Methods for reducing platelet degradation using FCRN antagonists

Abstract

Provided herein are methods of reducing platelet degradation in a subject in need thereof, such as a subject that has immune thrombocytopenia (ITP), using an antagonist of human neonatal Fc receptor (FcRn), which in certain embodiments is efgartigimod.

Description

METHODS FOR REDUCING PLATELET DEGRADATION USING FCRN ANTAGONISTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to US Provisional Patent Application No. 63 / 637,161, filed April 22, 2024, the entire contents of which are hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates to methods of reducing platelet degradation in a subject in need thereof, such as a subject that has immune thrombocytopenia (ITP), using an antagonist of human neonatal Fc receptor (FcRn), which in certain embodiments is efgartigimod.BACKGROUND

[0003] Thrombocytopenia is a condition in which blood platelet count is low. Thrombocytopenia can occur because the bone marrow does not produce enough platelets (z.e., hypoproliferative thrombocytopenia). Certain medications, chemotherapy, radiation therapy, infections, poor nutrition, or inherited genetic conditions can cause the bone marrow to stop or reduce platelet formation. Certain cancers and metabolic disorders can also affect bone marrow, leading to a reduction in platelet formation. Thrombocytopenia can also occur because platelets are being removed from the bloodstream by the immune system, spleen, or liver (i.e., consumptive thrombocytopenia). Common causes include infections, medications, autoimmune disease, inherited or acquired bleeding disorders, an enlarged spleen, liver disease, or an inherited immune deficiency or disorder.

[0004] Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, mediated in part by autoantibodies targeting platelet antigens and characterized by isolated thrombocytopenia (<100* 109platelets / L) without evident association with another disease. Affected individuals have bleeding events, fatigue, and sometimes a reduced quality of life. ITP is primarily driven by platelet degradation, although platelet production may also be impaired in some patients.

[0005] Thrombopoietin receptor agonists (TPO-RAs) have become more widely used for the treatment of ITP in recent years. TPO-RAs stimulate platelet production, thereby increasing platelet count. However, many of the newly produced platelets do not reach maturity since platelet degradation is still occurring in these patients at an elevated rate. Moreover, use of TPO-RAs can result in dangerously high platelet counts in some patients if platelet production increases rapidly. Other existing therapeutic approaches exist, including non-specific immunosuppression (e.g., glucocorticoids, IVIg) and splenectomy, but these treatments are variably burdensome, carry the risk of adverse effects, are inconvenient to patients, and do not produce a response in all patients. Furthermore, for various reasons, not all people with primary ITP are eligible for the available treatment options. There exists a need for ITP therapeutic agents that reduce platelet degradation, preferably without increasing platelet production, which are safe and efficacious.SUMMARY

[0006] The instant disclosure is broadly directed to methods for reducing platelet degradation with FcRn antagonists. Surprisingly, the FcRn antagonists disclosed herein have been shown to reduce platelet degradation in ITP patients while maintaining platelet production within ranges seen in healthy individuals. This provides a significant advantage for the treatment of ITP by increasing the number of mature functioning platelets with less risk of thrombosis.

[0007] The instant disclosure provides a method of reducing platelet degradation in a subject in need thereof, the method comprising administering to the subject an effective amount of a neonatal Fc receptor (FcRn) antagonist. In some embodiments, immature platelet fraction (IPF%) is reduced in the subject after administration of the effective amount of an FcRn antagonist to the subject.

[0008] The instant disclosure also provides a method of reducing immature platelet fraction (IPF%) in a subject in need thereof, the method comprising administering to the subject an effective amount of an FcRn antagonist.

[0009] 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 FcRn binding fragment thereof. In some embodiments, the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 as compared to a corresponding wild-type Fc region. In some embodiments, the variant Fc region or FcRn bindingfragment thereof binds to FcRn with a higher affinity at pH 7.4 as compared to a corresponding wild-type Fc region.

[0010] In some embodiments, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or heterodimer. In some embodiments, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0011] In some embodiments, the first Fc domain and / or the second Fc domain comprise or consist of 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: 4. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of 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: 4. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 4.

[0012] In some embodiments, the FcRn antagonist is administered to the subject as part of a composition comprising a population of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the population consists of a dimer of a first Fc domain and a second Fc domain, and wherein the population comprises:(a) a first subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the first subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3; and(b) at least one of:(i) a second subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the second subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 12, respectively;(ii) a third subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the third subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 9, respectively;(iii) a fourth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the fourth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated;(iv) a fifth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the fifth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 9, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated;(v) a sixth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the sixth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively;(vi) a seventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the seventh subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized;(vii) an eighth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eighth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 2;(viii) a ninth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the ninth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the ninth subpopulation is oxidized;(ix) a tenth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the tenth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein twoamino acid residues, independently selected from a methionine residue and a tryptophan residue, in each FcRn antagonist molecule in the tenth subpopulation is oxidized; and(x) an eleventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the eleventh subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 6, respectively.

[0013] In some embodiments, the FcRn antagonist is efgartigimod.

[0014] In some embodiments, 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.

[0015] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of from 2 mg / kg to 200 mg / kg once weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once weekly 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 weekly or once every two weeks. In some embodiments, the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or once every two weeks.

[0016] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 weekly or once every two weeks.

[0017] In some embodiments, the FcRn antagonist is administered once weekly for 4 doses, and wherein subsequent doses of the FcRn antagonist are administered once weekly or once every other week. In some embodiments, the subsequent doses of the FcRn antagonist are administered once every other week when the subject achieves a platelet count > 100 x 109 / L. In some embodiments, the subsequent doses of the FcRn antagonist are administered once every other week when the subject achieves a stable platelet count > 100 x 109 / L.

[0018] In some embodiments, the methods described herein further comprise administration of the FcRn antagonist once weekly when the subject exhibits a platelet count < 30 x 109 / L. In some embodiments, the methods described herein further comprise administration of the FcRn antagonist once weekly when the subject exhibits a stable platelet count > 30 x 109 / L and< 100 x 109 / L.

[0019] In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a single platelet count > 400 x 109 / L.

[0020] In some embodiments, administration of the FcRn antagonist is resumed at a dosing regimen of administration once every other week when the subject exhibits a single platelet count< 150 x 109 / L.

[0021] In some embodiments, the subject has a platelet count of < 30 x 109 / L prior to administering the FcRn antagonist.

[0022] In some embodiments, the subject is an adult human subject.

[0023] In some embodiments, the subject has consumptive thrombocytopenia. In some embodiments, the subject has immune thrombocytopenia (ITP). In some embodiments, the ITP is primary ITP. In some embodiments, the ITP is persistent or chronic ITP.

[0024] In some embodiments, the subject received at least 1 previous ITP treatment prior to administering the FcRn antagonist. In some embodiments, the subject received at least 2 previous ITP treatments prior to administering the FcRn antagonist.

[0025] In some embodiments, the subject had an insufficient response to at least one previous ITP treatment prior to administering the FcRn antagonist. In some embodiments, the previous ITP treatment is one or more of: a corticosteroid, a thrombopoietin receptor agonist (TPO- RA), IVIg or anti-D Ig, splenectomy, an immunosuppressant, danazol, dapsone, fostamatinib, and rituximab.

[0026] In some embodiments, the methods described herein further comprise administering to the subject one or more doses of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is one or more of a corticosteroid, a TPO-RA, IVIg or anti-D Ig, an immunosuppressant, danazol, dapsone, fostamatinib, and rituximab.

[0027] In some embodiments, the subject has an IPF% of > 20% prior to administration of the FcRn antagonist.

[0028] In some embodiments, the IPF% is reduced within 1 week of administration of theFcRn antagonist.

[0029] In some embodiments, the IPF% is reduced by at least 10% compared to a baseline value, following administration of the FcRn antagonist.

[0030] In some embodiments, the subject has an IPF% of <15% following administration of the FcRn antagonist.

[0031] In some embodiments, the IPF% is from 0.5%-9% following administration of the FcRn antagonist.

[0032] Also provided is an FcRn antagonist for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein.

[0033] Also provided is an FcRn antagonist for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces IPF% in accordance with any of the methods described herein.

[0034] Also provided is an FcRn antagonist for use in the manufacture of a medicament for reducing platelet degradation in a subject in need thereof, wherein the FcRn antagonist is administered to the subject according to any of the methods described herein.

[0035] Also provided is an FcRn antagonist for use in the manufacture of a medicament for treating ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein.

[0036] Also provided is the use of an FcRn antagonist for reducing platelet degradation according to any of the methods described herein.

[0037] Also provided is the use of an FcRn antagonist for treating ITP, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein.

[0038] Also provided is the use of an FcRn antagonist for the manufacture of a medicament for reducing platelet degradation according to any of the methods described herein.

[0039] Also provided is the use of an FcRn antagonist for the manufacture of a medicament for treating ITP, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0040] FIGs. 1A-1B are graphs showing immature platelet fraction (IPF%) measurements from participants in the ADVANCE study which examined safety and efficacy of intravenousefgartigimod in persistent / chronic primary ITP adult patients. The graph in FIG. 1A shows mean (±SE) IPF% measurements in efgartigimod-treated vs placebo-treated participants. The graph in FIG. IB shows mean (±SE) IPF% measurements in efgartigimod responders vs efgartigimod nonresponders.

[0041] FIGs. 2A-2B are graphs showing absolute immature platelet count (AIPC) measurements from participants in the ADVANCE study which examined safety and efficacy of intravenous efgartigimod in persistent / chronic primary ITP adult patients. The graph in FIG. 2A shows mean (±SE) total immature platelet count (IPF#) measurements in efgartigimod-treated vs placebo-treated participants. The graph in FIG. 2B shows mean (±SE) IPF# measurements in efgartigimod responders vs efgartigimod non-responders.DETAILED DESCRIPTION

[0042] The present disclosure provides engineered FcRn antagonists and methods for their use in reducing platelet degradation. Advantageously, the FcRn antagonists disclosed herein have been shown to reduce platelet degradation in ITP patients while maintaining platelet production within ranges seen in healthy individuals. As such, methods of treating ITP using FcRn antagonists which reduce platelet degradation without significantly increasing platelet production are also provided herein.Definitions

[0043] As used herein, the term “FcRn” refers to a neonatal Fc receptor. Exemplary FcRn molecules include human FcRn encoded by the FCGRT gene as set forth in RefSeq NM 004107. The amino acid sequence of the corresponding protein is set forth in RefSeq NP 004098.

[0044] As used herein, the term “FcRn antagonist” refers to any agent that binds specifically to FcRn and inhibits the binding of immunoglobulin to FcRn (e.g., human FcRn). In an embodiment, the FcRn antagonist is an Fc region (e.g., a variant Fc region disclosed herein) that specifically binds to FcRn through the Fc region and inhibits the binding of immunoglobulin to FcRn. In an embodiment, the FcRn antagonist is not a full-length IgG antibody. In an embodiment, the FcRn antagonist comprises an antigen binding site that binds a target antigen and a variant Fc region. In an embodiment, the FcRn antagonist is an Fc fragment comprising or consisting of an Fc region and lacking an antigen binding site. In an embodiment, the term “FcRnantagonist” refers to an antibody or 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 immunoglobulin (e. ., IgG autoantibodies) to FcRn.

[0045] As used herein, the terms “antibody” and “antibodies” include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, or VL regions. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multi-specific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain-antibody heavy chain pair, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (sdAb), monovalent antibodies, single chain antibodies or single-chain Fvs (scFv), camelid antibodies, affibody molecules, humanized antibodies, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFv), anti -idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), and antigen-binding fragments of any of the above. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgGi, IgGz, IgGs, IgG4, IgAi, or IgAz), or any subclass ( .g., IgGaor IgG2b) of immunoglobulin molecule.

[0046] As used herein, the term “Fc domain” refers to the portion of a single immunoglobulin heavy chain comprising both the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain comprises at least a portion of a hinge (e.g., upper, middle, and / or lower hinge region) region, a CH2 domain, and a CH3 domain. In some embodiments, the Fc domain does not include the hinge region.

[0047] As used herein, the term “hinge region” refers to the portion of a heavy chain molecule that joins the CHI domain to the CH2 domain. In some embodiments, the hinge region is at most 70 amino acid residues in length. In some embodiments, this hinge region comprises approximately 11-17 amino acid residues and is flexible, thus 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. Hinge regions can be subdivided into three distinct domains: upper, middle, and lower hinge domains. The FcRn antagonists of the instant disclosure can include all or any portion of a hinge region. In someembodiments, the hinge region is from an IgGl antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 35).

[0048] 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 can be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is homodimeric. The Fc region can be derived from any native immunoglobulin. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the IgG heavy chain constant region is an IgGl, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed from an IgGl heavy chain constant region. In some embodiments, the IgGl heavy chain constant region comprises a Glm 1(a), Glm2(x), Glm3(f), or Glml7(z) allotype. See, e.g., Jefferis and Lefranc (2009) mAbs l(4):332-338, and de Taeye et al. (2020) Front Immunol. 11 :740, incorporated herein by reference in their entirety.

[0049] As used herein, the term “variant Fc region” refers to an Fc region with one or more alteration(s) relative to a native Fc region. Alterations can include amino acid substitutions, additions and / or deletions, linkage of additional moieties, and / or alteration of the native glycans. The term encompasses heterodimeric Fc regions where each of the constituent Fc domains is different. The term also encompasses single chain Fc regions where the constituent Fc domains are linked together by a linker moiety.

[0050] As used herein, the term “FcRn binding fragment” refers to a portion of an Fc region that is sufficient to confer FcRn binding.

[0051] As used herein, the term “EU position” refers to the amino acid position in the EU numbering convention for the Fc region described in Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al., in “Sequences of Proteins of Immunological Interest,” U.S. Dept. Health and Human Services, 5th edition, 1991.

[0052] As used herein, the term “baseline” refers to a measurement (e.g., IgG levels) in a patient e.g., in a patient’s blood or urine) prior to the first administration (e.g., intravenous or subcutaneous administration) of a treatment (e.g., an FcRn antagonist).

[0053] As used herein, the term “platelet degradation" refers to removal of platelets from the bloodstream by Fc-mediated clearance, Fc-independent clearance, apoptosis, destruction by CD8+ cytotoxic T cells, or any combination thereof.

[0054] As used herein, the term “immature platelet fraction” or “IPF” or “IPF%” refers to the number of immature platelets relative to the total number of platelets and is a measure for enhanced platelet degradation. Newly produced (i.e., immature) platelets are characterized by having a larger RNA content and overall volume compared to mature platelets. These characteristics can be measured, for example, by hematology analyzers, such as Sysmex XE-2100.

[0055] As used herein, the term “ITP” refers to immune thrombocytopenia. Primary ITP is an autoimmune disease or disorder in which pathogenic IgG autoantibodies destroy plateletproducing cells and / or circulating blood platelets (thrombocytes). Primary ITP is characterized by isolated thrombocytopenia (<100x l09 / L) without evident association with another disease. Affected patients are generally at risk for spontaneous bleeding at platelet counts <30* 109 / L, including life-threatening bleeding at platelet counts <10* 109 / L. ITP can be acute or chronic. In some embodiments, ITP can be categorized as newly diagnosed ITP, persistent ITP, or chronicITP. Newly diagnosed ITP is ITP within three months of initial diagnosis. Persistent ITP is ITP lasting 3 to 12 months from diagnosis. Chronic ITP is ITP lasting more than 12 months from diagnosis.

[0056] As used herein, the term “stable platelet count” refers to a platelet count within a specified range as measured on at least two occasions within a specified time period. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least two out of four consecutive measurements. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least three out of four consecutive measurements.In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least two out of four consecutive weeks. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least three out of four consecutive weeks. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least three out of five consecutive measurements. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least four out of five consecutive measurements. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least three out of five consecutive weeks. In some embodiments, a stable platelet count refers to a platelet count within a specified range for at least four out of five consecutive weeks. In some embodiments, the specified range is a platelet count >30 x 109 / L. In some embodiments, the specified range is a platelet count >30 x 109 / L and <400 x 109 / L. In some embodiments, the specified range is a platelet count >30 x 109 / L and <100 x 109 / L. In some embodiments, thespecified range is a platelet count >100 x 109 / L. In some embodiments, the specified range is a platelet count >100 x 109 / L and <400 x 109 / L.

[0057] As used herein, the terms “treat,” “treating,” and “treatment” refer to therapeutic or preventative measures described herein. The methods of “treatment” employ administration of a polypeptide to a subject having a disease or disorder, or predisposed to having such a disease or disorder, in order to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or recurring disease or disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.

[0058] As used herein, the term “effective amount” in the context of the administration of a therapy to a subject refers to the amount of a therapy that achieves a desired prophylactic or therapeutic effect.

[0059] As used herein, the terms “dose” or “dosing” refer to an amount of an agent administered to a subject in a single administration.

[0060] As used herein, the terms “fixed dose” or “flat dose” both refer to a dose that does not vary based upon a characteristic (e.g., body mass, e.g., within a set range; sex; age, e.g., within a set range; etc.) of the subject.

[0061] As used herein, the term “biosimilar” refers to a biological product that is highly similar to and has no clinically meaningful differences from a reference product. As used herein, the term “reference product” refers to a biological product that has been approved for clinical use. In some embodiments, the reference product is approved in at least one of the U.S., Europe, China, or Japan. A biosimilar may have minor differences in clinically inactive components. A biosimilar may include minor modifications in amino acid sequence when compared to the reference product, such as N- or C-terminal truncations that are not expected to change the biosimilar performance.

[0062] As used herein, “no clinically meaningful differences” is determined in terms of safety, purity, and potency. For example, a biosimilar is compared to and evaluated against a reference product to verify that the biosimilar has no clinically meaningful differences in terms of safety, purity, and potency from the reference product. In some embodiments, a determination of no clinically meaningful differences between a biosimilar and a reference product is based upon data derived from: (a) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; (b) animal studies (including, for example, assessment of toxicity); and / or (c) a clinical study or studies (including, for example, assessment of immunogenicity andpharmacokinetics or pharmacodynamics) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar. A biosimilar may be an interchangeable product that may be substituted for the reference product at a pharmacy without intervention of a prescribing healthcare professional. To meet a standard of “interchangeability,” the biosimilar is expected to produce the same clinical result as the reference product in any given patient and, if the biosimilar is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch. In some embodiments, the biosimilar utilizes the same mechanisms of action as the reference product for the proposed conditions of use, to the extent the mechanisms are known for the reference product. In some embodiments, the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biosimilar have been previously approved for the reference product. In some embodiments, the route of administration, the dosage form, and / or the strength of a biosimilar are the same as those of the reference product and the biosimilar is manufactured, processed, packed, or held in a facility that meets standards designed to assure that the biosimilar continues to be safe, pure, and potent.

[0063] As used herein, the term “subject” or “patient” or “participant” includes any human or non-human animal. In an embodiment, the subject or patient or participant is a human or nonhuman mammal. In an embodiment, the subject or patient or participant is a human.

[0064] As used herein, the term “about” or “approximately” when referring to a measurable value, such as a dosage, encompasses variations of ±5% of a given value or range, as are appropriate to perform the methods disclosed herein.FcRn Antagonists

[0065] FcRn antagonists that are 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.

[0066] In some embodiments, the FcRn antagonists disclosed herein comprise two, three, or four FcRn binding regions, such as an Fc region.

[0067] Any Fc region can be altered to produce a variant Fc region for use in the methods disclosed herein. In an embodiment, the Fc region is an IgG Fc region (e. ., a human IgG region).In an embodiment, the Fc region is selected from IgGl, IgG2, IgG3, and IgG4. In an embodiment, the Fc region is an IgGl Fc region (e.g., a human IgGl region). A variety of Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of publicly accessible deposits.

[0068] An Fc region can be further truncated or internally deleted to produce a minimal FcRn binding fragment thereof. The ability of an Fc-region fragment to bind to FcRn can be determined using any art recognized binding assay (e.g., ELISA).

[0069] To enhance the manufacturability of the FcRn antagonists disclosed herein, it is preferable that the constituent Fc regions do not comprise any non-disulfide bonded cysteine residues. Accordingly, in an embodiment, the Fc regions do not comprise a free cysteine residue.

[0070] Any variant Fc region, or FcRn binding fragment thereof, that binds specifically to FcRn with increased affinity and reduced pH dependence relative to the native (z.e., wild-type) Fc region can be used in the methods disclosed herein. In an embodiment, the variant Fc region comprises amino acid alterations, substitutions, insertions, and / or deletions that confer the desired characteristics. In some embodiments, the FcRn antagonist comprises a variant Fc region, or FcRn binding fragment thereof, which binds to FcRn with a higher affinity at pH 5.5 as compared to a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region, or FcRn binding fragment thereof, which binds to FcRn with a higher affinity at pH 6.0 and / or at pH 7.4 as compared to a corresponding wild-type Fc region. In some embodiments, the FcRn antagonist comprises a variant Fc region, or FcRn binding fragment thereof, which binds to FcRn with a higher affinity at both acidic and neutral pH.

[0071] In some embodiments, the variant Fc region is derived from the Fc region of any native immunoglobulin. In some embodiments, the native immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, the IgG is IgGl, IgG2, IgG3, or IgG4. In some embodiments, the human IgG is human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region varies from the human IgGl Fc region. In some embodiments, the human IgGl Fc region comprises a Glml(a), Glm2(x), Glm3(f), or Glml7(z) allotype.

[0072] In an embodiment, the variant Fc region, or FcRn binding fragment thereof, consists of two Fc domains.

[0073] In an embodiment, the variant Fc region comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or heterodimer. In an embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In an embodiment, the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0074] In some embodiments, the FcRn antagonists disclosed herein comprise or consist 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: 22, provided below.Table 1

[0075] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NO: 22.

[0076] In some embodiments, the FcRn antagonists disclosed herein comprise or consist of an amino acid sequence 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 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 domain comprises or consists of an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1-21. In some embodiments, the dimer is a heterodimer or a homodimer.Table 2

[0077] In an embodiment, the first Fc domain and / or the second Fc domain comprise an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 4. In an embodiment, 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 4.

[0078] In some embodiments, the FcRn antagonist comprises a population of FcRn antagonist molecules. In some embodiments, a FcRn antagonist comprising a first Fc domain and a second Fc domain comprising an amino acid sequence independently selected from the group consisting of SEQ ID NOs: 1, 2, 3, and 4 is the predominant FcRn antagonist molecule in the population of FcRn antagonist molecules. In some embodiments, the predominant FcRn antagonist molecule makes up at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the population of FcRn antagonist molecules.

[0079] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1.

[0080] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2.

[0081] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0082] In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 4. In an embodiment, the amino acid sequence of the Fc domains of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 4.

[0083] In certain embodiments, the variant Fc region is a heterodimer, where the constituent Fc domains are different from each other. Methods of producing Fc heterodimers are known in the art (see, e.g., US 8,216,805, which is incorporated by reference herein in its entirety). In an embodiment, the FcRn antagonist consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains which form a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NOs: 1, 2, 3, or 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which 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: 1 and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NOs: 2, 3, or 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which 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 NOs: 1, 3, or 4. In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which 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: 3 and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NOs: 1, 2, or 4. In an embodiment, the FcRn antagonistconsists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which 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: 4 and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NOs: 1, 2, or 3.

[0084] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 1.

[0085] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 2.

[0086] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 3.

[0087] In an embodiment, the FcRn antagonist consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains which form a homodimer, wherein the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO: 4.

[0088] In some embodiments, the FcRn antagonist comprises glycanation on one or both of the Fc domains. In some embodiments, the FcRn antagonist molecules comprise glycanation at EU position 297 on one or both of the Fc domains. In some embodiments, the glycanation comprises an N-glycan. In some embodiments, the N-glycan comprises a G0F N-glycan, GIF N- glycan, G2F N-glycan, or GO N-glycan.

[0089] In some embodiments, 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 antagonists comprise galactose. In some embodiments, the populationcomprises or consists of FcRn antagonists, 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 population of Fc domains of the FcRn antagonists comprise fucose.

[0090] 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 comprise amidated proline at EU position 439.

[0091] In some embodiments, the FcRn antagonist comprises aspartate, lysine, threonine, histidine, threonine, and cysteine at EU positions 221, 222, 223, 224, 225, and 226, respectively. In some embodiments, the FcRn antagonist lacks an amino acid atEU positions 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 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 221-224, 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.

[0092] 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.

[0093] In some embodiments, a first subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of an amino acid sequence 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.

[0094] In some embodiments, a second subpopulation of FcRn antagonist molecules comprises or consists of a variant Fc region comprising or consisting of a dimer of a first Fc domainand a second Fc domain, wherein the amino acid sequence of the first and second Fc domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 13, respectively.

[0095] In some embodiments, a third subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 10, respectively.

[0096] In some embodiments, a fourth subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of an amino acid sequence 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 in the fourth subpopulation are deaminated.

[0097] In some embodiments, a fifth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence 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 one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation are deaminated.

[0098] In some embodiments, a sixth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively.

[0099] In some embodiments, a seventh subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence 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 one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0100] In some embodiments, an eighth subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of an amino acid sequence 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.

[0101] In some embodiments, a ninth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 3 and 7, respectively.

[0102] In some embodiments, a tenth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0103] In some embodiments, an eleventh subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of an amino acid sequence 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 amino acid residues, independently selected from a methionine residue or a tryptophan residue, in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0104] In some embodiments, a first subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0105] In some embodiments, a second subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 13, respectively.

[0106] In some embodiments, a third subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 10, respectively.

[0107] In some embodiments, a fourth subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated.

[0108] In some embodiments, a fifth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated.

[0109] In some embodiments, a sixth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2 and 3, respectively.

[0110] In some embodiments, a seventh subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized.

[0111] In some embodiments, an eighth subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0112] In some embodiments, a ninth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NOs: 3 and 7, respectively.

[0113] In some embodiments, a tenth subpopulation of FcRn antagonist molecules comprises or consists of a 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 domain comprises or consists of the amino acid sequence of SEQ ID NOs: 2 and 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the tenth subpopulation is oxidized.

[0114] In some embodiments, an eleventh subpopulation of FcRn antagonist molecules comprises or consists of a 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 both the first and second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue or a tryptophan residue in each FcRn antagonist molecule in the eleventh subpopulation is oxidized.

[0115] In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with one of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with two of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with three of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with four of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with five of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with six of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with sevenof the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with eight of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with nine of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations. In some embodiments, the population of FcRn antagonist molecules comprises or consists of the first subpopulation combined with all of the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh subpopulations.

[0116] In some embodiments, the population comprises or consists of the first and second subpopulations. In some embodiments, the population comprises or consists of the first and third subpopulations. In some embodiments, the population comprises or consists of the first and fourth subpopulations. In some embodiments, the population comprises or consists of the first and fifth subpopulations. In some embodiments, the population comprises or consists of the first and sixth subpopulations. In some embodiments, the population comprises or consists of the first and seventh subpopulations. In some embodiments, the population comprises or consists of the first and eighth subpopulations. In some embodiments, the population comprises or consists of the first and ninth subpopulations. In some embodiments, the population comprises or consists of the first and tenth subpopulations. In some embodiments, the population comprises or consists of the first and eleventh subpopulations. In some embodiments, the populations listed above further comprise or consist of 1, 2, 3, 4, 5, 6, 7, 8, or 9 additional subpopulations. In some embodiments, these additional subpopulations are one or more of those described above.

[0117] In some embodiments, the population comprises or consists of the first and seventh, ninth, or eleventh subpopulations. In some embodiments, the population comprises or consists of the first, seventh, ninth, and eleventh subpopulations.

[0118] In some embodiments, the first subpopulation makes up 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 makes up 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 makes up 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 makes up 40%-90%, 50%-80%, or 55%-70% of the population of FcRn antagonist molecules. In some embodiments, the first subpopulation makes up 56.9%-68.3% or 59.5%-67.9% of the population of FcRn antagonist molecules.

[0119] In some embodiments, the second subpopulation makes up 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 makes up 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 makes up 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 makes up 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the second subpopulation makes up 0.8%-2.0% or 0.8%-2.1% of the population of FcRn antagonist molecules.

[0120] In some embodiments, the third subpopulation makes up 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 makes up 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 makes up 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 makes up 0.5%-3.0%, 1.0%-2.5%, or 1.0%-2.0% of the population of FcRn antagonist molecules. In some embodiments, the third subpopulation makes up 1.1%-2.1% or 1.0%-1.9% of the population of FcRn antagonist molecules.

[0121] In some embodiments, the fourth subpopulation makes up 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 makes up about 5%, about 4%, about 3%, about 2%, or about 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 5%, 4%, 3%, 2%, or 1% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up l%-5%, 2%-4%, or 2%-3% of the population of FcRn antagonist molecules. In some embodiments, the fourth subpopulation makes up 2. l%-3.2% or 2.0%-3.1% of the population of FcRn antagonist molecules.

[0122] In some embodiments, the fifth subpopulation makes up 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 makes upabout 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 makes up 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up 5%-12%, 6%-10%, or 7%-8% of the population of FcRn antagonist molecules. In some embodiments, the fifth subpopulation makes up 6.8%-9.4% or 6.9%-8.7% of the population of FcRn antagonist molecules.

[0123] In some embodiments, the sixth subpopulation makes up 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 makes up 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 makes up 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 makes up 7%-17%, 10%-15%, or 11%-12% of the population of FcRn antagonist molecules. In some embodiments, the sixth subpopulation makes up 7.0%-14.0% or 10.0%-14.4% of the population of FcRn antagonist molecules.

[0124] In some embodiments, the seventh subpopulation makes up 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 population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up 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 population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up 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 population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up O.5%-5.5%, 1.0%-3.0%, or 1.5%-2.5% of the population of FcRn antagonist molecules. In some embodiments, the seventh subpopulation makes up 1.5%-5.5% or 1.4%-4.9% of the population of FcRn antagonist molecules.

[0125] In some embodiments, the eighth subpopulation makes up 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 makes up 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 makes up 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 makes up 2.5%-7.5%, 3.0%-5.0%, or 3.5%-4.5% of the population of FcRn antagonist molecules. In some embodiments, the eighth subpopulation makes up 2.9%-7.4% or 3.0%-6.3% of the population of FcRn antagonist molecules.

[0126] In some embodiments, the ninth subpopulation makes up 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 makes up 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 makes up 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 makes up 0.5%-3.5%, 1.5%-2.0%, or 1.0%-1.5% of the population of FcRn antagonist molecules. In some embodiments, the ninth subpopulation makes up 0.4%-3.2% or 0.5%-2.6% of the population of FcRn antagonist molecules.

[0127] In some embodiments, the tenth subpopulation makes up 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 makes up 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 makes up 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the tenth subpopulation makes up 0.5%-2.0%, 0.5%-1.5%, or 1.0%-1.5% of the population of FcRn antagonist molecules.

[0128] In some embodiments, the eleventh subpopulation makes up 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 subpopulation makes up about 2.0%, about 1.5%, about 1%, or about 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation makes up 2.0%, 1.5%, 1%, or 0.5% of the population of FcRn antagonist molecules. In some embodiments, the eleventh subpopulation makes up 0.5%-2.0%, 0.5%-1.5%, or 1.0%- 1.5% of the population of FcRn antagonist molecules.

[0129] In some embodiments, the population of FcRn antagonist molecules comprises one or more of the FcRn antagonists described herein. In some embodiments, the FcRn antagonist isany of those described in International Patent Application No. PCT / IB2023 / 000696, filed on November 14, 2023, incorporated herein by reference in its entirety. In some embodiments, the FcRn antagonist is a population of FcRn antagonists as described in International Patent Application No. PCT / IB2023 / 000696, filed on November 14, 2023, incorporated herein by reference in its entirety.

[0130] In an embodiment, the FcRn antagonist is efgartigimod (CAS Registry No. 1821402-21-4). The term “efgartigimod” as used herein is interchangeable with “efgartigimod alfa.” In some embodiments, efgartigimod is efgartigimod alfa-fcab.

[0131] In an embodiment, the anti-FcRn antibody is nipocalimab (M281), rozanolixizumab (UCB7665), orilanolimab (ALXN1830 / SYNT001), batoclimab (IMVT- 1401 / RVT1401 / HBM9161), or IMVT-1402 / RVT1402.

[0132] In an embodiment, an antibody that binds specifically to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is nipocalimab, also known as M281. Nipocalimab is a full-length “Fc dead” IgGl monoclonal antibody. Nipocalimab has been administered as an intravenous infusion in Phase 2 clinical trials for the treatment of idiopathic inflammatory myopathy (IIM), Sjogren’s disease, and systemic lupus erythematosus (SLE), and in ongoing Phase 3 clinical trials for myasthenia gravis (MG), warm autoimmune hemolytic anemia (WAIHA), chronic inflammatory demyelinating polyneuropathy (CIDP), and hemolytic disease of fetus and newborn (HDFN). Nipocalimab comprises the light chain (SEQ ID NO: 23) and heavy chain (SEQ ID NO: 24) sequences set forth in Table 3 below:Table 3. Heavy chain and light chain sequences of nipocalimab

[0133] In an embodiment, an antibody that binds specifically to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is rozanolixizumab, also known as UCB 7665. Rozanolixizumab is a full-length humanized IgG4 monoclonal antibody. Rozanolixizumab has been administered as a subcutaneous infusion in clinical trials for ITP and CIDP and is approved for the treatment of gMG. Rozanolixizumab comprises the light chain (SEQ ID NO: 25) and heavy chain (SEQ ID NO: 26) sequences set forth in Table 4 below:Table 4. Heavy chain and light chain sequences of rozanolixizumab

[0134] In an embodiment, an antibody that binds specifically to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is orilanolimab, also known as SYNT001. Orilanolimab is another full-length humanized IgG4 monoclonal antibody. Orilanolimab has been administered as an intravenous infusion in Phase 2 clinical trials for treatment of WAIHA. Orilanolimab comprises the light chain (SEQ ID NO: 27) and heavy chain (SEQ ID NO: 28) sequences set forth in Table 5 below:Table 5. Heavy chain and light chain sequences of orilanolimab

[0135] In an embodiment, an antibody that binds specifically to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is batoclimab, also known as IMVT1401 / RVT1401 / HBM9161. Batoclimab is another full-length “Fc dead” IgGl monoclonal antibody. Batoclimab has been administered as a subcutaneous injection in ongoing Phase 2 clinical trials for treatment of Graves’ ophthalmopathy and CIDP, and in ongoing Phase 3 clinical trials for MG and thyroid eye disease (TED). Batoclimab comprises the light chain (SEQ ID NO: 29) and heavy chain (SEQ ID NO: 30) sequences set forth in Table 6 below:Table 6. Heavy chain and light chain sequences of batoclimab

[0136] In an embodiment, anti-FcRn antibodies for use according to the methods and uses described herein are any of the anti-FcRn antibodies described in International Patent Application Publication No. WO2023235679A1, the contents of which are incorporated herein in their entirety. In some embodiments, an antibody that binds specifically to FcRn and inhibits the binding of the Fc region of immunoglobulin to FcRn is IMVT-1402, also known as RVT1402. IMVT-1402 has been administered as a subcutaneous injection in a Phase 1 clinical trial in healthy results. IMVT- 1402 comprises the light chain variable (SEQ ID NO: 31) and heavy chain variable (SEQ ID NO: 32) sequences set forth in Table 7 below:Table 7. Heavy chain and light chain variable sequences of IMVT-1402Pharmaceutical Compositions

[0137] In an aspect, the instant disclosure provides pharmaceutical compositions comprising an FcRn antagonist for use in methods of reducing platelet degradation.

[0138] In an embodiment, the FcRn antagonist is efgartigimod. Efgartigimod (ARGX-113) is a modified human immunoglobulin (Ig) gamma (IgG) 1-derived Fc of the za allotype that binds with nanomolar affinity to human FcRn. Efgartigimod encompasses the IgGl Fc-region and has been engineered using ABDEG™ technology to increase its affinity for FcRn at both physiological and acidic pH. The increased affinity for FcRn of efgartigimod at both acidic and physiological pH results in a blockage of FcRn-mediated recycling of IgG.

[0139] Efgartigimod is a prescription medicine registered as VYVGART®, which is approved in several countries for the treatment of adults with generalized myasthenia gravis (gMG)and in Japan for the treatment of primary ITP. Efgartigimod is under development for both the intravenous (IV) and subcutaneous (SC) administration route.

[0140] For IV administration, in certain embodiments, efgartigimod may be administered in a formulation comprising sodium phosphate, sodium chloride, L-arginine hydrochloride, and polysorbate 80. In certain embodiments, efgartigimod may 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), with about 0.02% (w / v) polysorbate 80. In certain embodiments, efgartigimod may be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), with 0.02% (w / v) polysorbate 80. In certain embodiments, efgartigimod may 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), with about 0.02% (w / v) polysorbate 80, via intravenous infusion in a total volume of about 250 mL over a period of about 2 hours. In certain embodiments, efgartigimod may be administered in a formulation comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride (pH 6.7), with 0.02% (w / v) polysorbate 80, via intravenous infusion in a total volume of 250 mL over a period of 2 hours. See, e.g., WO2019110823A1, which is incorporated by reference herein in its entirety.

[0141] In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising about 25 mM sodium phosphate, about 100 mM sodium chloride, and about 150 mM L-arginine hydrochloride with a pH of about 6.7, with about 0.02% (w / v) polysorbate 80, diluted for intravenous infusion to a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 25 mM sodium phosphate, 100 mM sodium chloride, and 150 mM L-arginine hydrochloride with a pH of 6.7, with 0.02% (w / v) polysorbate 80, diluted for intravenous infusion to a total volume of 125 mL over a period of 1 hour.

[0142] In certain embodiments, efgartigimod may be administered in a formulation comprising 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, with a pH of about 6.7. This formulation is administered via intravenous infusion in a total volume of about 125 mL over a period of about 1 hour. In certain embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 4 mM sodium phosphate, 146 mM sodiumchloride, 24 mM L-arginine, and 0.0032% (w / v) polysorbate 80, with a pH of 6.7. This formulation is administered via intravenous infusion in a total volume of 125 mL over a period of 1 hour.

[0143] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate solution at a concentration of about 20 mg / mL. In certain embodiments, efgartigimod is administered via IV infusion and is provided in a sterile, colorless, clear concentrate solution at a concentration of 20 mg / mL.

[0144] In certain embodiments, efgartigimod is administered via IV infusion and is provided in a vial (e.g. , a single-dose vial). In certain embodiments, a vial of efgartigimod contains about 400 mg of efgartigimod at a concentration of about 20 mg / mL. In certain embodiments, a vial of efgartigimod contains 400 mg of efgartigimod at a concentration of 20 mg / mL. In certain embodiments, each mL of solution in a vial of efgartigimod contains about 31.6 mg L-arginine hydrochloride, about 0.2 mg polysorbate 80, about 5.8 mg sodium chloride, about 2.4 mg sodium phosphate dibasic anhydrous, about 1.1 mg sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of about 6.7. In certain embodiments, each mL of solution in a vial of efgartigimod contains 31.6 mg L-arginine hydrochloride, 0.2 mg polysorbate 80, 5.8 mg sodium chloride, 2.4 mg sodium phosphate dibasic anhydrous, 1.1 mg sodium phosphate monobasic monohydrate, and water for injection, USP, at a pH of 6.7.

[0145] In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of about 10 mg / kg as an IV infusion over about one hour once weekly for about 4 weeks. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once weekly. In certain embodiments, for patients weighing under 120 kg, efgartigimod is administered at a dose of 10 mg / kg as an IV infusion over one hour once weekly for 4 weeks. In certain embodiments, for patients weighing 120 kg or more, efgartigimod isadministered at a dose of about 1200 mg per IV infusion. In certain embodiments, for patients weighing 120 kg or more, efgartigimod is administered at a dose of 1200 mg per IV infusion.

[0146] For SC administration, in certain embodiments, efgartigimod may be administered alone. Alternatively, for SC administration, in certain embodiments, efgartigimod may be administered co-formulated with hyaluronidase, for example, rHuPH20. The co-formulated material will allow SC dosing of larger volumes.

[0147] In some embodiments, efgartigimod may be administered in a formulation comprising 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 formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 180 mg / mL efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 20 mM L-histidine, 100 mM sodium chloride, 60 mM sucrose, 10 mM L-methionine, and 0.04% (w / v) polysorbate 20, wherein the formulation has a pH of 6.0. In some embodiments, the formulation comprises 180 mg / mL efgartigimod.

[0148] In some embodiments, efgartigimod may be administered in a formulation comprising 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 formulation has a pH of about 6.0. In some embodiments, the formulation comprises about 200 mg / mL efgartigimod. In some embodiments, efgartigimod may be administered in a formulation comprising an aqueous solution comprising 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 formulation has a pH of 6.0. In some embodiments, the formulation comprises 200 mg / mL efgartigimod.

[0149] rHuPH20 is the active ingredient of Halozyme’s commercial product HYLENEX® recombinant (hyaluronidase human injection), referred to as HYLENEX®, which was approved by FDA for marketed use in the U.S. in December 2005. HYLENEX® is a tissue permeability modifier indicated as an adjuvant in SC fluid administration for achieving hydration, to increase the dispersion and absorption of other injected drugs, and in SC urography, for improving resorption of radiopaque agents.

[0150] rHuPH20 is a recombinant enzyme human hyaluronidase produced by genetically engineered Chinese hamster ovary (CHO) cells containing a deoxyribonucleic plasmid encoding a soluble fragment of human hyaluronidase (posterior head protein 20 [PH20]).

[0151] The HZ202 rHuPH20 DS is currently registered in HYLENEX® and other biologic drug products co-formulated with rHuPH20 DS. As such, in certain embodiments HZ202 rHuPH20 DS is used in the efgartigimod / rHuPH20 co-formulated product for SC administration (i.e., efgartigimod PH20 SC).

[0152] Provided in the co-formulations, combinations, uses and methods herein are soluble hyaluronidases. Soluble hyaluronidases include any that, upon expression, are secreted from a cell and exist in soluble form. Such soluble hyaluronidases include, but are not limited to, bacterial soluble hyaluronidases, non-human soluble hyaluronidases, such as bovine PH20 and ovine PH20, human soluble PH20, and variants thereof. Generally soluble forms of PH20 are produced using protein expression systems that facilitate correct N-glycosylation to ensure the polypeptide retains activity, since glycosylation is important for the catalytic activity and stability of hyaluronidases. Such cells include, for example Chinese Hamster Ovary (CHO) cells (e. ., DG44 CHO cells).

[0153] In some embodiments, rHuPH20 refers to the composition produced upon expression in a cell, such as a CHO cell, of nucleic acid encoding residues 36-482 of SEQ ID NO: 33, generally linked to the native or a heterologous signal sequence (residues 1-35 of SEQ ID NO: 33). rHuPH20 is produced by expression of a nucleic acid molecule, such as encoding amino acids 1-482 (set forth in SEQ ID NO: 33) in a mammalian cell. Translational processing removes the 35 amino acid signal sequence. As produced in the culture medium there is heterogeneity at the C- terminus such that the product, designated rHuPH20, includes a mixture of species that can include any one or more of the polypeptides 36-480, 36-481, and 36-482 of SEQ ID NO: 33, and some shorter polypeptides, in various abundance. Typically, rHuPH20 is produced in cells that facilitate correct N-glycosylation to retain activity, such as CHO cells (c.g, DG44 CHO cells). In some embodiments, one of the most abundant species is the 446 amino acid polypeptide corresponding to residues 36-481 of SEQ ID NO: 33. In some embodiments, rHuPH20 refers to polypeptides that are soluble or secreted upon expression in a mammalian cell and have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more sequence identity with residues 36-482 of SEQ ID NO: 33. In some embodiments, the rHuPH20 is the 447 amino acid polypeptide of SEQ ID NO: 34.Table 3. Exemplary hyaluronidase sequences

[0154] In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 20 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 200 mg to about 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 300 mg to about 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 750 mg to about 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 1000 mg to about 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from about 1000 mg to about 2000 mg.

[0155] In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from 20 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from 200 mg to 20,000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from300 mg to 6000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from 750 mg to 3000 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from 1000 mg to 2500 mg. In some embodiments, the pharmaceutical formulation comprises an FcRn antagonist in an amount from 1000 mg to 2000 mg.

[0156] 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 efgartigimod.

[0157] In some embodiments, the pharmaceutical formulation comprises efgartigimod in an amount from about 800 mg to about 1200 mg. In some embodiments, the pharmaceutical formulation comprises efgartigimod in an amount from 800 mg to 1200 mg.

[0158] In some embodiments, the pharmaceutical formulation comprises about 1000 mg efgartigimod. In some embodiments, the pharmaceutical formulation comprises 1000 mg efgartigimod.

[0159] In some embodiments, the pharmaceutical formulation comprises from about 10 mg / mL to about 200 mg / mL efgartigimod. In some embodiments, the pharmaceutical formulation comprises from 10 mg / mL to 200 mg / mL efgartigimod.

[0160] In some embodiments, the pharmaceutical formulation comprises about 20 mg / mL efgartigimod. In some embodiments, the pharmaceutical formulation comprises 20 mg / mL efgartigimod.

[0161] In some embodiments, the pharmaceutical formulation comprises about 180 mg / mL efgartigimod. In some embodiments, the pharmaceutical formulation comprises 180 mg / mL efgartigimod.

[0162] In some embodiments, the pharmaceutical formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase PH20 (rHuPH20).

[0163] The hyaluronidase can be present in the pharmaceutical formulation in any suitable amount. In an embodiment, the amount of hyaluronidase enzyme is from about 1000 U / mL to about 3000 U / mL. In an embodiment, the amount of hyaluronidase enzyme is about 1000 U / mL, about 1500 U / mL, about 2000 U / mL, about 2500 U / mL, or about 3000 U / mL. In an embodiment, the amount of hyaluronidase enzyme is 2000 U / mL.

[0164] In some embodiments, the rHuPH20 is present in the pharmaceutical formulation in an amount of about 11,000 U. In some embodiments, the rHuPH20 is present in the pharmaceutical formulation in an amount of 11,000 U.

[0165] In some embodiments, the pharmaceutical formulation comprises at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase enzyme. 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, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of an endoglycosidase hydrolase enzyme.

[0166] In some embodiments, the pharmaceutical formulation comprises about 20,000 U of an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises at least about 500 U / mL to at least about 5000 U / mL of an endoglycosidase hydrolase enzyme. 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 pM, at least about 2500 pM, at least about 3000 pM, at least about 3500 pM, at least about 4000 pM, at least about 4500 U / mL, or at least about 5000 U / mL of an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical formulation comprises about 2000 U / mL of an endoglycosidase hydrolase enzyme.

[0167] In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at a hexosaminidic (1-4) or (1-3) linkage. In some embodiments, the endoglycosidase hydrolase enzyme comprises a catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme 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 to amino acids 36-490 of SEQ ID NO: 33. In some embodiments, the endoglycosidase hydrolase enzymecomprises a hyaluronidase. Tn some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant, and any isoform thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0168] In some embodiments, the endoglycosidase hydrolase enzyme 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 a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitution in an alpha-helix region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitution in linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme 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 a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitution in an alpha-helix region, a linker region, or both an alpha- helix region and a linker region relative to wild-type rHuPH20; ii. deletion of one or more N- terminal amino acid, one or more C-terminal amino acid, or one or more N-terminal amino acid and one or more C-terminal amino acid relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0169] "Hyaluronidase," as used herein, refers to an enzyme capable of catalyzing the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which is present in the subcutaneous space and contributes to the soluble gel-like component of 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 hyaluronan in the subcutaneous space locally at the site of injection in the skin. Depolymerization of hyaluronan by hyaluronidase is accomplished by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronan results in a transientreduction in the viscosity of the gel-like phase of the extracellular matrix and increased hydraulic conductance that facilitates the dispersion and absorption of the coadministered therapeutic agent. Thus, a hyaluronidase, e.g., rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologies and drugs by acting as a permeation enhancer. In certain embodiments, the hyaluronidase comprises ENHANZE™.

[0170] In any of the above embodiments, the pharmaceutical formulation may be a unit dosage form.

[0171] In an embodiment, the unit dosage form comprises the FcRn antagonist as a dry formulation for dissolution such as a lyophilized powder, freeze-dried powder, or water-free concentrate. In an embodiment, the dry formulation is comprised in a hermetically sealed container such as a vial, an ampoule, or a sachet.

[0172] In an embodiment, the unit dosage form comprises the FcRn antagonist as a liquid formulation, ( .g., injection or infusion solution). In an embodiment, the liquid formulation is comprised in a hermetically sealed container such as a vial, a sachet, a pre-filled syringe, a prefilled autoinjector, or a cartridge for a reusable syringe or applicator.

[0173] In an embodiment, the unit dosage per 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 ranging from about 500 to about 2500 mg or from about 1000 mg to about 2000 mg. In an embodiment, these preparations can be adjusted to a desired concentration by adding a sterile diluent to each vial.

[0174] The formulations disclosed herein include bulk drug compositions useful in the manufacture of pharmaceutical compositions (e.g., compositions that are suitable for administration to a subject or patient) which can be used in the preparation of unit dosage forms. In an embodiment, a composition of the invention is a pharmaceutical composition. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., an FcRn antagonist of the invention or other prophylactic or therapeutic agent), and a pharmaceutically acceptable carrier. In an embodiment, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject.Methods

[0175] In an aspect, methods for reducing platelet degradation using an FcRn antagonist are provided. In certain embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0176] Platelet degradation can be detected by any suitable method. Newly produced platelets are characterized by having a larger RNA content and overall volume compared to mature platelets. These characteristics can be measured, for example, by hematology analyzers, such as Sysmex XE-2100. Platelets in circulation continuously release a soluble extracellular fragment of the a-subunit of glycoprotein lb (GPIba), glycocalicin, from the platelet membrane via proteolytic cleavage. Thus, plasma glycocalicin levels and glycocalicin index (GCI) have been shown to be a measure of platelet destruction and turnover. In some embodiments, platelet degradation is detected by measuring one or more of the following: immature platelet fraction (IPF%), percentage of reticulated platelets (RP%), mean glycocalicin levels, or glycocalicin index. In a preferred embodiment, platelet degradation is detected by measuring IPF%.

[0177] IPF% in healthy individuals typically ranges from 0.5% to 9%. Thus, in some embodiments, the subject in need of reduction in platelet degradation has an IPF% >9% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% >20% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% >10%, >15%, >20%, >25%, >30%, >35%, >40%, >45%, >50%, >55%, >60%, >65%, >70%, >75%, >80%, >85%, >90%, or >95% prior to administration of an FcRn antagonist.

[0178] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from about 10% to about 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from about 10% to about 75%, from about 10% to about 70%, from about 10% to about65%, from about 10% to about 60%, from about 10% to about 55%, from about 10% to about50%, from about 10% to about 45%, from about 10% to about 40%, from about 10% to about35%, or from about 10% to about 30% prior to administration of an FcRn antagonist.

[0179] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from about 15% to about 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in arange from about 15% to about 75%, from about 15% to about 70%, from about 15% to about65%, from about 15% to about 60%, from about 15% to about 55%, from about 15% to about50%, from about 15% to about 45%, from about 15% to about 40%, from about 15% to about35%, or from about 15% to about 30% prior to administration of an FcRn antagonist.

[0180] In some embodiments, the subject in need of reduction in platelet degradation has an ZPF% in a range from about 20% to about 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from about 20% to about 75%, from about 20% to about 70%, from about 20% to about65%, from about 20% to about 60%, from about 20% to about 55%, from about 20% to about50%, from about 20% to about 45%, from about 20% to about 40%, from about 20% to about35%, or from about 20% to about 30% prior to administration of an FcRn antagonist.

[0181] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 10% to 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 10% to 75%, from 10% to 70%, from 10% to 65%, from 10% to 60%, from 10% to 55%, from 10% to 50%, from 10% to 45%, from 10% to 40%, from 10% to 35%, or from 10% to 30% prior to administration of an FcRn antagonist.

[0182] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 15% to 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 15% to 75%, from 15% to 70%, from 15% to 65%, from 15% to 60%, from 15% to 55%, from 15% to 50%, from 15% to 45%, from 15% to 40%, from 15% to 35%, or from 15% to 30% prior to administration of an FcRn antagonist.

[0183] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 20% to 80% prior to administration of an FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has an IPF% in a range from 20% to 75%, from 20% to 70%, from 20% to 65%, from 20% to 60%, from 20% to 55%, from 20% to 50%, from 20% to 45%, from 20% to 40%, from 20% to 35%, or from 20% to 30% prior to administration of an FcRn antagonist.

[0184] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% of about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%,about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, or about 80%, prior to administration of an FcRn antagonist.

[0185] In some embodiments, the subject in need of reduction in platelet degradation has an IPF% of 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%,25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%,59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%,76%, 77%, 78%, 79%, or 80%, prior to administration of an FcRn antagonist.

[0186] In some embodiments, the subject in need of reduction in platelet degradation has a platelet count of <100 x 109 / L prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has a platelet count of <50 x 109 / L prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has a platelet count of <30 x 109 / L prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has a platelet count of <20 x 109 / L prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation has a platelet count of <10 x 109 / L prior to administration of the FcRn antagonist.

[0187] In some embodiments, the subject in need of reduction in platelet degradation has thrombocytopenia. Thrombocytopenia can be characterized by impaired platelet production, increased removal of platelets, or both. As used herein, the term “consumptive thrombocytopenia” refers to thrombocytopenia due to increased removal of platelets from the bloodstream (i.e., increased platelet degradation). As used herein, the term “hypoproliferative thrombocytopenia” refers to thrombocytopenia due to impaired platelet production. In some embodiments, the subject in need of reduction in platelet degradation has consumptive thrombocytopenia. In someembodiments, the subject in need of reduction in platelet degradation has consumptive thrombocytopenia and hypoproliferative thrombocytopenia.

[0188] In some embodiments, the subject in need of reduction in platelet degradation has immune thrombocytopenia (ITP). In some embodiments, the subject in need of reduction in platelet degradation has primary ITP. In some embodiments, the subject in need of reduction in platelet degradation has newly diagnosed, persistent, or chronic primary ITP.

[0189] In some embodiments, the subject in need of reduction in platelet degradation received at least 1 previous ITP treatment prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation received at least 2 previous ITP treatments prior to administration of the FcRn antagonist. In some embodiments, the subject in need of reduction in platelet degradation had an insufficient response to at least 1 previous ITP treatment prior to administration of the FcRn antagonist. In some embodiments, insufficient response refers to failure to achieve a response as defined by the International Working Group (i.e., platelet count of >30x 109 / L and a two-fold increase in platelet count for at least two separate, consecutive analysis visits that were at least 7 days apart).

[0190] In some embodiments, a previous ITP treatment includes treatment with at least one compound approved for standard-of-care treatment for ITP. Exemplary classes of compounds approved for standard-of-care treatment for ITP that may be used in accordance with the methods provided herein include (i) immunosuppressants, such as corticosteroids, cyclosporine, and azathioprine; (ii) preparations of naturally occurring immunoglobulin, such as IVIg and anti-D I; (iii) anti-CD20 monoclonal antibodies, such as rituximab; (iv) TPO-RAs, such as eltrombopag,romiplostim, and avatrombopag; and (v) small molecule inhibitors of spleen tyrosine kinase (Syk), such as fostamatinib (Tavalisse).

[0191] In some embodiments, a compound approved for standard-of-care treatment for ITP is a corticosteroid, such as oral prednisone, intravenous prednisone, methylprednisone, dexamethasone, and combinations thereof.

[0192] In some embodiments, a compound approved for standard-of-care treatment for ITP is danazol.

[0193] In some embodiments, a compound approved for standard-of-care treatment for ITP is dap sone.

[0194] In some embodiments, a previous ITP treatment is splenectomy.

[0195] In some embodiments, the FcRn antagonist is administered at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 200 mg to about 20,000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 300 mg to about 6000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2500 mg. In some embodiments, the FcRn antagonist is administered at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0196] 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 efgartigimod, or a biosimilar version thereof.

[0197] In some embodiments, the FcRn antagonist is administered at a fixed dose 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 7000 mg, about 8000 mg, about 9000 mg, about 10,000 mg, about 11,000 mg, about 12,000 mg, about 13,000 mg, about 14,000 mg, about15,000 mg, about 16,000 mg, about 17,000 mg, about 18,000 mg, about 19,000 mg, or about 20,000 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0198] 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 efgartigimod, or a biosimilar version thereof.

[0199] 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 efgartigimod, or a biosimilar version thereof.

[0200] 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 efgartigimod, or a biosimilar version thereof.

[0201] In some embodiments, the FcRn antagonist is administered at a dose of 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, about190 mg / kg, or about 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0202] In some embodiments, the FcRn antagonist is administered at a dose of 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, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0203] In some embodiments, the FcRn antagonist is administered intravenously. In some embodiments, the FcRn antagonist is administered intravenously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0204] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 0.2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 2 mg / kg to about 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 2 mg / kg to about 120 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 3 mg / kg to about 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0205] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 0.2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 2 mg / kg to 200 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 2 mg / kg to 120 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 3 mg / kg to 60 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0206] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 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. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0207] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 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, 55 mg / kg, 60 mg / kg, 65 mg / kg, 70 mg / kg, 75 mg / kg, 80 mg / kg, 85 mg / kg, 90 mg / kg, 95 mg / kg, 100 mg / kg, 110 mg / kg, 120 mg / kg, 130 mg / kg, 140 mg / kg, 150 mg / kg, 160 mg / kg, 170 mg / kg, 180 mg / kg, 190 mg / kg, or 200 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0208] In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 10 mg / kg to about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of about 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 10 mg / kg to 30 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 10 mg / kg to 25mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 20 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is administered intravenously once weekly or once every two weeks at a dose of 30 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0209] In some embodiments, the FcRn antagonist is administered intravenously once weekly for 4 doses. In some embodiments, the FcRn antagonist is administered intravenously once weekly for 4 doses, with subsequent doses administered either once weekly or once every other week. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration based on platelet count response and / or clinical symptoms after the first 4 once-weekly doses are administered. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a platelet count of >100 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a stable platelet count of >100 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration when the subject exhibits a stable platelet count of >30 x 109 / L and <100x 109 / L depending on the subject’s condition. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration when the subject exhibits a platelet count <30 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0210] In some embodiments, the FcRn antagonist is administered intravenously once weekly at a dose of 10 mg / kg for 4 doses. In some embodiments, the FcRn antagonist is administered intravenously once weekly at a dose of 10 mg / kg for 4 doses, with subsequent 10 mg / kg doses administered either once weekly or once every other week. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to 10 mg / kg once every other week administration based on platelet count response and / or clinical symptoms after the first 4 once- weekly 10 mg / kg doses are administered. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 10 mg / kg when thesubject achieves a platelet count of >100 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 10 mg / kg when the subj ect achieves a stable platelet count of > 100 x 1 o9 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration at a dose of 10 mg / kg when the subject achieves a stable platelet count of >30 x 109 / L and <100 109 / L depending on the subject’s condition. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration at a dose of 10 mg / kg when the subject exhibits a platelet count <30 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0211] In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L. In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L and administration of the FcRn antagonist is resumed at a dosing regimen of once every other week when the subject exhibits a platelet count <150 x 109 / L. In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L and administration of the FcRn antagonist is resumed at a dose of 10 mg / kg administered once every other week when the subject exhibits a platelet count <150 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0212] In some embodiments, the FcRn antagonist is administered subcutaneously. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0213] In some embodiments, FcRn antagonist is administered subcutaneously at a fixed dose of about 20 mg to about 20,000 mg. In some embodiments, FcRn antagonist is administered subcutaneously at a fixed dose of about 100 mg to about 10,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0214] In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose 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 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 once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0215] 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0216] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of about 750 mg to about 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of about 1000 mg to about 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of about 1000 mg or about 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0217] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly or every two weeks at a fixed dose of 750 mg to 3000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly. 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 monthly. In some embodiments, the FcRn antagonist is administeredsubcutaneously once weekly or every two weeks at a fixed dose of 1000 mg to 2000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly or every two weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof

[0218] In some embodiments, the FcRn antagonist is first administered subcutaneously at a fixed dose of about 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is first administered subcutaneously at a fixed dose of 1000 mg twice on the same day. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0219] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg to about 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg to about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1500 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of about 1750 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0220] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg to 1750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg to 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 750 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 800 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1000 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1200 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1250 mg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a fixed dose of 1500 mg. In some embodiments, the FcRn antagonist is administeredsubcutaneously once weekly at a fixed dose of 1750 mg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0221] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly for 4 doses. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly for 4 doses, with subsequent doses administered either once weekly or once every other week. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration based on platelet count response and / or clinical symptoms after the first 4 once-weekly doses are administered. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a platelet count of >30 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a platelet count of >100 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a stable platelet count of >30 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a stable platelet count of >100 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration when the subject achieves a stable platelet count of >30 x 109 / L and <100x 109 / L depending on the subject’s condition. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration when the subject exhibits a platelet count <30 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0222] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 1000 mg for 4 doses. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 1000 mg for 4 doses, with subsequent 1000 mg doses administered either once weekly or once every other week. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to 1000 mg once every other week administration based on platelet count response and / or clinical symptoms after the first 4 once- weekly 1000 mg doses are administered. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 1000 mg when the subject achieves a platelet count of >30 x 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 1000 mg when the subject achieves a platelet count of >100 x 109 / L. In some embodiments, the dosing regimenof the FcRn antagonist is adjusted to once every other week administration at a dose of 1000 mg when the subject achieves a stable platelet count of >30 * 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 1000 mg when the subject achieves a stable platelet count of >100 * 109 / L. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once every other week administration at a dose of 1000 mg when the subject achieves a stable platelet count of >30 x io9 / L and <100 x 109 / L depending on the subject’s condition. In some embodiments, the dosing regimen of the FcRn antagonist is adjusted to once weekly administration at a dose of 1000 mg when the subject exhibits a platelet count <30 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0223] In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L. In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L and administration of the FcRn antagonist is resumed at a dosing regimen of once every other week when the subject exhibits a platelet count <150 x 109 / L. In some embodiments, administration of the FcRn antagonist is suspended when the subject exhibits a platelet count >400 x 109 / L and administration of the FcRn antagonist is resumed at a dose of 1000 mg administered once every other week when the subject exhibits a platelet count <150 x 109 / L. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0224] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg to about 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 20 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of about 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0225] In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg to 25 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 10 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 15 mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 20mg / kg. In some embodiments, the FcRn antagonist is administered subcutaneously once weekly at a dose of 25 mg / kg. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0226] In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously. In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously at fixed dose of 100 mg to 10,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is first administered intravenously and is subsequently administered subcutaneously at fixed dose of 1000 mg or 2000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0227] In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously. In some embodiments, one or more doses of the FcRn antagonist are administered intravenously and subsequent doses of the FcRn antagonist are administered subcutaneously at fixed dose of 100 mg to 10,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, 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 at fixed dose of 1000 mg or 2000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0228] In some embodiments, the FcRn antagonist is administered for 6, 12, 24, 39, 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 52 weeks or less. In some embodiments, the FcRn antagonist is administered for at least 6, 12, 24, 39, 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 24 weeks. In some embodiments, the FcRn antagonist is administered for at least 52 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0229] In some embodiments, the method further comprises administering to the subject one or more doses of an additional therapeutic agent.

[0230] In some embodiments, the method further comprises administering to the subject an effective amount of a compound approved for standard-of-care treatment for ITP.

[0231] In an embodiment, the method further comprises administering to the subject an effective amount of a corticosteroid, a TPO-RA, IVIg or anti-D Ig, an immunosuppressant, an anti- CD20 monoclonal antibody, danazol, dapsone, and / or fostamatinib.

[0232] In some embodiments, the corticosteroid is oral prednisone, intravenous prednisone, methylprednisone, dexamethasone, and combinations thereof.

[0233] In some embodiments, the TPO-RA is eltrombopag, romiplostim, or avatrombopag.

[0234] In some embodiments, the anti-CD20 monoclonal antibody is rituximab or a biosimilar version thereof.

[0235] In some embodiments, IPF% is reduced in the subject within 1 week of administration of the FcRn antagonist. In some embodiments, IPF% is reduced in the subject within 2 weeks, within 3 weeks, within 4 weeks, within 8 weeks, within 12 weeks, within 18 weeks, or within 24 weeks of administration of the FcRn antagonist. In some embodiments, IPF% is reduced in the subject within 2 weeks, within 3 weeks, within 4 weeks, within 8 weeks, within 12 weeks, within 18 weeks, or within 24 weeks of administration of the FcRn antagonist once weekly or once every other week. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0236] In some embodiments, the subject has an IPF% of <15% following administration of the FcRn antagonist. In some embodiments, the subject has an IPF% of <10% following administration of the FcRn antagonist. In some embodiments, the subject has an IPF% between 0.5% and 9% following administration of the FcRn antagonist. In some embodiments, IPF% is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following administration of the FcRn antagonist. In some embodiments, IPF% is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following an initial administration of an initial dose of the FcRn antagonist. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration. In some embodiments, IPF% is measured 24 weeks following administration of the FcRn antagonist. In some embodiments, IPF% is measured 24 weeksfollowing an initial administration of an initial dose of the FcRn antagonist. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly or once every other week for 24 weeks. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration for 20 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0237] In some embodiments, IPF% is reduced by at least 10% compared to a baseline IPF% value, following administration of the FcRn antagonist. In some embodiments, IPF% is reduced by at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, or at least 40% compared to a baseline IPF% value, following administration of the FcRn antagonist. In some embodiments, the baseline IPF% value is measured prior to administration of the FcRn antagonist. In some embodiments, the baseline IPF% value is measured prior to an initial administration of an initial dose of the FcRn antagonist. In some embodiments, IPF% is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following administration of the FcRn antagonist. In some embodiments, IPF% is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following an initial administration of an initial dose of the FcRn antagonist. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration. In some embodiments, IPF% is measured 24 weeks following administration of the FcRn antagonist. In some embodiments, IPF% is measured 24 weeks following an initial administration of an initial dose of the FcRn antagonist. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly or once every other week for 24 weeks. In some embodiments, IPF% is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration for 20 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0238] In some embodiments, IPF% is reduced to a mean [+ / -SE] value of 13.6 [+Z-2.7], compared to a mean [+ / -] baseline value of 29.2 [+Z-5.3] following administration of the FcRn antagonist. In some embodiments, IPF% is reduced to a mean [+ / -SE] value of 13.6 [+Z-2.7], compared to a mean [+ / -] baseline value of 29.2 [+Z-5.3] following administration of the FcRn antagonist for 24 weeks. In some embodiments, IPF% is measured in a group of adult humansubjects with persistent or chronic TTP receiving 10 mg / kg of an FcRn antagonist intravenously once weekly for 4 weeks, followed by once weekly or once every other week administration based on platelet count response and clinical symptoms. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0239] In some embodiments, platelet production is not markedly different in the subject following administration of the FcRn antagonist. In some embodiments, platelet production is within a normal range in the subject before and following administration of the FcRn antagonist. In some embodiments, absolute immature platelet count (AIPC) is <20 x 109 / L, <15 x 109 / L, <10x109 / L, or <5 x 109 / L following administration of the FcRn antagonist. In some embodiments, AIPC is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following administration of the FcRn antagonist. In some embodiments, AIPC is measured 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks following an initial administration of an initial dose of the FcRn antagonist. In some embodiments, AIPC is measured after administration of the FcRn antagonist once weekly for 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks, 18 weeks, or 24 weeks. In some embodiments, AIPC is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration. In some embodiments, AIPC is measured 24 weeks following administration of the FcRn antagonist. In some embodiments, AIPC is measured 24 weeks following an initial administration of an initial dose of the FcRn antagonist. In some embodiments, AIPC is measured after administration of the FcRn antagonist once weekly or once every other week for 24 weeks. In some embodiments, AIPC is measured after administration of the FcRn antagonist once weekly for 4 weeks, followed by once weekly or once every other week administration for 20 weeks. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0240] In an embodiment, the subject is any human or non-human animal. In an embodiment, the subject is a human or non-human mammal. In an embodiment, the subject is a human. In an embodiment, the subject is an adult human.

[0241] In an aspect, an FcRn antagonist is provided for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein. In an aspect, an FcRn antagonist is provided for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces IPF% inaccordance with any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0242] In an aspect, an FcRn antagonist is provided for use in the manufacture of a medicament for reducing platelet degradation in a subject in need thereof, wherein the FcRn antagonist is administered to the subject according to any of the methods described herein. In an aspect, an FcRn antagonist is provided for use in the manufacture of a medicament for reducing IPF% in a subject in need thereof, wherein the FcRn antagonist is administered to the subject according to any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0243] In an aspect, an FcRn antagonist is provided for use in the manufacture of a medicament for treating ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein. In an aspect, an FcRn antagonist is provided for use in the manufacture of a medicament for treating ITP in a subject in need thereof, wherein the FcRn antagonist reduces IPF% in accordance with any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0244] In an aspect, provided herein is the use of an FcRn antagonist for reducing platelet degradation according to any of the methods described herein. In an aspect, provided herein is the use of an FcRn antagonist for reducing IPF% according to any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0245] In an aspect, provided herein is the use of an FcRn antagonist for treating ITP, wherein the FcRn antagonist reduces platelet degradation in accordance with any of the methods described herein. In an aspect, provided herein is the use of an FcRn antagonist for treating ITP, wherein the FcRn antagonist reduces IPF% in accordance with any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0246] In an aspect, provided herein is the use of an FcRn antagonist for the manufacture of a medicament for reducing platelet degradation according to any of the methods described herein. In an aspect, provided herein is the use of an FcRn antagonist for the manufacture of a medicament for reducing IPF% according to any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.

[0247] In an aspect, provided herein is the use of an FcRn antagonist for the manufacture of a medicament for treating ITP, wherein the FcRn antagonist reduces platelet degradation inaccordance with any of the methods described herein. In an aspect, provided herein is the use of an FcRn antagonist for the manufacture of a medicament for treating ITP, wherein the FcRn antagonist reduces IPF% in accordance with any of the methods described herein. In some embodiments, the FcRn antagonist is efgartigimod, or a biosimilar version thereof.EXAMPLES

[0248] The following examples are offered by way of illustration, and not by way of limitation.Example 1: Effect of efgartigimod on immature platelet fraction in adults with primary ITP

[0249] Immature platelet fraction (IPF%) is the number of immature platelets relative to the total number of platelets and is a measure for enhanced platelet degradation. IPF% is increased in patients with primary ITP. Efgartigimod (EFG) is a human IgG Fc fragment engineered to bind competitively to the neonatal Fc receptor (FcRn) with high affinity, preventing endogenous IgG recycling and reducing IgG levels, including pathogenic IgG autoantibodies.

[0250] Efficacy and safety of EFG IV were evaluated in ADVANCE, a phase 3, multicenter, double-blinded, placebo (PBO)-controlled trial in adults with persistent (lasting 3-12 months from diagnosis, including individuals not reaching spontaneous remission or not maintaining their response after stopping treatment 3-12 months from diagnosis) or chronic (lasting for >12 months) primary ITP. Patients had to have an average platelet count of less than 30x 107L over two qualifying counts during screening, and a previous response to at least one ITP therapy as established by the investigator. In addition, patients had to be on either concurrent therapy at baseline or have received a second previous ITP therapy that was discontinued for 4 weeks or more (>6 months for anti-CD20 therapy) before baseline. This study is registered with ClinicalTrials.gov (NCT04188379) and is completed.

[0251] A screening period of up to 2 weeks was followed by a 24-week treatment period. The end-of-treatment visit was performed on trial day 169 after the baseline visit. Upon treatment period completion, patients were eligible to enter an open-label extension study (ADVANCE+; ClinicalTrials.gov identifier NCT04225156; EudraCT number 2019-002101-21); those who did not were followed up for an additional 4 weeks. The maximum trial duration was 31 weeks,including a screening period of up to 2 weeks, a treatment period of 24 weeks, an end-of-treatment visit, and a follow-up period of 4 weeks.

[0252] Concurrent immune thrombocytopenia therapy (oral corticosteroids, oral thrombopoietin receptor agonist, fostamatinib, non-corticosteroid immunosuppressants, dapsone, or danazol, or a combination) was permitted at a stable dose and regimen (no changes in dose or frequency) during the study. An increase in concurrent ITP therapy was allowed starting at week 12 for patients who did not have a platelet count of 30*109 / L or more on any visit during the preceding 4 weeks; these patients were considered non-responders in the primary and secondary endpoint analyses.

[0253] A total of 205 patients were screened and 131 (86 in the EFG group; 45 in the PBO group) were randomly assigned 2: 1 to receive either EFG (10 mg / kg) or PBO intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients’ platelet count. The dosing schedule could change at the discretion of the investigator to every other week from weeks 4 to 15 in patients who had platelet counts of >100* 109 / L or more for 3 of 4 consecutive weeks, including the fourth week. Treatment could change back from every other week to once per week in patients whose platelet counts decreased to <100* 109 / L for 2 consecutive weeks or <30* 109 / L for 1 week or in patients who received rescue therapy. Treatment was temporarily withheld if the participant was at undue risk (e.g., they had a COVID-19 infection) followed by reintroduction once the investigator considered the undue risk passed. Treatment was also temporarily withheld if the participant had platelet counts of >400 x 109 / L and was resumed with every-other-week dosing when the platelet count decreased to <150* 109 / L. The dosing schedule the participant was receiving at week 15 was fixed for weeks 16-24 for each individual participant.

[0254] These patients represented a population with long-term disease who had a mean time since diagnosis of 10.6 years and 67% (88 / 131) of whom had received at least three previous immune thrombocytopenia treatments.

[0255] The primary endpoint, evaluated in the chronic population, was proportion of patients with sustained platelet count response (>50* 109 / L for at least 4 of the last 6 weeks). 22% (17 / 78) of patients with chronic ITP receiving EFG reached the primary endpoint compared with 5% (2 / 40) of those receiving PBO (p=0 032; adjusted difference in response, 16% [95% CI 2.6- 26.4]). The median number of weeks of disease control (cumulative weeks with platelet counts of >50* 109 / L) in patients with chronic ITP was 2.0 (IQR 0.0-11.0) for EFG versus 0.0 (0.0—1.0) forPBO (p=0.0009). EFG was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in EFG and 13% in PBO), hematuria (16% in EFG and 16% in PBO), and petechiae (15% in EFG and 27% in PBO).

[0256] Absolute immature platelet count (AIPC) and fraction of immature platelets (IPF%) were also measured to examine the effect of EFG on platelet formation and platelet degradation, respectively.

[0257] In the 40 assessed participants, mean [+ / -SE] IPF% was reduced following EFG treatment (baseline IPF%, 21.6 [+7-2.6]; week 24 IPF%, 13.6 [+7-2.7]) vs PBO (baseline IPF%, 29.2 [+7-5.3]; week 24 IPF%, 33.8 [+7-4.5]) (FIG. 1A). There was a clear distinction in IPF% in EFG responders vs EFG non-responders (FIG. IB). In the EFG responders, mean [+ / -SE] IPF% was reduced from 19.6 [+ / -4.2] at baseline to 6.9 [+ / - 1.1] at week 24. In the EFG non- responders, IPF% was 22.9 [+ / - 3.2] at baseline and 20.4 [+7-4.1] at week 24. Platelet production (measured by mean AIPC) was not markedly different following treatment with EFG vs PBO (FIGs. 2A-2B).

[0258] Observed platelet count responses in EFG-treated participants with primary ITP were likely mediated by a reduction in platelet degradation.* * *

[0259] The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

Claims1. A method of reducing platelet degradation in a subject in need thereof, the method comprising administering to the subject an effective amount of a neonatal Fc receptor (FcRn) antagonist.

2. The method of claim 1 , wherein immature platelet fraction (IPF%) is reduced in the subject after administration of the effective amount of a neonatal Fc receptor (FcRn) antagonist to the subject.

3. A method of reducing immature platelet fraction (IPF%) in a subject in need thereof, the method comprising administering to the subject an effective amount of a neonatal Fc receptor (FcRn) antagonist.

4. The method of any one of claims 1-3, wherein the FcRn antagonist comprises two, three, or four FcRn binding regions.

5. The method of any one of claims 1-4, wherein the FcRn antagonist comprises or consists of a variant Fc region or FcRn binding fragment thereof.

6. The method of claim 5, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 6.0 as compared to a corresponding wild-type Fc region.

7. The method of claim 5 or 6, wherein the variant Fc region or FcRn binding fragment thereof binds to FcRn with a higher affinity at pH 7.4 as compared to a corresponding wild-type Fc region.

8. The method of any one of claims 5-7, wherein the variant Fc region comprises or consists of a first Fc domain and a second Fc domain which form a homodimer or heterodimer.

9. The method of claim 8, wherein the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively.

10. The method of claim 8 or 9, wherein the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

11. The method of any one of claims 8-10, wherein the first Fc domain and / or the second Fc domain comprise or consist of 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: 4.

12. The method of any one of claims 8-11, wherein the first Fc domain and the second Fc domain comprise or consist of 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: 4.

13. The method of any one of claims 8-12, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 1.

14. The method of any one of claims 8-12, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 2.

15. The method of any one of claims 8-12, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 3.

16. The method of any one of claims 8-12, wherein the first Fc domain and the second Fc domain comprise or consist of the amino acid sequence set forth in SEQ ID NO: 4.

17. The method of any one of claims 1-3, wherein the FcRn antagonist is administered to the subject as part of a composition comprising a population of FcRn antagonist molecules, wherein each FcRn antagonist molecule in the population consists of a dimer of a first Fc domain and a second Fc domain, and wherein the population comprises:(a) a first subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the first subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3; and(b) at least one of:(i) a second subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the second subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 12, respectively;(ii) a third subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the third subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 9, respectively;(iii) a fourth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the fourth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two asparagine residues in each FcRn antagonist molecule in the fourth subpopulation are deaminated;(iv) a fifth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the fifth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 9, respectively, and wherein one asparagine residue in each FcRn antagonist molecule in the fifth subpopulation is deaminated;(v) a sixth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the sixth subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively;(vi) a seventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the seventh subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the seventh subpopulation is oxidized;(vii) an eighth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the eighth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 2;(viii) a ninth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the ninthsubpopulation consist of the amino acid sequences set forth in SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and wherein one methionine residue or one tryptophan residue in each FcRn antagonist molecule in the ninth subpopulation is oxidized;(ix) a tenth subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of both the first and the second Fc domains of the FcRn antagonist molecules in the tenth subpopulation consist of the amino acid sequence set forth in SEQ ID NO: 3, and wherein two amino acid residues, independently selected from a methionine residue and a tryptophan residue, in each FcRn antagonist molecule in the tenth subpopulation is oxidized; and(x) an eleventh subpopulation of FcRn antagonist molecules, wherein the amino acid sequences of the first and the second Fc domains of the FcRn antagonist molecules in the eleventh subpopulation consist of the amino acid sequences set forth in SEQ ID NO: 3 and SEQ ID NO: 6, respectively.

18. The method of any one of claims 1-3, wherein the FcRn antagonist is efgartigimod.

19. The method of any one of claims 1-18, 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.

20. The method of any one of claims 1-19, wherein the FcRn antagonist is administered intravenously once weekly or once every two weeks.

21. The method of claim 20, wherein the FcRn antagonist is administered intravenously at a dose of from 2 mg / kg to 200 mg / kg once weekly or once every two weeks.

22. The method of claim 20 or 21, wherein the FcRn antagonist is administered intravenously at a dose of 3 mg / kg to 60 mg / kg once weekly or once every two weeks.

23. The method of any one of claims 20-22, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg to 30 mg / kg once weekly or once every two weeks.

24. The method of any one of claims 20-23, wherein the FcRn antagonist is administered intravenously at a dose of 10 mg / kg once weekly or once every two weeks.

25. The method of any one of claims 1-19, wherein the FcRn antagonist is administered subcutaneously once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks.

26. The method of claim 25, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 200 mg to 20,000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks.

27. The method of claim 25 or 26, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 750 mg to 3000 mg once weekly, once every two weeks, once every three weeks, once every four weeks, once monthly, or once every six weeks.

28. The method of any one of claims 25-27, wherein the FcRn antagonist is administered subcutaneously at a fixed dose of 1000 mg or 2000 mg once weekly or once every two weeks.

29. The method of any one of claims 1-28, wherein the FcRn antagonist is administered once weekly for 4 doses, and wherein subsequent doses of the FcRn antagonist are administered once weekly or once every other week.

30. The method of claim 29, wherein the subsequent doses of the FcRn antagonist are administered once every other week when the subject achieves a platelet count > 100 x 109 / L.

31. The method of claim 30, wherein the subsequent doses of the FcRn antagonist are administered once every other week when the subject achieves a stable platelet count > 100 x 109 / L.

32. The method of any one of claims 29-31, further comprising administration of the FcRn antagonist once weekly when the subject exhibits a platelet count < 30 x 109 / L.

33. The method of any one of claims 29-31, further comprising administration of the FcRn antagonist once weekly when the subject exhibits a stable platelet count > 30 x 109 / L and < 100 x 109 / L.

34. The method of any one of claims 1-33, wherein administration of the FcRn antagonist is suspended when the subject exhibits a single platelet count > 400 x 109 / L.

35. The method of claim 34, wherein administration of the FcRn antagonist is resumed at a dosing regimen of administration once every other week when the subject exhibits a single platelet count < 150 x 109 / L.

36. The method of any one of claims 1-35, wherein the subject has a platelet count of < 30 x 109 / L prior to administering the FcRn antagonist.

37. The method of any one of claims 1-36, wherein the subject is an adult human subject.

38. The method of any one of claims 1-37, wherein the subject has consumptive thrombocytopenia.

39. The method of any one of claims 1-38, wherein the subject has immune thrombocytopenia (ITP).

40. The method of claim 39, wherein the ITP is primary ITP.

41. The method of claim 39 or 40, wherein the ITP is persistent or chronic ITP.

42. The method of any one of claims 39-41, wherein the subject received at least 1 previous ITP treatment prior to administering the FcRn antagonist.

43. The method of any one of claims 39-42, wherein the subject received at least 2 previous ITP treatments prior to administering the FcRn antagonist.

44. The method of any one of claims 39-43, wherein the subject had an insufficient response to at least one previous ITP treatment prior to administering the FcRn antagonist.

45. The method of any one of claims 42-44, wherein the previous ITP treatment is one or more of: a corticosteroid, a thrombopoietin receptor agonist (TPO-RA), IVIg or anti-D Ig, splenectomy, an immunosuppressant, danazol, dapsone, fostamatinib, and rituximab.

46. The method of any one of claims 1-45, further comprising administering to the subject one or more doses of an additional therapeutic agent.

47. The method of claim 46, wherein the additional therapeutic agent is one or more of a corticosteroid, a TPO-RA, IVIg or anti-D Ig, an immunosuppressant, danazol, dapsone, fostamatinib, and rituximab.

48. The method of any one of claims 1-47, wherein the subject has an IPF% of > 20% prior to administration of the FcRn antagonist.

49. The method of any one of claims 2-48, wherein the IPF% is reduced within 1 week of administration of the FcRn antagonist.

50. The method of any one of claims 2-49, wherein the IPF% is reduced by at least 10% compared to a baseline value, following administration of the FcRn antagonist.

51. The method of any one of claims 2-50, wherein the subject has an IPF% of <15% following administration of the FcRn antagonist.

52. The method of any one of claims 2-51, wherein the IPF% is from 0.5%-9% following administration of the FcRn antagonist.

53. An FcRn antagonist for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with the method of any one of claims 1, 2, or 4-52.

54. An FcRn antagonist for use in the treatment of ITP in a subject in need thereof, wherein the FcRn antagonist reduces IPF% in accordance with the method of any one of claims 3-52.

55. An FcRn antagonist for use in the manufacture of a medicament for reducing platelet degradation in a subject in need thereof, wherein the FcRn antagonist is administered to the subject according to the method of any one of claims 1, 2, or 4-52.

56. An FcRn antagonist for use in the manufacture of a medicament for treating ITP in a subject in need thereof, wherein the FcRn antagonist reduces platelet degradation in accordance with the method of any one of claims 1, 2, or 4-52.

57. Use of an FcRn antagonist for reducing platelet degradation according to the method of any one of claims 1, 2, or 4-52.

58. Use of an FcRn antagonist for treating ITP, wherein the FcRn antagonist reduces platelet degradation in accordance with the method of any one of claims 1, 2, or 4-52.

59. Use of an FcRn antagonist for the manufacture of a medicament for reducing platelet degradation according to the method of any one of claims 1, 2, or 4-52.

60. Use of an FcRn antagonist for the manufacture of a medicament for treating ITP, wherein the FcRn antagonist reduces platelet degradation in accordance with the method of any one of claims 1, 2, or 4-52.

Images