TW202428303A - Methods for treating primary membranous nephropathy using fcrn antagonists - Google Patents

Abstract

Provided herein are methods of treating primary membranous nephropathy using an effective amount of a human neonatal Fc receptor (FcRn) antagonist. FcRn antagonists for use in the treatment of primary membranous nephropathy and for use in the manufacture of a medicament for the treatment of primary membranous nephropathy are also provided herein.

Description

Methods for treating primary membranous nephropathy using FCRN antagonists

The present invention relates to methods for treating primary membranous nephropathy (pMN). The methods involve the use of an antagonist of the human neonatal Fc receptor (FcRn), which in certain embodiments is efgartigimod.

Related inventions

This invention claims priority to U.S. Provisional Patent Application No. 63/382,569 filed on November 7, 2022, the entire disclosure of each of which is incorporated herein by reference.

It is estimated that more than 2.5% of the population is affected by autoantibody-driven autoimmune diseases, in which the autoreactive antibodies are directly pathogenic. pMN is an immune-mediated glomerular disease and one of the most common causes of nephrotic syndrome in adults.

The main pathological feature of pMN is the presence of immune deposits containing immunoglobulins and complement bodies in the subcutaneous location. Podocyte antigens are most commonly involved in immune deposits, and IgG4 is usually the most prominent subtype of IgG deposited in pMN. Activation of these immune deposits and complement bodies leads to damage to the glomerular filtration membrane and the formation of proteinuria. The discovery of the major antigen, M-type phospholipase A2 receptor (PLA2R), has significantly enhanced the understanding of the mechanism of pMN. PLA2R is a 180 kDa transmembrane glycoprotein expressed by human podocytes, and its exact function is still unclear. Autoantibodies to PLA2R may be the cause of pMN in up to 75% of patients. The data clearly show a causal relationship between anti-PLA2R antibodies and the pathogenesis of pMN. Anti-PLA2R antibodies are associated with disease activity, providing prognostic information about disease severity and can serve as a useful marker for assessing treatment efficacy. Other target antigens identified in pMN to date include thrombospondin type 1 domain-containing 7A (THSD7A), neuroepidermal growth factor-like 1 (NELL-1), and semaphorin-3B (Sema3B). In 10% to 20% of cases, there are still uncharacterized antigens.

Although approximately 30 to 35% of pMN patients experience spontaneous remission, for most patients, the disease course is long and the disease is relatively difficult to treat. Approximately 30 to 40% of patients develop renal failure within 5 to 15 years, requiring dialysis or kidney transplantation. In the Caucasian population, pMN accounts for approximately 30% to 40% of primary nephrotic syndromes, with the peak age of onset being 40 to 50 years old. In China, the incidence of pMN has recently increased significantly in cases of renal examinations. It has been reported that the incidence of membranous nephropathies (MN) has almost doubled from 10.4% (2003-2006) to 24.1% (2011-2014). Based on data calibration, it was found that MN increases by 13% each year, and its incidence tends to exceed that of IgA nephropathy.

6個月。隨機分配的對照試驗及群組研究已顯示，利妥昔單抗及CNI會增加完全及部分緩解率。相對於環磷醯胺，該等藥物之有益副作用概況有利於其用作pMN患者之初始療法及維持腎功能。然而，用CNI治療後的高復發率為關注原因，且此等藥劑之單一療法僅在具有中度的疾病進展風險之患者中為合理的。對於利妥昔單抗而言，雖然研究中已取得一些令人鼓舞的結果，但無反應率仍相當大。 Currently, immunosuppressive therapy is limited to patients with pMN who are considered to be at risk for progressive renal damage. For patients with pMN who are at high risk for disease progression, immunosuppressive therapy is recommended, including rituximab or cyclophosphamide and monthly glucocorticoids for 6 months or calcineurin inhibitor (CNI)-based therapy for 6 months.

6 months. Randomized controlled trials and cohort studies have shown that rituximab and CNIs increase complete and partial remission rates. The favorable side effect profile of these drugs compared to cyclophosphamide favors their use as initial therapy for patients with pMN and maintenance of renal function. However, the high relapse rate after treatment with CNIs is a cause for concern, and monotherapy with these agents is only reasonable in patients with a moderate risk of disease progression. For rituximab, although some encouraging results have been obtained in studies, the non-response rate is still considerable.

Therefore, improved pMN treatment options are needed in this technology.

Therapeutic antagonism of FcRn (a molecule similar to the class I major histocompatibility complex that is involved in the recycling of immunoglobulin G (IgG) and thus causes the long half-life of IgG) has been explored as a strategy for treating IgG-mediated autoimmune diseases such as generalized Myasthenia Gravis (gMG), Immune Thrombocytopenia Purpura (ITP), and pemphigus (Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF)). The remarkable clinical efficacy of FcRn antagonism appears to be directly related to the early removal of pathogenic IgG autoantibodies from circulation.

Pathogenic autoantibodies and complement deposits are critically involved in the pathogenesis of pMN, among which subepithelial deposition of immune complexes is a hallmark of the disease. By reducing the accumulation of pathogenic autoantibodies in the glomeruli, FcRn antagonists may provide a safer and more effective treatment option for pMN patients.

The present disclosure generally relates to methods of treating primary membranous nephropathy (pMN) with FcRn antagonists.

The present disclosure provides a method for treating pMN in an individual in need thereof, the method comprising administering to the individual an effective amount of a human neonatal Fc receptor (FcRn) antagonist. In some embodiments, the FcRn antagonist comprises two, three, or four FcRn binding regions. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 compared to a corresponding wild-type Fc region. In some embodiments, the variant Fc region or an FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to a corresponding wild-type Fc region.

In some embodiments, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. In some embodiments, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

In some embodiments, the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 30. In some embodiments, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, and SEQ ID NO: 30. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is an anti-FcRn antibody.

In some embodiments, the FcRn antagonist is administered to a subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg/kg to 200 mg/kg. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks.

In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

In some embodiments, the method also includes administering to the individual an effective amount of angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blockers (ARB), statins, diuretics, glucocorticoids, or any combination thereof.

10mg普賴蘇穠(prednisolone)的劑量經口投與。在一些實施例中，糖皮質激素以穩定劑量投與24週。 In some embodiments, the glucocorticoid is prednisone. In some embodiments, the glucocorticoid is administered at a dose equivalent to

A dose of 10 mg of prednisolone is administered orally. In some embodiments, the glucocorticoid is administered at a steady dose for 24 weeks.

In some embodiments, ACEi and/or ARB are administered at the maximum tolerated or allowed dose. In some embodiments, the FcRn antagonist is administered after at least 12 weeks of ACEi and/or ARB administration. In some embodiments, ACEi and/or ARB are administered for at least 36 weeks. In some embodiments, the dose of ACEi and/or ARB is maintained at a stable dose.

50RU/mL。 In some embodiments, the subject's anti-phospholipase A2 receptor (PLA2R) antibody is serum positive. In some embodiments, the subject's anti-PLA2R antibody serum level is

50RU/mL.

8g/24小時。在一些實施例中，個體之蛋白尿基線含量>8g/24小時。 In some embodiments, the individual's baseline proteinuria level is

In some embodiments, the individual has a baseline proteinuria level of >8 g/24 hours.

In some embodiments, the anti-PLA2R antibody of the individual is serum negative. In some embodiments, the anti-PLA2R antibody serum level of the individual is <2RU/mL.

In some embodiments, after administration of an FcRn antagonist to an individual, the individual exhibits a post-dose urine protein and creatinine ratio (UPCR) of at most 0.5 mg/mg. In some embodiments, after administration of an FcRn antagonist to an individual, the individual exhibits a post-dose UPCR that is at least 50% lower than the baseline UPCR obtained from the individual before administration of the FcRn antagonist. In some embodiments, post-dose UPCR is measured at week 24, week 36, week 48, or week 72 after administration of an FcRn antagonist to an individual.

0.3g/24小時的投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後，該個體展現的投藥後蛋白尿相較於自FcRn拮抗劑投與之前之個體獲得的基線蛋白尿減少至少50%。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後，個體展現的投藥後蛋白尿相較於自FcRn拮抗劑投與之前之個體獲得的基線蛋白尿減少至少50%且其中個體展現>0.3g且

3.5g/24小時的投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週、第36週、第48週或第72週量測投藥後蛋白尿。 In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits

In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose proteinuria that is at least 50% less than the baseline proteinuria obtained from the subject before administration of the FcRn antagonist. In some embodiments, post-dose proteinuria is measured at week 24 after administration of the FcRn antagonist to the subject. In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose proteinuria that is at least 50% less than the baseline proteinuria obtained from the subject before administration of the FcRn antagonist and wherein the subject exhibits >0.3 g and

3.5 g/24 hours post-dose proteinuria. In some embodiments, post-dose proteinuria is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the subject.

3.5g/dL的投藥後血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週、第36週、第48週或第72週量測投藥後血清白蛋白。 In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits

In some embodiments, post-dose serum albumin is measured at week 24, week 36, week 48, or week 72 following administration of the FcRn antagonist to the subject.

In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m ^2. In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose eGFR that is less than 20% lower than the baseline eGFR obtained by the subject before administration of the FcRn antagonist. In some embodiments, the post-dose eGFR is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the subject.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-dose EuroQoL 5-dimension 5-level (EQ5D-5L) score that is reduced compared to a baseline EQ5D-5L score obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-dose EQ5D-5L score is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the subject.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-dose Patient Reported Outcomes Information System (PROMIS) Short Form v.1.0 Fatigue-4a score that is reduced compared to a baseline PROMIS Short Form v.1.0 Fatigue-4a score obtained for the subject before administration of the FcRn antagonist. In some embodiments, the post-dose PROMIS Short Form v.1.0 Fatigue-4a score is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the subject.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration serum autoantibody level that is reduced compared to a baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum autoantibody level is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum autoantibody level is measured at week 24, week 36, week 48, or week 72 following administration of the FcRn antagonist to the subject. In some embodiments, the serum autoantibody is selected from the group consisting of anti-PLA2R, anti-THSD7a, anti-NELL-1, and anti-Sema3B. In some embodiments, the serum autoantibody is anti-PLA2R.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-dose serum complement level that is reduced compared to a baseline serum complement level obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-dose serum complement level is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline serum complement level obtained from the subject before administration of the FcRn antagonist. In some embodiments, the post-dose serum complement level is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the subject.

In some embodiments, after administration of an FcRn antagonist to an individual, the individual exhibits a post-dose serum IgG level that is reduced compared to a baseline serum IgG level obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-dose serum IgG level is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a baseline serum IgG level obtained from the individual before administration of the FcRn antagonist. In some embodiments, the post-dose serum IgG level is measured at week 24, week 36, week 48, or week 72 after administration of the FcRn antagonist to the individual.

In some embodiments, the FcRn antagonist is present in an aqueous solution comprising about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine, and about 0.0032% (w/v) polysorbate 80, wherein the composition has a pH of about 6.7. In some embodiments, the aqueous solution comprises about 3.2 mg/ml FcRn antagonist.

In some embodiments, the FcRn antagonist is present in an aqueous solution comprising about 20 mM L-histidine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 20, wherein the composition has a pH of about 6.0. In some embodiments, the aqueous solution comprises about 180 mg/ml FcRn antagonist.

In some embodiments, the FcRn antagonist is present in an aqueous solution comprising about 20 mM L-histidine, about 50 mM L-arginine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 80, wherein the composition has a pH of about 6.0. In some embodiments, the aqueous solution comprises about 200 mg/ml FcRn antagonist.

The present disclosure also provides FcRn antagonists for treating pMN, wherein the treatment is performed according to the methods described above and herein.

The present disclosure also provides an FcRn antagonist for use in the manufacture of a medicament for treating pMN, wherein the treatment is performed according to the methods described above and herein.

This disclosure also provides the use of FcRn antagonists for treating pMN according to the methods described above and herein.

The present disclosure also provides the use of FcRn antagonists for the manufacture of a medicament for treating pMN, wherein the treatment is performed according to the methods described above and herein.

FIG1 is a set of graphs showing the levels of IgG circulating immune complexes (IgG CIC) (upper graph) and disease severity (lower graph) in human subjects with pemphigus vulgaris (PV; n=6) and pemphigus foliaceus (PF; n=6) after treatment with ergacimod. The black line indicates the median. The dashed line indicates clinical significance (CS). PDAI: pemphigus disease area index; CR: complete clinical remission; EoT: end of treatment; EoS: end of study. The data show that ergacimod reduces the levels of circulating immune complexes.

References to Sequence Listings

This invention contains a sequence listing that has been submitted electronically in ST.26 format and is hereby incorporated by reference in its entirety (the ST.26 copy was created on November 6, 2023, is named "205217_SL.xml", and is 40,663 bytes in size).

The present disclosure provides engineered FcRn antagonists and methods for their use in treating pMN. Advantageously, the methods disclosed herein allow for long-term maintenance of renal function, prevention of relapse, prevention of organ damage, management of comorbidities, improved patient survival, and improved disease-related quality of life.

Definition

As used herein, the term "FcRn" refers to the neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as shown in RefSeq NM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn (e.g., human FcRn). In one embodiment, the FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn via the Fc region and inhibits the binding of immunoglobulins to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist includes an antigen binding site that binds to a target antigen and a variant Fc region. In one embodiment, the FcRn antagonist includes an Fc region or an Fc fragment consisting of an Fc region and lacking an antigen binding site. In one embodiment, the term "FcRn antagonist" refers to an antibody or an antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or via its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., IgG autoantibody) to FcRn.

As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising an antibody CDR, VH region, or VL region. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heterojunction antibodies, antibody drug conjugates, single domain antibodies (sdAb), monovalent antibodies, single chain antibodies or single chain Fv (scFv), camel antibodies, affinity antibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab') ₂ fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. The antibody can be an immunoglobulin molecule of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ , or IgA ₂ ) or any subclass (e.g., IgG _2a or IgG _2b ).

As used herein, the term "Fc domain" refers to a portion of a single immunoglobulin heavy chain that includes the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain includes at least a portion of a hinge region (e.g., an upper, middle, and/or lower hinge region), a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not include a hinge region,

As used herein, the term "hinge region" refers to the portion of the heavy chain molecule that joins the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, the hinge region comprises about 25 amino acid residues and is flexible, thereby allowing the two N-terminal antigen binding regions to move independently. In some embodiments, this hinge region comprises about 11 to 17 amino acid residues and is flexible, thereby allowing the two N-terminal antigen binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. The hinge region can be divided into three different domains: upper, middle and lower hinge domains. The FcRn antagonists of the present invention may include all or any portion of the hinge region. In some embodiments, the hinge region is derived from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 12).

As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region may be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is a homodimer. The Fc region may be derived from any native immunoglobulin. In some embodiments, it is formed by IgA, IgD, IgE or IgG heavy chain constant regions. In some embodiments, the Fc region is formed by IgG heavy chain constant regions. In some embodiments, the IgG heavy chain is IgG1, IgG2, IgG3 or IgG4 heavy chain constant regions. In some embodiments, the Fc region is formed by IgG1 heavy chain constant regions. In some embodiments, the IgG1 heavy chain constant region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) isoform. See, e.g., Jefferis and Lefranc (2009) mAbs 1(4):332-338 and de Taeye et al. (2020) Front Immunol. 11:740, which are incorporated herein by reference in their entirety.

As used herein, the term "variant Fc region" refers to an Fc region that has one or more alterations relative to a native Fc region. The alterations may include amino acid substitutions, additions and/or deletions, linkages of additional moieties, and/or alterations of native glycans. The term includes heterodimeric Fc regions that are each different from the other Fc domains. The term also includes single-chain Fc regions that are linked together by linker moieties that make up the Fc domain.

As used herein, the term "FcRn binding fragment" refers to a portion of the Fc region sufficient to confer FcRn binding.

As used herein, the term "EU position" refers to the amino acid position of the Fc region in the EU numbering convention, as described in the following references: Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al., "Sequences of Proteins of Immunological Interest", U.S. Dept. Health and Human Services, 5th edition, 1991.

As used herein, the term "baseline" refers to a measurement (e.g., B cell frequency, IgG level) in a patient, such as in the patient's blood or urine, prior to the first administration (e.g., intravenous or subcutaneous) of a therapeutic agent (e.g., an FcRn antagonist).

As used herein, the term "autoantibody-mediated disease" refers to any disease or condition in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or preventive measures as described herein. "Treatment" methods employ the administration of antibodies to an individual suffering from a disease or disorder or susceptible to such a disease or disorder in order to prevent, cure, delay the disease or disorder or recurrence of the disease or disorder, lessen its severity, or ameliorate one or more symptoms, or in order to prolong the survival of the individual beyond the expected survival in the absence of such treatment.

As used herein, the term "effective amount" in the context of administering a therapy to an individual refers to that amount of the therapy that achieves the desired preventive or therapeutic effect.

As used herein, the term "dose" or "dosage" refers to the amount of a drug administered to a subject in a single administration.

As used herein, the term "fixed dose" or "uniform dose" refers to a dose that does not vary based on individual characteristics (e.g., weight within a set range; gender; age within a set range, etc.).

0.3g/24小時且血清白蛋白

3.5g/dL。在一些實施例中，部分緩解(PR)定義為蛋白尿相對於基線降低

50%，且最終蛋白尿在0.3-3.5g/24小時之間(包括3.5)。 As used herein, the term "remission" refers to patients who have no novel markers of autoantibody-mediated disease and who have complete resolution or healing of baseline markers of the disease. In some embodiments, remission is a "complete remission" or a "partial remission." In some embodiments, complete remission (CR) is defined as proteinuria.

0.3g/24 hours and serum albumin

3.5 g/dL. In some embodiments, partial remission (PR) is defined as a decrease in proteinuria relative to baseline.

50%, and the final proteinuria is between 0.3-3.5g/24 hours (including 3.5).

As used herein, the term "relapse" refers to the development of physical symptoms and/or increased markers of autoantibody-mediated disease in a patient with autoantibody-mediated disease following a period of remission of the autoantibody-mediated disease. In some embodiments, relapse is defined as the development of nephrotic-range proteinuria after CR or PR; e.g., >3.5 g/24 hours.

As used herein, the term "individual" or "patient" or "participant" includes any human or non-human animal. In one embodiment, the individual or patient or participant is a human or non-human mammal. In one embodiment, the individual or patient or participant is a human. In some embodiments, the human individual or patient or participant is of Asian descent.

As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses a deviation of ±5% of a given value or range that is appropriate for performing the methods disclosed herein.

Primary membranous nephropathy

pMN, an immune-mediated glomerular disease, is one of the most common causes of adult nephrotic syndrome. It is a slightly male-predominant disease that occurs more often in the elderly. Although approximately 30 to 35% of pMN patients experience spontaneous remission, for most patients, the disease course is long and relatively difficult to treat. Approximately 30 to 40% of patients eventually develop kidney failure within 5 to 15 years, requiring dialysis or kidney transplantation. In the Caucasian population, pMN accounts for approximately 30 to 40% of primary nephrotic syndrome, with a peak age of onset of 40 to 50 years. In China, the incidence of pMN has recently increased significantly in cases of renal examinations. According to reports, the incidence of MN has almost doubled from 10.4% (2003-2006) to 24.1% (2011-2014). Based on data calibration, it was found that MN increases by 13% each year, and its incidence tends to exceed that of IgA nephropathy.

The clinical presentation of pMN typically involves features of the nephrotic syndrome: heavy proteinuria, hypoalbuminemia, edema or generalized edema, hyperlipidemia, and lipuria. These features tend to develop slowly and can be overlooked for months. In its earliest stages, pMN can have an indolent course. Conceptually, this is attributed to the gradual but progressive growth of immune deposits and the resulting podocyte damage. Proteinuria typically persists at subclinical levels for months to even years before diagnosis. The degree of proteinuria at presentation can vary, ranging from subnephrotic to over 20 g/day. Hyperlipidemia is common in the presence of nephrotic-range proteinuria. At presentation, in 70% of patients, blood pressure is normal, and glomerular filtration rate (GFR) is maintained in most patients. However, the longer proteinuria persists, the higher the chance of a reduced GFR. Venous thromboembolic events may be present and may be the initial cause for clinical concern.

The main pathological feature of pMN is the presence of immune deposits containing immunoglobulins and complement bodies in a subepithelial location. Podocyte antigens are most frequently implicated in immune deposits, and IgG4 is usually the most prominent isotype of IgG deposited in pMN. Activation of these immune deposits and complement bodies leads to damage to the glomerular filtration membrane and the formation of proteinuria. The discovery of the major antigen, the M-type phospholipase A2 receptor (PLA2R), has significantly enhanced the understanding of the mechanism of pMN. PLA2R is a 180 kDa transmembrane glycoprotein expressed by human podocytes, where its precise function is unknown. Autoantibodies to PLA2R may be the cause of pMN in up to 75% of patients. Data clearly indicate a causal relationship between anti-PLA2R antibodies and the pathogenesis of pMN. Anti-PLA2R antibodies are associated with disease activity, providing prognostic information about disease severity and can serve as a useful marker for assessing treatment efficacy. Other target antigens identified in pMN to date include thrombospondin type 1 domain-containing 7A (THSD7A), neuroepidermal growth factor-like 1 (NELL-1), and semaphorin-3B (Sema3B). In 10-20% of cases, there are still uncharacterized antigens.

6個月。 For patients with MN, the risk of progressive renal loss is assessed using clinical and laboratory criteria. Key determinants include renal function, persistent proteinuria, and antibody biomarkers in serum or urine, such as anti-PLA2R antibodies, IgG, etc. Best supportive care is recommended for all patients with pMN and proteinuria. Best supportive care includes but is not limited to the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) to reduce proteinuria, statins to reduce cholesterol, and/or antiplatelet adhesion agents or anticoagulant therapy to prevent thrombosis, especially renal venous thrombosis. For patients with pMN at high risk of disease progression, immunosuppressive therapy, including rituximab or cyclophosphamide and monthly glucocorticoids for 6 months, or CNI-based therapy is recommended.

6 months.

Exemplary treatment regimens are described in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines and include, for example, cyclic cyclophosphamide therapy, continuous cyclophosphamide therapy, rituximab therapy, tacrolimus therapy, and cyclosporine therapy. In some embodiments, cyclic cyclophosphamide therapy comprises methylprednisolone (e.g., 1 g) administered intravenously (IV) for 3 consecutive days starting at months 1, 3, and 5; prednisolone (e.g., 0.5 mg/kg/day) administered at months 1, 3, and 5; and cyclophosphamide (e.g., 2.5 mg/kg/day) administered at months 2, 4, and 6. In some embodiments, continuous cyclophosphamide therapy comprises methylprednisolone (e.g., 1 g) administered IV for 3 consecutive days starting at months 1, 3, and 5; prazosin (e.g., 0.5 mg/kg/day) administered every other day during months 1-6, followed by a gradual taper; and cyclophosphamide (e.g., 1.5 mg/kg/day) administered during months 1-6. In some embodiments, rituximab therapy comprises two IV doses of 1 g rituximab over 2 weeks, followed by 375 mg/m ² administered 1 to 4 times per week. In some embodiments, tacrolimus therapy comprises administering 0.05-0.1 mg/kg of tacrolimus daily for 12 months, wherein the target minimum level is 3-8 ng/mL (3.7-9.9 nmol/L). In some embodiments, cyclosporine therapy comprises administering 3.5 mg/kg of cyclosporine daily, wherein the target minimum level is 125-225 ng/mL (104-187 nmol/L). See KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases, Kidney Intl. (2021) 100(45): S1-S276, which is incorporated herein by reference in its entirety.

Treatment goals include patient survival, long-term maintenance of renal function, prevention of recurrence, prevention of organ damage, management of comorbidities, and improvement of disease-related quality of life.

Proteinuria is a parameter that correlates closely with disease progression and is expected to provide a sensitive and objective way to measure treatment efficacy compared to baseline. A reduction in proteinuria is a surrogate marker for improved renal outcomes. Therefore, proteinuria or UPCR are applicable parameters for assessing treatment efficacy and are preferred outcome measures for regulatory agencies.

FcRn antagonists

FcRn antagonists useful in the methods and uses provided herein include any molecule that binds to and inhibits FcRn, including but not limited to any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region.

In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions.

Any Fc region can be altered to produce a variant Fc region for use in the methods disclosed herein. In general, the Fc region or its FcRn binding fragment is from a human immunoglobulin. However, it should be understood that the Fc region can be derived from an immunoglobulin of any other mammalian species, including, for example, camel species, rodents (e.g., mice, rats, rabbits, guinea pigs) or non-human primates (e.g., orangutans, macaques) species. In addition, the Fc region or a portion thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3 and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in US 2011/0243966A1, which is incorporated herein by reference in its entirety. A variety of Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly available deposits.

The Fc region can be further truncated or internally deleted to generate a minimal FcRn binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any binding assay recognized in the art (e.g., ELISA).

To enhance the manufacturability of the FcRn antagonists disclosed herein, preferably, the Fc region does not include any non-disulfide bonded cysteine residues. Therefore, in one embodiment, the Fc region does not include free cysteine residues.

Any Fc variant or FcRn binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to a native ( i.e., wild-type) Fc region can be used in the methods disclosed herein. In one embodiment, the variant Fc region comprises amino acid changes, substitutions, insertions, and/or deletions that impart the desired characteristics. In one embodiment, the FcRn antagonist comprises a variant Fc region or FcRn binding fragment thereof that binds to FcRn with higher affinity at pH 5.5 than a corresponding wild-type Fc region. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof, which binds to FcRn with a higher affinity at pH 6.0 and/or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region or an FcRn binding fragment thereof, which binds to FcRn with a higher affinity at acidic and neutral pH.

In some embodiments, the variant Fc region is derived from the Fc region of any natural immunoglobulin. In some embodiments, the natural immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgA, IgD, IgE, or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE, or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, IgG is IgG1, IgG2, IgG3, or IgG4. In some embodiments, human IgG is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region is different from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) isotype.

In one embodiment, the variant Fc region or FcRn binding fragment thereof consists of two Fc domains.

In one embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. In one embodiment, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively. In one embodiment, the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively.

In some embodiments, the FcRn antagonist disclosed herein comprises at least one Fc domain or consists of at least one Fc domain, wherein the amino acid sequence of the at least one Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 13 provided in Table 1 below.

In some embodiments, the FcRn antagonist disclosed herein comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the following: amino acid sequence SEQ ID NO: 13.

In some embodiments, the FcRn antagonist disclosed herein comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of a variant Fc region, the amino acid sequence of the variant Fc region comprising or consisting of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1-3 and 14-31. In some embodiments, the dimer is a heterodimer or a homodimer.

Table 2.

In one embodiment, the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.

In one embodiment, the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1, 2, 3 and 30. In one embodiment, the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1, 2, 3 and 30.

In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, the FcRn antagonist comprising a first Fc domain and a second Fc domain is the major FcRn antagonist molecule in the population of FcRn antagonist molecules, and the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, and 3. In some embodiments, the FcRn antagonist comprising a first Fc domain and a second Fc domain is the major FcRn antagonist molecule in the population of FcRn antagonist molecules, and the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 30. In some embodiments, the major FcRn antagonist molecules comprise at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the population of FcRn antagonist molecules.

In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence SEQ ID NO: 30. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence SEQ ID NO: 30.

In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region comprises two Fc domains, wherein the amino acid sequence of each Fc domain is independently selected from SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region comprises two Fc domains, wherein the amino acid sequence of each Fc domain is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 30.

In certain embodiments, the variant Fc region is a heterodimer, wherein the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art ( see , e.g., US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a heterodimer, wherein the amino acid sequence of each Fc domain is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

In one embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of each Fc domain is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 30. In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3 or SEQ ID NO: 30. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 30. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 30. In one embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 30, and the amino acid sequence of the second Fc domain consists of or comprises the following: amino acid sequence SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 1.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 2.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 3.

In one embodiment, the FcRn antagonist comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each Fc domain comprises or consists of the amino acid sequence SEQ ID NO: 30.

In some embodiments, the FcRn antagonist comprises glycans on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecule comprises glycans at EU position 297 on one or both of the Fc domains. In some embodiments, the glycans comprise N-glycans. In some embodiments, the N-glycans comprise G0F N-glycans, G1F N-glycans, G2F N-glycans, or G0 N-glycans.

In some embodiments, the FcRn antagonist comprises or consists of a population of FcRn antagonists, wherein at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, or at least 57% of the population of Fc domains of the FcRn antagonist comprises galactose. In some embodiments, the population comprises or consists of an FcRn antagonist, wherein at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the Fc domain population of the FcRn antagonist comprises fucose.

In some embodiments, the FcRn antagonist lacks an amino acid at EU position 441 of one or both Fc domains. In some embodiments, the FcRn antagonist comprises glycine and lysine at EU positions 440 and 441, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441. In some embodiments, the FcRn antagonist comprises amidated proline at EU position 439. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 440 and 441 and comprises amidated proline at EU position 439.

In some embodiments, the FcRn antagonist comprises aspartic acid, lysine, threonine, histidine, threonine, and cysteine at EU positions 221, 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acid at EU position 221 and comprises lysine, threonine, histidine, threonine, and cysteine at EU positions 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks the amino acids at EU positions 221 and 222 and comprises threonine, histidine, threonine, and cysteine at EU positions 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221 to 224 and comprises threonine and cysteine at EU positions 225 and 226, respectively. In some embodiments, the FcRn antagonist lacks amino acids at EU positions 221, 222, 223, 224, 225, and 226.

In some embodiments, the FcRn antagonist is a population of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of multiple subpopulations of FcRn antagonist molecules. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 subpopulations.

In some embodiments, the first subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3.

In some embodiments, the second subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the following: amino acid sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences of SEQ ID NOs: 3 and 22, respectively.

In some embodiments, the third subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the following: amino acid sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences of SEQ ID NOs: 3 and 19, respectively.

In some embodiments, the fourth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule of the fourth subgroup are deaminated.

In some embodiments, the fifth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3 and 19, respectively, and wherein an asparagine residue in each FcRn antagonist molecule of the fifth subgroup is deaminated.

In some embodiments, the sixth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the following: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 2 and 3, respectively.

In some embodiments, the seventh subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the following: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 2 and 3, respectively, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the seventh subgroup is oxidized.

In some embodiments, the eighth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the following: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 2.

In some embodiments, the ninth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the following: amino acid sequences that are at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequences of SEQ ID NOs: 3 and 16, respectively.

In some embodiments, the tenth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of: an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 2 and 3, respectively, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the tenth subgroup is oxidized.

In some embodiments, the eleventh subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 3, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the eleventh subgroup is oxidized.

In some embodiments, the first subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3.

In some embodiments, the second subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, which comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 22, respectively.

In some embodiments, the third subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 19, respectively.

In some embodiments, the fourth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule of the fourth subgroup are deaminated.

In some embodiments, the fifth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 19, respectively, and wherein an asparagine residue in each FcRn antagonist molecule of the fifth subgroup is deaminated.

In some embodiments, the sixth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively.

In some embodiments, the seventh subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the seventh subgroup is oxidized.

In some embodiments, the eighth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 2.

In some embodiments, the ninth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, wherein the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 3 and 16, respectively.

In some embodiments, the tenth subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequences of the first and second Fc domains comprise or consist of the amino acid sequences of SEQ ID NOs: 2 and 3, respectively, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the tenth subgroup is oxidized.

In some embodiments, the eleventh subgroup of FcRn antagonist molecules comprises or consists of a variant Fc region, the variant Fc region comprises or consists of a dimer of a first Fc domain and a second Fc domain, wherein the amino acid sequence of the first and second Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein a methionine residue or a tryptophan residue in each FcRn antagonist molecule of the eleventh subgroup is oxidized.

In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and one of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and two of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and three of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and four of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and five of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and six of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and seven of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and eight of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and nine of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups. In some embodiments, the FcRn antagonist molecule group comprises or consists of a combination of the first subgroup and all of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth or eleventh subgroups.

In some embodiments, the group includes or consists of the first and second subgroups. In some embodiments, the group includes or consists of the first and third subgroups. In some embodiments, the group includes or consists of the first and fourth subgroups. In some embodiments, the group includes or consists of the first and fifth subgroups. In some embodiments, the group includes or consists of the first and sixth subgroups. In some embodiments, the group includes or consists of the first and seventh subgroups. In some embodiments, the group includes or consists of the first and eighth subgroups. In some embodiments, the group includes or consists of the first and ninth subgroups. In some embodiments, the group includes or consists of the first and tenth subgroups. In some embodiments, the group includes or consists of the first and eleventh subgroups. In some embodiments, the groups listed above further include or consist of 1, 2, 3, 4, 5, 6, 7, 8 or 9 additional subgroups. In some embodiments, these additional subgroups are one or more of the above subgroups.

In some embodiments, the group includes or consists of the first and seventh, ninth or eleventh subgroups. In some embodiments, the group includes or consists of the first, seventh, ninth and eleventh subgroups.

In some embodiments, the first subpopulation constitutes at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or at least 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation constitutes about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation constitutes 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation constitutes 40% to 90%, 50% to 80%, or 55% to 70% of the FcRn antagonist molecule population. In some embodiments, the first subpopulation constitutes 56.9% to 68.3% or 59.5% to 67.9% of the FcRn antagonist molecule population.

In some embodiments, the second subpopulation constitutes less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation constitutes 0.5% to 3.0%, 1.0% to 2.5%, or 1.0% to 2.0% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation constitutes 0.8% to 2.0% or 0.8% to 2.1% of the population of FcRn antagonist molecules.

In some embodiments, the third subpopulation constitutes less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation constitutes about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation constitutes 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation constitutes 0.5% to 3.0%, 1.0% to 2.5%, or 1.0% to 2.0% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation constitutes 1.1% to 2.1% or 1.0% to 1.9% of the population of FcRn antagonist molecules.

In some embodiments, the fourth subpopulation constitutes less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation constitutes about 5%, about 4%, about 3%, about 2%, or about 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation constitutes 5%, 4%, 3%, 2%, or 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation constitutes 1% to 5%, 2% to 4%, or 2% to 3% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation constitutes 2.1% to 3.2% or 2.0% to 3.1% of the population of FcRn antagonist molecules.

In some embodiments, the fifth subpopulation constitutes less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, or less than 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation constitutes about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, about 6%, or about 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation constitutes 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation constitutes 5% to 12%, 6% to 10%, or 7% to 8% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation constitutes 6.8% to 9.4% or 6.9% to 8.7% of the population of FcRn antagonist molecules.

In some embodiments, the sixth subpopulation constitutes less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, or less than 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation constitutes about 17%, about 16%, about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%, about 8%, about 7%, or about 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation constitutes 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, or 6% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation constitutes 7% to 17%, 10% to 15% or 11% to 12% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation constitutes 7.0% to 14.0% or 10.0% to 14.4% of the population of FcRn antagonist molecules.

In some embodiments, the seventh subpopulation constitutes less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1% or less than 0.5% of the FcRn antagonist molecule population. In some embodiments, the seventh subpopulation constitutes about 6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1% or about 0.5% of the FcRn antagonist molecule population. In some embodiments, the seventh subpopulation constitutes 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1% or 0.5% of the FcRn antagonist molecule population. In some embodiments, the seventh subpopulation constitutes 0.5% to 5.5%, 1.0% to 3.0% or 1.5% to 2.5% of the FcRn antagonist molecule population. In some embodiments, the seventh subpopulation constitutes 1.5% to 5.5% or 1.4% to 4.9% of the FcRn antagonist molecule population.

In some embodiments, the eighth subpopulation constitutes less than 7.5%, less than 7.0%, less than 6.5%, less than 6.0%, less than 5.5%, less than 5.0%, less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, or less than 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation constitutes about 7.5%, about 7.0%, about 6.5%, about 6.0%, about 5.5%, about 5.0%, about 4.5%, about 4.0%, about 3.5%, about 3.0%, or about 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation constitutes 7.5%, 7.0%, 6.5%, 6.0%, 5.5%, 5.0%, 4.5%, 4.0%, 3.5%, 3.0%, or 2.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation constitutes 2.5% to 7.5%, 3.0% to 5.0% or 3.5% to 4.5% of the FcRn antagonist molecule population. In some embodiments, the eighth subpopulation constitutes 2.9% to 7.4% or 3.0% to 6.3% of the FcRn antagonist molecule population.

In some embodiments, the ninth subpopulation constitutes less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation constitutes about 3.5%, about 3.0%, about 2.5%, about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation constitutes 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation constitutes 0.5% to 3.5%, 1.5% to 2.0%, or 1.0% to 1.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation constitutes 0.4% to 3.2% or 0.5% to 2.6% of the population of FcRn antagonist molecules.

In some embodiments, the tenth subpopulation constitutes less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation constitutes about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation constitutes 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation constitutes 0.5% to 2.0%, 0.5% to 1.5%, or 1.0% to 1.5% of the population of FcRn antagonist molecules.

In some embodiments, the eleventh subgroup constitutes less than 2.0%, less than 1.5%, less than 1%, or less than 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subgroup constitutes about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subgroup constitutes 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subgroup constitutes 0.5% to 2.0%, 0.5% to 1.5%, or 1.0% to 1.5% of the population of FcRn antagonist molecules.

In some embodiments, the FcRn antagonist molecule population comprises one or more FcRn antagonists described herein. In some embodiments, the FcRn antagonist is any of those described in U.S. Patent Application No. 63/383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a group of FcRn antagonists described in U.S. Patent Application No. 63/383,599, filed on November 14, 2022, which is incorporated herein by reference in its entirety.

In one embodiment, the FcRn antagonist is igatimod (CAS registration number 1821402-21-4). As used herein, the term "igatimod" is interchangeable with "igatimod-α". In some embodiments, igatimod is igatimod-α fcab.

In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830/SYNT001) or batoclimab (IMVT-1401/RVT1401/HBM9161).

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nikalimab, also known as M281. Nicalimab is a full-length "Fc dead" IgG1 monoclonal antibody. Nicalimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of myasthenia gravis (MG), warm immune autoimmune hemolytic anemia (WAIHA), and hemolytic disease of the fetus and newborn (HDFN). Nicalimab comprises the light chain (SEQ ID NO: 4) and heavy chain (SEQ ID NO: 5) sequences shown in Table 3 below (the VL region of SEQ NO: 4 and the VH region of SEQ ID NO: 5 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is lolixizumab, also known as UCB 7665. Lolixizumab is a full-length humanized IgG4 monoclonal antibody. Lolixizumab is administered by subcutaneous infusion in ongoing clinical trials for MG, immune thrombocytopenia (FTP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Lolixizumab comprises the light chain (SEQ ID NO: 6) and heavy chain (SEQ ID NO: 7) sequences shown in Table 4 below (the VL region of SEQ NO: 6 and the VH region of SEQ ID NO: 7 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Onorimab, also known as SYNT001. Onorimab is another full-length humanized IgG4 monoclonal antibody. Onorimab is administered by intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA. Onorimab comprises the light chain (SEQ ID NO: 8) and heavy chain (SEQ ID NO: 9) sequences shown in Table 5 below (the VL region of SEQ NO: 8 and the VH region of SEQ ID NO: 9 are underlined):

In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Bartolimumab, also known as IMVT1401/RVT1401/HBM9161. Bartolimumab is a full-length "Fc-null" IgG1 monoclonal antibody. Bartolimumab is administered by subcutaneous injection in an ongoing Phase 2 clinical trial for the treatment of MG and Grave's ophthalmopathy. Bartolimumab comprises the light chain (SEQ ID NO: 10) and heavy chain (SEQ ID NO: 11) sequences shown in Table 6 below (the VL region of SEQ NO: 10 and the VH region of SEQ ID NO: 11 are underlined):

Pharmaceutical ingredients

In one aspect, the present disclosure provides pharmaceutical compositions comprising an FcRn antagonist for use in a method of treating pMN. In certain embodiments, such compositions comprise or consist of a variant Fc region or an FcRn binding fragment thereof that specifically binds to FcRn, particularly human FcRn, with increased affinity and reduced pH dependence relative to a native Fc region. In other embodiments, the FcRn antagonist composition is an antibody or an antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain and inhibits the binding of the Fc region of an immunoglobulin to FcRn. Generally speaking, these FcRn antagonists inhibit the binding of Fc-containing agents (such as antibodies and immunoadhesins) to FcRn in vivo, which results in an increased degradation rate of Fc-containing agents and a concomitant decrease in the serum levels of these agents.

In one embodiment, the FcRn antagonist is igatimod. Igatimod (ARGX-113) is a modified human immunoglobulin (Ig) gamma (IgG) 1-derived Fc, which is a za isotype that binds to human FcRn with nanomolar affinity. Igatimod encompasses the IgG1 Fc region and has been engineered using ABDEG ^™ technology to increase its affinity for FcRn at physiological and acidic pH. The increased affinity of igatimod for FcRn at acidic and physiological pH results in FcRn-mediated blockade of IgG recycling.

Due to the increased affinity for FcRn at acidic and neutral pH, efatimod blocks the formation of FcRn/IgG complexes, leading to the degradation of endogenous IgG, including autoantibodies that cause IgG-mediated autoimmune diseases. This blockade of FcRn by efatimod results in a rapid and dramatic reduction in autoantibody levels, which is the basis of therapeutic strategies for treating autoimmune indications, in which IgG autoantibodies are expected to play a central role in disease pathology. Without wishing to be bound by theory, efatimod may also be used to prevent the onset or progression of pMN by reducing circulating immune complexes, preventing their deposition under the epithelium. In fact, efatimod has been shown to reduce circulating immune complexes (Example 1; Figure 1 ).

Igatimod is being developed for intravenous (IV) and subcutaneous (SC) administration routes.

For IV administration, in certain embodiments, efatimod can be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, efatimod can be administered in a formulation comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7) and about 0.02% (w/v) polysorbate 80. In certain embodiments, efatimod can be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w/v) polysorbate 80. In certain embodiments, Egativod may comprise a formulation of about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride (pH 6.7) and about 0.02% (w/v) polysorbate 80, administered via intravenous infusion in a total volume of about 250 mL for about 2 hours. In certain embodiments, efatimod may comprise a formulation of 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7) and 0.02% (w/v) polysorbate 80, administered via intravenous infusion in a total volume of 250 mL for 2 hours. See, for example, WO2019110823A1, which is incorporated herein by reference in its entirety.

In certain embodiments, efatimod may be administered by a formulation comprising an aqueous solution of about pH 6.7 containing about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride and about 0.02% (w/v) polysorbate 80 (diluted to a total volume of about 125 mL for intravenous infusion over about 1 hour). In certain embodiments, efatimod may be administered by a formulation comprising an aqueous solution of pH 6.7 containing 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride and 0.02% (w/v) polysorbate 80 (diluted to a total volume of 125 mL for intravenous infusion over 1 hour).

In certain embodiments, efatimod may be administered as a formulation comprising an aqueous solution of about pH 6.7 containing about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine, and about 0.0032% (w/v) polysorbate 80. The formulation is administered in a total volume of about 125 mL via intravenous infusion over about 1 hour. In certain embodiments, efatimod may be administered as a formulation comprising an aqueous solution of pH 6.7 containing 4 mM sodium phosphate, 146 mM sodium chloride, 24 mM L-arginine, and 0.0032% (w/v) polysorbate 80. The formulation is administered in a total volume of about 125 mL via intravenous infusion over 1 hour.

In certain embodiments, efatimod is administered by intravenous infusion and is provided as a sterile, colorless, transparent concentrate solution at a concentration of about 20 mg/mL. In certain embodiments, efatimod is administered by intravenous infusion and is provided as a sterile, colorless, transparent concentrate solution at a concentration of 20 mg/mL.

In certain embodiments, igatimod is administered by intravenous infusion and is provided in a vial (e.g., a single-dose vial). In certain embodiments, a vial of igatimod contains about 400 mg of igatimod at a concentration of about 20 mg/mL. In certain embodiments, a vial of igatimod contains 400 mg of igatimod at a concentration of 20 mg/mL. In certain embodiments, each milliliter of solution in a vial of igatimod contains about 31.6 mg of L-arginine hydrochloride, about 0.2 mg of polysorbate 80, about 5.8 mg of sodium chloride, about 2.4 mg of anhydrous sodium dihydrogen phosphate, about 1.1 mg of sodium dihydrogen phosphate monohydrate, and water for injection, USP, at a pH of about 6.7. In certain embodiments, each milliliter of solution in a vial of efatimod contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg anhydrous dibasic sodium hydrogen phosphate, 1.1 mg monohydrated sodium dibasic sodium phosphate, and water for injection USP, pH 6.7.

In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of about 10 mg/kg via intravenous infusion. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of about 10 mg/kg via intravenous infusion for about one hour. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of about 10 mg/kg via intravenous infusion once a week for about one hour. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of about 10 mg/kg via intravenous infusion once a week for about 4 weeks. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of 10 mg/kg via intravenous infusion. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of 10 mg/kg via intravenous infusion for one hour. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of 10 mg/kg via intravenous infusion for one hour once a week. In certain embodiments, for patients weighing less than 120 kg, igatimod is administered at a dose of 10 mg/kg via intravenous infusion for one hour once a week for 4 weeks. In certain embodiments, for patients weighing 120 kg or more, igatimod is administered via intravenous infusion at a dose of about 1200 mg. In certain embodiments, for patients weighing 120 kg or more, igatimod is administered via intravenous infusion at a dose of 1200 mg.

For SC administration, in certain embodiments, igatimod can be administered alone. Alternatively, for SC administration, in certain embodiments, igatimod can be co-formulated with hyaluronidase, for example, particularly rHuPH20. Co-formulated materials will allow for larger volumes of SC administration.

In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of about 20 mM L-histidine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 20, wherein the composition has a pH of about 6.0. In some embodiments, the formulation comprises about 180 mg/ml igatimod. In some embodiments, igatimod may be administered as a formulation comprising an aqueous solution of 20 mM L-histidine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w/v) polysorbate 20, wherein the composition has a pH of 6.0. In some embodiments, the formulation comprises 180 mg/ml igatimod.

In some embodiments, efatimod may be administered as a formulation comprising an aqueous solution of about 20 mM L-histidine, about 50 mM L-arginine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 80, wherein the composition has a pH of about 6.0. In some embodiments, the formulation comprises about 200 mg/ml efatimod. In some embodiments, efatimod may be administered as a formulation comprising an aqueous solution of 20 mM L-histidine, 50 mM L-arginine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w/v) polysorbate 80, wherein the composition has a pH of 6.0. In some embodiments, the formulation comprises 200 mg/ml igatimod.

rHuPH20 is the active ingredient of Halozyme's commercial product HYLENEX® recombinant (hyaluronidase human injection), also known as HYLENEX®, which was approved by the FDA for marketing in the United States in December 2005. HYLENEX® is a tissue permeability regulator indicated as an adjuvant in SC fluid administration to achieve hydration, increase the dispersion and absorption of other injected drugs, and improve the reabsorption of radiopaque agents in SC urological radiography.

rHuPH20 is a recombinant human hyaluronidase produced by genetically engineered Chinese hamster ovary (CHO) cells containing a DNA plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biopharmaceuticals co-formulated with rHuPH20 DS. Therefore, in certain embodiments, HZ202 rHuPH20 DS is used in an elgativimud/rHuPH20 co-formulated product for SC administration ( i.e., elgativimud PH20 SC).

Soluble hyaluronidases are provided in the co-formulations, combinations, uses and methods herein. Soluble hyaluronidases include any hyaluronidase that is secreted from a cell after expression and is present in a soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases, such as bovine PH20, ovine PH20, human soluble PH20 and variants thereof. Soluble forms of PH20 are generally produced using protein expression systems that facilitate correcting N-glycosylation to ensure that the polypeptide retains activity, as glycosylation is extremely important for the catalytic activity and stability of hyaluronidase. Such cells include, for example, Chinese hamster ovary (CHO) cells (e.g., DG44 CHO cells).

rHuPH20 refers to a composition produced following expression in cells, such as CHO cells, of a nucleic acid encoding residues 36-482 of SEQ ID NO:32, which residues are typically linked to a native or heterologous signal sequence (residues 1-35 of SEQ ID NO:32). rHuPH20 is produced by expression of a nucleic acid molecule, such as one encoding amino acids 1-482 (shown in SEQ ID NO:32), in mammalian cells. The translation process removes the 35 amino acid signal sequence. When produced in culture medium, there is heterogeneity at the C-terminus, so that the product designated as rHuPH20 includes a mixture of species, which may include any one or more of polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 32 and some shorter polypeptides in varying abundance. rHuPH20 is typically produced in cells that facilitate correct N-glycosylation to maintain activity, such as CHO cells (e.g., DG44 CHO cells). In some embodiments, one of the most abundant species is a 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 32. Also included are polypeptides that are soluble or secreted after expression in mammalian cells, which have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or greater sequence identity with residues 36-482 of SEQ ID NO: 32.

In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 20 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 200 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 300 mg to about 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 750 mg to about 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of about 1000 mg to about 2000 mg.

In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 20 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 200 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 300 mg to 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 750 mg to 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount of 1000 mg to 2000 mg.

In some embodiments, the pharmaceutical formulation comprises about 1000 mg or about 2000 mg of an FcRn antagonist. In some embodiments, the pharmaceutical formulation comprises 1000 mg or 2000 mg of an FcRn antagonist. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the pharmaceutical formulation comprises an amount of about 800 mg to about 1200 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises about 1000 mg of igatimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 10 mg/mL to about 200 mg/mL of igatimod. In some embodiments, the pharmaceutical formulation comprises 10 mg/mL to 200 mg/mL of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 20 mg/mL of igatimod. In some embodiments, the pharmaceutical formulation comprises 20 mg/mL of igatimod.

In some embodiments, the pharmaceutical formulation comprises about 180 mg/ml of igatimod. In some embodiments, the pharmaceutical formulation comprises 180 mg/ml of igatimod.

In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

Hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In one embodiment, the amount of hyaluronidase is about 1000U/ml to about 3000U/ml. In one embodiment, the amount of hyaluronidase is about 1000U/mL, about 1500U/mL, about 2000U/mL, about 2500U/mL or about 3000U/mL. In one embodiment, the amount of hyaluronidase is 2000U/mL.

In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U/mL. In some embodiments, rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U/mL.

In some embodiments, the pharmaceutical formulation comprises at least about 5 U to at least about 100,000 U of endoglycosidase hydrolase. In some aspects, the pharmaceutical formulation comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, to At least about 6000U, at least about 7000U, at least about 8000U, at least about 9000U, at least about 10,000U, at least about 20,000U, at least about 30,000U, at least about 40,000U, at least about 50,000U, at least about 60,000U, at least about 70,000U, at least about 80,000U, at least about 90,000U, or at least about 100,000U of endoglycosidase hydrolase.

In some embodiments, the pharmaceutical formulation comprises about 20,000 U of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises at least about 500 U/mL to at least about 5000 U/mL of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises at least about 1500 U/mL, at least about 1600 U/mL, at least about 1700 U/mL, at least about 1800 U/mL, at least about 1900 U/mL, at least about 2000 U/mL, at least about 2100 U/mL, at least about 2200 U/mL, at least about 2300 U/mL, at least about 2400 μM, at least about 2500 U/mL, at least about 3000 U/mL, at least about 3500 U/mL, at least about 4000 U/mL, at least about 4500 U/mL, or at least about 5000 U/mL of endoglycosidase hydrolase. In some embodiments, the pharmaceutical formulation comprises about 2000 U/mL of endoglycosidase hydrolase.

In some embodiments, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine β (1-4) or (1-3) bond. In some embodiments, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% sequence identity with amino acids 36-490 of SEQ ID NO: 32. In some embodiments, the endoglycosidase hydrolase comprises hyaluronidase. In some embodiments, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of: HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms thereof. In some embodiments, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase wherein one or more N-terminal and/or C-terminal amino acids are deleted relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitutions in the α-helical region, the linker region, or the α-helical region and the linker region relative to wild-type rHuPH20; ii. one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids are missing relative to wild-type rHuPH20; or iii. (i) and (ii).

As used herein, "hyaluronidase" refers to an enzyme that can catalyze the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which exists in the subcutaneous space and contributes to the soluble gel-like component in the extracellular matrix of the skin and is restored by rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, which is a glycosylated 447 amino acid single-chain polypeptide that depolymerizes hyaluronic acid in the local subcutaneous space of the skin injection site. The depolymerization of hyaluronic acid by hyaluronic acid is achieved by hydrolysis of polysaccharide polymers. The depolymerization of hyaluronic acid causes the viscosity of the gel-like phase of the extracellular matrix to decrease instantly and enhances water conduction, promoting the dispersion and absorption of the co-administered therapeutic agent. Therefore, hyaluronidase (eg, rHuPH20) can improve the speed and ease of subcutaneous delivery of injectable biologics and drugs by acting as a penetration enhancer. In certain embodiments, the hyaluronidase comprises ENHANZE ^™ .

In any of the above embodiments, the pharmaceutical formulation may be in unit dosage form.

In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a dry formulation for dissolution, such as a lyophilized powder, a freeze-dried powder, or an anhydrous concentrate. In one embodiment, the dry formulation is contained in a hermetically sealed container, such as a vial, an ampoule, or a sachet.

In one embodiment, the unit dosage form comprises an FcRn antagonist in the form of a liquid formulation, such as an injectable or infusible solution. In one embodiment, the liquid formulation is contained in a hermetically sealed container, such as a vial, a sachet, a prefilled syringe, a prefilled autoinjector, or a cartridge for a reusable syringe or applicator.

In one embodiment, the unit dose of each vial may contain 0.5 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml or 20 ml of an FcRn antagonist in the range of about 500 mg to about 2500 mg or about 1000 mg to about 2000 mg. In one embodiment, such formulations may be adjusted to a desired concentration by adding a sterile diluent to each vial.

The formulations disclosed herein include bulk pharmaceutical compositions that can be used to make pharmaceutical compositions (e.g., compositions suitable for administration to an individual or patient), which can be used to prepare unit dosage forms. In one embodiment, the composition of the present invention is a pharmaceutical composition. Such compositions contain a preventive or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., FcRn antagonists or other prophylactic or therapeutic agents of the present invention) and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to an individual.

method

In one aspect, a method for treating pMN using an FcRn antagonist is provided. In certain embodiments, the FcRn antagonist is efatimod. An important goal and feature of the methods disclosed herein is to improve renal function in patients with pMN. Other goals and features of the methods disclosed herein include, but are not limited to, patient survival, long-term maintenance of renal function, prevention of organ damage, management of comorbidities, and improvement of disease-related quality of life. Effective treatment of pMN using an FcRn antagonist may include at least one of the elements of the group consisting of: reduced UPCR, reduced proteinuria, reduced urine creatinine, increased serum albumin, reduced serum anti-PLA2R antibodies, and/or improved estimated glomerular filtration rate (eGFR). In some embodiments, UPCR is calculated by dividing the protein content (mg/dl) in a urine sample by the creatinine content (mg/dl). In some embodiments, the urine sample is a 24-hour urine sample, a 2×24-hour urine sample, or a single-point urine sample. In some embodiments, the UPCR is calculated as the average of the UPCR from two consecutive 24-hour urine samples (e.g., 2×24-hour UPCR). In some embodiments, the individual treated according to the methods provided herein experiences complete remission (CR). In some embodiments, the individual treated according to the methods provided herein experiences partial remission (PR). In some embodiments, the individual treated according to the methods provided herein experiences CR or PR. In some embodiments, the individual treated according to the methods provided herein experiences a reduction in circulating immune complexes. In some embodiments, the circulating immune complexes are selected from the group consisting of: C3, C4, CH50, and C1q-bound circulating immune complexes.

60mL/min/1.73m²。在一些實施例中，pMN的特徵可為個體之血清總IgG

6g/L。在一些實施例中，pMN的特徵可為個體之血清總IgG

4g/L。 In some embodiments, pMN in an individual can be confirmed by nephrology. In some embodiments, pMN in an individual can be confirmed by nephrology within 24 months of administration of an FcRn antagonist. In some embodiments, pMN can be characterized by urine protein > 3.5 g/24 hours in an individual. In some embodiments, pMN can be characterized by eGFR

60mL/min/1.73m ² . In some embodiments, pMN can be characterized by total serum IgG in an individual

6 g/L. In some embodiments, pMN can be characterized by the individual's total serum IgG

4g/L.

50RU/mL。 In some embodiments, the subject is serum positive for anti-PLA2R antibodies. In some embodiments, serum positive for anti-PLA2R antibodies is defined as a serum level of anti-PLA2R antibodies of

50RU/mL.

8g/24小時。在一些實施例中，個體之抗PLA2R抗體呈血清陽性且蛋白尿含量>8g/24小時。 In some embodiments, the subject is serum positive for anti-PLA2R antibodies and has a proteinuria level of

In some embodiments, the subject is serum positive for anti-PLA2R antibodies and has a proteinuria level of >8 g/24 hours.

2RU/mL之先前病史及/或腎切片中之PLA2R抗原染色呈陽性。 In some embodiments, the subject is seronegative for anti-PLA2R antibodies. In some embodiments, seronegative for anti-PLA2R antibodies is defined as a serum level of anti-PLA2R antibodies <2RU/mL. In some embodiments, seronegative for anti-PLA2R antibodies is defined as a serum level of anti-PLA2R antibodies <2RU/mL and no prior history of anti-PLA2R antibodies. In some embodiments, prior history of anti-PLA2R antibodies is defined as serum anti-PLA2R antibodies <2RU/mL.

Previous medical history of 2RU/mL and/or positive PLA2R antigen staining in kidney sections.

9.0%)。 In some embodiments, the individual does not have diabetic glomerulopathy greater than type I. In some embodiments, the individual does not have diabetic glomerulopathy type I and has no history of poor diabetes control (e.g., HbA1c

9.0%).

In some embodiments, the individual has not had unstable renal function within 3 months prior to administration of the FcRn antagonist. In some embodiments, unstable renal function is defined as a decrease in eGFR >20%.

In some embodiments, the individual does not have an autoimmune disease other than pMN.

In some embodiments, the subject does not have one or more of the following: alanine transaminase (ALT) and/or aspartate transaminase (AST) > 3X upper limit of normal (ULN); total bilirubin > 1.5X ULN; platelets < 75 X 10 ⁹ /L; neutrophils < 1.5 X 10 ⁹ /L; or hemoglobin < 8 g/dL.

In some embodiments, the FcRn antagonist is administered in a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered in a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 200 mg to 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 300 mg to 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered in an amount of about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 2500 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 70 00mg, about 8000mg, about 9000mg, about 10,000mg, about 11,000mg, about 12,000mg, about 13,000mg, about 14,000mg, about 15,000mg, about 16,000mg, about 17,000mg, about 18,000mg, about 19,000mg or about 20,000mg of fixed dose administration. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered at a fixed dose of 20 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 2500 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11,000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg or 20,000 mg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered at a dose of about 0.2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 120 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 3 mg/kg to about 60 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 10 mg/kg to about 25 mg/kg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered at a dose of 0.2 mg/kg to 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of about 2 mg/kg to about 200 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 2 mg/kg to 120 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 3 mg/kg to 60 mg/kg. In some embodiments, the FcRn antagonist is administered at a dose of 10 mg/kg to 25 mg/kg. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is present at about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12.5 mg/kg, about 15 mg/kg, about 17.5 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50mg/kg, about 55mg/kg, about 60mg/kg, about 65mg/kg, about 70mg/kg, about 75mg/kg, about 80mg/kg, about 85mg/kg, about 90mg/kg, about 95mg/kg, about 100mg/kg, about 110mg/kg, about 120mg/kg, about 130mg/kg, about 140mg/kg, about 150mg/kg, about 160mg/kg, about 170mg/kg, about 180mg/kg, about 190mg/kg or about 200mg/kg. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, the FcRn antagonist is administered at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 5 0mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg/kg, 100mg/kg, 110mg/kg, 120mg/kg, 130mg/kg, 140mg/kg, 150mg/kg, 160mg/kg, 170mg/kg, 180mg/kg, 190mg/kg or 200mg/kg. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 0.2 mg/kg to about 200 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg/kg to about 200 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 2 mg/kg to about 120 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 3 mg/kg to about 60 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is present at about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12.5 mg/kg, about 15 mg/kg, about 17.5 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg. , about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, about 95 mg/kg, about 100 mg/kg, about 110 mg/kg, about 120 mg/kg, about 130 mg/kg, about 140 mg/kg, about 150 mg/kg, about 160 mg/kg, about 170 mg/kg, about 180 mg/kg, about 190 mg/kg or about 200 mg/kg intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered at 0.2 mg/kg, 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55mg/kg, 60mg/kg, 65mg/kg, 70mg/kg, 75mg/kg, 80mg/kg, 85mg/kg, 90mg/kg, 95mg/kg, 100mg/kg, 110mg/kg, 120mg/kg, 130mg/kg, 140mg/kg, 150mg/kg, 160mg/kg, 170mg/kg, 180mg/kg, 190mg/kg or 200mg/kg is administered intravenously once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 30 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg to about 25 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 10 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 15 mg/kg, once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 20 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 25 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of about 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 25 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 15 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 20 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 25 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 30 mg/kg once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered intravenously once every two weeks for 52 weeks. In some embodiments, the FcRn antagonist is administered intravenously once every two weeks for 24 weeks. In some embodiments, the FcRn antagonist is administered intravenously once every two weeks for 36 weeks. In some embodiments, the FcRn antagonist is administered intravenously once every two weeks for 47 weeks. In some embodiments, the FcRn antagonist is administered intravenously once every week for 52 weeks. In some embodiments, the FcRn antagonist is administered intravenously once a week for 24 weeks. In some embodiments, the FcRn antagonist is administered intravenously once a week for 36 weeks. In some embodiments, the FcRn antagonist is administered intravenously once a week for 47 weeks. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered in an amount of about 20 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1500 mg, about 2000 mg, about 3000 mg, about 4000 mg, about 5000 mg, about 6000 mg, about 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about g, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about 15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg or about 20,000 mg of a fixed dose administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once a month or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 20 mg, 50 mg, 100 mg, 250 mg, 500 mg, 750 mg, 1000 mg, 1500 mg, 2000 mg, 3000 mg, 4000 mg, 5000 mg, 6000 mg, 7000 mg, 8000 mg, 9000 mg, 10,000 mg, 11,000 mg, 12,000 mg, 13,000 mg, 14,000 mg, 15,000 mg, 16,000 mg, 17,000 mg, 18,000 mg, 19,000 mg or 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 3000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg to about 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once every three weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a month. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg to 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is first administered subcutaneously twice on the same day at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg to about 1750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 800 mg to about 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 800 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1250 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1500 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1750 mg once a week. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 1750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 800 mg to 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 800 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1200 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1250 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1500 mg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1750 mg once a week. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg/kg to about 25 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 10 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 15 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 20 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of about 25 mg/kg once a week. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 10 mg/kg to 25 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 10 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 15 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 20 mg/kg once a week. In some embodiments, the FcRn antagonist is administered subcutaneously at a dose of 25 mg/kg once a week. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 100 mg to 10,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and then subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and a subsequent dose of the FcRn antagonist is administered subcutaneously, at a fixed dose of 100 mg to 10,000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously, with a fixed dose of 1000 mg or 2000 mg, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, the FcRn antagonist is administered for 6, 12, 24, 36, 39, 47, or 52 weeks or less. In some embodiments, the FcRn antagonist is administered for 24 weeks or less. In some embodiments, the FcRn antagonist is administered for 36 weeks or less. In some embodiments, the FcRn antagonist is administered for 47 weeks or less. In some embodiments, the FcRn antagonist is administered for 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 6, 12, 24, 36, 39, 47, or 52 weeks. In some embodiments, the FcRn antagonist is administered for at least 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 36 weeks. In some embodiments, the FcRn antagonist is administered for at least 47 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks.

In some embodiments, the FcRn antagonist is lorixizumab. In some embodiments, lorixizumab is administered subcutaneously or intravenously. In some embodiments, lorixizumab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41 mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg /kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, About 68mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76 mg/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every three weeks.

In some embodiments, loliximab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg g, about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, lorixizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63 mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76 mg/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the FcRn antagonist is nikalimab. In some embodiments, nikalimab is administered subcutaneously or intravenously. In some embodiments, nikalimab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg. , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every three weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, nikalimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the FcRn antagonist is oronorimab. In some embodiments, oronorimab is administered subcutaneously or intravenously. In some embodiments, oronorimab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, oronolimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, oronolimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, oronolizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every three weeks.

In some embodiments, oronolizumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, oronolimab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, oronorimab is administered intravenously at a dose of about 30 mg/kg once a week for three weeks, and then administered intravenously at a dose of 10 mg/kg every other week.

In some embodiments, the FcRn antagonist is Batolimumab. In some embodiments, Batolimumab is administered subcutaneously or intravenously. In some embodiments, Batolimumab is administered at a dose of about 0.2 mg/kg to about 200 mg/kg or at a fixed dose of about 20 mg to about 20,000 mg once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg. , about 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a week.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51 mg/kg, about 52 mg/kg, about 53 mg/kg, about 54 mg/kg, about 55 mg/kg, about 56 mg/kg, about 57 mg/kg, about 58 mg/kg, about 59 mg/kg, about 60 mg/kg, about 61 mg/kg, about 62 mg/kg, about 63 mg/kg, about 64 mg/kg, about 65 mg/kg, about 66 mg/kg, about 67 mg/kg, about 68mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every two weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96 mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once every three weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 4 2mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/k g, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76mg /kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg once every four weeks.

In some embodiments, Batolimumab is administered at about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 12.5 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, About 25mg/kg, about 26mg/kg, about 27mg/kg, about 28mg/kg, about 29mg/kg, about 30 mg/kg, about 31mg/kg, about 32mg/kg, about 33mg/kg, about 34mg/kg, about 35mg/kg, about 36mg/kg, about 37mg/kg, about 38mg/kg, about 39mg/kg, about 40mg/kg, about 41mg/kg, about 42mg/kg, about 43mg/kg, about 44mg/kg, about 45mg/kg, about 46mg/kg, about 47mg/kg, about 48mg/kg, about 49mg/kg, about 50mg/ kg, about 51mg/kg, about 52mg/kg, about 53mg/kg, about 54mg/kg, about 55mg/kg, about 56mg/kg, about 57mg/kg, about 58mg/kg, about 59mg/kg, about 60mg/kg, about 61mg/kg, about 62mg/kg, about 63mg/kg, about 64mg/kg, about 65mg/kg, about 66mg/kg, about 67mg/kg, about 6 8mg/kg, about 69mg/kg, about 70mg/kg, about 71mg/kg, about 72mg/kg, about 73mg/kg, about 74mg/kg, about 75mg/kg, about 76m g/kg, about 77mg/kg, about 78mg/kg, about 79mg/kg, about 80mg/kg, about 81mg/kg, about 82mg/kg, about 83mg/kg, about 84mg/kg, about 85mg/kg, about 86mg/kg, about 87mg/kg, about 88mg/kg, about 89mg/kg, about 90mg/kg, about 91mg/kg, about 92mg/kg, about 93mg/kg, about 94mg/kg, about 95mg/kg, about 96mg/kg, about 97mg/kg, about 98mg/kg, about 99mg/kg or about 100mg/kg is administered once a month.

In some embodiments, the method further comprises administering to the individual a compound designated as supportive therapy for pMN. In some embodiments, the compound designated as supportive therapy for pMN is a compound designated as best supportive therapy for pMN. In some embodiments, supportive therapy for pMN or best supportive therapy for pMN includes therapy for one or more of proteinuria, hypertension, or hyperlipidemia. In some embodiments, supportive therapy for pMN or best supportive therapy for pMN includes therapy for proteinuria, hypertension, and hyperlipidemia. In some embodiments, the method further comprises administering to the individual an effective amount of one or more of the following compounds: corticosteroids (e.g., glucocorticoids), diuretics, statins, anticoagulants, angiotensin converting enzyme inhibitors (ACEi), and angiotensin receptor blockers (ARBs).

In one embodiment, the method further comprises administering an ACEi and/or an ARB to the individual. In some embodiments, the ACEi and/or ARB is administered to the individual at a maximum tolerated dose. In some embodiments, the ACEi and/or ARB is administered to the individual at a maximum permitted dose. In some embodiments, the dose of the ACEi and/or ARB is maintained at a stable level during the FcRn antagonist treatment. In some embodiments, the method comprises administering an FcRn antagonist to the individual once a week and administering an ACEi and/or ARB to the individual at a maximum tolerated or permitted dose for at least 24 weeks.

In one embodiment, the method further comprises administering an effective amount of a glucocorticoid and/or an immunosuppressant to the individual. In one embodiment, the method further comprises administering an effective amount of a corticosteroid (e.g., a glucocorticoid) to the individual. In one embodiment, the method further comprises administering an effective amount of a corticosteroid to the individual for up to six months. In one embodiment, the method further comprises gradually reducing the dose of the corticosteroid after six months. In one embodiment, the method further comprises administering an effective amount of a corticosteroid intravenously to the individual and/or administering an effective amount of a corticosteroid orally to the individual. In one embodiment, the method further comprises administering an effective amount of a corticosteroid intravenously to the individual and administering an effective amount of a corticosteroid orally to the individual.

每天10mg普賴蘇穠的劑量將皮質類固醇投與個體。 In one embodiment, the method further comprises performing a

Corticosteroids are administered to individuals at a dose of 10 mg of pralidone per day.

In one embodiment, the method further comprises administering an effective amount of prazolone to the subject. In one embodiment, the method further comprises administering prazolone to the subject at a dose of 7.5 mg/day to 75 mg/day (up to 1 mg/kg/day). In one embodiment, the method further comprises administering prazolone to the subject at a dose of 8 mg/day to 72 mg/day (up to 1 mg/kg/day). In one embodiment, the method further comprises administering prazolone to the subject at a dose of 9 mg/day to 66 mg/day (up to 1 mg/kg/day). In one embodiment, the method further comprises administering prazolone to the subject at a dose of 10 mg/day to 60 mg/day (up to 1 mg/kg/day). In one embodiment, the method further comprises administering to the subject a dose of 0.5 mg/kg/day to 1 mg/kg/day of prazol. In one embodiment, the method further comprises administering to the subject a dose of 0.6 mg/kg/day to 1 mg/kg/day of prazol. In one embodiment, the method further comprises administering to the subject a dose of 0.6 mg/kg/day to 1 mg/kg/day of prazol (up to 80 mg/day). In one embodiment, prazol is administered orally.

In one embodiment, the method further comprises administering to the subject an effective amount of methylprednisolone. In one embodiment, the method further comprises administering to the subject methylprednisolone in an amount of 100 mg to 1250 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone in an amount of 150 mg to 1200 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone in an amount of 200 mg to 1100 mg for up to three days. In one embodiment, the method further comprises administering to the subject methylprednisolone in an amount of 500 mg to 1000 mg for up to three days. In one embodiment, the method further comprises administering methylprednisolone to the subject in an amount of 0.25 g/day to 0.5 g/day. In one embodiment, the method further comprises administering methylprednisolone to the subject in an amount of 0.25 g/day to 0.5 g/day for one to three days. In one embodiment, methylprednisolone is administered intravenously.

In one embodiment, the method further comprises administering to the individual an effective amount of prazolone orally and administering to the individual an effective amount of methylprednisolone intravenously. In one embodiment, the method further comprises administering to the individual a dose of 10 mg/day to 60 mg/day of prazolone orally (up to 1 mg/kg/day) and administering to the individual a dose of 500 mg to 1000 mg of methylprednisolone intravenously for up to three days. In one embodiment, the method further comprises administering to the individual a dose of 0.5 mg/kg/day to 1 mg/kg/day of prazolone orally and administering to the individual a dose of 500 mg to 1000 mg of methylprednisolone intravenously for up to three days. In one embodiment, the method further comprises orally administering to the subject a dose of 0.5 mg/kg/day to 1 mg/kg/day of prazolone daily or every other day for up to six months and administering 500 mg to 1000 mg of methylprednisolone intravenously for up to three days at the beginning of each month. In one embodiment, the method further comprises orally administering to the subject a dose of 0.5 mg/kg/day to 1 mg/kg/day of prazolone daily or every other day for up to six months and administering 500 mg to 1000 mg of methylprednisolone intravenously for up to three days at the beginning of every other month. In one embodiment, the method further comprises orally administering to the individual 0.5 mg/kg/day of prazolone daily or every other day for up to six months and administering intravenously 1000 mg of methylprednisolone for up to three days at the beginning of each month. In one embodiment, the method further comprises orally administering to the individual 0.5 mg/kg/day of prazolone daily or every other day for up to six months and administering intravenously 1000 mg of methylprednisolone for up to three days at the beginning of every other month.

In one embodiment, the method further comprises administering an effective amount of cyclophosphamide to the individual. In one embodiment, the method further comprises administering an effective amount of cyclophosphamide to the individual for up to six months. In one embodiment, the method further comprises administering cyclophosphamide to the individual at a dose of 1 mg/kg/day to 5 mg/kg/day. In one embodiment, the method further comprises administering cyclophosphamide to the individual at a dose of 1.5 mg/kg/day to 2.5 mg/kg/day. In one embodiment, the method further comprises administering cyclophosphamide to the individual at a dose of 1.5 mg/kg/day or 2.5 mg/kg/day.

In some embodiments, the method further comprises administering a cyclical treatment regimen of cyclophosphamide. In one embodiment, the cyclical treatment regimen is administered for up to six months. In one embodiment, an effective amount of cyclophosphamide is administered to the subject during alternate months. In one embodiment, an effective amount of a corticosteroid is administered to the subject during months when cyclophosphamide is not administered to the subject. In one embodiment, an effective amount of a corticosteroid is administered to the subject during months 1, 3, and 5 of the cyclical treatment regimen, and an effective amount of cyclophosphamide is administered to the subject during months 2, 4, and 6 of the cyclical treatment regimen. In one embodiment, the cyclical treatment regimen comprises administering cyclophosphamide to the subject at a dose of 2.5 mg/kg/day during the 2nd, 4th and 6th months. In one embodiment, the cyclical treatment regimen further comprises administering 0.5 mg/kg/day of prazolone to the subject during the 1st, 3rd and 5th months. In one embodiment, the cyclical treatment regimen further comprises administering 1000 mg of methylprednisolone intravenously at the beginning of the 1st, 3rd and 5th months for one to three days. In one embodiment, at the beginning of the 1st, 3rd and 5th months, 1000 mg of methylprednisolone is administered intravenously to the subject for three consecutive days.

In one embodiment, the method further comprises administering to the individual an effective amount of a calcineurin inhibitor. In one embodiment, the method further comprises administering to the individual an effective amount of tacrolimus. In one embodiment, the method further comprises administering to the individual tacrolimus, wherein the minimum level is about 3-8 ng/mL (3.7-9.9 nmol/L). In one embodiment, the method further comprises administering tacrolimus to the individual for 12 months, wherein the minimum level is about 3-8 ng/mL (3.7-9.9 nmol/L). In one embodiment, the method further comprises administering tacrolimus to the individual at a dose of 0.05-0.1 mg/kg/day. In one embodiment, the method further comprises administering tacrolimus to the individual at a dose of 0.05-0.1 mg/kg/day for 12 months. In one embodiment, the method further comprises administering to the individual an effective amount of tacrolimus and an effective amount of a corticosteroid. In one embodiment, the method further comprises administering to the individual a dose of 0.05-0.1 mg/kg/day of tacrolimus and a dose of 10 mg/day of prazolone. In one embodiment, the method further comprises administering to the individual a dose of 0.05-0.1 mg/kg/day of tacrolimus and a dose of 10 mg/day of prazolone for up to 12 months. In one embodiment, the method further comprises administering to the individual a dose of 0.05-0.1 mg/kg/day of tacrolimus and a dose of 10 mg/day of prazolone for 12 months. In one embodiment, the method further comprises administering to the individual a dose of 0.05-0.1 mg/kg/day of tacrolimus and a dose of 10 mg/day of prazol for 12 months, followed by a gradual reduction in the dose of tacrolimus and/or prazol. In one embodiment, the method further comprises administering to the individual an effective amount of cyclosporine. In one embodiment, the method further comprises administering to the individual cyclosporine, wherein the minimum level is about 125-225 ng/mL (104-187 nmol/L). In one embodiment, the method further comprises administering to the individual cyclosporine for 12 months, wherein the minimum level is about 125-225 ng/mL (104-187 nmol/L). In one embodiment, the method further comprises administering cyclosporine to the individual at a dose of 3.5 mg/kg/day. In one embodiment, the method further comprises administering cyclosporine to the individual at a dose of 3.5 mg/kg/day for 12 months. In one embodiment, the method further comprises administering to the individual an effective amount of cyclosporine and an effective amount of a corticosteroid. In one embodiment, the method further comprises administering to the individual cyclosporine at a dose of 3.5 mg/kg/day and 10 mg/day of prasona. In one embodiment, the method further comprises administering to the individual cyclosporine at a dose of 3.5 mg/kg/day and 10 mg/day of prasona for up to 12 months. In one embodiment, the method further comprises administering 3.5 mg/kg/day of cyclosporine and 10 mg/day of prasona to the individual for 12 months. In one embodiment, the method further comprises administering 3.5 mg/kg/day of cyclosporine and 10 mg/day of prasona to the individual for 12 months, followed by a gradual reduction in the dose of cyclosporine and/or prasona.

In one embodiment, the method further comprises administering to the individual an effective amount of mycophenolic acid morpholinate (MMF), mycophenolic acid (MPA) or an analog thereof.

In one embodiment, the method further comprises administering to the individual an effective amount of a B lymphocyte-targeted biologic. Examples of B lymphocyte-targeted biologics include, but are not limited to, belimumab, rituximab, and obinutuzumab. In one embodiment, the method further comprises administering to the individual an effective amount of rituximab. In one embodiment, the method further comprises administering rituximab to the individual twice within 2 weeks at a dose of 1 g. In one embodiment, the method further comprises administering rituximab twice within 2 weeks at a dose of 1 g to the individual; for individuals with persistent nephrotic syndrome, stable eGFR, and/or if anti-PLA2R antibodies remain positive after the first administration of rituximab, then further administering rituximab twice within 2 weeks of the sixth month after the first administration. In one embodiment, the method further comprises administering an effective amount of Oligizumab to the individual.

In some embodiments, the FcRn antagonist is administered intravenously once a week in conjunction with best supportive care. In some embodiments, the FcRn antagonist is administered intravenously once a week for 24 weeks in conjunction with best supportive care. In some embodiments, best supportive care comprises administration of an effective amount of one or more of an ACEi or ARB, a statin, and a diuretic. In some embodiments, the FcRn antagonist is efatimod.

In one embodiment, the subject is pre-treated with ACEi and/or ARB. In one embodiment, the subject is pre-treated with ACEi and/or ARB for at least 12 weeks prior to administration of the FcRn antagonist. In one embodiment, the subject is pre-treated with a stable dose of ACEi and/or ARB for at least 12 weeks prior to administration of the FcRn antagonist. In one embodiment, the subject is pre-treated with a maximum tolerated stable dose of ACEi and/or ARB for at least 12 weeks prior to administration of the FcRn antagonist. In one embodiment, the subject is pre-treated with a maximum allowed stable dose of ACEi and/or ARB for at least 12 weeks prior to administration of the FcRn antagonist. In one embodiment, the method comprises administering to a subject an FcRn antagonist and an ACEi and/or an ARB.

In some embodiments, pMN therapy is characterized by a subject exhibiting a UPCR of at most 0.5 mg/mg. In some embodiments, a subject exhibits a UPCR of at most 0.45 mg/mg, 0.4 mg/mg, 0.35 mg/mg, 0.3 mg/mg, 0.25 mg/mg, 0.2 mg/mg, 0.15 mg/mg, 0.1 mg/mg. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of efatimod.

In some embodiments, pMN therapy is characterized by a decrease in UPCR of the individual by at least 50% compared to a baseline UPCR obtained in the individual prior to administration of the FcRn antagonist. In some embodiments, pMN therapy is characterized by a decrease in UPCR of the individual by at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% compared to a baseline UPCR obtained in the individual prior to administration of the FcRn antagonist. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of efatimod.

In some embodiments, pMN therapy is characterized by the individual achieving a CR. In some embodiments, pMN therapy is characterized by the individual achieving a CR within 24 weeks after treatment. In some embodiments, pMN therapy is characterized by the individual achieving a CR within 36 weeks after treatment. In some embodiments, pMN therapy is characterized by the individual achieving a CR within 48 weeks after treatment. In some embodiments, pMN therapy is characterized by the individual achieving a CR within 52 weeks after treatment. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of efatimod.

In some embodiments, pMN therapy is characterized by a subject achieving a PR. In some embodiments, pMN therapy is characterized by a subject achieving a PR within 24 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a PR within 36 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a PR within 48 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a PR within 52 weeks after treatment. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of efatimod.

In some embodiments, pMN therapy is characterized by a subject achieving a CR or PR. In some embodiments, pMN therapy is characterized by a subject achieving a CR or PR within 24 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a CR or PR within 36 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a CR or PR within 48 weeks after treatment. In some embodiments, pMN therapy is characterized by a subject achieving a CR or PR within 52 weeks after treatment. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of efatimod.

0.3g/24小時之蛋白尿。在一些實施例中，pMN療法的特徵為個體展現

0.25g/24小時、

0.2g/24小時、

0.15g/24小時之蛋白尿。在一些實施例中，治療係投與有效量之FcRn拮抗劑。在一些實施例中，治療係投與有效量之依加替莫德。 In some embodiments, pMN therapy is characterized by individuals showing

0.3 g/24 hours of proteinuria. In some embodiments, pMN therapy is characterized by an individual exhibiting

0.25g/24 hours,

0.2g/24 hours,

0.15 g/24 hours of proteinuria. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of elgativmod.

In some embodiments, pMN therapy is characterized by a decrease in proteinuria of the individual by at least 50% compared to a baseline proteinuria obtained in the individual prior to administration of the FcRn antagonist. In some embodiments, pMN therapy is characterized by a decrease in proteinuria of the individual by at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% compared to a baseline proteinuria obtained in the individual prior to administration of the FcRn antagonist. In some embodiments, treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, treatment is administration of an effective amount of efatimod.

3.5g/24小時的個體。在一些實施例中，pMN療法的特徵為相較於基線蛋白尿，個體的蛋白尿展現至少50%的降幅，該基線蛋白尿獲自FcRn拮抗劑投與之前且展現蛋白尿>0.3且

3g/24小時、>0.3且

2.5g/24小時、>0.3且

2g/24小時、>0.3且

1.5g/24小時、>0.3且

1g/24小時、>0.3且

0.5g/24小時的個體。在一些實施例中，pMN療法的特徵為相較於基線蛋白尿，個體的蛋白尿展現至少50%的降幅，該基線蛋白尿獲自FcRn拮抗劑投與之前且展現蛋白尿>0.4且

3.5g/24小時、>0.5且

3.5g/24小時、>0.75且

3.5g/24小時、>1且

3.5g/24小時、>1.5且

3.5g/24小時、>2且

3.5g/24小時、>2.5且

3.5g/24 小時、>3且

3.5g/24小時的個體。在一些實施例中，治療係投與有效量之FcRn拮抗劑。在一些實施例中，治療係投與有效量之依加替莫德。 In some embodiments, pMN therapy is characterized by a decrease in proteinuria of at least 50% in the subject compared to baseline proteinuria obtained prior to administration of the FcRn antagonist and exhibiting proteinuria > 0.3 and

In some embodiments, pMN therapy is characterized by a decrease in proteinuria of at least 50% compared to baseline proteinuria obtained prior to administration of the FcRn antagonist and exhibiting proteinuria > 0.3 and

3g/24 hours, >0.3 and

2.5g/24 hours, >0.3 and

2g/24 hours, >0.3 and

1.5g/24 hours, >0.3 and

1g/24 hours, >0.3 and

In some embodiments, pMN therapy is characterized by a decrease in proteinuria of at least 50% compared to baseline proteinuria obtained prior to administration of the FcRn antagonist and exhibiting proteinuria > 0.4 and

3.5g/24 hours, >0.5 and

3.5g/24 hours, >0.75 and

3.5g/24 hours, >1 and

3.5g/24 hours, >1.5 and

3.5g/24 hours, >2 and

3.5g/24 hours, >2.5 and

3.5g/24 hours, >3 and

3.5 g/24 hours for an individual. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of efatimod.

3.5g/dL。在一些實施例中，pMN療法的特徵為個體展現血清白蛋白

3.6g/dL、

3.7g/dL、

3.8g/dL、

3.9g/dL、

4g/dL、

4.1g/dL、

4.2g/dL、

4.3g/dL、

4.4g/dL、

4.5g/dL、

4.6g/dL、

4.7g/dL、

4.8g/dL、

4.9g/dL、

5.0g/dL、

5.1g/dL、

5.2g/dL、

5.3g/dL、

5.4g/dL。在一些實施例中，pMN療法的特徵為個體展現3.5-5.5g/dL的血清白蛋白。在一些實施例中，治療係投與有效量之FcRn拮抗劑。在一些實施例中，治療係投與有效量之依加替莫德。 In some embodiments, pMN therapy is characterized by a subject exhibiting serum albumin

3.5 g/dL. In some embodiments, pMN therapy is characterized by an individual exhibiting serum albumin

3.6 g/dL,

3.7 g/dL,

3.8 g/dL,

3.9 g/dL,

4 g/dL,

4.1 g/dL,

4.2 g/dL,

4.3 g/dL,

4.4 g/dL,

4.5 g/dL,

4.6 g/dL,

4.7 g/dL,

4.8 g/dL,

4.9 g/dL,

5.0 g/dL,

5.1 g/dL,

5.2 g/dL,

5.3 g/dL,

In some embodiments, pMN therapy is characterized by the subject exhibiting serum albumin of 3.5-5.5 g/dL. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of efatimod.

In some embodiments, pMN therapy is characterized by the individual exhibiting an eGFR of at least 25 mL/min/1.73 m ² . In some embodiments, the subject exhibits at least 30 mL/min/1.73 m ² , at least 35 mL/min/1.73 m ² , at least 40 mL/min/1.73 m ² , at least 45 mL/min/1.73 m ² , at least 50 mL/min/1.73 m ² , at least 55 mL/min/1.73 m ² , at least 60 mL/min/1.73 m ² , at least 65 mL/min/1.73 m ² , at least 70 mL/min/1.73 m ² , at least 75 mL/min/1.73 m ² , at least 80 mL/min/1.73 m ² , at least 85 mL/min/1.73 m ² , at least 90 mL/min/1.73 m ² , at least 95 mL/min/1.73 m ² , at least 100 mL/min/1.73 m ² , at least 105 mL/min/1.73 m ² , at least 110 mL/min/1.73 m ² , at least 115 mL/min/1.73 m ² , at least 120 mL/min/1.73 m ^2. In some embodiments, the subject exhibits an eGFR of at least 60 mL/min/1.73 m ^2. In some embodiments, pMN therapy is characterized by the subject exhibiting a decrease in eGFR of less than 20% compared to a baseline eGFR obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the subject's eGFR exhibits a decrease of less than 15%, less than 10%, less than 5%, less than 1% compared to a baseline eGFR obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of elgativimud.

In some embodiments, the pMN therapy is characterized by a reduction in circulating immune complexes. In some embodiments, the circulating immune complexes are selected from the group consisting of C3, C4, CH50, and C1q-bound circulating immune complexes. In some embodiments, the prevalence of circulating immune complexes is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% after administration of one or more therapies described herein. In some embodiments, circulating immune complexes are undetectable in the subject after administration of one or more therapies described herein. In some embodiments, the treatment is administration of an effective amount of an FcRn antagonist. In some embodiments, the treatment is administration of an effective amount of elgativmod.

In some embodiments, after the FcRn antagonist is administered to the subject, the subject exhibits a post-dose UPCR of at most 0.5 mg/mg. In some embodiments, after the FcRn antagonist is administered to the subject, the subject exhibits a post-dose UPCR of at most 0.45 mg/mg, 0.4 mg/mg, 0.35 mg/mg, 0.3 mg/mg, 0.25 mg/mg, 0.2 mg/mg, 0.15 mg/mg, 0.1 mg/mg. In some embodiments, after the FcRn antagonist is administered to the subject, the subject exhibits a post-dose UPCR that is at least 50% lower than the baseline UPCR obtained from the subject before the FcRn antagonist is administered. In some embodiments, after the FcRn antagonist is administered to the individual, the individual exhibits a post-dose UPCR that is at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80% lower than the baseline UPCR obtained by the individual before the FcRn antagonist was administered. In some embodiments, the post-dose UPCR is measured at the 24th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose UPCR is measured at the 36th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose UPCR is measured at the 48th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose UPCR is measured at the 52nd week after the FcRn antagonist is administered to the individual. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, after the FcRn antagonist is administered to the subject, the subject achieves CR. In some embodiments, the post-dose CR is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose CR is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose CR is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose CR is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after the FcRn antagonist is administered to the subject, the subject achieves a PR. In some embodiments, the post-administration PR is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the post-administration PR is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the post-administration PR is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the post-administration PR is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after the FcRn antagonist is administered to the subject, the subject achieves a CR or PR. In some embodiments, the CR or PR after administration is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the CR or PR after administration is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the CR or PR after administration is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the CR or PR after administration is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

0.3g/24小時的蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後，該個體展現

0.25g/24小時、

0.2g/24小時、

0.15g/24小時的蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第36週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第48週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第52週量測投藥後蛋白尿。在一些實施例中，FcRn拮抗劑係依加替莫德。 In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits

0.25g/24 hours,

0.2g/24 hours,

In some embodiments, post-dose proteinuria is measured at 24 weeks after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at 36 weeks after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at 48 weeks after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at 52 weeks after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, following administration of the FcRn antagonist to the subject, the subject exhibits at least a 50% reduction in proteinuria compared to a baseline proteinuria obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, pMN therapy is characterized by a subject exhibiting at least a 25%, at least a 30%, at least a 35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, at least a 75%, at least a 80% reduction in proteinuria compared to a baseline proteinuria obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, post-dose proteinuria is measured at week 24 following administration of the FcRn antagonist to the subject. In some embodiments, post-dose proteinuria is measured at week 36 after administration of the FcRn antagonist to the subject. In some embodiments, post-dose proteinuria is measured at week 48 after administration of the FcRn antagonist to the subject. In some embodiments, post-dose proteinuria is measured at week 52 after administration of the FcRn antagonist to the subject. In some embodiments, the FcRn antagonist is efatimod.

3.5g/24小時。在一些實施例中，在FcRn拮抗劑投與個體之後，該個體的蛋白尿相較於基線蛋白尿展現至少50%的降幅， 該基線蛋白尿獲自FcRn拮抗劑投與之前且展現蛋白尿>0.3且

3g/24小時、>0.3且

2.5g/24小時、>0.3且

2g/24小時、>0.3且

1.5g/24小時、>0.3且

1g/24小時、>0.3且

0.5g/24小時的個體。在一些實施例中，在FcRn拮抗劑投與個體之後，該個體的蛋白尿相較於基線蛋白尿展現至少50%的降幅，該基線蛋白尿獲自FcRn拮抗劑投與之前且展現蛋白尿>0.4且

3.5g/24小時、>0.5且

3.5g/24小時、>0.75且

3.5g/24小時、>1且

3.5g/24小時、>1.5且

3.5g/24小時、>2且

3.5g/24小時、>2.5且

3.5g/24小時、>3且

3.5g/24小時的個體。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第36週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第48週量測投藥後蛋白尿。在一些實施例中，在FcRn拮抗劑投與個體之後的第52週量測投藥後蛋白尿。在一些實施例中，FcRn拮抗劑係依加替莫德。 In some embodiments, after administration of an FcRn antagonist to a subject, the subject's proteinuria exhibits a decrease of at least 50% compared to baseline proteinuria obtained from the subject prior to administration of the FcRn antagonist and exhibiting proteinuria > 0.3 and

In some embodiments, after administration of an FcRn antagonist to a subject, the subject's proteinuria exhibits a decrease of at least 50% compared to baseline proteinuria obtained prior to administration of the FcRn antagonist and exhibiting proteinuria>0.3 and

3g/24 hours, >0.3 and

2.5g/24 hours, >0.3 and

2g/24 hours, >0.3 and

1.5g/24 hours, >0.3 and

1g/24 hours, >0.3 and

In some embodiments, after administration of the FcRn antagonist to the subject, the subject's proteinuria exhibits a decrease of at least 50% compared to baseline proteinuria obtained prior to administration of the FcRn antagonist and exhibiting proteinuria>0.4 and

3.5g/24 hours, >0.5 and

3.5g/24 hours, >0.75 and

3.5g/24 hours, >1 and

3.5g/24 hours, >1.5 and

3.5g/24 hours, >2 and

3.5g/24 hours, >2.5 and

3.5g/24 hours, >3 and

3.5 g/24 hours. In some embodiments, post-dose proteinuria is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, post-dose proteinuria is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

3.5g/dL的血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後，該個體展現血清白蛋白

3.6g/dL、

3.7g/dL、

3.8g/dL、

3.9g/dL、

4g/dL、

4.1g/dL、

4.2g/dL、

4.3g/dL、

4.4g/dL、

4.5g/dL、

4.6g/dL、

4.7g/dL、

4.8g/dL、

4.9g/dL、

5.0g/dL、

5.1g/dL、

5.2g/dL、

5.3g/dL、

5.4g/dL。 在一些實施例中，在FcRn拮抗劑投與個體之後，該個體展現3.5至5.5g/dL的血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後的第24週量測投藥後血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後的第36週量測投藥後血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後的第48週量測投藥後血清白蛋白。在一些實施例中，在FcRn拮抗劑投與個體之後的第52週量測投藥後血清白蛋白。在一些實施例中，FcRn拮抗劑係依加替莫德。 In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits

3.5 g/dL of serum albumin. In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits serum albumin

3.6 g/dL,

3.7 g/dL,

3.8 g/dL,

3.9 g/dL,

4 g/dL,

4.1 g/dL,

4.2 g/dL,

4.3 g/dL,

4.4 g/dL,

4.5 g/dL,

4.6 g/dL,

4.7 g/dL,

4.8 g/dL,

4.9 g/dL,

5.0 g/dL,

5.1 g/dL,

5.2 g/dL,

5.3 g/dL,

In some embodiments, after the FcRn antagonist is administered to the subject, the subject exhibits 3.5 to 5.5 g/dL of serum albumin. In some embodiments, the post-dose serum albumin is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose serum albumin is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose serum albumin is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose serum albumin is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits an eGFR of at least 60 mL/min/1.73 m ^2. In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose eGFR that is less than 20% lower than the baseline eGFR obtained by the subject before administration of the FcRn antagonist. In some embodiments, the post-dose eGFR is measured at week 24 after administration of the FcRn antagonist to the subject. In some embodiments, the post-dose eGFR is measured at week 36 after administration of the FcRn antagonist to the subject. In some embodiments, the post-dose eGFR is measured at week 48 after administration of the FcRn antagonist to the subject. In some embodiments, post-administration eGFR is measured at week 52 following administration of the FcRn antagonist to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after administration of the FcRn antagonist to the subject, the subject exhibits a post-dose EuroQoL 5-dimension 5-grade (EQ5D-5L) score that is reduced compared to the baseline EQ5D-5L score obtained for the subject before administration of the FcRn antagonist. In some embodiments, the post-dose EQ5D-5L score is measured at week 24 after administration of the FcRn antagonist to the subject. In some embodiments, the post-dose EQ5D-5L score is measured at week 36 after administration of the FcRn antagonist to the subject. In some embodiments, the post-dose EQ5D-5L score is measured at week 48 after administration of the FcRn antagonist to the subject. In some embodiments, the post-dose EQ5D-5L score is measured at week 52 after administration of the FcRn antagonist to the subject. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, after the FcRn antagonist is administered to the individual, the individual exhibits a post-dose patient reported outcome information system (PROMIS) score that is reduced compared to the baseline PROMIS score obtained from the individual before the FcRn antagonist is administered. In some embodiments, the post-dose PROMIS score is measured at the 24th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose PROMIS score is measured at the 36th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose PROMIS score is measured at the 48th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose PROMIS score is measured at the 52nd week after the FcRn antagonist is administered to the individual. In some embodiments, the FcRn antagonist is egatimod.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration serum autoantibody level that is reduced compared to a baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum autoantibody level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to a baseline level of serum autoantibodies obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the post-administration serum autoantibody level is measured at week 24 after administration of the FcRn antagonist to the subject. In some embodiments, the post-administration serum autoantibody level is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the post-administration serum autoantibody level is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the post-administration serum autoantibody level is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the serum autoantibody is selected from the group consisting of anti-PLA2R, anti-THSD7A, anti-NELL-1, and anti-Sema3B. In some embodiments, the serum autoantibody is anti-PLA2R. In some embodiments, the FcRn antagonist is igatimod.

In some embodiments, after the FcRn antagonist is administered to a subject, the subject exhibits a post-administration serum complement level that is reduced compared to the baseline serum complement level obtained from the subject before the FcRn antagonist is administered. In some embodiments, the post-administration serum complement level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or 100% compared to the baseline serum complement level obtained from the subject before the FcRn antagonist is administered. In some embodiments, the post-administration serum complement level is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the serum complement level after administration is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the serum complement level after administration is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the serum complement level after administration is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the serum complement is selected from the group consisting of: circulating immune complexes bound by C3, C4, CH50, and C1q. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after administration of an FcRn antagonist to a subject, the subject exhibits a post-administration circulating immune complex level that is reduced compared to a baseline level of circulating immune complexes obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the circulating immune complexes are selected from the group consisting of C3, C4, CH50, and C1q-bound circulating immune complexes. In some embodiments, the post-administration circulating immune complex level is reduced by at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% compared to a baseline level of circulating immune complexes obtained from the subject prior to administration of the FcRn antagonist. In some embodiments, the circulating immune complex content is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the circulating immune complex content is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the circulating immune complex content is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the circulating immune complex content is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is Egativimud.

In some embodiments, after the FcRn antagonist is administered to the individual, the individual exhibits a post-dose serum IgG level that is reduced compared to the baseline serum IgG level obtained from the individual before the FcRn antagonist is administered. In some embodiments, the post-dose serum IgG level is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% compared to the baseline serum IgG level obtained from the individual before the FcRn antagonist is administered. In some embodiments, the post-dose serum IgG level is measured at the 24th week after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose serum IgG level is measured at the 36th week after the FcRn antagonist is administered to the individual. In some embodiments, the serum IgG level after administration of the FcRn antagonist is measured at week 48 after the individual is administered. In some embodiments, the serum IgG level after administration of the FcRn antagonist is measured at week 52 after the individual is administered. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after the FcRn antagonist is administered to the individual, the albumin level of the individual after the FcRn antagonist is not reduced compared to the albumin baseline level. In some embodiments, after the FcRn antagonist is administered to the individual, the individual exhibits a post-dose albumin level that is not reduced compared to the albumin baseline level obtained from the individual before the FcRn antagonist is administered. In one embodiment, a decrease in albumin of less than about 1%, 2%, 3%, 4% or 5% is observed compared to the baseline albumin level. In one embodiment, a decrease in albumin of less than about 10% is observed compared to the baseline albumin level. In some embodiments, the post-dose albumin level is measured at week 24 after the FcRn antagonist is administered to the individual. In some embodiments, the post-dose albumin level is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose albumin level is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the post-dose albumin level is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In some embodiments, after administration of an FcRn antagonist to an individual, the serum albumin level of the individual after administration of the FcRn antagonist is not reduced compared to the serum albumin baseline level. In some embodiments, after administration of an FcRn antagonist to an individual, the individual exhibits a post-administration serum albumin level that is not reduced compared to the serum albumin baseline level obtained from the individual before administration of the FcRn antagonist. In one embodiment, a decrease in serum albumin of less than about 1%, 2%, 3%, 4% or 5% is observed compared to the baseline serum albumin level. In one embodiment, a decrease in serum albumin of less than about 10% is observed compared to the baseline serum albumin level. In some embodiments, the serum albumin level after administration is measured at week 24 after the FcRn antagonist is administered to the subject. In some embodiments, the serum albumin level after administration is measured at week 36 after the FcRn antagonist is administered to the subject. In some embodiments, the serum albumin level after administration is measured at week 48 after the FcRn antagonist is administered to the subject. In some embodiments, the serum albumin level after administration is measured at week 52 after the FcRn antagonist is administered to the subject. In some embodiments, the FcRn antagonist is efatimod.

In one embodiment, the individual is any human or non-human animal. In one embodiment, the individual is a human or a non-human mammal. In one embodiment, the individual is a human. In one embodiment, the individual is of Asian descent.

Examples

The following examples are provided by way of illustration and not limitation.

Example 1: Study on the efficacy of igatimod in reducing circulating immune complexes

Immune complexes are found in healthy individuals, but their formation is expected to be elevated in autoimmune diseases and in part drive and/or amplify their pathology. Egaltimod is an engineered Fc fragment that inhibits FcRn function by outcompeting endogenous IgG for binding, resulting in decreased IgG circulation and increased IgG degradation. Since the half-life of immune complexes containing mainly IgG can also be biologically affected by FcRn, circulating immune complex (CIC) levels were studied in participants with mild to moderate pemphigus vulgaris (PV) or pemphigus foliaceus (PF) as part of an open-label, adaptive phase 2 trial of extended ergacimod treatment (ClinicalTrials.gov: NCT03334058; Maho-Vaillant M et al., Front Immunol (2022). 13: 863095). Briefly, seven participants in cohort 3 (7 PV) were treated for 15 weeks, and 15 participants in cohort 4 (8 PV, 7 PF) were treated for up to 34 weeks, as previously reported (Goebeler M et al., Br J Dermatol (2021) 186(3): 429-39). PV or PF diagnosis was confirmed by positive direct immunofluorescence and positive indirect immunofluorescence and/or Dsg-1/3 ELISA. Participants were newly diagnosed or relapsed, with mild to moderate disease severity (pemphigoid disease area index [PDAI] <45 at baseline). The treatment period was preceded by a screening period of up to 3 weeks and followed by a 10-week treatment-free follow-up period. In Cohort 3, 10 mg/kg of elgativimud was administered intravenously (IV) weekly for 4 weeks as an induction period, followed by every other week for 12 weeks as a maintenance period. In Cohort 3, elgativimud was initially administered as monotherapy or in combination with 20 mg of prazol per day at the discretion of the investigator, and prazol was tapered from the start of the maintenance period. In Cohort 4, 25 mg of efatimod per kg of body weight was administered intravenously weekly until EoC, defined as the time when no new lesions appeared for a minimum of 2 weeks and the majority (i.e., about 80%) of established lesions had healed. Thereafter, participants were dosed every other week. In Cohort 4, all newly diagnosed participants and participants who relapsed after completion of treatment were initially dosed with efatimod and prazol (20 mg per day) or at a gradually decreasing dose at the time of relapse. The oral dose of prazol may be gradually reduced until EoC. Other systemic treatments for pemphigus were not allowed during the study period, but topical corticosteroids, analgesics, and supportive care for corticosteroid therapy (e.g., vitamin D, proton pump inhibitors, and specific diets) were allowed.

4.0mg Eq/ml，則視為臨床上顯著的。 CIC inhibition was measured in six participants with PV and six participants with PF in Cohorts 3 and 4 who had received extended igatimod treatment and achieved a sustained clinical response. These participants were analyzed for IgG CIC by C1q ELISA, which detects complement-immobilized IgG antibodies (information on the antigenic specificity of CIC was not provided). Briefly, the C1q-related IgG aggregate levels in the sera of the selected participants at different time points were detected using the CIC-C1q EIA kit (A001, Quidel) according to the manufacturer's protocol. The calibrator provided in the kit was used to determine the expression level. If the IgG CIC level

4.0mg Eq/ml is considered clinically significant.

Four participants had elevated CIC levels at baseline, but during igatimod treatment, a significant reduction in CIC was observed ( Figure 1 ), which was consistent with the observed improvement in their clinical symptoms. This demonstrates that igatimod treatment reduces CIC in patients with pemphigus.

Case 2: Study on the efficacy and safety of efatimod in Chinese patients with primary membranous nephropathy (pMN)

pMN, an immune-mediated glomerular disease, is one of the most common causes of primary nephrotic syndrome in adults. It is a slightly male-predominant disease that occurs more often in the elderly. Although approximately 30 to 35% of pMN patients experience spontaneous remission, for most patients, the disease course is long and relatively difficult to treat. Approximately 30 to 40% of patients eventually develop kidney failure within 5 to 15 years, requiring dialysis or kidney transplantation. In the Caucasian population, pMN accounts for approximately 30 to 40% of primary nephrotic syndrome, with a peak age of onset of 40 to 50 years. In China, the incidence of pMN has recently increased significantly in renal biopsy cases. According to reports, the incidence of MN has almost doubled from 10.4% (2003-2006) to 24.1% (2011-2014). Based on data calibration, it was found that MN increases by 13% each year, and its incidence tends to exceed that of IgA nephropathy.

The clinical manifestations of pMN typically involve features of the nephrotic syndrome: heavy proteinuria, hypoalbuminemia, edema or generalized edema, hyperlipidemia, and lipuria. These features tend to develop slowly and can be overlooked for months. In the earliest stages, pMN can have an indolent course. Conceptually, this is attributed to the gradual but progressive growth of immune deposits and the resulting podocyte damage. Proteinuria typically persists at subclinical levels for months to even years before diagnosis. The degree of proteinuria at presentation can vary, ranging from subnephrotic to over 20 g/day. Hyperlipidemia is common in the presence of nephrotic-range proteinuria. In 70% of patients, blood pressure is normal at presentation, and most patients maintain their glomerular filtration rate (GFR). However, the longer proteinuria persists, the higher the chance of a reduced GFR. Venous thromboembolic events may be present and may be the initial cause for clinical concern.

The main pathological feature of pMN is the presence of immune deposits containing immunoglobulins and complement bodies in a subepithelial location. Podocyte antigens are most commonly involved in immune deposits, and IgG4 is usually the most prominent subtype of IgG deposited in pMN. Activation of these immune deposits and complement bodies leads to damage to the glomerular filtration membrane and the formation of proteinuria. The discovery of the major antigen, M-type phospholipase A2 receptor (PLA2R), has significantly enhanced the understanding of the mechanism of pMN. PLA2R is a 180 kDa transmembrane glycoprotein expressed by human podocytes, and its exact function is still unclear. Autoantibodies against PLA2R may be the cause of pMN in up to 75% of patients. Data clearly indicate a causal relationship between anti-PLA2R antibodies and the pathogenesis of pMN. Anti-PLA2R antibodies correlate with disease activity, thus providing prognostic information about disease severity and serving as a useful marker for assessing treatment efficacy. Other target antigens identified in pMN to date include thrombospondin type 1 domain-containing 7A (THSD7A), neuroepidermal growth factor-like 1 (NELL-1), and semaphorin-3B (Sema3B). In 10-20% of cases, there are still uncharacterized antigens.

6個月。 For patients with MN, the risk of progressive renal loss is assessed using clinical and laboratory criteria. Key determinants include renal function, persistent proteinuria, and antibody biomarkers in serum or urine, such as anti-PLA2R antibodies, IgG, etc. Best supportive care is recommended for all patients with pMN and proteinuria. Best supportive care includes but is not limited to the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARBs) to reduce proteinuria, statins to reduce cholesterol, and/or antiplatelet adhesion agents or anticoagulant therapy to prevent thrombosis, especially renal venous thrombosis. For patients with pMN who are at higher risk of disease progression, immunosuppressive therapy is recommended, including rituximab or cyclophosphamide and monthly glucocorticoids for 6 months, or CNI-based therapy for

6 months.

Neonatal Fc receptors (FcRn) maintain constant levels of IgG in serum by rescuing IgG antibodies from lysosomal degradation after absorption into cells. Given the mechanism of action of igatimod in reducing IgG levels, igatimod may benefit patients with pMN. In addition, igatimod has been shown to reduce circulating immune complexes in patients with pemphigus (Example 1; Figure 1 ). Since subepithelial deposition of immune complexes is a major pathological feature of pMN, this provides further proof of concept for the use of igatimod in the treatment of pMN and/or prevention of the onset or progression of pMN.

A. Research Design

Overall design

This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of intravenous igatimod in Chinese pMN patients.

The study includes a screening period of up to 4 weeks, a treatment period of 24 weeks, and a follow-up period of 8 weeks. The expected study duration for each individual participant is approximately 9 months.

50RU/mL；2)抗PLA2R抗體呈血清陰性的群體-至多12位參與者，其抗PLA2R抗體在篩檢時<2RU/mL且其先前無與抗PLA2R抗體相關之MN的病史。 Up to 72 participants who met eligibility criteria during the screening period were randomized in a 1:1 ratio to receive weekly administration of intravenous egatimod or placebo for 24 weeks, both in combination with best supportive care (e.g., ACEi or ARB, statins, diuretics). Participants included the entire study population and consisted of the following two subpopulations: 1) Anti-PLA2R antibody serum positive group - a total of 60 participants whose anti-PLA2R antibodies were positive at screening

50RU/mL; 2) Anti-PLA2R antibody seronegative group - up to 12 participants whose anti-PLA2R antibodies were <2RU/mL at screening and who had no previous history of MN associated with anti-PLA2R antibodies.

50RU/mL；及血清陰性：抗PLA2R<2RU/mL)進行分層。另外，抗PLA2R抗體呈血清陽性的參與者將另外根據基線時的蛋白尿含量(

8g/24小時及>8g/24小時)進行分層。基線定義為活動時程(表S2)中所排定之第1天執行評估的結果。 Randomization was based on anti-PLA2R antibody status at screening (serum positive: anti-PLA2R

50RU/mL; and serum negative: anti-PLA2R <2RU/mL). In addition, participants with serum positive anti-PLA2R antibodies will be further divided according to the baseline proteinuria level (

Baseline was defined as the assessment performed on day 1 as scheduled in the activity schedule ( Table S2 ).

The primary endpoint was the change in UPCR from baseline to week 24 in the anti-PLA2R antibody serum-positive population. Secondary endpoints included other efficacy indicators, PK, PD, immunogenicity, biomarkers, safety, and quality of life ( see Table S3 ).

Participants who fail treatment at any time will discontinue the IMP and receive appropriate rescue therapy based on clinical judgment. Participants who permanently discontinue the IMP are encouraged to remain in the study and attend any scheduled visits, even if only by telephone.

After the Week 24 visit, eligible participants (i.e., those who did not meet the protocol-defined treatment failure criteria and who had signed informed consent for the OLE period) could choose to move to an open-label extension (OLE) period, which was conducted as appropriate, to assess the long-term safety of efatimod in this patient population. Participants who did not participate in the OLE period remained in the main study for an 8-week safety follow-up.

Selection of main indicators

The reduction in proteinuria from baseline to week 24 in the anti-PLA2R antibody serum positive group was selected as the primary endpoint. Regular monitoring of proteinuria (UPCR or 24-hour urine collection) is recommended and the efficacy of immunosuppressive therapy is evaluated according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Proteinuria is a parameter that is closely related to disease progression and is expected to provide a sensitive and objective way to measure treatment efficacy (compared to baseline). The reduction in proteinuria is a surrogate marker for improved renal outcomes. Therefore, proteinuria and UPCR are suitable parameters for evaluating treatment efficacy and are preferred outcome measures for regulatory agencies.

The early reduction in UPCR indicates that the anti-PLA2R antibody serum positive group benefits from pMN treatment in the long term, which supports its use as the primary endpoint in this study.

Basic principles of placebo control group

The design of this placebo-controlled study is acceptable for this patient population, given that best supportive care (e.g., ACEi or ARB, statins, diuretics) is administered in addition to placebo. A placebo-controlled study that does not include best supportive care in patients with pMN would represent inadequate treatment for a population at risk for severe renal damage.

Dosage adjustment

Based on the results of previous clinical studies, including a Phase 3 study in patients with generalized myasthenia gravis (gMG), 10 mg/kg eqatimod (4 infusions) administered intravenously q7d achieved nearly maximal reductions in total IgG, caused a reduction in pathogenic autoantibodies, and correlated with clinical efficacy in patients with gMG. In addition, this dose was well tolerated with no safety issues in all populations tested to date.

60ml/min/1.73m²，但

90mL/min/1.73m²)之AUC_0-168h比率的中值及90%信賴區間(CI)經估算為1.28(1.19、1.37)，表明輕度腎損傷患者的藥物暴露增加28%(90% CI：19%、37%)。另一方面，至多25mg/kg之多次IV劑量在健康自願者中具有良好耐受性。考慮到輕度腎損傷患者之藥物暴露的潛在增加不可能超過劑量自10mg/kg變化至25mg/kg之1.5倍增加所致的該暴露，因此，假定輕度腎損傷患者之藥物暴露的潛在增加與臨床無關。因此，為了在此群體中達成最大藥力學(IgG減少)功效，選擇10mg/kg靜脈內週劑量用於此研究。 pMN patients may have a certain degree of renal impairment and nephrotic proteinuria. Igatimod has a molecular weight of approximately 54 kDa and is therefore at the molecular limit of renal filtration. Following intravenous administration of a single dose of 10 mg/kg of Igatimod to healthy individuals, less than 0.1% of the administered dose was recovered in the urine. Population covariate analysis methods were used to evaluate the potential effect of eGFR as a marker of renal function on the PK profile of Igatimod. Statistically significant reductions in elimination rate and eGFR were identified, which resulted in increased exposure. Compared with patients with normal renal function, patients with mild renal impairment (eGFR

60ml/min/ ^1.73m2 , but

The median and 90% confidence interval (CI) of the AUC _0-168h ratio for the 10 mg/kg to 25 mg/kg dose (90 mL/min/1.73 m ² ) was estimated to be 1.28 (1.19, 1.37), indicating an increase in drug exposure of 28% (90% CI: 19%, 37%) in patients with mild renal impairment. On the other hand, multiple IV doses up to 25 mg/kg were well tolerated in healthy volunteers. Considering that the potential increase in drug exposure in patients with mild renal impairment is unlikely to exceed that resulting from a 1.5-fold increase in dose from 10 mg/kg to 25 mg/kg, it is assumed that the potential increase in drug exposure in patients with mild renal impairment is not clinically relevant. Therefore, to achieve maximal pharmacokinetic (IgG reduction) efficacy in this population, a 10 mg/kg intravenous weekly dose was selected for this study.

To demonstrate that the dose of igatimod selected for this study will achieve a reduction in total IgG and anti-PLA2R antibodies, blood samples were collected and unblinded monitoring was performed 1 week after the fourth infusion of IMP in a small group of participants recruited at the earliest time. IgG and anti-PLA2R antibody data were not visible or available to site staff involved in the study.

B. Research Group

Prospective approval of agreed deviations from recruitment and selection criteria, also known as protocol waivers or exemptions, is not permitted.

Inclusion criteria

50RU/mL(定義為血清陽性參與者)或抗 PLA2R抗體狀態<2RU/mL(定義為血清陰性參與者)；- 在篩檢時，尿蛋白>3.5g/24小時，且在基線訪診時確認；- 在篩檢時，eGFR

60mL/min/1.73m²，如使用慢性腎病流行病學協作(CKD-EPI)所計算；- 在隨機分配之前，以最大耐受或允許劑量接受穩定劑量的ACEi及/或ARB，歷時至少12週；- 篩檢時血清總IgG

6g/L。篩檢時總IgG在4與6g/L之間的參與者資格需要與試驗委託者的醫療監測員逐案討論；- 未絕育的男性參與者及有生育能力的女性(Women Of Childbearing Potential，WOCBP)的避孕措施使用將符合當地對參與臨床研究之個人的規定(若有)。WOCBP在篩檢期間必須接受陰性血清妊娠測試且在接受研究性醫藥產品(Investigational Medicinal Product，IMP)之前，在基線接受陰性血清或尿液妊娠測試。 Participants were eligible for inclusion in the study only if all of the following criteria applied:- Age at least 18 years at the time of signing informed consent;- Able to provide signed informed consent, including compliance with the requirements and restrictions outlined in the Informed Consent Form (ICF) and this protocol;- A diagnosis of idiopathic (primary) MN confirmed by renal biopsy within 24 months prior to randomization. If the most recent biopsy was performed more than 24 months prior to randomization, a renal biopsy may be obtained at any time during the screening period to confirm the diagnosis of MN to achieve participant eligibility;- Anti-PLA2R antibody status at screening

50RU/mL (defined as serum-positive participants) or anti-PLA2R antibody status <2RU/mL (defined as serum-negative participants); - Urine protein >3.5g/24h at screening and confirmed at baseline visit; - eGFR at screening

60mL/min/1.73m ² as calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI);- Receiving a stable dose of ACEi and/or ARB at maximum tolerated or permitted dose for at least 12 weeks prior to randomization;- Total serum IgG at screening

6g/L. The eligibility of participants with total IgG between 4 and 6g/L at screening will need to be discussed on a case-by-case basis with the trial sponsor's medical monitor; - Contraceptive use by non-sterilized male participants and women of childbearing potential (WOCBP) will comply with local regulations for individuals participating in clinical research (if any). WOCBP must receive a negative serum pregnancy test during screening and a negative serum or urine pregnancy test at baseline before receiving the investigational medicinal product (IMP).

Exclusion criteria

2RU/mL的先前病史，或b.腎生檢中的PLA2R抗原染色呈陽性；- 抗PLA2R抗體狀態在篩檢時

2且<50RU/mL的所有MN參與者；- 在篩檢之前的6個月內，抗PLA2R抗體含量或24小時尿蛋白減少>50%的證據；- 惡性疾病病史，除非經充分治療而被視為治癒且在隨機分配之前

3年無復發證據。以下癌症不排除：a.經充分治療之基底細胞或鱗狀細胞皮膚癌，b.子宮頸原位癌，c.乳房原位癌，d.前列腺癌之偶然組織學發現(T1a或T1b期TNM)；- 腎生檢關於糖尿病腎小球病變的任何證據，亦即：自生檢時間以來，大於I類糖尿病腎小球病變，或I類糖尿病腎小球病變與不良糖尿病控制病史(例如HbA1c

9.0%)；- 腎功能不穩定的證據，其定義為在篩檢之前的先前3個月期間，eGFR降低>20%；- 當前正接受腎透析或預期需要在研究期期間透析；- 先前的腎臟移植或計劃在研究期期間進行的移植；- 任何其他已知的自體免疫疾病，其需要全身免疫抑制性治療或在研究者看來，會干擾對pMN臨床症狀的準確評估或將參與者置於過度的風險；- 其他顯著或不可控嚴重疾病(亦即，心血管、肺、血液學、胃腸道、肝、腎或神經)、最近已經歷大手術或存在在研究者看來可混淆研究結果或將參與者置於過度風險之任何其他病狀的臨床證據；- 在篩檢之前不到4週接受不為抗CD20抗體的單株抗體；- 在篩檢之前不到6個月接受抗CD20抗體；- 在篩檢之前不到4週接受靜脈內免疫球蛋白(IVIg)或血漿清除術/血漿置換(PLEX)；- 在隨機分配之前的3個月內，預先經小分子免疫抑制劑治療，包括但不 限於環磷醯胺、苯丁酸氮芥(chlorambucil)、黴酚酸嗎啉乙酯(mycophenolate mofetil)(或等效物)、環孢素、他克莫司、硼替佐米(bortezomib)或硫唑嘌呤(azathioprine)；- 在隨機分配之前的4週內使用補充療法，包括可潛在地干擾參與者之功效及安全性的傳統中藥、草藥或程序(例如針灸)，如研究者所評估；- 在隨機分配前28天內接受活/活減毒疫苗。在篩檢之前的任何時間接受任何滅活的亞單元、多醣或結合物疫苗不考慮排除在外。建議參與者在第一劑IMP前及時接種疫苗；- 先前參與依加替莫德的臨床研究；- 在隨機分配之前的3個月或5個半衰期內(以較長者為準)使用任何研究性療法；- 篩檢時的SARS-CoV-2陽性測試。不論參與者是否已接種疫苗，均需測試；- 在篩檢時針對任一以下病狀之活動性病毒感染進行的陽性血清測試：a.指示急性或慢性感染的B型肝炎病毒(Hepatitis B Virus，HBV)，除非根據疾病控制與預防中心(Centers for Disease Control and Prevention)建議，該病毒與陰性HBV DNA測試相關，b.基於HCV抗體分析的C型肝炎病毒(Hepatitis C Virus，HCV)，除非該病毒與陰性HCV RNA測試相關，c.基於與以下相關之測試結果的HIV：(1)AIDS定義的病狀或CD4計數<200個細胞/mm³，(2)抗逆轉錄病毒療法的治療不充分；- 篩檢時血清總IgG<4g/L；- 篩檢時存在任一以下實驗室測試值：a.丙胺酸轉胺酶(Alanine Transaminase，ALT)及/或天冬胺酸轉胺酶(Aspartate Transaminase，AST)>3×正常值上限(Upper Limit Of Normal，ULN)，b.總膽紅素>1.5×ULN，c.血小板<75×10⁹/L， d.嗜中性球<1.5×10⁹/L，e.血紅素<8g/dL；- 對依加替莫德或IMP之任何賦形劑存在已知的超敏反應或禁忌；- 在研究者看來，當前濫用酒精、藥物或藥品或存在酒精、藥物或藥品濫用的歷史(亦即，在隨機分配之12個月內)；- 妊娠或哺乳期女性及意欲在研究參與期間妊娠的女性；- 在研究者看來使得參與者不適於研究的任何狀況或環境。 Participants were excluded from the study if any of the following criteria applied: - Active or chronic infection requiring treatment: a. Currently receiving any treatment for a chronic infection, including but not limited to tuberculosis, pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, or atypical mycobacteria, b. Active infection of any kind (excluding fungal infection of the nail bed) or any major infectious event requiring hospitalization or parenteral (intravenous or intramuscular) antibiotic treatment (e.g., antibacterial, antiviral, antifungal, or antiparasitic agents) within 60 days prior to randomization or oral antibiotics within 2 weeks prior to randomization; - Secondary etiology of MN (e.g., systemic autoimmune disease, solid or hematologic malignancies, infection) or chronic drug intake (e.g., gold salts, nonsteroidal anti-inflammatory drugs [NSAIDs], penicillamine); - Evidence of crescent formation in the glomeruli on diagnostic renal examination, suggesting an alternative diagnosis of pMN or another diagnosis; - Evidence of >50% stromal fibrosis/ductal atrophy in cortical areas on renal examination; - Evidence of anti-PLA2R antibody-related MN in seronegative participants, anti-PLA2R antibody <2 RU/mL; a. Anti-PLA2R antibody status on serum testing

2RU/mL, or b. positive PLA2R antigen staining in renal examination; - Anti-PLA2R antibody status at screening

2 and <50RU/mL for all MN participants; - Evidence of >50% reduction in anti-PLA2R antibodies or 24-hour urine protein in the 6 months prior to screening; - History of malignant disease unless adequately treated and considered cured before randomization

3 years without evidence of recurrence. The following cancers are not excluded: a. Adequately treated basal cell or squamous cell skin cancer, b. Cervical carcinoma in situ, c. Breast carcinoma in situ, d. Incidental histological findings of prostate cancer (TNM stage T1a or T1b); - Any evidence of diabetic glomerulopathy on renal examination, i.e., greater than type I diabetic glomerulopathy since the time of examination, or type I diabetic glomerulopathy and a history of poor diabetes control (e.g. HbA1c

9.0%); - evidence of unstable renal function, defined as a decrease in eGFR >20% in the previous 3 months before screening; - currently receiving renal dialysis or expected to require dialysis during the study period; - previous renal transplant or planned transplant during the study period; - any other known autoimmune disease that requires systemic immunosuppressive therapy or that, in the opinion of the investigator, would interfere with the accurate assessment of clinical symptoms of pMN or place the participant at undue risk; - other significant or uncontrolled serious illness (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, or neurologic), recent major surgery, or clinical evidence of any other condition that, in the opinion of the investigator, could confound the study results or place the participant at undue risk; - - Receipt of a monoclonal antibody other than anti-CD20 antibody less than 4 weeks before screening; - Receipt of an anti-CD20 antibody less than 6 months before screening; - Receipt of intravenous immunoglobulin (IVIg) or plasmapheresis/plasma exchange (PLEX) less than 4 weeks before screening; - Prior treatment with small molecule immunosuppressants including but not limited to cyclophosphamide, chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus, bortezomib, or azathioprine within 3 months before randomization; - Use of complementary therapies within 4 weeks prior to randomization, including traditional Chinese medicine, herbs, or procedures (e.g., acupuncture) that could potentially interfere with efficacy and safety in participants, as assessed by the investigator;- Receipt of live/live attenuated vaccines within 28 days prior to randomization. Receipt of any killed subunit, polysaccharide, or conjugate vaccine at any time prior to screening is not considered exclusion. Participants are recommended to be vaccinated promptly before the first dose of IMP;- Previous participation in clinical studies of efatimod;- Use of any investigational therapy within 3 months or 5 half-lives (whichever is longer) prior to randomization;- Positive test for SARS-CoV-2 at screening. Participants must be tested regardless of whether they have been vaccinated or not; - A positive serological test for active viral infection with any of the following conditions at screening: a. Hepatitis B Virus (HBV) indicating acute or chronic infection unless associated with a negative HBV DNA test as recommended by the Centers for Disease Control and Prevention, b. Hepatitis C Virus (HCV) based on an HCV antibody assay unless associated with a negative HCV RNA test, c. HIV based on test results associated with: (1) AIDS-defining conditions or CD4 count <200 cells/ ^mm3 , (2) inadequate treatment with antiretroviral therapy; - Total serum IgG <4 g/L at screening; - Any of the following laboratory test values at screening: a. Alanine Transaminase (ALT) and/or Aspartate Transaminase (AST) > 3×Upper Limit Of Normal (ULN), b. Total bilirubin > 1.5×ULN, c. Platelets < 75×10 ⁹ /L, d. Neutrophils < 1.5×10 ⁹ /L, e. Hemoglobin <8g/dL; - Known hypersensitivity or contraindications to igatimod or any formulation of IMP; - Current or history of alcohol, drug or medication abuse in the opinion of the investigator (i.e., within 12 months of randomization); - Pregnant or lactating women and women who intend to become pregnant during study participation; - Any condition or environment that, in the opinion of the researcher, renders a participant unsuitable for research.

C. IMP and concomitant therapy

An investigational medicinal product (IMP) is defined as any investigational intervention, marketed product, placebo, or medical device that is intended to be administered to study participants in accordance with a study protocol. IMPs will be manufactured in accordance with Good Manufacturing Practice regulations.

IMP

The IMPs in this study included intravenous egatimod and matching placebo (using the same formulation but without the egatimod active ingredient), as described in Table S1 :

AxMP = adjunctive medicinal product; IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal product

120kg的參與者而言，每次輸注依加替莫德的最大總劑量為1200mg。若在24週治療期期間，研究參與者之體重相對於基線已改變超過10%，則重新計算IMP劑量。 Weight at visit and infusion

For participants weighing 120 kg, the maximum total dose of elgativimud per infusion was 1200 mg. If a study participant's body weight changed by more than 10% from baseline during the 24-week treatment period, the IMP dose was recalculated.

Any medications or vaccines (including over-the-counter or prescription medications, vitamins and/or herbal supplements) received by participants within 30 days of signing the Informed Consent Form (ICF) or during study participation must be recorded.

In addition, the participant's vaccination history (including any vaccination for COVID-19) within 12 months prior to signing the ICF is recorded. The brand name of the vaccine and the date of vaccination (if known) are also recorded.

Any questions regarding concomitant or prior therapy should be directed to the trial sponsor's medical monitor.

All participants received best supportive care for proteinuria, hypertension, and marked hyperlipidemia throughout the study. Participants were required to take ACEi or ARB (up to maximum tolerated or permitted dose) as first-line therapy unless contraindicated. Participants with hypertension or edema received diuretics as appropriate based on clinical evaluation. Participants received statins as first-line therapy for persistent hyperlipidemia as appropriate or based on clinical evaluation for other risks (e.g., cardiovascular risks, including hypertension and diabetes). Participants who could not tolerate statins or were dissatisfied with statins could be considered for non-statin therapy.

The dose of ACEi and/or ARB and/or statin should be stable throughout the treatment period unless a change is indicated due to safety concerns.

Anticoagulation may be considered based on the investigator's judgment.

每天10mg普賴蘇穠)， 但在整個治療期期間，劑量應穩定。 Low-dose systemic corticosteroid therapy (equivalent to

10 mg pralidone per day), but the dosage should be stable throughout the treatment period.

Rescue therapy was assigned at the investigator's discretion if the participant met treatment failure criteria defined by any of the following: ˙ Renal instability, defined as a >20% decrease in eGFR from baseline during treatment; ˙ Disease relapse, defined as the development of nephrotic-range proteinuria, i.e., >3.5 g/24 hours, after CR or PR; ˙ Proteinuria reduction of less than 25% from baseline and >3.5 g/24 hours in the third month after randomization.

In these cases, the investigator may consider one or more of the following therapies, at the investigator's discretion: 1) rituximab; 2) calcineurin inhibitors ± glucocorticoids; 3) cyclophosphamide + glucocorticoids.

Participants who received rescue therapy discontinued IMP but remained in the study to allow for safety tracking according to the activity schedule ( Table S2 ).

Prohibited drugs

Unless any of the treatment failure criteria listed above are met, participants should not receive any of the prohibited medications listed below during the study: ˙Investigational therapy; ˙Treatment with any monoclonal antibody; ˙Treatment with B-cell depleting agents or B-cell modulating agents, including but not limited to rituximab, belimumab, daratumumab, or bortezomib; ˙Treatment with immunosuppressive agents other than B-cell depleting agents or B-cell modulating agents, including but not limited to cyclophosphamide, Chlorambucil, mycophenolate mofetil (or equivalent), cyclosporine, tacrolimus, or azathioprine; Intravenous corticosteroids for the treatment of pMN, or oral corticosteroids (equivalent to >10 mg pralidone per day); Complementary therapies, including traditional Chinese medicines, herbs, or procedures (e.g., acupuncture) that could potentially interfere with the efficacy and safety of participants, as assessed by the investigator; Live/live attenuated vaccines; Other immunosuppressive agents not specifically permitted in the study described.

D. Research Evaluation and Procedures

^qUrine analysis parameters include specific gravity, pH, glucose, blood, ketones, bilirubin, urobilinogen, nitrites, leukocytes, urinary casts, and microscopic examination for RBC count and WBC count. Testing is performed in a central laboratory. For V2, results obtained within 7 days before V2 are acceptable.

^r Vital sign parameters included blood pressure (systolic and diastolic), pulse rate, respiratory rate, and temperature. Participants were required to rest in a quiet environment for at least 5 minutes before measurements were taken. Blood pressure and pulse rate were measured in a sitting position. During the visit, when IMP was administered, vital signs were measured before and after IMP infusion.

^sA complete physical examination includes evaluation of the following: general appearance, respiratory, cardiovascular, abdominal, skin, head and neck, lymph nodes, thyroid, musculoskeletal (including spine and extremities), and nervous systems.

^tPK sample collection for V2 was performed within 1 hour before dosing, at the end of infusion (EOI; ±5 minutes), and at 4 hours after infusion (±30 minutes); PK sample collection for V3 was performed at 48 hours after infusion on the first day (±1 hour); and PK sample collection for V5, V7, V11, V15, V19, and V23 was performed within 1 hour before dosing and at EOI (±5 minutes).

^u PD parameters include total IgG content. Pre-dose, collected within 2 hours before the start of IMP administration.

^vCollect blood samples (serum) for determination of ADA against elgativimud for immunogenicity assessment. Immunogenicity samples obtained during screening are used for validation purposes only. Pre-dose, collect within 2 hours before the start of IMP administration.

wWeight was measured ^with participants wearing light clothing and without shoes. Height was measured without shoes at V2. Weight was measured before each IMP administration during treatment. Dosage was calculated based on the participant's baseline (V2, Day 1) weight but was recalculated if there was a significant change in weight (>10% compared to baseline).

^x Administer the first dose on Day 1. Administer the IMP weekly via 1-hour intravenous infusion. Observe participants for at least 30 minutes after the end of the infusion for routine safety monitoring.

Urine protein to creatinine ratio (UPCR)

UPCR (mg/mg) was measured in 24-h, 2×24-h, and single-point urine samples. The 2×24-h UPCR (defined as the average of the UPCR from two consecutive 24-h urine samples) was used to assess the primary variables. See Table S2 for the sequence and instructions for urine sample collection. Instructions on the procedure for collecting 24-h urine samples at home were given to participants. Parameters included: ˙proteinuria; ˙urine creatinine; ˙UPCR.

Definition of Clinical Outcomes

0.3g/24小時且血清白蛋白

3.5g/dL。 Secondary efficacy endpoints of the study included evaluation of clinical outcomes in participants with pMN, which were defined as: complete remission (CR) defined as proteinuria

0.3g/24 hours and serum albumin

3.5 g/dL.

50%，且最終蛋白尿介於0.3至3.5g/24小時(包括3.5)之間。 Partial response (PR) was defined as a decrease in proteinuria relative to baseline.

50%, and final proteinuria is between 0.3 and 3.5 g/24 hours (inclusive).

Relapse was defined as the development of nephrotic-range proteinuria after CR or PR, i.e. >3.5 g/24 hours.

Treatment failure was defined as: ˙renal instability, defined as a >20% decrease in eGFR from baseline during the treatment period, or ˙disease relapse as defined above, or ˙less than a 25% decrease in proteinuria from baseline and >3.5 g/24 h in the third month after randomization.

E. Pharmacokinetics

Blood samples for PK analysis were collected at the time points described in Table S2 . Serum ergativmod concentrations were determined using a validated method.

F. Pharmacokinetics

Blood samples were collected at the time points described in Table S2 for determination of total IgG levels in serum for PD assessment. Total IgG levels were determined using a validated method.

G. Biomarkers

Anti-PLA2R antibodies were assessed as a marker of disease activity. Blood samples for biomarker studies were collected according to the schedule described in Table S2 and as detailed in the laboratory manual provided to the study sites respectively.

H. Immunogenicity Assessment

Blood samples were collected at the time points described in Table S2 to assess serum levels of ADA against elgativitmod.

Samples are analyzed by designated laboratories using a validated immunogenicity assay in a tiered approach. Initially, samples are screened for positive assay responses (Tier 1). Screen-positive samples are then tested in a confirmatory assay (Tier 2). Finally, positive Tier 2 samples are titrated for ADA responses to characterize the magnitude of the antibody response (Tier 3).

I. Health Economics or Medical Resource Utilization and Health Economics

Participants completed health-related quality of life questionnaires (EQ-5D-5L and PROMIS Short Form v.1.0 Fatigue-4a) at the scheduled times shown in Table S2 .

The EQ-5D-5L questionnaire is a standardized test recognized by many health authorities as a universal measure of health status for clinical and economic assessment. The descriptive system includes 5 dimensions: mobility, self-care, daily activities, pain/discomfort, and anxiety/depression. The score for each dimension includes 5 levels: no problem, slight problem, moderate problem, severe problem, and extreme problem.

The EQ-5D-5L includes a visual analog scale (VAS). Participants rate their health status from 0 (the worst health you can imagine) to 100 (the best health you can imagine).

The PROMIS Fatigue (Short Form 4a) instrument assesses the impact and experience of fatigue over the past 7 days. This validated 4-question scale has 5 response options and is rated on a scale of 1 to 5. A decrease in score (negative change from baseline) indicates improvement in fatigue.

J. Goals and targets

Example 3: Open-label extension study of the efficacy and safety of elgativimide in Chinese patients with pMN

Participants in the Phase 2 study described in Example 2 who meet all of the following conditions may elect to be transferred to the open-label extension (OLE) phase, as appropriate, in which they receive up to 24 weeks of intravenous elgativod treatment or are monitored for clinical status after achieving complete remission (CR): - Completed the Week 24 visit in the double-blind (DB) phase described in Example 2; - Able to understand the requirements of the OLE phase and provide written informed consent (including consent for the use and disclosure of research-related health information); Willing and able to comply with the protocol-defined procedures of this trial (including required trial visits); - Negative serum or urine pregnancy test during the DB phase described in Example 2 for women of childbearing potential (WOCBP); - No clinical evidence of other significant or uncontrolled serious medical conditions (i.e., cardiovascular, pulmonary, hematologic, gastrointestinal, hepatic, renal, and neurologic diseases), recent major surgery, or any other condition that, in the opinion of the investigator, could confound the study results or place the participant at undue risk.

The maximum duration of the OLE was 48 weeks (from Week 24 crossover to Week 72 completion). During the OLE, participants who achieved a CR at Week 24 were followed monthly without IMP use until Week 72 (OLE completion). Participants who did not meet CR or TF criteria at Week 24 received igatimod intravenously weekly for up to 24 weeks. At Week 36, another assessment was performed and those participants who had achieved a CR discontinued IV igatimod treatment and were followed monthly until the completion of the OLE. At Week 48, all participants discontinued IV igatimod and were followed until the completion of the OLE. Please see the event schedule shown in Table S5 for more details.

Participants who experienced treatment failure (TF) at any time during the OLE period discontinued the IMP and received appropriate rescue therapy based on clinical judgment. During the follow-up period after Week 48, participants who had not achieved an adequate treatment response were allowed to receive alternative therapies based on clinical judgment and at the discretion of the investigator.

^a Extended Visit 1 (E1) during the OLE phase overlaps with Visit 27/Week 24 during the DB phase. Tests and procedures common to these 2 visits do not need to be repeated.

^bConverted participants received IMP therapy at Weeks 0, 12, or 24 during the OLE period. After achieving a CR at Week 24 or Week 36, participants discontinued IMP therapy and were followed until Week 72 (OLE completion). At Week 48, all participants discontinued IMP and were followed until Week 72. Weekly visits were only for participants still receiving IMP. For participants who achieved a CR, IMP administration and weight were discontinued, and vital signs were measured at the same frequency as physical examinations. For participants who achieved a CR and discontinued IMP, the visit window was extended to ±7 days.

^c Participants in the OLE who received at least 1 dose of IMP and who withdrew from the study (other than by withdrawal of consent) completed the assessments listed for the ED visit within 1 week after receiving their final IMP dose. They also attended the SFU visit at week 9 (±3 days) after receiving their final IMP dose.

^dFor security reasons, participants may visit the study site for UNS visits.

^eFor the OLE conducted at Visit 27, participants were required to sign a separate informed consent form (ICF).

^f Eligibility criteria for the OLE period included completion of the Week 24 visit of the DB period without meeting treatment failure criteria or permanent discontinuation of IMP; ability to understand the requirements of the OLE period and provide written informed consent; willingness and ability to follow protocol-defined procedures: Negative serum or urine pregnancy test during the DB period for females of childbearing potential: No clinical evidence of other significant or uncontrolled serious illness, recent major surgery, or any other condition that, in the opinion of the investigator, could confound the study results or place the participant at undue risk.

^gSerum or urine pregnancy tests may be used.

^h Participants who were seronegative for anti-PLA2R Ab were exempted from anti-PLA2R Ab assessment. For participants receiving IMP, blood samples were collected before the start of IMP administration for participants who were seronegative for anti-PLA2R Ab. Testing was performed at a central laboratory.

ⁱ Participants collect 1 x 24-hour urine sample and give it to field staff at the clinical clinic. Sample collection must begin within 2 days before each scheduled visit. Evaluation of the 24-hour urine sample includes total protein, creatinine, albumin, and IgG. Analysis of urine samples is performed in a central laboratory.

^jAt Weeks 36, 48, and 72, participants collected 2 consecutive 24-hour urine samples (7 to 14 days apart) and gave them to field staff at the clinical clinic. The second sample collection for V2 must have started approximately 7 days before this visit. The second sample collection must have started within 2 days before the visit. Analysis of urine samples was performed at a central laboratory. The average of the 2 samples was used to determine CR.

^k Participants provided urine samples for single-site UPCR testing. Urine samples were analyzed in a central laboratory.

^Hematology parameters include WBC count, RBC count, platelet count, hemoglobin and hematocrit. RBC indices obtained for MCV, MCH and MCHC. WBC differential counts (% and absolute numbers) obtained for neutrophils, eosinophils, lymphocytes, basophils and monocytes. Tests are performed locally or in a central laboratory.

^mSamples were collected after fasting (no food or beverages except water) for at least 8 hours. Clinical chemistry parameters included ALT, AST, ALP, lactate dehydrogenase, GGT, albumin, total protein, uric acid, blood urea/BUN, total cholesterol, HDL/HDL-C, LDL/LDL-C, triglycerides, total and direct bilirubin, glucose, creatinine, creatinine kinase, potassium, sodium, calcium, and chloride. Tests were performed locally or in a central laboratory.

^Urinalysis parameters include specific gravity, pH, glucose, blood, ketones, bilirubin, urobilinogen, nitrites, leukocytes, urinary casts, and microscopic examination for RBC count and WBC count. Testing is performed in a central laboratory.

^o Vital sign parameters included blood pressure (systolic and diastolic), pulse rate, respiratory rate, and temperature. Participants were required to rest in a quiet environment for at least 5 minutes before measurements were taken. Blood pressure and pulse rate were measured in a sitting position. Vital signs were measured during visits, when IMPs were administered, before and after IMP infusion. For participants who achieved CR and discontinued IMPs, vital signs were measured according to the physical examination schedule.

^pA complete physical examination includes assessment of the following: general appearance, respiratory, cardiovascular, abdominal, skin, head and neck, lymph nodes, thyroid, musculoskeletal (including spine and extremities), and nervous systems.

^qFor participants who received IMP during the OLE period, when IMP was administered, a pre-dose blood sample was collected within 1 hour before the start of the IMP visit. For participants who showed a confirmed CR at Week 24, only PK samples were collected at Weeks 5 and 9 after the last IMP dose (i.e., Weeks 28 and 32). For participants who showed a confirmed CR at Week 36, only PK samples were collected at Weeks 4 and 8 after the last IMP dose (i.e., Weeks 40 and 44).

^r PD parameters included total IgG levels. For participants receiving IMP, pre-dose samples were collected within 2 hours prior to the start of IMP administration. For participants with confirmed CR at Week 24 and Week 36, all PD samples were collected according to the sampling schedule from Week 24 to Week 48 as shown in the table. No samples were collected during the follow-up period unless an unscheduled sample was to be collected.

Blood samples (serum) were ^collected for the determination of ADA against elgativod for immunogenicity assessment. Pre-dose samples were collected within 2 hours before the start of IMP administration. For participants who showed a confirmed CR at Week 24, ADA samples were only collected at Week 9 after the last administration (i.e., Week 32) and at Week 72. For participants who showed a confirmed CR at Week 36, ADA samples were only collected at Week 8 after the last administration (i.e., Week 44) and at Week 72.

tWeight was measured while ^participants were wearing light clothing and no shoes. For those participants who continued to receive IMP, only weight was measured before each IMP administration. In the event of a significant change in weight (>10% compared to baseline), the dose was recalculated.

^uAll participants who switched and had not achieved a CR at Week 24 received intravenous igatimod during the OLE period. The first dose was administered on Day 176 (Week 25). Administer 10 mg/kg igatimod intravenously once a week via 1-hour intravenous infusion. Participants were observed for at least 30 minutes after the end of the infusion for routine safety monitoring. Participants who had a CR at Week 24 and Week 36 discontinued igatimod (if previously receiving igatimod therapy). All participants discontinued igatimod at Week 48. The final dose was administered at Week 47 to maintain drug exposure until Week 48 (Week 0 to Week 47).

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The scope of the present invention is not limited to the specific embodiments described herein. In fact, various modifications of the present invention in addition to the modifications described will become apparent to those skilled in the art based on the foregoing description and drawings. Such modifications are also intended to be within the scope of the attached patent application.

Claims (74)

A method for treating primary membranous nephropathy (pMN) in a subject in need thereof, the method comprising administering to the subject an effective amount of a human neonatal Fc receptor (FcRn) antagonist. The method of claim 1, wherein the FcRn antagonist comprises two, three or four FcRn binding regions. The method of claim 1 or 2, wherein the FcRn antagonist comprises or consists of a variant Fc region or an FcRn binding fragment thereof. The method of claim 3, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with higher affinity at pH 6.0 compared to the corresponding wild-type Fc region. A method as claimed in claim 3 or 4, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 compared to the corresponding wild-type Fc region. A method as claimed in any one of claims 3 to 5, wherein the variant Fc region comprises or consists of a first Fc domain and a second Fc domain that form a homodimer or a heterodimer. The method of claim 6, wherein the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively. The method of claim 6 or 7, wherein the first Fc domain and/or the second Fc domain comprises amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively. The method of any one of claims 6 to 8, wherein the first Fc domain and/or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 30. The method of any one of claims 6 to 9, wherein the first Fc domain and the second Fc domain comprise amino acid sequences independently selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 30. A method as claimed in any one of claims 1 to 10, wherein the FcRn antagonist is efgartigimod. The method of claim 1, wherein the FcRn antagonist is an anti-FcRn antibody. The method of any one of claims 1 to 12, wherein the FcRn antagonist is administered to the subject at a fixed dose of 20 mg to 20,000 mg or at a dose of 0.2 mg/kg to 200 mg/kg. A method as claimed in any one of claims 1 to 13, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg/kg to 30 mg/kg, once a week or once every two weeks. A method as claimed in any one of claims 1 to 14, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg/kg once a week. A method as claimed in any one of claims 1 to 12, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once a week, once every two weeks, once every three weeks, once every four weeks or once a month. The method of claim 16, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once a week or once every two weeks. The method of any one of claims 1 to 17, wherein the FcRn antagonist is administered for 52 weeks or less. The method of any one of claims 1 to 18, wherein the FcRn antagonist is administered for 24 weeks or less. A method as claimed in any one of claims 1 to 18, wherein the FcRn antagonist is administered for 24 weeks. The method of any one of claims 1 to 18, wherein the FcRn antagonist is administered for at least 24 weeks. The method of any one of claims 1 to 17, wherein the FcRn antagonist is administered for at least 52 weeks. The method of any one of claims 1 to 22, further comprising administering to the individual an effective amount of angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB), statin, diuretic, glucocorticoid or any combination thereof. The method of claim 23, wherein the glucocorticoid is prednisone. The method of claim 23 or 24, wherein the glucocorticoid is equivalent to

Prednisolone is administered orally at a dose of 10 mg per day. A method as claimed in any one of claims 23 to 25, wherein the glucocorticoid is administered at a steady dose for 24 weeks. The method of claim 23, wherein the ACEi and/or ARB is administered at the maximum tolerated or permitted dose. The method of claim 27, wherein the ACEi and/or ARB is administered for at least 12 weeks prior to administration of the FcRn antagonist. The method of claim 27 or 28, wherein the ACEi and/or ARB is administered for at least 36 weeks. A method as claimed in any one of claims 27 to 29, wherein the dosage of the ACEi and/or ARB is maintained at a stable dosage. A method as claimed in any one of claims 1 to 30, wherein the anti-phospholipase A2 receptor (PLA2R) antibody in the individual is serum positive. The method of any one of claims 1 to 31, wherein the serum anti-PLA2R antibody level of the individual

50RU/mL. The method of any one of claims 1 to 32, wherein the individual has a baseline level of proteinuria

8g/24 hours. A method as claimed in any one of items 1 to 32, wherein the individual's baseline proteinuria level is >8g/24 hours. A method as claimed in any one of claims 1 to 30, wherein the anti-PLA2R antibody in the individual is seronegative. The method of claim 35, wherein the serum anti-PLA2R antibody content of the individual is <2RU/mL. The method of any one of claims 1 to 36, wherein after administering the FcRn antagonist to the subject, the subject exhibits a post-administration urine protein to creatinine ratio (UPCR) of at most 0.5 mg/mg. The method of any one of claims 1 to 37, wherein after administering the FcRn antagonist to the individual, the individual exhibits a post-administration UPCR that is reduced by at least 50% compared to a baseline UPCR obtained from the individual before administration of the FcRn antagonist. The method of claim 37 or 38, wherein the post-administration UPCR is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 39, wherein after administering the FcRn antagonist to the subject, the subject exhibits

0.3g/24 hours of proteinuria after administration. The method of any one of claims 1 to 40, wherein after administering the FcRn antagonist to the individual, the individual exhibits post-administration proteinuria that is reduced by at least 50% compared to baseline proteinuria obtained from the individual prior to administration of the FcRn antagonist. The method of claim 40 or 41, wherein the post-administration proteinuria is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 42, wherein after administering the FcRn antagonist to the subject, the subject exhibits post-administration proteinuria that is reduced by at least 50% compared to baseline proteinuria obtained from the subject prior to administration of the FcRn antagonist and wherein the subject exhibits >0.3 and

3.5 g/24 hours of proteinuria after administration. The method of claim 43, wherein the post-administration proteinuria is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 44, wherein after administering the FcRn antagonist to the subject, the subject exhibits

Post-dose serum albumin of 3.5 g/dL. The method of claim 45, wherein the post-administration serum albumin is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 46, wherein after administering the FcRn antagonist to the subject, the subject exhibits a post-administration estimated glomerular filtration rate (eGFR) of at least 60 mL/min/1.73 m ² . The method of any one of claims 1 to 47, wherein after administering the FcRn antagonist to the individual, the individual exhibits a post-administration eGFR that is less than 20% lower than a baseline eGFR obtained from the individual prior to administration of the FcRn antagonist. The method of claim 48, wherein the post-administration eGFR is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 49, wherein after administering the FcRn antagonist to the individual, the individual exhibits a post-dose EuroQoL 5-dimension 5-level (EQ5D-5L) score that is reduced compared to a baseline EQ5D-5L score obtained from the individual before administration of the FcRn antagonist. The method of claim 50, wherein the post-administration EQ5D-5L score is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 51, wherein after administering the FcRn antagonist to the individual, the individual exhibits a decrease in a Post-Administration Patient Reported Outcomes Information System (PROMIS) Short Form v.1.0 Fatigue-4a score compared to a baseline PROMIS Short Form v.1.0 Fatigue-4a score obtained from the individual prior to administration of the FcRn antagonist. The method of claim 52, wherein the post-administration PROMIS Short Form v.1.0 Fatigue-4a score is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 53, wherein after the FcRn antagonist is administered to the individual, the individual exhibits a post-administration serum autoantibody level that is reduced compared to a baseline serum autoantibody level obtained from the individual before administration of the FcRn antagonist. The method of claim 54, wherein the serum autoantibody level after administration is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the baseline level of serum autoantibodies obtained from the individual before administration of the FcRn antagonist. The method of claim 54 or 55, wherein the post-administration serum autoantibody level is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. A method as claimed in any one of claims 54 to 56, wherein the serum autologous antibody is selected from the group consisting of anti-PLA2R, anti-THSD7a, anti-NELL-1 and anti-Sema3B. A method as claimed in any one of claims 54 to 57, wherein the serum autoantibody is anti-PLA2R. The method of any one of claims 1 to 58, wherein after the FcRn antagonist is administered to the individual, the individual exhibits a post-administration serum complement level that is reduced compared to a serum complement baseline level obtained from the individual before administration of the FcRn antagonist. The method of claim 59, wherein the serum complement level after administration is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the baseline level of serum complement obtained from the individual before administration of the FcRn antagonist. The method of claim 59 or 60, wherein the post-administration serum complement level is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. The method of any one of claims 1 to 61, wherein after the FcRn antagonist is administered to the individual, the individual exhibits a post-administration serum IgG level that is reduced compared to a baseline serum IgG level obtained from the individual before administration of the FcRn antagonist. The method of claim 62, wherein the serum IgG level after administration is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% compared to the baseline serum IgG level obtained from the individual before administration of the FcRn antagonist. The method of claim 62 or 63, wherein the post-administration serum IgG level is measured at week 24, week 36, week 48, or week 72 after the FcRn antagonist is administered to the individual. A method as claimed in any of the preceding claims, wherein the FcRn antagonist is present in an aqueous solution comprising about 4 mM sodium phosphate, about 146 mM sodium chloride, about 24 mM L-arginine and about 0.0032% (w/v) polysorbate 80, wherein the composition has a pH of about 6.7. The method of claim 65, wherein the aqueous solution contains about 3.2 mg/ml of the FcRn antagonist. The method of any one of claims 1 to 64, wherein the FcRn antagonist is present in an aqueous solution comprising about 20 mM L-histidine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 20, wherein the composition has a pH of about 6.0. The method of claim 67, wherein the aqueous solution contains about 180 mg/ml of the FcRn antagonist. The method of any one of claims 1 to 64, wherein the FcRn antagonist is present in an aqueous solution comprising about 20 mM L-histidine, about 50 mM L-arginine, about 100 mM sodium chloride, about 60 mM sucrose, about 10 mM L-methionine, and about 0.04% (w/v) polysorbate 80, wherein the composition has a pH of about 6.0. The method of claim 69, wherein the aqueous solution contains about 200 mg/ml of the FcRn antagonist. An FcRn antagonist for use in treating pMN, wherein the treatment is performed according to the method of any one of claims 1 to 70. An FcRn antagonist for use in the manufacture of a medicament for treating pMN, wherein the treatment is performed according to the method of any one of claims 1 to 70. A use of an FcRn antagonist for treating pMN according to the method of any one of claims 1 to 70. A use of an FcRn antagonist for the manufacture of a medicament for treating pMN, wherein the treatment is carried out according to the method of any one of claims 1 to 70.

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