Compositions and methods for treating fetal and neonatal alloimmune thrombocytopenia

Abstract

Provided herein are methods for treating fetal and neonatal alloimmune thrombocytopenia using compositions comprising anti-FcRn antibodies.

Description

COMPOSITIONS AND METHODS FOR TREATING FETAL AND NEONATAL ALLOIMMUNE THROMBOCYTOPENIACROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to and the benefit of United States patent application no. 63 / 562,934, titled “COMPOSITIONS AND METHODS FOR TREATING FETAL AND NEONATAL ALLOIMMUNE THROMBOCYTOPENIA,” which was filed on March 8, 2024, the disclosure of which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which is being submitted herewith electronically in XML format and is hereby incorporated by reference in its entirety. Said .XML copy, created on February 19, 2025, is named 103693.006094_Sequence listing. xml and is 11 kilobytes in size.FIELD

[0003] The present application is related to treating and preventing fetal and neonatal alloimmune thrombocytopenia in a fetal subject using a composition comprising an anti-FcRn antibody.BACKGROUND

[0004] Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the main cause of severe thrombocytopenia (platelet count <50x109 / L) in otherwise healthy term infants (Dreyfus 1997). FNAIT is a rare disease occurring in approximately 6 to 100 per 100,000 births (Ulusoy 2013; Knight 2011; Tiller 2009; Kjeldsen-Kragh 2007; Turner 2005; Ohto 2004; Davoren 2002; Durand-Zaleski 1996; Doughty 1995). FNAIT is caused by human platelet antigen (HP A) incompatibility between mother and fetus. The most common HPA subtype is HPA-la, which occurs in 80%-85% of cases (Davoren 2002; de Vos 2020; Kjeldsen-Kragh 2019; Tiller 2017; Mueller-Eckhardt 1989). The second most common HPA subtype is HPA-5b, which is implicated in 10%- 15% of cases (Davoren 2004; Tiller 2013). In FNAIT, maternal IgG antibodies against fetal HPA cross the placenta and destroy fetal and neonatal platelets resulting in thrombocytopenia (de Vos 2020). Low platelet counts correlate with an increased risk of bleeding, with intracranial hemorrhage (ICH) being the most severe complication (Bussel 2005;Winkelhorst 2017; de Vos 2020). Extracranial hemorrhage such as pulmonary, gastrointestinal, and others can also occur due to FNAIT (Winkelhorst 2016).

[0005] Currently there is no approved prenatal treatment for FNAIT and there is no routine global prenatal screening for risk of FNAIT; therefore, FNAIT is often diagnosed only after a first affected baby is born with clinical signs such as petechiae, bruising, or bleeding, or incidental lab identification of thrombocytopenia (Bussel 2008; Kamphuis 2010). Once a woman has 1 child with FNAIT, in subsequent pregnancies, the recurrence rate of FNAIT is high and has been reported to be up to 90% (Bussel 1997; Newman 1989). Studies of alloantibodies in mothers with subsequent pregnancies have shown that high titers of alloantibodies can be detected by 12 to 14 weeks of gestation (Bussel 2008).

[0006] Management of neonates with thrombocytopenia includes close monitoring in the intensive care unit, platelet transfusions (matched platelets preferred over unmatched), and / or neonatal IVIG. However, both platelet transfusions and IVIG are not without risk. The immunogenicity of platelet, and / or the hemodynamic shifts related to platelet transfusion volume can lead to an increased risk of hemorrhage due to the fragility of the germinal matrix and disturbances in organ and brain blood flow (Curley 2019; Bassan 2009; Poryo 2018; Christensen 2014).

[0007] Thus, there remains an urgent unmet medical need for an effective intervention to treat pregnant women at risk for FNAIT. The embodiments provided for herein fulfil these needs as well as others.DRAWINGS

[0008] FIG. 1 shows a diagram of the study design.

[0009] FIG. 2 is a graph of serum IgG concentration (g / L) as a function of gestation age(weeks) for 30 mg / kg QW and 45 mg / kg QW treatment regimens.

[0010] FIG. 3 is a graph of serum IgG change from baseline (%) as a function of gestation age (weeks) for 30 mg / kg QW and 45 mg / kg QW treatment regimens.SUMMARY

[0011] The application provides a method of treating, preventing, or reducing severity of, fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the methodcomprising administering an anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.

[0012] In certain embodiments, the anti-FcRn antibody is administered to the pregnant woman intravenously at about 15 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, about 45 mg / kg to about 60 mg / kg, about 15 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 45 mg / kg based on the weight of the pregnant woman.

[0013] In certain embodiments, the anti-FcRn antibody is administered at about 45 mg / kg based on the weight of the pregnant woman.

[0014] In certain embodiments, the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed a week before the subsequent administration.

[0015] In certain embodiments, the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

[0016] In certain embodiments, the anti-FcRn antibody is administered weekly from gestational week 13, week 14, week 15, or week 16.

[0017] In certain embodiments, the anti-FcRn antibody is administered for weekly for at least 23 weeks.

[0018] In certain embodiments, the anti-FcRn antibody is administered weekly until delivery.

[0019] In certain embodiments, the anti-FcRn antibody is administered via intravenous infusion.

[0020] In certain embodiments, the fetal subject is positive for an antigen, and the pregnant woman is negative for the antigen, wherein the antigen is HPA-la, HP A- 5b, or any combination thereof. In specific embodiments, the antigen is HPA-la.

[0021] In certain embodiments, the pregnant woman has maternal alloantibodies to the antigen.

[0022] In certain embodiments, the maternal alloantibodies are of an isotype selected from IgGl, IgG2, IgG3, or IgG4.

[0023] In certain embodiments, the pregnant subject has previously been pregnant with a fetus, wherein said fetus had or was diagnosed with FNAIT.

[0024] In certain embodiments, after the treatment, the fetal subject is liveborn at or after gestational week 34.

[0025] In certain embodiments, after the treatment, the fetal subject has a platelet count above 30 109 / L at birth.

[0026] In certain embodiments, after the treatment, the fetal subject has a platelet count above 50 109 / L at birth.

[0027] In certain embodiments, after the treatment, the fetal subject has a platelet count above 150* 109 / L at birth.

[0028] In certain embodiments, after the treatment, the fetal subject does not receive an intravenous immune globulin (IVIG) within 12 weeks following birth.

[0029] In certain embodiments, after the treatment, the fetal subject does not receive a platelet transfusion within 12 weeks following birth.

[0030] In certain embodiments, during the treatment, the fetal subject does not have an adjudicated severe bleeding in utero or up to the end of the first week following birth.

[0031] In certain embodiments, the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDRL1, CDRL2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDRL1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3 have the ammo acid sequences of the CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2 and CDR H3, respectively, of is nipocalimab.

[0032] In certain embodiments, the anti-FcRn antibody comprises: a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDR LI, CDRL2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDRL1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3 have the ammo acid sequences of SEQ ID NOs: 3-8, respectively.

[0033] In certain embodiments, the VL comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the VH comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10.

[0034] In certain embodiments, the VL comprises the amino acid sequence of SEQ ID NO: 9, and the VH comprises the amino acid sequence of SEQ ID NO: 10.

[0035] In certain embodiments, the anti-FcRn antibody comprises a light chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 1, and a heavy chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 2.

[0036] In certain embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 1 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 2.

[0037] In certain embodiments, the anti-FcRn antibody is nipocalimab.

[0038] Also provided is an anti-FcRn antibody for use in a method of treating, reducing severity of, or preventing fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering the anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.DETAILED DESCRIPTION

[0039] The present disclosure provides compositions and methods of treating, preventing, or reducing the severity of fetal and neonatal alloimmune thrombocytopenia (FNAIT) and related symptoms or pathologies associated with the same in a fetal subject. The method comprises administering an antibody against human neonatal Fc receptor (FcRn) to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.

[0040] The antibody against human FcRn can be referred to as an “anti-FcRn antibody.” The anti-FcRn antibodies disclosed herein are useful, e.g., to promote clearance of autoantibodies in a subject, to suppress antigen presentation in a subject, to block an immune response (e.g., block an immune complex-based activation of the immune response in a subject), and / or to treat or prevent immunological diseases (e.g., autoimmune diseases or alloimmune diseases) in a subject.

[0041] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0042] As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments.

[0043] As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any composition or method that recites the term “comprising” should also be understood to also describe such compositions as consisting, consisting of, or consisting essentially of the recited components or elements.

[0044] As used herein, the term “individual,” “subject,” or “patient,” can be used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. As used herein, the term “mammal” means a rodent (i.e., a mouse, a rat, or a guinea pig), a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.

[0045] As used herein, the phrase “in need thereof’ means that the subject has been identified as having a need for the particular method or treatment. In some embodiments in which the subject is a pregnant subject, “in need thereof’ means that the fetus of the pregnant subject has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the subject can be in need thereof. In some embodiments, the subject is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent.

[0046] As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5.

[0047] The term “antibody” herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies,multispecific antibodies (e.g., bispecific antibodies), scFVs, nanobodies, VHH, and antibody fragments so long as they exhibit FcRn antigen-binding activity.

[0048] Additionally, antibody or antibody molecule, as that term is used herein, refers to a polypeptide, e.g., an immunoglobulin chain or fragment thereof, comprising at least one functional immunoglobulin variable domain sequence. An antibody molecule encompasses antibodies (e.g., full-length antibodies) and antibody fragments. In some embodiments, an antibody molecule comprises an antigen binding or functional fragment of a full-length antibody, or a full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that is naturally occurring or formed by normal immunoglobulin gene fragment recombinatorial processes. In some embodiments, an antibody molecule refers to an immunologically active, antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. An antibody fragment (e.g., a functional fragment) comprises a portion of an antibody, e.g., Fab, Fab', F(ab')2, F(ab)2, variable fragment (Fv), domain antibody (dAb), or single chain variable fragment (scFv). A functional antibody fragment binds to the same antigen as that recognized by the intact (e.g., full-length) antibody. The terms “antibody fragment” or “functional fragment” also include isolated fragments consisting of the variable regions, such as the “Fv” fragments consisting of the variable regions of the heavy and light chains or recombinant single chain polypeptide molecules in which light and heavy variable regions are connected by a peptide linker (“scFv proteins”). In some embodiments, an antibody fragment does not include portions of antibodies without antigen binding activity, such as Fc fragments or single amino acid residues. Exemplary antibody molecules include full length antibodies and antibody fragments, e.g., dAb (domain antibody), single chain, Fab, Fab’, and F(ab’)2 fragments, and single chain variable fragments (scFvs).

[0049] Immunoglobulin chains exhibit the same general structure of relatively conserved framework regions (FRs) joined by three hypervariable regions, also called complementarity determining regions (CDRs). The CDRs from the two chains of each pair are aligned by the framework regions, enabling binding to a specific epitope. From N-terminus to C-terminus, both light and heavy chains comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is in accordance with the definitions of Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md.(1987 and 1991)), or Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).

[0050] The term “antibody molecule” also encompasses whole or antigen binding fragments of domain, or single domain, antibodies, which can also be referred to as “sdAb” or “VHH.” Domain antibodies comprise either VH or VL that can act as stand-alone, antibody fragments. Additionally, domain antibodies include heavy-chain-only antibodies (HCAbs). Domain antibodies also include a CH2 domain of an IgG as the base scaffold into which CDR loops are grafted. It can also be generally defined as a polypeptide or protein comprising an amino acid sequence that is comprised of four framework regions interrupted by three complementarity determining regions. This is represented as FR1- CDR1 -FR2-CDR2-FR3-CDR3-FR4. sdAbs can be produced in camelids such as llamas, but can also be synthetically generated using techniques that are well known in the art. The numbering of the amino acid residues of a sdAb or polypeptide is according to the general numbering for VH domains given by Kabat et al. (“Sequence of proteins of immunological interest,” US Public Health Services, NIH Bethesda, MD, Publication No. 91, which is hereby incorporated by reference). According to this numbering, FR1 of a sdAb comprises the amino acid residues at positions 1-30, CDR1 of a sdAb comprises the amino acid residues at positions 31-36, FR2 of a sdAb comprises the amino acids at positions 36-49, CDR2 of a sdAb comprises the amino acid residues at positions 50-65, FR3 of a sdAb comprises the amino acid residues at positions 66- 94, CDR3 of a sdAb comprises the amino acid residues at positions 95-102, and FR4 of a sdAb comprises the amino acid residues at positions 103-113. Domain antibodies are also described in International Publication Nos. W02004 / 041862 and WO2016 / 065323, both of which are hereby incorporated by reference in their entireties.

[0051] In some embodiments, as provided for herein, antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetravalent, pentavalent, hexavalent), or with higher orders of specificity (e.g., tetraspecific) and / or higher orders of valency beyond hexavalency. An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains can be fused together into a single polypeptide.

[0052] As used herein, the terms “variable region” and “variable domain” refer to the portions of the light and heavy chains of an antibody that include amino acid sequences of complementary determining regions (e.g., CDR L1, CDR L2, CDRL3, CDR H1, CDR H2, and CDR H3) and framework regions. According to the methods used in this disclosure, the amino acid positions assigned to CDRs and FRs are defined according to Kabat (“Sequences of Proteins of Immunological Interest”, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Using this numbering system, the actual linear amino acid sequence can contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a CDR (defined further herein) or FR (defined further herein) of the variable region. For example, a heavy chain variable region can include a single inserted residue (i.e., residue 52a according to Kabat) after residue 52 of CDRH2 and inserted residues (i.e., residues 82a, 82b, 82c, etc. according to Kabat) after residue 82 of heavy chain FR. The Kabat numbering of residues cam be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

[0053] As used herein, the terms “complementary determining regions” and “CDRs” refer to the regions of an antibody variable domain or variable region which are hypervariable in sequence and / or form structurally defined loops. A CDR is also known as a hypervariable region. The light chain and heavy chain variable regions each has three CDRs. The light chain variable region contains CDR LI, CDR L2, and CDR L3. The heavy chain variable region contains CDR Hl , CDR H2, and CDR H3. Each CDR can include amino acid residues from a complementarity determining region as defined by Kabat, i.e., about residues 24-34 (CDR LI), 50-56 (CDRL2) and 89-97 (CDR L3) in the light chain variable region and about residues 31-35 (CDR Hl), 50-65 (CDR H2) and 95-102 (CDR H3) in the heavy chain variable region.

[0054] As used herein, the term “FcRn” refers a neonatal Fc receptor that binds to the Fc region of an IgG antibody, e.g., an IgGl antibody. An exemplary FcRn is human FcRn having UniProt ID No. P55899, which is hereby incorporated by reference in its entirety. Without being bound to any particular theory, human FcRn is believed to be responsible for maintaining the half-life of IgG by binding and trafficking constitutively internalized IgG back to the cell surface for the recycling of IgG.

[0055] In some embodiments, the anti -FcRn antibody comprises a heavy chain or light chain. In some embodiments, the anti-FcRN antibody comprises a heavy chain and a light chainin a scFv format. In some embodiments, the heavy and light chain are linked with a peptide linker, such a glycine / serine or glycine / alanine linker.

[0056] In some embodiments, the anti-FcRn antibody is nipocalimab, which is also known as M281. Nipocalimab is a human monoclonal IgGl -lambda antibody that specifically binds to human FcRn. It is described in US Patent No. 10,676,526, PCT Publication No.W02020 / 023310, PCT Publication No. W02020 / 018910, each of which are hereby incorporated by reference in their entirety. In some embodiments, nipocalimab comprises or consists of: a light chain comprising or consisting of the sequence:QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQH PGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAE DEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPP S SEELQ ANKATLVCLISDF YPGAVTVAWKADS SPVKAGVE TTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGST VEKTVAPTECS (SEQ ID NO: 1); and a heavy chain comprising or consisting of the sequence:EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQA PGKGLEWVSSIGASGSQTRYADSVKGRFUSRDNSKNTLYL QMNSLRAEDTAVYYC ARLAIGD S YWGQGTMVTVS S ASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGA LTSGVHTFPAVLQS S GLYSLS S WTVPS S SLGTQTYICNVNH KPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHN AI<TI<PREEQYASTYRVVSVLTVLHQDWLNGI<EYI<CI<VSN KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTC LVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 2).

[0057] In certain embodiments, the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDRL1, CDRL2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein theCDRL1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3 have the amino acid sequences of the CDR L1, CDR L2, CDRL3, CDR H1, CDRH2 and CDR H3, respectively, of mpocalimab.

[0058] In certain embodiments, the anti-FcRn antibody comprises: a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDRL1, CDRL2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDRL1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3 have the ammo acid sequences of SEQ ID NOs: 3-8, respectively.

[0059] In certain embodiments, the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10.

[0060] In certain embodiments, wherein the VL comprises the amino acid sequence of SEQ ID NO: 9, and the VH comprises the amino acid sequence of SEQ ID NO: 10.

[0061] In certain embodiments, the anti-FcRn antibody comprises a light chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 1, and a heavy chain comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the sequence of SEQ ID NO: 2.

[0062] In certain embodiments, the light chain comprises the amino acid sequence of SEQ ID NO: 1 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 2.

[0063] In some embodiments, some of the heavy chains of nipocalimab can comprise an additional Lysine (K) residue at its C-terminal end, compared to SEQ ID NO: 2.

[0064] The term "nipocalimab” as used herein is intended to encompass biosimilar anti- FcRn antibodies that are equivalent to the nipocalimab protein developed and marketed by Johnson and Johnson. For example, a biosimilar of nipocalimab can be acceptable to the European Medicines Agency (EMA) and / or the United States Food and Drug Administration (FDA) when it has essentially the same pharmacological effects as the reference product nipocalimab. For example, a biosimilar of nipocalimab can comprise or consist of the same heavy and light chains sequences as nipocalimab, with the exception of a C-terminal modification. For example, the C-terminal amino acid or acids of the heavy chain can be absent,e.g. compared to SEQ ID NO: 2. The present disclosure extends to the use of antibody that uses the International Nonproprietary Name (INN) “nipocalimab”.

[0065] In some embodiments, the antibodies can further comprise amino acid substitutions, additions, and / or deletions outside of the CDRs (i.e., in framework regions (FRs)). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion of eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, three or fewer, or two or fewer single amino acids.

[0066] In some embodiments, the antibodies described herein can include amino acid substitutions, additions, and / or deletions in the constant regions (e.g., Fc region) of the antibody that, e.g., lead to decreased effector function, e.g., decreased complement-dependent cytolysis (CDC), antibody-dependent cell-mediated cytolysis (ADCC), and / or antibody-dependent cell- mediated phagocytosis (ADCP), and / or decreased B-cell killing. The constant regions are not involved directly in binding an antibody to its target, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity. In some embodiments, the antibodies described herein are characterized by decreased binding (i.e., absence of binding) to human complement factor Clq and / or human Fc receptor on natural killer (NK) cells. In other embodiments, the antibodies are characterized by decreased binding (i.e., absence of binding) to human FcyRI, FcyRIIA, and / or FcyRIIIA. In some embodiments, the antibodies described herein contain asparagine (N) at position 297 (numbering according to the EU System). In some embodiments, an anti-FcRn antibody described herein is aglycosylated at position 297 (numbering according to the EU System). In some cases, an anti-FcRn antibody described herein does not have an N at position 297 (EU numbering) in SEQ ID NO: 2, such that the antibody is aglycosylated at that position. The resulting effectorless antibody shows very little binding to complement or Fc receptors (i.e., complement Clq binding), indicating low CDC potential. In some embodiments, the Fc region is an effectorless Fc region.

[0067] In some embodiments, the heavy chain of the isolated antibody comprises a sequence having no more than 5, 4, 3, 2 or 1 single amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 2. In some embodiments, the light chain of the isolated antibody comprises a sequence having no more than 5, 4, 3, 2 or 1 single amino acid substitutions relative to the sequence of SEQ ID NO: 1.

[0068] As used herein, the term “percent (%) identity” refers to the percentage of amino acid (or nucleic acid) residues of a candidate sequence, e.g., an anti-FcRn antibody of the disclosure, that are identical to the amino acid (or nucleic acid) residues of a reference sequence, e.g., a wild-type anti-FcRn antibody, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity (i.e., gaps can be introduced in one or both of the candidate and reference sequences for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). Alignment for purposes of determining percent identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, the percent amino acid (or nucleic acid) sequence identity of a given candidate sequence to, with, or against a given reference sequence (which can alternatively be phrased as a given candidate sequence that has or includes a certain percent amino acid (or nucleic acid) sequence identity to, with, or against a given reference sequence) is calculated as follows:100 x (fraction of A / B) where A is the number of amino acid (or nucleic acid) residues scored as identical in the alignment of the candidate sequence and the reference sequence, and where B is the total number of amino acid (or nucleic acid) residues in the reference sequence. In some embodiments where the length of the candidate sequence does not equal to the length of the reference sequence, the percent amino acid (or nucleic acid) sequence identity of the candidate sequence to the reference sequence would not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence to the candidate sequence.

[0069] In some embodiments, a reference sequence aligned for comparison with a candidate sequence can show that the candidate sequence exhibits from 50% to 100% identity across the full length of the candidate sequence or a selected portion of contiguous amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purpose is at least 30%, e.g., at least 40%, e.g., at least 50%, 60%, 70%, 80%, 90%, or 100% of the length of the reference sequence. When a position in the candidate sequence is occupied by the same amino acid (or nucleic acid) residue as the corresponding position in thereference sequence, then the molecules are identical at that position. A position can be altered by a substitution, deletion, or insertion. A substitution, deletion, or insertion can comprise a certain number of amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or more). When describing a substitution, deletion, or insertion of no more than n amino acids, this is meant that the substitution, deletion, or insertion comprises, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or n amino acids. The number or substitutions, deletions, or insertions can comprise a percent of the total sequence (e.g., 1%, 5%, 10%, 15%, 20%, or more) where the number of substitutions, deletions, or insertions alters 5%, 10%, 15%, 20% or more, of the amino acids in the total sequence.

[0070] In some embodiments, the Fc domain of the antibody is not fucosylated. In some embodiments, the Fc domain of the antibody is not glycosylated. In some embodiments, the antibody lacks effector function. In some embodiments, the antibody is an IgGl antibody.

[0071] In some embodiments, the anti-FcRn antibody is nipocalimab, RVT-1401 (HL161), rozanolixizumab (UCB7665), ALXN1830, ABY-039, or efgartigimod. RVT-1401 (also referred to as HL161BKN) is described in PCT Publication No. W02020 / 097099, rozanolixizumab is described in PCT Publication No. WO2014 / 019727, and efgartigimod (ARGX-113) is described in PCT Publication No. WO2015 / 100299, each of which is hereby incorporated by reference in its entirety. In some embodiments, the anti-FcRn antibody is a biosimilar of any of anti-FcRn antibodies provided for herein. In some embodiments, the anti-FcRn antibody comprises the heavy and light chain CDRs of nipocalimab. In a preferred embodiments, the anti-FcRn antibody is nipocalimab. In some embodiments, the anti-FcRn antibody is RVT-1401 (HL161). In some embodiments, the anti-FcRn antibody is rozanolixizumab (UCB7665). In some embodiments, the anti-FcRn antibody is ALXN1830. In some embodiments, the anti-FcRn antibody is ABY- 039. In some embodiments, the anti-FcRn antibody is efgartigimod.

[0072] In some embodiments, the methods described herein comprise administering the anti-FcRn antibody to the pregnant woman carrying the fetal subject. In some embodiments, the antibody is administered as part of a pharmaceutical composition and about 15 mg / kg to 60 mg / kg of the antibody is administered based on the weight of the pregnant subject. In some embodiments, the antibody is administered at a dose from about 15 mg / kg to about 60 mg / kg, about 15 mg / kg to about 45 mg / kg, about 30 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 60 mg / kg. In some embodiments the antibody is administered at a dose of 15 mg / kg. Insome embodiments the antibody is administered at a dose of 30 mg / kg. In some embodiments the antibody is administered at a dose of 45 mg / kg. In some embodiments the antibody is administered at a dose of 60 mg / kg. In some embodiments, the antibody is administered at a dose of 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mg / kg.

[0073] In some embodiments, the maximum dose can be 6,500 mg. For example, the pharmaceutical composition can be administered at a dose of 45 mg / kg, with the proviso that the dose does not exceed 6,500 mg.

[0074] In some embodiments, the calculated dose can be rounded to the nearest 0.1 kg.

[0075] In some embodiments, the antibody is administered weekly, once every two weeks, or monthly. In some embodiments the antibody is administered for at least 23 weeks. In some embodiments, the antibody is administered starting from gestation week (GW) 13, GW 14, GW 15, or GW 16. In some embodiments, the antibody is administered until delivery. In some embodiments, the antibody is administered weekly from GW13 until delivery. In some embodiments, the antibody is administered weekly from GW 14 until delivery. In some embodiments, the antibody is administered weekly from GW 15 until delivery. In some embodiments, the antibody is administered weekly from GW 16 until delivery. As used herein, the terms “weekly” or “every week” refer to every 7 days (±1 day), and the terms “biweekly” or “every two weeks” refer to every 14 days (±1 day). As used herein, the terms “a week” or “one week” refer to 7 days (±1 day), and the term “two weeks” refers to 14 days (±1 day).

[0076] In some embodiments, the antibody is administered as part of a pharmaceutical composition and about 15 mg / kg to 60 mg / kg of the antibody is administered weekly based on the pregnant woman’s weight. In some embodiments, the dose is based on the weight of the pregnant woman on the day of the first administration. In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed a week before the subsequent administration. In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed a week before the subsequent administration. In some embodiments, the administration takes place within about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0077] In some embodiments, the antibody is administered as part of a pharmaceutical composition and about 15 mg / kg to 60 mg / kg of the antibody is administered every two weeks based on the pregnant woman’s weight. In some embodiments, the dose is based on the weight of the pregnant woman on the day of the first administration. In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed two weeks before the subsequent administration. In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed two weeks before the subsequent administration. In some embodiments, the administration takes place within about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0078] In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration. In some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediate previous administration. “Immediate previous administration” as used herein refers to the administration of the composition or anti-FcRn antibody that took place immediately before the subsequent administration for which a dose is being determined (for example, the administration of the composition or anti-FcRn antibody that took place one week before, in the case of weekly administrations).

[0079] In some embodiments, for example where the weight of the pregnant woman as assessed on the day of the immediate previous administration is not available, the dose of a subsequent administration can be based on the weight of the pregnant women assessed on the day of said subsequent administration. For example, in some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediate previous administration, with the proviso that where, for a given subsequent administration the weight of the pregnant woman on the dayof the immediate previous administration is not available, the dose of said subsequent administration is be based on the weight of the pregnant women assessed on the day of said subsequent administration.

[0080] The composition can be administered by any suitable route. In some embodiments, the composition is administered intravenously, such as by intravenous infusion.

[0081] In some embodiments, the pharmaceutical composition comprises one or more of sodium phosphate, sodium chloride, trehalose, or polysorbate.

[0082] As used herein, the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains an active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration. The pharmaceutical composition of the present disclosure includes, for example, pharmaceutically acceptable components that are compatible with the anti-FcRn antibody. The pharmaceutical composition can be in aqueous form for intravenous administration.

[0083] In some embodiments, the pharmaceutical composition that comprises an anti-FcRn antibody as the therapeutic can be formulated for intravenous administration.

[0084] As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, the pharmaceutically acceptable carrier must provide adequate pharmaceutical stability to the Fc construct. The nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used; for oral administration, a solid carrier is preferred.

[0085] As used herein, the term “therapeutically effective amount” refers to an amount (e.g., pharmaceutical dose) effective in inducing a desired biological effect in a subject or patient or in treating or preventing a patient having a condition or disorder described herein. It is also to be understood herein that a “therapeutically effective amount” can be interpreted as an amount giving a desired therapeutic effect, either taken in one dose or in any dosage or route, taken alone or in combination with other therapeutic agents.

[0086] As used herein, the term “no more than” refers to an amount that is less than equal to. This can be an amount in integers. For example, no more than two substitutions can refer to 0, 1 , or 2 substitutions.

[0087] As used herein, the terms “treat”, “treatment” or “treating” refer to reducing, decreasing, or decreasing the side effects of a particular disease or condition. Reducing, decreasing, or decreasing the side effects of are relative to a subject who did not receive treatment, e.g., a control, a baseline, or a known control level or measurement.

[0088] As used herein, the terms “prevent”, “prevention” or “preventing” refer to decreasing the risk of, avoiding or inhibiting the initiation, occurrence or development of a particular disease or condition. Decreasing the risk of, avoiding or inhibiting the initiation, occurrence or development of a particular disease or condition are relative to a subject who did not receive treatment, e.g., a control, a baseline, or a known control level or measurement.

[0089] Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease in which a neonate is born with a platelet count <150xl09 / L due to HPA incompatibility between mother and fetus. As used herein, “severe FNAIT” is defined as a platelet count in a fetus / neonate of <30*109 / L at birth.

[0090] In some embodiments, methods of treating, preventing or reducing severity of, fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject are provided. In some embodiments, the fetal subject is a fetal subject with, or at risk for, FNAIT. In some embodiments, the FNAIT is severe FNAIT. In some embodiments, the fetal subject with, or at risk for, FNAIT is a fetus positive for an antigen. In some embodiments, the fetal subject with, or at risk for, FNAIT is a fetus positive for an antigen, wherein the antigen is HPA- la, HPA-5b, or any combination thereof. In some embodiments, the fetal subject with, or at risk for, FNAIT is a fetus positive for an antigen, wherein the antigen is HPA- la, HPA-5b, or any combination thereof, and wherein the pregnant woman carrying the fetal subject is antigen negative. In some embodiments, the pregnant woman carrying the fetal subject is antigen negative. In some embodiments, the pregnant woman is antigen negative, wherein the antigen is HPA- la, HPA-5b, or any combination thereof. In some embodiments, the fetal subject with, or at risk for, FNAIT is a fetus positive for an antigen, wherein the antigen is HPA- la, HPA- 5b, or any combination thereof, and wherein the pregnant woman carrying the fetal subject is antigen negative, wherein the antigen is HPA- la, HPA- 5b, or any combination thereof. In some embodiments, the fetal subject with, or at risk for, FNAIT is positive for an antigen selected from the group consisting of HPA- la, HPA-5b, and any combination thereof and the pregnant woman carrying the fetal subject is negative for the same antigen. In some embodiments, the fetal subject with, or at riskfor, FNAIT is a fetus positive for an antigen, wherein the antigen is HPA-la, and wherein the pregnant woman carrying the fetal subject is antigen negative, wherein the antigen is HPA-la. In some embodiments, the fetal subject with, or at risk for, FNAIT is a subject whose pregnant mother has alloantibodies to an antigen, wherein the antigen is HPA-la, HP A- 5b, or any combination thereof. In some embodiments, the fetal subject with, or at risk for, FNAIT is positive for an antigen selected from the group consisting of HPA-la, HPA-5b, and any combination thereof and the pregnant woman carrying the fetal subject has maternal alloantibodies to the same antigen. In some embodiments, the fetal subject with, or at risk for, FNAIT is a fetus positive for an antigen, wherein the antigen is HPA-la, and wherein the pregnant woman carrying the fetal subject is antigen negative, wherein the antigen is HPA-la and the pregnant woman carrying the fetal subject has maternal alloantibodies to the same antigen. In some embodiments, the maternal alloantibodies are of an IgG isotype. In some embodiments, the maternal alloantibodies are of an isotype selected from IgGl, IgG2, IgG3, and IgG4.

[0091] In some embodiments, the pregnant subject has been determined as having maternal alloantibodies to an antigen and / or the fetus has been determined as having an antigen-positive genotype, for example as confirmed by cell-free fetal DNA in maternal blood. In some embodiments, the antigen is HPA-la, HPA-5b, or any combination thereof. In some embodiments, the pregnant subject has been determined as having maternal anti-HPA-la alloantibodies and / or the fetus has been determined as having a HPA-la positive genotype, for example as confirmed by cell-free fetal DNA in maternal blood.

[0092] In some embodiments, the pregnant woman carrying the fetal subject is a pregnant woman with obstetrical history. In some embodiments, the obstetrical history comprises previous pregnancy with a fetus, wherein said fetus is: a fetus with FNAIT (including neonatal platelet count <150X 109 / L), with none of them affected by fetal / neonatal intracranial hemorrhage (ICH) or severe hemorrhage.

[0093] In some embodiments, the pregnant woman does not receive intravenous immune globulin (IVIG) prior to the last administration of the composition.

[0094] As provided for herein, in some embodiments, pharmaceutical compositions comprising an anti-FcRn antibody are provided. In some embodiments, pharmaceutical compositions comprising an anti-FcRn antibody for administration to the pregnant womancarrying the fetal subject suffering from, or at risk for, FNAIT of the fetus and newborn wherein the anti-FcRn antibody is administered to the pregnant woman in a therapeutically effective amount from about 15 mg / kg to about 60 mg / kg, based on the weight of the pregnant woman, every week are provided. In some embodiments, the pharmaceutical composition is administered to the pregnant woman carrying the fetal subject in a therapeutically effective amount of about 45 mg / kg, based on the weight of the pregnant woman, every week. In some embodiments, the pregnant woman is pregnant with a fetus positive for an antigen. In some embodiments, the antigen is HPA-la, HPA-5b, or any combination thereof. In some embodiments, the pregnant woman carrying the fetal subject is a pregnant woman with alloantibodies to an antigen. In some embodiments, the antigen is HPA-la, HPA-5b, or any combination thereof.

[0095] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly for at least 23 weeks, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed one week before the subsequent administration.

[0096] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed one week before the subsequent administration.

[0097] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly for at least 23 weeks, the dose of the first administration isbased on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed one week before the subsequent administration.

[0098] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed one week before the subsequent administration.

[0099] In some embodiments, for example where the weight of the pregnant woman as assessed one week before a subsequent administration is not available, said subsequent administration may be based on the weight of the pregnant women assessed on the day of the subsequent administration. For example, in some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed one week before the subsequent administration, with the proviso that where, for a given subsequent administration the weight of the pregnant woman assessed one week before the subsequent administration is not available, the dose of said subsequent administration is based on the weight of the pregnant women assessed on the day of said subsequent administration.

[0100] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered every 2 weeks for at least 23 weeks, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed two weeks before the subsequent administration.

[0101] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered every 2 weeks until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed two weeks before the subsequent administration.

[0102] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered every 2 weeks for at least 23 weeks, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed two weeks before the subsequent administration.

[0103] In some embodiments, a method of treating, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered every 2 weeks until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed two weeks before the subsequent administration.

[0104] In some embodiments, for example where the weight of the pregnant woman as assessed two weeks before a subsequent administration is not available, said subsequent administration may be based on the weight of the pregnant women assessed on the day of the subsequent administration. For example, in some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed two weeks before the subsequent administration, with the proviso thatwhere, for a given subsequent administration the weight of the pregnant woman two weeks before the subsequent administration is not available, the dose of said subsequent administration is based on the weight of the pregnant women assessed on the day of said subsequent administration.

[0105] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly for at least 23 weeks, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

[0106] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

[0107] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; wherein nipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly for at least 23 weeks, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

[0108] In some embodiments, a method of treating, preventing, or reducing severity of, FNAIT in a fetal subject, is provided, wherein the method comprises administering a composition comprising nipocalimab to a pregnant woman carrying the fetal subject; whereinnipocalimab is administered at about 45 mg / kg based on the weight of the pregnant woman; wherein the composition is administered weekly until delivery, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

[0109] In some embodiments, for example where the weight of the pregnant woman on the day of the immediate previous administration is not available, a subsequent administration may be based on the weight of the pregnant women assessed on the day of said subsequent administration. For example, in some embodiments, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose of each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediate previous administration, with the proviso that where, for a given subsequent administration the weight of the pregnant woman assessed on the day of the immediate previous administration is not available, the dose of said subsequent administration is based on the weight of the pregnant women assessed on the day of said subsequent administration.

[0110] In certain embodiments, after treatment, the fetal subject is liveborn at or after gestational week 34. In certain embodiments, after treatment, the fetal subject has a platelet count above 30 109 / L at birth. In certain embodiments, after treatment, the fetal subject has a platelet count above 50 109 / L at birth. In certain embodiments, after treatment, the fetal subject has a platelet count above 150xl09 / L at birth. In certain embodiments, after treatment, the fetal subject does not receive an intravenous immune globulin (IVIG) within 12 weeks following birth. In certain embodiments, after treatment, the fetal subject does not receive an platelet transfusion within 12 weeks following birth. In certain embodiments, during treatment, the fetal subject does not have an adjudicated severe bleeding in utero or up to the end of the first week following birth.

[0111] As used herein, the term “severe bleeding” refers to: (i) fatal bleeding; (ii) clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g / L (2 g / dL) in a 24-hour period; (iii) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the central nervous system; and (iv) bleeding that requires surgical intervention in an operating suite; or a composite of (i) overt bleeding for which a blood product is administered and which is not directly attributable to the subject’s underlying medical condition and (ii) bleeding that requiresmedical or surgical intervention to restore hemostasis, other than in an operating suite. As used herein, “severe bleeding” and “sever hemorrhage” are used interchangeably.

[0112] In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglycerides after being treated with the antibody. In some embodiments, the antibody is M281 (nipocalimab). In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of total cholesterol after being treated with the antibody. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of high-density lipoprotein (HDL) after being treated with the antibody. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of calculated low-density lipoprotein (LDL) after being treated with the antibody. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of triglycerides after being treated with the antibody. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of total cholesterol after being treated with nipocalimab. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of high-density lipoprotein (HDL) after being treated with nipocalimab. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of calculated low-density lipoprotein (LDL) after being treated with nipocalimab. In some embodiments, the pregnant woman carrying the fetal subject being treated for FNAIT with an anti-FcRn antibody does not experience significantly increased levels of triglycerides after being treated with nipocalimab.

[0113] In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglycerides in the pregnant woman after administration of the pharmaceutical compositioncomprising the anti-FcRn antibody. In some embodiments, the anti-FcRn antibody is nipocalimab. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of total cholesterol in the pregnant woman after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of high-density lipoprotein (HDL) in the pregnant woman after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of calculated low-density lipoprotein (LDL) in the pregnant woman after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of triglycerides in the pregnant woman after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of total cholesterol in the pregnant woman after administration of the pharmaceutical composition comprising nipocalimab. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of high-density lipoprotein (HDL) in the pregnant woman after administration of the pharmaceutical composition comprising nipocalimab. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of calculated low-density lipoprotein (LDL) in the pregnant woman after administration of the pharmaceutical composition comprising nipocalimab. In some embodiments, the administration of the pharmaceutical composition to the pregnant woman carrying the fetal subject does not significantly increase levels of triglycerides in the pregnant woman after administration of the pharmaceutical composition comprising nipocalimab.

[0114] The present disclosure includes uses, such as medical uses, corresponding to all of the methods disclosed herein, including all optional and / or preferred features of such methods. For example, the present disclosure provides an anti-FcRn antibody, or a composition or pharmaceutical composition comprising the same, for use in a method of treating, reducingseverity of, or preventing fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering the anti-FcRn antibody to a pregnant woman carrying the fetal subject. The present disclosure also provides use of an anti-FcRn antibody, or the use of a composition or pharmaceutical composition comprising the same, in the manufacture of a medicament for treating, reducing severity of, or preventing fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject.

[0115] As used herein, the phrase “does not significantly increase” when used in reference to levels (measurements) of total cholesterol, high-density lipoprotein (HDL), calculated low- density lipoprotein (LDL), or triglycerides” means that any increase is less than 25% as compared to the level(s) prior (baseline) to the administration of the antibody or compositions provided for herein. In some embodiments, the increase is less than 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, or 5%. In some embodiments, the increase is no greater than about 1 to about 30%, about 5% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 5% to about 15%, about 5% to about 20%, about 10% to about 20%, about 1%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%m about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or about 25%. In some embodiments, the subject being treated for FNAIT is a subject in need thereof.

[0116] The following examples are illustrative, but not limiting, of the compounds, compositions and methods described herein. Other suitable modifications and adaptations known to those skilled in the art are within the scope of the following embodiments.Enumerated EmbodimentsSet A1. A method of treating, preventing, or reducing severity of, fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering an anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.2. The method of embodiment 1, wherein the anti-FcRn antibody is administered to the pregnant woman intravenously at about 15 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, about 45 mg / kg to about 60 mg / kg, about 15 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 45 mg / kg based on the weight of the pregnant woman.3. The method of embodiment 1 or 2, wherein the anti-FcRn antibody is administered at about 45 mg / kg based on the weight of the pregnant woman.4. The method of any one of embodiments 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed a week before the subsequent administration.5. The method of any one of embodiments 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.6. The method of any one of embodiments 1-5, wherein the anti-FcRn antibody is administered weekly from gestational week 13, week 14, week 15, or week 16.7. The method of any one of embodiments 1-6, wherein the anti-FcRn antibody is administered for weekly for at least 23 weeks.8. The method of any one of embodiments 1-7, wherein the anti-FcRn antibody is administered weekly until delivery.9. The method of any one of embodiments 1-8, wherein the anti-FcRn antibody is administered via intravenous infusion.10. The method of any one of embodiments 1-9, wherein the fetal subject is positive for an antigen, and the pregnant woman is negative for the antigen, wherein the antigen is HPA-la, HPA-5b, or any combination thereof.11. The method of embodiment 10, wherein the antigen is HPA-la.12. The method of embodiment 10 or 11, wherein the pregnant woman has maternal alloantibodies to the antigen.13. The method of embodiment 12, wherein the maternal alloantibodies are of an isotype selected from IgGl, IgG2, IgG3, or IgG4.14. The method of any one of the preceding embodiments, wherein the pregnant subject has previously been pregnant with a fetus, wherein said fetus had or was diagnosed with FNAIT.15. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject is liveborn at or after gestational week 34.16. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 30 109 / L at birth.17. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 50 109 / L at birth.18. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 150xl09 / L at birth.19. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject does not receive an intravenous immune globulin (IVIG) within 12 weeks following birth.20. The method of any one of the preceding embodiments, wherein after the treatment, the fetal subject does not receive an platelet transfusion within 12 weeks following birth.21. The method of any one of the preceding embodiments, wherein during the treatment, the fetal subject does not have an adjudicated severe bleeding in utero or up to the end of the first week following birth.22. The method of one of the preceding embodiments, wherein the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDR Ls) CDR LI , CDR L2 and CDR L3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDRH2 and CDR H3, wherein the CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2 and CDR H3 have the ammo acid sequences of the CDR L1, CDRL2, CDRL3, CDRH1, CDR H2 and CDRH3, respectively, of is nipocalimab.23. The method of any one of the preceding embodiments, wherein the anti-FcRn antibody comprises: a light chain variable region (VL) comprising light chain complementarity determining regions (CDR Ls) CDR LI, CDR L2 and CDR L3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2 and CDR H3 have the amino acid sequences of SEQ ID NOs: 3-8, respectively.24. The method of embodiment 23, wherein the VL comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the VH comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10.25. The method of embodiment 24, wherein the VL comprises the amino acid sequence of SEQ ID NO: 9, and the VH comprises the amino acid sequence of SEQ ID NO: 10.26. The method of any one of embodiment 21-25, wherein the anti-FcRn antibody comprises a light chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 1, and a heavy chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 2.27. The method of embodiment 26, where the light chain comprises the amino acid sequence of SEQ ID NO: 1 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 2.28. The method of any one of the preceding embodiments, wherein the anti-FcRn antibody is nipocalimab.Set B1. An anti-FcRn antibody for use in a method of treating, reducing severity of, or preventing fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering the anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.2. The anti-FcRn antibody for use of embodiment 1, wherein the anti-FcRn antibody is administered to the pregnant woman intravenously at about 15 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, about 45 mg / kg to about 60 mg / kg, about 15 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 45 mg / kg based on the weight of the pregnant woman.3. The anti-FcRn antibody for use of embodiment 1 or 2, wherein the anti-FcRn antibody is administered at about 45 mg / kg based on the weight of the pregnant woman.4. The anti-FcRn antibody for use of any one of embodiments 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed a week before the subsequent administration.5. The anti-FcRn antibody for use of any one of embodiments 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequentadministrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.6. The anti-FcRn antibody for use of any one of embodiments 1-5, wherein the anti-FcRn antibody is administered weekly from gestational week 13, week 14, week 15, or week 16.7. The anti-FcRn antibody for use of any one of embodiments 1-6, wherein the anti-FcRn antibody is administered for weekly for at least 23 weeks.8. The anti-FcRn antibody for use of any one of embodiments 1-7, wherein the anti-FcRn antibody is administered weekly until delivery.9. The anti-FcRn antibody for use of any one of embodiments 1-8, wherein the anti-FcRn antibody is administered via intravenous infusion.10. The anti-FcRn antibody for use of any one of embodiments 1-9, wherein the fetal subject is positive for an antigen, and the pregnant woman is negative for the antigen, wherein the antigen is HPA-la, HPA-5b, or any combination thereof.11. The anti-FcRn antibody for use of embodiment 10, wherein the antigen is HPA-la.12. The anti-FcRn antibody for use of embodiment 10 or 11, wherein the pregnant woman has maternal alloantibodies to the antigen.13. The anti-FcRn antibody for use of embodiment 12, wherein the maternal alloantibodies are of an isotype selected from IgGl, IgG2, IgG3, or IgG4.14. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein the pregnant subject has previously been pregnant with a fetus, wherein said fetus had or was diagnosed with FNAIT.15. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject is liveborn at or after gestational week 34.16. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 30 109 / L at birth.17. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 50 109 / L at birth.18. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject has a platelet count above 150 109 / L at birth.19. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject does not receive an intravenous immune globulin (IVIG) within 12 weeks following birth.20. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein after the treatment, the fetal subject does not receive a platelet transfusion within 12 weeks following birth.21. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein during the treatment, the fetal subject does not have an adjudicated severe bleeding in utero or up to the end of the first week following birth.22. The anti-FcRn antibody for use of one of the preceding embodiments, wherein the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDRL1, CDR L2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl , CDR H2 and CDR H3, wherein the CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2 and CDR H3 have the amino acid sequences of the CDRL1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3, respectively, of is nipocalimab.23. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein the anti- FcRn antibody comprises : a light chain variable region (VL) comprising light chain complementarity determining regions (CDRLs) CDR LI, CDR L2 and CDRL3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDRH2 and CDRH3, wherein the CDR LI, CDR L2, CDRL3, CDR Hl, CDR H2 and CDRH3 have the amino acid sequences of SEQ ID NOs: 3-8, respectively.24. The anti-FcRn antibody for use of embodiment 23, wherein the VL comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the VH comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10.25. The anti-FcRn antibody for use of embodiment 24, wherein the VL comprises the amino acid sequence of SEQ ID NO: 9, and the VH comprises the amino acid sequence of SEQ ID NO: 10.26. The anti-FcRn antibody for use of any one of embodiment 21-25, wherein the anti-FcRn antibody comprises a light chain comprising an amino acid sequence that is at least 98%, 99% or100% identical to the sequence of SEQ ID NO: 1, and a heavy chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 2.27. The anti-FcRn antibody for use of embodiment 26, where the light chain comprises the amino acid sequence of SEQ ID NO: 1 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 2.28. The anti-FcRn antibody for use of any one of the preceding embodiments, wherein the anti- FcRn antibody is nipocalimab.ExamplesExample 1. Double-blind, Randomized, Placebo-controlled Study Evaluating the Safety and Efficacy of Nipocalimab in Reducing the Risk of Fetal and Neonatal Alloimmune Thrombocytopenia (FNATT) in At-risk Pregnancies: FREESIA-1.

[0117] This is an ongoing global randomized, double-blind, placebo-controlled, multicenter, interventional study in pregnant participants with a prior FNAIT-affected pregnancy without intracranial hemorrhage (ICH) or severe hemorrhage in the fetus or newborn. For this study, this population is defined as standard- risk for FNAIT. The total duration of the study is up to 140 weeks and consists of 4 study periods:

[0118] Up to 8-week screening period: To be completed from gestational age (GA) Week 8 to 15 (prior to randomization [Day 1 / baseline]).

[0119] Double-blind treatment period up to 28 weeks: Randomization to occur between GA Week 13 to 16. Treatment will be given every 7 days ±1 day until before delivery.

[0120] Follow-up period for maternal participant: From delivery until Week 24 postpartum.

[0121] Follow-up period for neonate / infant participant: From birth until Week 104.

[0122] Approximately 39 participants will be randomized in a 2: 1 ratio (nipocalimab to placebo) to 1 of 2 treatment groups, respectively, as described below:

[0123] Group 1: Participants will receive nipocalimab 45 mg / kg IV qw every 7 days ±1 day before delivery.

[0124] Group 2: Participants will receive placebo IV qw every 7 days ±1 day before delivery.

[0125] Study intervention will be administered weekly by IV infusion at a dose of 45 mg / kg based on the participant’s body weight (rounded to the nearest 0.1 kg) beginning fromrandomization Day 1 to until before delivery. Weight measurement will be used to calculate the study intervention dose as follows:

[0126] On Day 1 , the weight measured at the Day 1 visit is used to calculate the dose of study intervention to be administered at that visit.

[0127] For subsequent visits, the weight measured at the prior week is used to calculate the study intervention dose to be administered. If the weight measurement from the prior week is missing or if the last dose is >9 days, the weight measured on the same day as the study intervention infusion is used. Adjusting the dose of the composition according to the weight of the participant as measured at the prior week is intended to provide a more efficacious treatment and to improve patient outcomes, compared to embodiments in which the dose of the composition is based only on the weight of the participant at the start of the study. Basing the dose of the composition based on the weight of the participant at the prior week of administration also allows the composition to be prepared prior to the day of administration.

[0128] The maximum dose amount given to any participant at any dosing visit should not exceed 6.5 grams, regardless of the participant’s body weight.

[0129] Day 1 (first dose of study intervention) should occur during the randomization period, GA Weeks 13 to 16. All weekly study intervention infusions should occur every 7 days (±1 day) from the previous infusion. The minimum interval between 2 doses is 6 days, and the maximal interval between 2 doses should not exceed 8 days.

[0130] Each maternal participant is anticipated to receive a minimum of 23 IV infusions and a maximum of 28 IV infusions during pregnancy.

[0131] A diagram of the study design is provided in Figure 1.

[0132] Study Population

[0133] The inclusion and exclusion criteria for enrolling participants in this study are described below.

[0134] Inclusion Criteria

[0135] Each potential participant must satisfy all of the following criteria to be enrolled in the study:1. Female, >18 years of age at the time of informed consent.2. Pregnant and an estimated GA (based on ultrasound dating) between Week 13 to 16 at randomization.3. Has a history of >1 prior pregnancy with FNAIT (including neonatal platelet count<150xl0A9 / L), with none of them affected by fetal / neonatal ICH or severe hemorrhage based on medical records.4. Current pregnancy with presence of maternal anti-HPA-la alloantibody and positive fetal HPA-la genotype as confirmed by cell-free fetal DNA in maternal blood.5. Health status considered stable by the investigator on the basis of physical examination, medical history, vital signs, 12-lead ECG, and clinical laboratory tests performed at screening.6. Must sign an informed consent form (ICF) indicating that maternal participant understands the purpose of and procedures required for the study and is willing to participate in the study up to 24 weeks of follow-up. The parents(s) / guardian(s) of the neonate / infant must also sign an ICF to permit 104-week follow-up for the neonate / infant and agree to complete caregiver-reported outcomes for the infant.7. For maternal participant and neonate / infant, willing to forego participation in another clinical study of an investigational therapy until the last follow-up visit.8. Willing to forego collection of cord blood for stem cell storage or other non-study purposes.9. Must agree not to donate blood through the final follow-up visit at Week 24 postpartum.

[0136] Exclusion Criteria

[0137] Any potential participant who meets any of the following criteria will be excluded from participating in the study:1. Currently pregnant with multiple gestations (twins or more).2. History of severe preeclampsia in a previous pregnancy.3. History of severe fetal growth restriction (FGR) (estimated fetal weight (EFW) <3rd percentile) in a previous pregnancy.4. History of myocardial infarction, unstable ischemic heart disease, or stroke.5. Known allergies, hypersensitivity, or intolerance to nipocalimab or its excipients.6. Has a history of severe and / or uncontrolled medical disorder(s) that might interfere with the participant’s full participation in the study or confound the protocol-specified assessments, and / or might jeopardize the safety of the participant or her fetus or thevalidity of the study results.7. Has any confirmed or suspected clinical immunodeficiency syndrome or has a family history of congenital or hereditary immunodeficiency unless confirmed absent in the participant.8. History of solid organ or bone marrow transplantation (except for a corneal transplant performed >12 weeks before screening).9. Currently has a malignancy or has a history of malignancy within 3 years before screening (except for localized basal cell carcinoma and / or squamous cell carcinoma skin cancer that has been adequately treated with no evidence of recurrence for at least 12 weeks before the first study intervention administration or cervical carcinoma in situ that has been treated with no evidence of recurrence for at least 12 weeks before the first study intervention administration).10. Has shown a previous severe immediate hypersensitivity reaction such as anaphylaxis to therapeutic proteins (eg, mAbs).11. History of serious infection that required hospitalization or parenteral antibiotics within 8 weeks of screening or a history of recurring severe infections.12. Has a severe infection including opportunistic infections (e.g., pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection, Cytomegalovirus (CMV), pneumocystosis, aspergillosis) requiring parenteral anti-infectives or hospitalization, or is assessed as serious / clinically significant by the investigator, within 8 weeks prior to screening.13. Has a severe chronic infection (eg, bronchiectasis, chronic osteomyelitis, chronic pyelonephritis) or requires chronic treatment with anti-infectives (e.g., antibiotics, antivirals).14. COVID- 19 infection: Have tested positive for or been exposed to COVID- 19 within 4 weeks prior to the first dose of study intervention. (Exceptions: Participants who have tested positive for or been exposed to COVID-19 may participate if they have both an absence of symptoms and a negative validated COVID- 19 test obtained at least 2 weeks after symptoms onset (or the first positive test for asymptomatic infection) or exposure.)15. Has received rituximab, eculizumab, or FcRn antagonists (e.g., efgartigimod) within 26 weeks prior to screening.16. Is currently receiving systemic corticosteroids or other immunosuppressants for chronic disorders that may jeopardize the safety of the participant. (Note: Use of topical corticosteroids, nasal / inhaled corticosteroids or acute regimen of oral corticosteroids (<7 days duration), or intra-articular corticosteroids is permitted. Use of systemic corticosteroids is permitted prior to delivery for fetal lung maturation as needed.)17. Has received or is planning to receive IVIG, plasmapheresis, immunoadsorption therapy, or any IgGFc-related therapeutics during the current pregnancy.18. Has received a live virus vaccination during the current pregnancy or has a known need to receive a live virus vaccination during the study while receiving study intervention or within at least 8 weeks after the last administration of study intervention in this study.19. Has received a Bacille Calmette-Guerin (BCG) vaccination within 1 year prior to the first dose of study intervention or has a known need to receive BCG vaccine during the study or within at least 8 weeks after the last administration of study intervention.20. Has previously received nipocalimab or was enrolled and received study intervention in this study in a previous pregnancy.21. Is currently enrolled or plans to enroll in an investigational study and receive investigational intervention during the study.22. Has received an investigational intervention within the period equal or shorter than 5 half-lives of the investigational compound prior to conception of or during the current pregnancy or used an invasive investigational medical device within 12 weeks prior to conception of or during the current pregnancy.23. Has positive laboratory test results for HBV infection.24. History of any positive test for HIV at screening.25. Has an active infection at screening or baseline with Coxsackie, syphilis, CMV, toxoplasmosis, or herpes simplex 1 or 2, as evidenced by clinical signs and symptoms or screening serology results from the central laboratory. (Note: Serology evidence of prior infection or exposure, but without clinical signs and symptoms of active infection is acceptable to participate.)26. Has antibodies to HCV, unless they satisfy 1 of the following conditions: a) has a history of successful treatment, defined as being negative for HCV RNA at least 24weeks after completing antiviral treatment, and has a negative HCV RNA test result at screening b) has a negative HCV RNA test result >24 weeks prior to screening and a negative HCV RNA test result at screening.27. Has screening laboratory test result of total IgG <6 g / L.28. Has screening laboratory test result of albumin <26 g / L.29. Has screening laboratory test result of hemoglobin <80 g / L.30. Has screening laboratory test result of WBC count <3.0 GI / L.31. Has screening laboratory test result of absolute neutrophil count <1.5 GI / L.32. Has screening laboratory test result of platelet count <100 GI / L.33. Has screening laboratory test result of AST >3 ULN. (Note: Values for ULN should be based on normal reference range for the second trimester in pregnancy (Abbassi-Ghanavati 2009).34. Has screening laboratory test result of ALT >3 xULN. (Note: Values for ULN should be based on normal reference range for the second trimester in pregnancy (Abbassi-Ghanavati 2009).35. Has screening laboratory test result of estimated glomerular filtration rate<90 mL / min per 1.73mA2.36. Has any condition in the current pregnancy (including known genetic defects of the fetus or umbilical cord abnormality) for which, in the opinion of the investigator, participation would not be in the best interest of the participant or fetus / neonate / infant (eg, compromise the well-being) or that could prevent, limit, or confound the protocol- specified assessments.37. Has history of moderate or severe substance or alcohol use disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5thedition, (DSM-V) criteria, except nicotine and caffeine, within 1 year prior to screening and during the current pregnancy.Table 1. Study Objectives and Endpoints

[0138] Evaluations

[0139] Efficacy, safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD)(e.g., IgG), and biomarkers will be assessed.

[0140] Efficacy assessments include ultrasound during pregnancy to assess fetal viability and fetal bleeding, cranial ultrasound after birth to assess for neonatal bleeding, and assessment of neonate platelet counts at birth and thereafter. Management of neonatal / infant bleeding and thrombocytopenia will also be assessed.

[0141] Patient-reported outcome assessments for the maternal participant include 36-Item Short Form Health Survey version 2 (SF-36 v2) Acute and EuroQol-5 Dimensions 5 Level (EQ- 5D-5L). Health-related quality of life reported by caregivers for the neonate / infant will beassessed using the Infant Health-Related Quality of Life Instrument (IQI).

[0142] Safety assessments for the maternal participants include monitoring for adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESIs), bleeding, infections, infusion reactions, concomitant medications, clinical labs (hematology, chemistry [including lipid panel]), vaccine response to tetanus, vital signs, body weight, physical examination, ultrasound monitoring of fetal growth and development, placenta evaluation; for the neonate / infant participants include Bayley Scales (3rd Edition) for infant development, and neonatal / infant immune system development (Ig profile, vaccine response to tetanus).

[0143] Fetal Ultrasound

[0144] Fetal ultrasound for assessment of fetal viability will be performed. Growth measurements (biometry) including biparietal diameter, head circumference, abdominal circumference, femur length, and amniotic fluid volume status will be obtained >GA Week 14.

[0145] A full anatomical assessment for the fetus will be done once between GA Week 18 to 22. A biophysical profde for the fetus will be done prior to delivery to evaluate heart rate, breathing movement, tone and body movement, and amniotic fluid volume. Any abnormal ultrasound findings that are clinically significant will be reported as AEs. Ultrasound assessment will include evaluation of any signs of hemorrhage (intracranial or extracranial).

[0146] Bleeding Assessments

[0147] Ultrasound assessments will be performed during pregnancy to monitor fetal growth and abnormalities including bleeding.

[0148] Cranial ultrasounds will be performed on all neonates to monitor for ICH. If the cranial ultrasound shows suspected cranial bleeding, then additional testing (i.e., MRI) may be warranted per local standard of care.

[0149] Neonates will be evaluated for any signs and symptoms of bleeding using the study- specified neonatal assessment tool with the data recorded in the CRFs.

[0150] Neonatal Platelet Counts

[0151] Neonatal platelet count will be checked from the cord blood at birth. If the platelet count is <150X 109 / L, the platelet count will be checked at minimum daily while in the hospital or at minimum every 72 hours if further testing is needed as an outpatient until the treating physician decides testing is no longer needed. If the platelet count at birth is >150xl09 / L, another platelet count will be obtained prior to discharge.

[0152] Pharmacokinetics

[0153] Venous blood samples will be collected for the determination of nipocalimab concentrations and immunogenicity in maternal blood over time during pregnancy and postpartum. Samples must be collected before study intervention administration at visits when a study intervention administration is scheduled. At visits where 2 PK blood samples will be collected, a blood sample before study intervention administration and another blood sample at 45 minutes (±15 minutes) after the end of infusion will be collected. The sample will be drawn from the opposite arm than the IV line. Blood collections for PK will be kept as close to the specified time as possible. The actual sample date and time of collection will be documented in the source documentation and CRF.

[0154] PK samples will be collected for the determination of serum nipocalimab concentrations in cord blood at birth, and in blood of neonates / infants.

[0155] If a participant sustains fetal loss in between scheduled collection times, if feasible a sample will be collected for the assessment of nipocalimab concentration in the fetus from the cord blood. An additional maternal blood sample should also be obtained as soon as possible to assess the nipocalimab concentration in the associated maternal blood circulation.

[0156] At birth, cord blood samples will be collected to assess nipocalimab concentration in serum.

[0157] Serum and colostrum, transitional milk, and / or mature breast milk samples from participants who received >1 dose of nipocalimab will be analyzed to determine concentrations of nipocalimab using a validated, specific, and sensitive immunoassay method by the sponsor’s bioanalytical facility or under the supervision of the sponsor.

[0158] In addition, serum and colostrum / breast milk PK samples may be stored for future analysis of other co-administered treatments as appropriate.

[0159] Based on the individual serum concentration-time data, using the actual dose taken and the actual sampling times, PK parameters and exposure information of nipocalimab will be derived using population PK modeling. Baseline covariates (eg, body weight, age, sex, CrCL, race) may be included in the model, if relevant.

[0160] The relationship between serum nipocalimab concentrations and efficacy measures or relevant PD (e.g., IgG lowering) endpoints will be examined when appropriate.

[0161] Pharmacodynamics

[0162] Samples for the analysis of PD biomarkers will be collected from the mother and neonate / infant.

[0163] Blood samples for PD analysis of total circulating IgG and alloantibody levels will be collected for the maternal participant and neonate / infant. If >9 days elapsed since the last infusion, a blood sample for total serum IgG and alloantibody levels should be collected from the maternal participant prior to the next infusion even if a sample is not scheduled at that visit.

[0164] Blood samples for serum biomarker analysis will be collected from all participants. Serum will be analyzed for levels of specific proteins, and other inflammation-related molecules and / or disease-associated serologies relevant to FNAIT and treatment and response to nipocalimab.

[0165] Biopsies of the placenta may be collected from participants at peripartum, as fixed tissue, blocks, or slides, where local regulations permit. Tissue samples may be analyzed for levels of protein, transcripts, and other inflammation-mediated molecules and / or soluble factors relevant to FNAIT pathogenesis and nipocalimab treatment. Analysis may include, but is not limited to, tissue proteomic and transcriptomic assessment of cell populations to identify cellular biomarkers associated with FNAIT pathogenesis and / or nipocalimab treatment as permitted by relevant and advancing technologies.

[0166] Biomarkers

[0167] Biomarker assessments will be made to examine the biologic response to treatment and to identify biomarkers that are relevant to nipocalimab treatment and / or FNAIT. Data collected from these samples will be used for exploratory research that will include, but are not limited to, the following objectives:• To understand the molecular effects of nipocalimab;• To understand FNAIT pathogenesis;• To understand why individual participants may respond differently to nipocalimab;• To develop diagnostic tests to identify populations at risk for FNAIT that may be responsive or nonresponsive to treatment with nipocalimab.

[0168] Immunogenicity Assessments

[0169] Antibodies to nipocalimab from maternal participants who received >1 dose of nipocalimab will be evaluated in serum samples collected during pregnancy and postpartum. Additionally, serum samples should also be collected at the final visit from maternal participantswho discontinued study intervention or were withdrawn from the study. These samples will be tested by the sponsor or sponsor's designee. Serum samples will be screened for antibodies binding to nipocalimab and the titer of confirmed positive samples will be reported. Other analyses may be performed to verify the stability of antibodies to nipocalimab and / or further characterize the immunogenicity ofnipocalimab (such as the presence of NAbs). Samples collected for immunogenicity analyses may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or after the study period. Genetic analyses will not be performed on these serum samples. Participant confidentiality will be maintained.

[0170] The detection and characterization of antibodies to nipocalimab will be performed using a validated assay method by or under the supervision of the sponsor. All samples collected for detection of antibodies to nipocalimab will also be evaluated for nipocalimab serum concentration to enable interpretation of the antibody data. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of the study intervention(s).

[0171] Statistical Methods

[0172] The sample size calculation is based on the primary endpoint: adverse outcome of death or adjudicated severe bleeding in utero up to the first week post birth, or platelet count at birth <30 109 / L in a fetus / neonate. In the Norway historical standard-risk group of 63 participants who did not receive active treatment, no deaths or severe bleeding events were observed, and 60% had platelet count at birth <30 109 / L. It is therefore assumed that in the placebo group, approximately 60% of participants will meet the primary endpoint.

[0173] The proportion of fetuses / neonates meeting the primary endpoint for the nipocalimab treated group is indirectly based on published literature of weekly IVIG antenatal treatment in standard-risk FNAIT pregnancies, that reported data using the relevant platelet count threshold of <30X109 / L at birth.Example 2. Effects of Nipocalimab on IgG reduction.

[0174] A population PK-RO IgG indirect response model was developed that describes the effects of nipocalimab on IgG reduction. Using the established PK-RO-IgG model for pregnancy, simulations for FNAIT were performed with the dosing regimen of 45 mg / kg weekly (QW) until delivery (Week 37). The selected dosing regimen generates maximal blockage of maternal IgG concentration up until birth, as shown by the profiles of IgG (FIG. 2) and IgG%reduction from baseline (FIG. 3).Sequence ListingSEQ ID NO: 1QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVT LFPPS SEELQ ANKATLVCLISDF YPGAVTVAWKAD S SPVKAGVETTTPSKQSNNKYAAS SYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECSSEQ ID NO: 2EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQT RYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLS S WTVPS S SLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCP APELLGG PSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQY ASTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDK SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGSEQ ID NO: 3TGTGSDVGSYNLVSSEQ ID NO: 4GDSERPSSEQ ID NO: 5SSYAGSGIYVSEQ ID NO: 6TYAMGSEQ ID NO: 7SIGASGSQTRYADSSEQ ID NO: 8LAIGDSYSEQ ID NO: 9QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGV SNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLSEQ ID NO: 10EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSSReferencesBassan H (2009). Intracranial hemorrhage in the preterm infant: understanding it, preventing it. Clin Perinatol. 2009;36(4):737-762.Bussel JB (1997), Zabusky MR, Berkowitz RL, McFarland JG. Fetal alloimmune thrombocytopenia. N Engl J Med. 1997;337(l):22-26.Bussel JB (2005), Zacharoulis S, Kramer K, McFarland JG, Pauliny J, Kaplan C. Clinical and diagnostic comparison of neonatal alloimmune thrombocytopenia to non-immune cases of thrombocytopenia. Pediatr Blood Cancer. 2005 ;45(2): 176-183.Bussel JB (2008), Primiani A. Fetal and neonatal alloimmune thrombocytopenia: progress and ongoing debates. Blood Rev. 2008;22(l):33-52.Christensen (2014), Baer VL, Lambert DK, Ilstrup SJ, Eggert LD, Henry E. Association, among very-low birth weight neonates, between red blood cell transfusions in the week after birth and severe intraventricular hemorrhage. Transfusion. 2014;54:104-108.Curley A (2019), Stanworth SJ, Willoughby K, et al. Randomized trial of platelet-transfusion thresholds in neonates. N Engl J Med. 2019;380(3):242-251.Davoren A (2002), McParland P, Barnes CA, Murphy WG. Neonatal alloimmune thrombocytopenia in the Irish population: a discrepancy between observed and expected cases. J Clin Pathol. 2002;55(4):289- 292.Davoren A (2004), Curtis BR, Aster RH, et al. Human platelet antigen-specific alloantibodies implicated in 1162 cases of neonatal alloimmune thrombocytopenia. Transfusion. 2004;44(8): 1220-1225. de Vos TW (2020), Winkelhorst D, de Haas M, Lopriore E, Oepkes D. Epidemiology and management of fetal and neonatal alloimmune thrombocytopenia. Transfus Apher Sci. 2020;59(l): 102704.Doughty HA (1995), Murphy MF, Metcalfe P, Waters AH. Antenatal screening for fetal alloimmune thrombocytopenia: the results of a pilot study. Br J Haematol. 1995 ;90(2): 321-325.Dreyfus M (1997), Kaplan C, Verdy E, Schlegel N, Durand-Zaleski I, Tchemia G. Frequency of immune thrombocytopenia in newborns: a prospective study. Immune thrombocytopenia working group. Blood. 1997;89(12):4402-4406.Durand-Zaleski I (1996), Schlegel N, Blum-Boisgard C, Uzan S, Dreyfus M, Kaplan C. Screening primiparous women and newborns for fetal / neonatal alloimmune thrombocytopenia: a prospective comparison of effectiveness and costs. Immune Thrombocytopenia Working Group. Am J Perinatol. 1996;13(7):423-431.Kamphuis MM (2010), Paridaans N, Porcelijn L, et al. Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: systematic review. BJOG. 2010;l 17(11): 1335-1343.Kjeldsen-Kragh J (2007), Killie MK, Tomter G, et al. A screening and intervention program aimed to reduce mortality and serious morbidity associated with severe neonatal alloimmune thrombocytopenia. Blood. 2007;110(3):833-839.Kjeldsen-Kragh J (2019), Olsen KJ. Risk of HPA- la-immunization in HPA- la-negative women after giving birth to an HPA- la-positive child. Transfusion. 2019;59(4): 1344-1352.Knight M (2011), Pierce M, Allen D, et al. The incidence and outcomes of fetomatemal alloimmune thrombocytopenia: a UK national study using three data sources. Br J Haematol. 2011;152(4):460-468.Meuller-Eckerdt C (1989), Kiefel V, Grubert A, et al. 348 cases of suspected neonatal alloimmune thrombocytopenia. Lancet. 1989;l(8634):363-366.Newman PJ (1989), Derbes RS, Aster RH. The human platelet alloantigens, P1A1 and P1A2, are associated with a Ieucine33 / proline33 amino acid polymorphism in membrane glycoprotein Illa, and are distinguishable by DNA typing. J Clin Invest. 1989;83(5): 1778-1781.Ohto H (2004), Miura S, Ariga H, et al. The natural history of maternal immunization against foetal platelet alloantigens. Transfus Med. 2004;14(6):399-408.Poryo M (2018), Boeckh JC, Gortner L, et al. Ante-, peri- and postnatal factors associated with intraventricular hemorrhage in very premature infants. Early Hum Dev. 2018;l 16: 1-8.Tiller H (2009), Killie MK, Skogen B, 0ian P, Husebekk A. Neonatal alloimmune thrombocytopenia in Norway: poor detection rate with nonscreening versus a general screening programme. BJOG.2009;116(4):594-598.Tiller H (2013), Kamphuis MM, Flodmark O, et al. Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry. BMJ Open. 2013;3(3):e002490.Tiller H (2017), Husebekk A, Ahlen MT, Stage TB, Skogen B. Current perspectives on fetal and neonatal alloimmune thrombocytopenia - increasing clinical concerns and new treatment opportunities. Int J Womens Health. 2017;9:223-234.Turner ML (2005), Bessos H, Fagge T, et al. Prospective epidemiologic study of the outcome and costeffectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-la. Transfusion. 2005;45(12): 1945-1956.Ulusoy E, Tiifckci O, Duman N, Kumral A, Irken G, Oren H. Thrombocytopenia in neonates: causes and outcomes. Ann Hematol. 2013;92(7):961-967.Winkelhorst D (2016), Kamphuis MM, de Kloet LC, Zwaginga JJ, Oepkes D, Lopriore E. Severe bleeding complications other than intracranial hemorrhage in neonatal alloimmune thrombocytopenia: a case series and review of the literature. Transfusion. 2016;56(5): 1230-1235.Winkelhorst D (2017), Murphy MF, Greinacher A, et al. Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review. Blood. 2017; 129(11): 1538-1547.

Claims

CLAIMSWhat is claimed is:

1. A method of treating, preventing, or reducing severity of fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering an anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.

2. The method of claim 1, wherein the anti-FcRn antibody is administered to the pregnant woman intravenously at about 15 mg / kg to about 30 mg / kg, about 30 mg / kg to about 60 mg / kg, about 45 mg / kg to about 60 mg / kg, about 15 mg / kg to about 45 mg / kg, or about 30 mg / kg to about 45 mg / kg based on the weight of the pregnant woman.

3. The method of claim 1 or 2, wherein the anti-FcRn antibody is administered at about 45 mg / kg based on the weight of the pregnant woman.

4. The method of any one of claims 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed a week before the subsequent administration.

5. The method of any one of claims 1-3, wherein the anti-FcRn antibody is administered weekly, the dose of the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses of subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediate previous administration.

6. The method of any one of claims 1-5, wherein the anti-FcRn antibody is administered weekly from gestational week 13, week 14, week 15, or week 16.

7. The method of any one of claims 1-6, wherein the anti-FcRn antibody is administered for weekly for at least 23 weeks.

8. The method of any one of claims 1-7, wherein the anti-FcRn antibody is administered weekly until delivery.

9. The method of any one of claims 1-8, wherein the anti-FcRn antibody is administered via intravenous infusion.

10. The method of any one of claims 1-9, wherein the fetal subject is positive for an antigen, and the pregnant woman is negative for the antigen, wherein the antigen is HPA-la, HPA-5b, or any combination thereof.

11. The method of claim 10, wherein the antigen is HPA-la.

12. The method of claim 10 or claim 11, wherein the pregnant woman has maternal alloantibodies to the antigen.

13. The method of claim 12, wherein the maternal alloantibodies are of an isotype selected from IgGl, IgG2, IgG3, or IgG4.

14. The method of any one of the preceding claims, wherein the pregnant subject has previously been pregnant with a fetus, wherein said fetus had or was diagnosed with FNAIT.

15. The method of any one of the preceding claims, wherein after the treatment, the fetal subject is liveborn at or after gestational week 34.

16. The method of any one of the preceding claims, wherein after the treatment, the fetal subject has a platelet count above 30 109 / L at birth.

17. The method of any one of the preceding claims, wherein after the treatment, the fetal subject has a platelet count above 50 109 / L at birth.

18. The method of any one of the preceding claims, wherein after the treatment, the fetal subject has a platelet count above 150xl09 / L at birth.

19. The method of any one of the preceding claims, wherein after the treatment, the fetal subject does not receive an intravenous immune globulin (IVIG) within 12 weeks following birth.

20. The method of any one of the preceding claims, wherein after the treatment, the fetal subject does not receive a platelet transfusion within 12 weeks following birth.

21. The method of any one of the preceding claims, wherein during the treatment, the fetal subject does not have an adjudicated severe bleeding in utero or up to the end of the first week following birth.

22. The method of one of the preceding claims, wherein the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDR Ls) CDR LI , CDR L2 and CDR L3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDR LI, CDR L2, CDR L3, CDR Hl, CDR H2 and CDR H3 have the amino acid sequences of the CDR L1, CDR L2, CDRL3, CDR H1, CDR H2 and CDR H3, respectively, of nipocalimab.

23. The method of any one of the preceding claims, wherein the anti-FcRn antibody comprises a light chain variable region (VL) comprising light chain complementarity determining regions (CDR Ls) CDR LI, CDR L2 and CDR L3, and a heavy chain variable region (VH) comprising heavy chain complementarity determining regions (CDR Hs) CDR Hl, CDR H2 and CDR H3, wherein the CDR LI , CDR L2, CDR L3, CDR Hl , CDR H2 and CDR H3 have the ammo acid sequences of SEQ ID NOs: 3-8, respectively.

24. The method of claim 23, wherein the VL comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 9, and the VH comprises an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 10.

25. The method of claim 24, wherein the VL comprises the amino acid sequence of SEQ ID NO: 9, and the VH comprises the amino acid sequence of SEQ ID NO: 10.

26. The method of any one of claims 21-25, wherein the anti-FcRn antibody comprises a light chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 1, and a heavy chain comprising an amino acid sequence that is at least 98%, 99% or 100% identical to the sequence of SEQ ID NO: 2.

27. The method of claim 26, where the light chain comprises the amino acid sequence of SEQ ID NO: 1 and the heavy chain comprises the amino acid sequence of SEQ ID NO: 2.

28. The method of any one of the preceding claims, wherein the anti-FcRn antibody is nipocalimab.

29. An anti-FcRn antibody for use in a method of treating, reducing severity of, or preventing fetal and neonatal alloimmune thrombocytopenia (FNAIT) in a fetal subject, the method comprising administering the anti-FcRn antibody to a pregnant woman carrying the fetal subject, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg based on the weight of the pregnant woman.

30. The anti-FcRn antibody for use according to claim 29, wherein the method is a method as defined in any one of claims 2 to 28.

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