamab 600 mg group. None of these SAEs was related to the study treatment and the outcome for all the SAEs was recovered/resolved.

[0535] IRRs were only reported in the mezagitamab-treated subjects and were observed in 25% of subjects of mezagitamab 300 mg and mezagitamab 600 mg group, respectively. Clinical events of interest such as lymphopenia and anemia were balanced across study groups.

[0536] There were no clinically significant results related to laboratory evaluations, vital signs, or ECGs.

[0537] Decrease in vaccine-induced antibodies was not dose-dependent, with less than 25% change from baseline observed in the mezagitamab-treated groups. All vaccine-induced antibodies returned near baseline or showed an increase by Week 32. Only 3 subjects who already had antibodies at baseline near the LLOQ had a decrease below the LLOQ for diphtheria and rubella antibodies in each mezagitamab 300 mg and mezagitamab 600 mg group.

EXAMPLE 5: DISCUSSION AND OVERALL CONCLUSIONS

EXECUTIVE SUMMARY

[0538] Demographics and baseline characteristics: No significant differences were identified among baseline characteristics.

[0539] Safety: Mezagitamab TAK-was well tolerated up to 600 mg with no new safety concerns identified. SAEs and Grade 3 or higher TEAE were infrequent and balanced across study groups. Infections, anemia, and lymphopenia were infrequent with no apparent dose dependency.

[0540] Efficacy: Mezagitamab dose 300 mg showed clinically relevant decrease in both MG- ADL and QMG for both amplitude of response and percentage of responders. Mezagitamab dose 600 mg showed variable efficacy signal despite biochemical response. Higher than expected placebo response.

[0541] Pharmacodynamics: Mezagitamab elicited moderate PD response, with maximum mean depletion of -30% for IgG and -50% for anti-AChR antibody.

[0542] Durability: Mezagitamab sustained beyond treatment period up to Week 32 in most subjects with data for IgG/AChR antibodies for both dose levels. Clinical response was sustained for the 300 mg dose for both MG-ADL and QMG.

[0543] Pharmacokinetics/immunogenicity: Exposures in expected range with PK profile consistent with MM, trending towards higher end of exposure predictions. Only 1 subject treated with mezagitamab (300 mg group) developed low-titer ADA response.

DISCUSSION

[0544] The primary objective of this study was to evaluate the safety and tolerability of mezagitamab in subjects with generalized MG. This was the second study in which mezagitamab was administered to an autoimmune patient population, after the systemic lupus erythematosus (SLE) study (TAK-079-2001). In contrast to the SLE study, TAK-079-2001, in which the top dose level was 135 mg and mezagitamab was administered every 3 weeks for a total of 12 weeks, MG subjects in this study received doses up to 600 mg weekly for 8 weeks. The totality of the safety data collected in this study suggests that mezagitamab is well tolerated with a favorable safety profile at substantially higher dose and consequently higher exposures than those assessed in subjects with SLE. The mezagitamab AEs reported in this study were consistent with that observed in the first-in-human study in healthy volunteers (TAK-079-101) and in subjects with SLE. No new safety events were identified in myasthenia gravis subjects.

[0545] Events of clinical interest based on the mechanism of action of mezagitamab were hypersensitivity reactions, CRS, and systemic infections. There were no cases of CRS and observed cases of IRRs were mild and reported in 25% of subjects of each mezagitamab-treated group. These IRRs occurred predominantly with the first dosing event and resolved within a few days. With regards to infections, nasopharyngitis (one event in one placebo subject and 2 events in two 600 mg subjects) and gastroenteritis (two events in the same placebo subject) were reported in the study; none of these infections were deemed related to study drug and no dose dependency appeared evident. All cases of nasopharyngitis were mild (<Grade 1). Additional clinical events that were monitored carefully during the study were anemias and thrombocytopenia due to the expression of CD38 on erythrocytes 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 higher doses of mezagitamab are not expected to increase the risk of anemia or thrombopenia. No dose dependency was apparent for another event of clinical interest, lymphopenia, with only one event reported in the mezagitamab 300 mg group. This event was Grade 3 and deemed to be study drug related, however the subject was also receiving moderately high doses of concomitant systemic corticosteroids which may have contributed to the lymphocyte decrease.

[0546] While mezagitamab effectively decreased immunoglobulins at both doses evaluated, its impact on already existing vaccine-induced antibodies did not appear to be clinically significant in this study and patient population. This provides preliminary evidence that the administration of mezagitamab may not negatively impact existing vaccine-induced immunity.

[0547] The low treatment-emergent ADA incidence rate of 5.56% observed in this study is consistent with previous findings that suggest a low risk of immunogenicity with mezagitamab. Limited ADA data precludes conclusive determination of ADA impact on exposure. ADA response did not appear to be dose-dependent, and no apparent associations were observed between ADA response and safety or efficacy.

[0548] From a PK perspective, a dose-proportional increase in drug concentrations from 300 mg to 600 mg was observed. This suggests that at these doses mezagitamab exhibits linear PK behavior. Mezagitamab has been reported to have nonlinear PK at lower dose ranges tested in healthy subjects (TAK-079-101) and in subjects with systemic lupus erythematosus (TAK- 079- 2001) due to CD38-mediated elimination, which appears to be saturated in this patient population at doses of 300 mg and above. [0549] The secondary objective of the study was to assess the effect of mezagitamab on MG disease severity. The mezagitamab 300 mg group but not the mezagitamab 600 mg group met the clinically relevant threshold for the following clinical scales assessed in the study: MG-ADL, QMG, MGC, and MGII; however, this potential signal of preliminary clinical benefit was confounded by the higher than expected placebo response observed within this 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 inflated placebo response was particularly evident for MG-ADL, and less pronounced for other clinical scales. When stratified by region, MG-ADL placebo response within European subjects was found to be comparable with that observed in other MG trials while the placebo response within North American subjects was found to be substantially inflated. A number of factors in this study may explain the inflated placebo response including but not limited to baseline score inflation due to enrollment solely on MG-ADL (a patient reported outcome) and a predominance of female and younger subjects with less severe disease in the placebo group (Katz (2021) Pain Rep. 6(1): e845; Landin et al. (2000) Biometrics 56(1): 271-278). In addition to this, there are inherent limitations of MG-ADL as an instrument in capturing accurate and relevant subject symptoms.

[0550] Additional confounders in the study include non-standardized withholding of acetylcholinesterase inhibitors prior to clinical assessments and the extended additional use of prophylactic corticosteroids beyond Week 1 in some subjects. The inconsistent timing of when the subject took acetylcholinesterase inhibitors with respect to clinical assessments, particularly QMG, may have confounded the true treatment effect and/or inflated the placebo response. The use of prophylactic CS with the first dose was necessary to mitigate potential IRRs; however, the additional use of CS beyond the first treatment is believed to have incurred an imbalanced treatment benefit in those subjects who received additional CS for up to 4 weeks into the study.

[0551] From a PD perspective, mezagitamab demonstrated reductions in CD38+ target cells and immunoglobulin reductions, including depletion of anti-AChR antibodies. Dose-dependent trends were not observed in immunoglobulin response or any other evaluated PD parameters, indicating apparent saturation of biochemical response at 300 mg with weekly dosing, with no added benefit at the 600 mg dose. Moderate depletion of IgG and autoantibodies was observed in certain subjects in the 600mg cohort. Changes in all Ig isotypes were substantially greater in the mezagitamab-treated groups when compared to placebo, presenting evidence for proof of mechanism in this disease. Notably, depletion of Ig was maintained up to 6 months after the end of therapy. The greatest magnitude of change was seen for the IgA class, in line with observations from other studies with mezagitamab.

[0552] In this study, subjects were predominantly positive for anti-AChR antibody, which reflects higher prevalence of this autoantibody type in the MG subject population. Reductions in anti-AChR concentrations confirmed the therapeutic hypothesis that targeting CD38-expressing plasma cells and plasmablasts leads to reduction in pathogenic antibodies involved in MG. Attenuation of pathophysiology was similar between the two tested doses but was accompanied by an efficacy signal in the 300 mg dose group only.

CONCLUSIONS

[0553] The results of this Phase 2 study illustrate that weekly dose of mezagitamab up to 600 mg had a favorable safety profile in subjects with generalized MG who are receiving concomitant stable background therapy. No new safety events unique to MG subjects were identified and no dose dependencies in AEs of clinical interest were apparent in study.

[0554] Improvement in MG symptom severity as assessed by various MG rating scales (namely, MG-ADL, QMG, MGC, MG-QoL15r, and MGII) was present in all 3 cohorts, including placebo, over the 16-week blinded study period, albeit with different magnitudes and durations of response.

[0555] Persistent and durable reductions in both IgG and anti-AChR antibody levels were seen in both mezagitamab-treated groups, confirming that the anti-CD38 mechanism is pertinent for modulation of this autoantibody-driven disease.

[0556] To conclude, this study established a favorable safety profile and provided proof of mechanism for mezagitamab in subjects with generalized myasthenia gravis.

Incorporation by Reference

[0557] The contents of all cited references (including literature references, patents, patent applications, and websites) that may be cited throughout this application are hereby expressly incorporated by reference in their entirety for any purpose, as are the references cited therein, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference in its entirety for any purposes.

Equivalents

[0558] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the disclosure. Scope of the disclosure is thus indicated by the appended claims rather than by 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 disclosure that are obvious to persons of skill in the art are intended to be within the scope of the appended claims.

Claims

We Claim:

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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

2. A method of 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

3. A method of reducing the level 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

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

5. 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

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

7. A method of reducing myasthenia gravis disease activity and/or progression 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 (VH) chain region comprising a 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 (VL) chain region comprising a 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; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered in a dosage of from about 100 to about 800 milligrams.

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), revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r), and/or Myasthenia Gravis Impairment Index (MGII).

9. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof further comprises one or more engineered glycoforms, wherein the engineered glycoform comprises glycosylation of one or more polypeptides, optionally wherein the glycosylation is N-linked glycosylation or O-linked glycosylation, and optionally wherein the glycosylation is N-linked glycosylation.

10. The method of any one of the preceding claims, wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NON, and/or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% to SEQ ID NO: 10; optionally wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NON, and/or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% to SEQ ID NOTO; optionally wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NON, and/or the variable light chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 99% to SEQ ID NOTO; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% 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 an identity of at least 95% to SEQ ID NO: 12; optionally wherein the isolated antibody or antigen binding fragment thereof interacts with at least KI 21 , Fl 35, QI 39, DI 41 , E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO:1 and SEQ ID NO:2, based on human sequence numbering; optionally wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO: 1) with a KD of 10'⁸ M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay; optionally wherein the variable heavy chain region comprises SEQ ID NO:9 and the variable light chain region comprises SEQ ID NO: 10; and optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12.

11. The method of any one of the preceding claims, wherein 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 wherein the isolated antibody or antigen binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgGl antibody.

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

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

14. The method of any one of the preceding claims, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade events (TEAEs); optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, pyrexia, Herpes Zoster, urinary tract infection, skin and cutaneous 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 wherein administering the isolated 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.

15. The method of any one of the preceding claims, 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 wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg or about 600 mg.

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

17. 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 wherein the pharmaceutically acceptable composition comprises the isolated antibody or antigen binding fragment thereof and at least one pharmaceutically acceptable carrier, excipient or stabilizer.

18. The method of any one of the preceding claims, wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and wherein the antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

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

20. A unit dosage form comprising an isolated antibody or antigen binding fragment thereof that comprises a variable heavy (VH) chain region comprising a CDR1 having the amino acid sequence of SEQ ID NO:3, a CDR2 having the amino acid sequence of SEQ ID NON, and a CDR3 having the amino acid sequence of SEQ ID NO:5; and a variable light (VL) chain region comprising a 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 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 dosage of from 100 milligrams to 800 milligrams in the treatment myasthenia gravis.

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

22. The unit dosage form claims 20 or 21, wherein the variable heavy chain region of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 90% 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 an identity of at least 90% to SEQ ID NOTO; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NO:9, and/or the variable light chain region comprises an amino acid sequence having an identity of at least 95% to SEQ ID NOTO; optionally wherein the variable heavy chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO:9, and/or the variable light chain region comprises an amino acid sequence having an identity of at least 99% to SEQ ID NO: 10; optionally wherein the heavy chain of the isolated antibody or antigen binding fragment thereof comprises an amino acid sequence having an identity of at least 95% 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 an identity of at least 95% to SEQ ID NO: 12; optionally wherein the isolated antibody or antigen binding fragment thereof interacts with at least K121, F135, QI 39, D141, E239, W241, C275, K276, F284, P291 and E292 of SEQ ID NO: 1 and SEQ ID NO:2, based on human sequence numbering; optionally wherein the isolated antibody or antigen binding fragment thereof binds to human CD38 (SEQ ID NO:1) with a KD of 10'⁸ M or a greater affinity, and wherein the affinity is measured by a standard Biacore® assay; optionally wherein the variable heavy chain region comprises SEQ ID NO:9 and the variable light chain region comprises SEQ ID NO: 10; and optionally wherein the isolated antibody or antigen binding fragment thereof comprises a heavy chain as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12.

23. The unit dosage form of any one of claims 20-22, wherein 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 wherein the isolated antibody or antigen binding fragment is a human IgG antibody, optionally wherein the human IgG antibody is a human IgGl antibody.

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 medication(s), optionally wherein the background myasthenia gravis medication(s) is selected from the group consisting of immunosuppressants, steroids, anticholinergics, and cholinesterase inhibitors, and combinations thereof; optionally wherein the background myasthenia gravis medication(s) is selected from the group consisting of methylprednisolone, prednisone, budesonide, fluticasone propionate, pyridostigmine, mycophenolate mofetil, dicycloverine, azathioprine and cyclosporine, and combinations thereof.

25. The unit dosage form of any one of claims 20-24, wherein administering the isolated antibody or antigen binding fragment thereof results in less than 10% incidence of grade 3 or 4 of one or more treatment-related adverse events (TRAEs) or treatment-emergent adverse events (TEAEs); optionally wherein the TRAEs or TEAEs are selected from the group consisting of gastrointestinal disorders, nausea, infestations, pyrexia, Herpes Zoster, urinary tract infection, skin and cutaneous 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 wherein administering the isolated 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.

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 wherein the isolated antibody or antigen binding fragment thereof is administered in a dosage of about 300 mg or about 600 mg.

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

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

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 as set forth in SEQ ID NO: 11 and a light chain as set forth in SEQ ID NO: 12; and wherein the isolated antibody or antigen binding fragment thereof is subcutaneously administered once per week for 8 weeks.

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