Compositions and methods for treating hemolytic disease of the fetus and newborn

Abstract

Provided herein are methods for treating hemolytic disease of the fetus or newborn using compositions comprising anti-FcRn antibodies.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 483,266, filed February 4, 2023, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present application relates to treating hemolytic disease of the fetus and newborn (HDFN) in fetal subjects using compositions comprising anti-FcRn antibodies. [Background technology]

[0003] Hemolytic disease of the fetus and newborn (HDFN) is a rare and potentially life-threatening condition that occurs when the mother and fetus have incompatible blood types and the mother develops alloantibodies against antigens on fetal red blood cells (RBCs). During pregnancy, maternal alloantibodies cross the placenta and bind to fetal RBCs bearing the corresponding antigens, thereby causing RBC destruction and anemia in the fetus or newborn. Although maternal alloantibodies against many RBC antigens have been observed, the RBC antigens most commonly implicated in severe HDFN (defined as fetal anemia requiring intrauterine transfusion (IUT) or fetal death or hydrops fetalis as a result of HDFN) are RhD and, less frequently, Kell, RhC, Rhc, and RhE. Typically, the severity of HDFN disease increases with each pregnancy with an antigen-positive fetus due to repeated alloimmunization, and the gestational age (GA) of onset decreases (Urbaniak 2000, Lobato 2008, Jacobs 1962), although exceptions exist (Zwiers 2018a). The implementation of prenatal and postnatal anti-D immunoglobulin prophylaxis programs has resulted in a significant decrease in the frequency of RhD alloimmunization (from 16% to 0.3% or less) in RhD-negative women and associated fetal / neonatal complications (Bowman 1985, 1988; Koelewijn 2008; Huchet 1987). However, D alloimmunization has not been completely eliminated due to the inability to administer anti-D immunoglobulin according to published guidelines and due to unsuspected maternal-fetal bleeding in early pregnancy before third-trimester prophylaxis (Badami 2014). Together with non-RhD alloimmunization, for which prophylaxis is not available, HDFN affects approximately 3–80 people per 100,000 patients per year in countries with well-established healthcare infrastructure and Rh disease immunoprophylaxis (Koelewijn 2009, Delaney 2015).

[0004] The clinical manifestations of HDFN range from mild to life-threatening. While mildly affected newborns may require only postnatal phototherapy for jaundice (Ree 2017), fetal anemia in severe cases of HDFN requires intervention to prevent the development of hydrops fetalis (severe edema of the skin and serous cavities). In such cases, fetal red blood cell production cannot compensate for the loss of RBCs, and fetal splenic and hepatic enlargement may occur along with a high-output circulation, leading to cardiac enlargement and congestive heart failure. If fetal anemia is untreated, fetal death is almost certain. There are no approved medications for the treatment of severe HDFN. In the current standard of care, HDFN pregnancies at risk for fetal anemia are frequently monitored by fetal middle cerebral artery (MCA) Doppler (Mari 2000, Oepkes 2006). If the peak systolic velocity (PSV) of blood flow is greater than or equal to 1.5 times the median (MoM) and moderate to severe fetal anemia is confirmed by cordocentesis, intrauterine transfusion (IUT) of matched donor blood is performed. A large retrospective analysis of all IUTs for RBC alloimmunization performed in the Netherlands between 1988 and 2015 found that an average of three IUTs (range, one to seven) per fetus over the course of pregnancy were required to treat fetal anemia (Zwiers 2017). IUT is a resource-intensive procedure performed by trained personnel (maternal-fetal medicine specialists, anesthesiologists, specially trained nurses, and technicians) in the operating rooms of major medical centers. Therefore, there remains an urgent unmet medical need for effective non-surgical interventions to treat pregnant women at risk for severe HDFN. The embodiments provided herein fulfill these and other needs. [Brief explanation of the drawings]

[0005] [Figure 1A]Graph showing the proportion of participants with a live birth at GA 32 weeks or greater and no IUT throughout pregnancy across regimen arms in the UNITY trial. [Figure 1B] Graph showing the proportion of maternal subjects with a live birth at GA 32 weeks or later and no IUT throughout pregnancy by dose. [Figure 2] 1 is a graph showing the median serum nipocalimab concentrations in participants across regimen groups in the UNITY trial. [Figure 3A] Figure 3A shows the outcomes of nipocalimab administered to mothers at high risk for severe HDFN in the UNITY trial. Figure 3A shows the proportion of newborns requiring phototherapy. [Figure 3B] 3A and 3B are graphs showing the outcomes of nipocalimab administered to mothers at high risk for severe HDFN in the UNITY trial. Figure 3B shows the proportion of newborns and infants requiring uncomplicated blood transfusions. [Figure 3C] Figure 3C shows the mean number of simple transfusions required by neonates and infants. [Figure 3D] Figure 3D shows the mean volume of simple transfusion required by neonates and infants. [Figure 4] Graph comparing the proportion of participants who had a live birth at GA ≥ 32 weeks without IUT between the UNITY and CLARITY trials. [Figure 5] Graph comparing each of the 13 pregnant participants' on-study pregnancies (right panel) with their previous eligible pregnancies (left panel). DETAILED DESCRIPTION OF THE INVENTION

[0006] (Summary of the Invention) In some embodiments, methods are provided for treating or reducing the severity of hemolytic disease of the fetal newborn (HDFN) in a fetal subject, hi some embodiments, the methods comprise administering a composition comprising an anti-FcRn antibody to a pregnant woman carrying the fetal subject.

[0007] In some embodiments, a method of treating or reducing the severity of HDFN in a fetal subject comprises administering a composition comprising nipocalimab to a pregnant woman who is carrying the fetal subject, wherein nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman, and wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration.

[0008] (Mode for Carrying Out the Invention) The present disclosure provides embodiments relating to compositions and methods for treating or reducing the severity of hemolytic disease of the fetus and newborn (HDFN) and related symptoms or conditions associated with HDFN in a fetal subject. The methods include administering an antibody against human neonatal Fc receptor (FcRn) to a pregnant woman carrying the fetal subject. Antibodies against human FcRn may also be referred to as "anti-FcRn antibodies." The anti-FcRn antibodies disclosed herein are useful, for example, for promoting clearance of autoantibodies in a subject, suppressing antigen presentation in a subject, blocking an immune response (e.g., blocking immune complex-based activation of an immune response in a subject), and / or treating an immune disease (e.g., an autoimmune disease or an alloimmune disease) in a subject.

[0009] In some embodiments, the anti-FcRn antibody is nipocalimab, which may also be referred to as M281. Nipocalimab is an antibody that binds to FcRn and is described, for example, in U.S. Pat. No. 10,676,526, WO 2020 / 023310, and WO 2020 / 018910, all of which are incorporated herein by reference in their entireties.

[0010] The term "antibody" as used 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, VHHs, and antibody fragments, as long as they exhibit FcRn antigen-binding activity.

[0011] Additionally, an antibody or antibody molecule, as the term is used herein, refers to a polypeptide comprising at least one functional immunoglobulin variable domain sequence, e.g., an immunoglobulin chain or fragment thereof. Antibody molecules encompass 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 full-length immunoglobulin chain. For example, a full-length antibody is an immunoglobulin (Ig) molecule (e.g., an IgG antibody) that occurs naturally or is formed by normal immunoglobulin gene fragment recombination processes. In some embodiments, an antibody molecule refers to an immunologically active antigen-binding portion of an immunoglobulin molecule, such as an antibody fragment. Antibody fragments (e.g., functional fragments) include portions of antibodies, e.g., Fab, Fab', F(ab'), F(ab), variable fragments (Fv), domain antibodies (dAbs), or single-chain variable fragments (scFv). Functional antibody fragments bind to the same antigen recognized by an intact (e.g., full-length) antibody. The term "antibody fragment" or "functional fragment" also includes isolated fragments consisting of the variable regions, such as an "Fv" fragment consisting of the variable regions of the heavy and light chains, or a recombinant single-chain polypeptide molecule ("scFv protein") in which the light and heavy chain variable regions are connected by a peptide linker. In some embodiments, an antibody fragment does not include a portion of an antibody that does not have antigen-binding activity, such as an Fc fragment or a single amino acid residue. Exemplary antibody molecules include full-length antibodies and antibody fragments, such as dAb (domain antibodies), single chain, Fab, Fab', and F(ab')2 fragments, and single-chain variable fragments (scFv).

[0012] Immunoglobulin chains share the same general structure, with relatively conserved framework regions (FR) connected 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. Both light and heavy chains contain, from N- to C-terminus, the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain follows the Kabat Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991)) or the definitions in Chothia & Lesk J. Mol. Biol. 196:901-917 (1987); Chothia et al. Nature 342:878-883 (1989).

[0013] The term "antibody molecule" also encompasses whole or antigen-binding fragments of domain or single domain antibodies, which may also be referred to as "sdAbs" or "VHHs." Domain antibodies are VHs that can act as standalone antibody fragments. H or V LIn addition, domain antibodies include heavy chain-only antibodies (HCAbs). Domain antibodies also include the CH2 domain of an IgG as the basic scaffold onto which the CDR loops are grafted. It can also be generally defined as a polypeptide or protein comprising an amino acid sequence consisting 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 produced using techniques well known in the art. The numbering of the amino acid residues in sdAbs or polypeptides follows the general numbering of 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 incorporated herein by reference). According to this numbering, FR1 of the sdAb comprises the amino acid residues at positions 1 to 30, CDR1 of the sdAb comprises the amino acid residues at positions 31 to 36, FR2 of the sdAb comprises the amino acid residues at positions 36 to 49, CDR2 of the sdAb comprises the amino acid residues at positions 50 to 65, FR3 of the sdAb comprises the amino acid residues at positions 66 to 94, CDR3 of the sdAb comprises the amino acid residues at positions 95 to 102, and FR4 of the sdAb comprises the amino acid residues at positions 103 to 113. Domain antibodies are also described in WO 2004 / 041862 and WO 2016 / 065323, both of which are incorporated herein by reference in their entireties.

[0014] In some embodiments, as provided 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 of higher specificity (e.g., tetraspecific) and / or higher valency than hexavalent. 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 the heavy and light chains can be fused together into a single polypeptide.

[0015] As used herein, the terms "variable region" and "variable domain" refer to the portions of the light and heavy chains of an antibody comprising the amino acid sequences of the complementarity determining regions (e.g., CDR L1, CDR L2, CDR L3, CDR H1, CDR H2, and CDR H3) and framework regions. According to the method used in this disclosure, the amino acid positions assigned to the 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 may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a CDR (further defined herein) or FR (further defined herein) of the variable region. For example, the heavy chain variable region may include a single inserted residue after residue 52 in CDR H2 (i.e., residue 52a according to Kabat) and inserted residues after residue 82 in the heavy chain FR (i.e., residues 82a, 82b, 82c, etc. according to Kabat). The Kabat numbering of residues may be determined for a given antibody by aligning the sequence of that antibody with a "standard" Kabat numbered sequence at the region of homology.

[0016] As used herein, the terms "complementarity-determining region" and "CDR" refer to regions of an antibody variable domain or variable region that are hypervariable in sequence and / or form structurally defined loops. CDRs are also known as hypervariable regions. Light chain and heavy chain variable regions each have three CDRs. The light chain variable region contains CDR L1, CDR L2, and CDR L3. The heavy chain variable region contains CDR H1, CDR H2, and CDR H3. Each CDR may comprise amino acid residues from a complementarity-determining region as defined by Kabat (i.e., approximately residues 24-34 (CDR L1), 50-56 (CDR L2), and 89-97 (CDR L3) in the light chain variable region, and approximately residues 31-35 (CDR H1), 50-65 (CDR H2), and 95-102 (CDR H3) in the heavy chain variable region).

[0017] As used herein, the term "FcRn" refers to a neonatal Fc receptor that binds to the Fc region of an IgG antibody, e.g., an IgG1 antibody. An exemplary FcRn is human FcRn with UniProt ID number P55899, which is incorporated herein by reference in its entirety. Human FcRn is thought to be involved in maintaining the half-life of IgG by constitutively binding to internalized IgG and transporting it back to the cell surface for IgG recycling.

[0018] In some embodiments, the anti-FcRn antibody comprises a heavy chain or a light chain. In some embodiments, the anti-FcRn antibody comprises a heavy chain and a light chain in an scFv format. In some embodiments, the heavy chain and the light chain are linked by a peptide linker, such as a glycine / serine or glycine / alanine linker.

[0019] In some embodiments, the anti-FcRn antibody is M281 (nipocalimab). In some embodiments, nipocalimab is QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVLGQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 1) and a light chain comprising or consisting of: EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVT VSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCP PCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 2) and a heavy chain comprising or consisting of:

[0020] In some embodiments, the anti-FcRn antibody has (a) a light chain sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, wherein CDR L1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO: 3), CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 4), and CDR L3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 5); and (b) a heavy chain sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, wherein CDR H1 comprises the sequence TYAMG (SEQ ID NO: 6), CDR H2 comprises the sequence SIGASGSQTRYADS (SEQ ID NO: 7), and CDR H3 comprises the sequence LAIGDSY (SEQ ID NO: 8).

[0021] In some embodiments, the anti-FcRn antibody In some embodiments, the light chain variable region comprises a light chain variable region comprising an amino acid sequence at least 95%, 97%, 99%, or 100% identical to QSALTQPASVSGSPGQSITISCTGTGSDVGSYNLVSWYQQHPGKAPKLMIYGDSERPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYAGSGIYVFGTGTKVTVL (SEQ ID NO: 9). In some embodiments, the light chain variable region contains CDR L1 having the sequence of SEQ ID NO: 3, CDR L2 having the sequence of SEQ ID NO: 4, and CDR L3 having the sequence of SEQ ID NO: 5.

[0022] In some embodiments, the anti-FcRn antibody In some embodiments, the heavy chain variable region comprises a heavy chain variable region comprising an amino acid sequence at least 95%, 97%, 99%, or 100% identical to EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMGWVRQAPGKGLEWVSSIGASGSQTRYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLAIGDSYWGQGTMVTVSS (SEQ ID NO: 10). In some embodiments, the heavy chain variable region contains CDR H1 having the sequence of SEQ ID NO: 6, CDR H2 having the sequence of SEQ ID NO: 7, and CDR H3 having the sequence of SEQ ID NO: 8.

[0023] In some embodiments, the portion of the heavy chain of nipocalimab may include an additional lysine (K) residue at the C-terminus of SEQ ID NO:2.

[0024] As used herein, the term "nipocalimab" is intended to encompass biosimilar anti-FcRn antibodies equivalent to the nipocalimab protein developed and marketed by Johnson and Johnson. For example, a nipocalimab biosimilar may be acceptable to the European Medicines Agency (EMA) and / or the United States Food and Drug Administration (FDA) if it has essentially the same pharmacological effect as the reference product, nipocalimab. For example, a nipocalimab biosimilar may comprise or consist of the same heavy and light chain sequences as nipocalimab, except for C-terminal modifications. For example, one or more C-terminal amino acids of the heavy chain may be absent, e.g., compared to SEQ ID NO: 2. The present invention extends to the use of antibodies using the International Nonproprietary Name (INN) "nipocalimab."

[0025] In some embodiments, the fragment may further comprise amino acid substitutions, additions, and / or deletions outside the CDRs (i.e., in the framework regions (FR)). The amino acid substitutions, additions, and / or deletions may be of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8 or more). The amino acid substitutions, additions, and / or deletions may be of 8 or fewer, 7 or fewer, 6 or fewer, 5 or fewer, 4 or fewer, 3 or fewer, or 2 or fewer single amino acids.

[0026] In some embodiments, the antibodies described herein may contain amino acid substitutions, additions, and / or deletions in the constant region (e.g., Fc region) of the antibody that result in, for example, reduced effector function, e.g., reduced complement-dependent cytolysis (CDC), antibody-dependent cell-mediated cytolysis (ADCC), and / or antibody-dependent cell-mediated phagocytosis (ADCP), and / or reduced B-cell killing. The constant region is not directly involved in binding of the antibody to its target, but exhibits various effector functions, such as the involvement of the antibody in antibody-dependent cellular cytotoxicity. In some embodiments, the antibodies described herein are characterized by reduced binding (i.e., absent binding) to human complement factor C1q and / or human Fc receptors on natural killer (NK) cells. In other embodiments, the antibody is characterized by reduced binding (i.e., absent binding) to human FcγRI, FcγRIIA, and / or FcγRIIIA. In some embodiments, the antibodies described herein contain an asparagine (N) at position 297 (EU System numbering). In some embodiments, the anti-FcRn antibodies described herein are aglycosylated at position 297 (EU System numbering). Optionally, the anti-FcRn antibodies described herein do not have an N at position 297 (EU numbering) in any one of SEQ ID NOs: 2, such that the antibody is aglycosylated at that position. The resulting effectorless antibodies exhibit little binding to complement or Fc receptors (i.e., complement C1q binding), indicating low CDC capability. In some embodiments, the Fc region is an effector-less Fc region.

[0027] In some embodiments, the heavy chain of the isolated antibody comprises a sequence with 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 with no more than 5, 4, 3, 2, or 1 single amino acid substitutions relative to the sequence of SEQ ID NO: 1.

[0028] 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 present 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, if necessary, introducing gaps 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 by various methods within the skill of the art, for example, 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 maximum alignment over the entire 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 expressed as a given candidate sequence having or comprising a certain percent amino acid (or nucleic acid) sequence identity to, with, or against a given reference sequence) is calculated as follows: 100 x (A / B ratio) A is the number of amino acid (or nucleic acid) residues scored as identical in the alignment of the candidate and reference sequences, and 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 is not equal to the length of the reference sequence, the percent amino acid (or nucleic acid) sequence identity of the candidate sequence relative to the reference sequence is not equal to the percent amino acid (or nucleic acid) sequence identity of the reference sequence relative to the candidate sequence.

[0029] In some embodiments, a reference sequence aligned for comparison to a candidate sequence may show that the candidate sequence exhibits 50% to 100% identity over the entire length of the candidate sequence or over a selected portion of consecutive amino acid (or nucleic acid) residues of the candidate sequence. The length of the candidate sequence aligned for comparison purposes 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 the reference sequence, the molecules are identical at that position. Positions may be altered by substitution, deletion, or insertion. The substitution, deletion, or insertion may involve a specific 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 n or fewer amino acids, this means that the substitution, deletion, or insertion includes, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or n amino acids. The number of substitutions, deletions, or insertions can include a percentage of the total sequence (e.g., 1%, 5%, 10%, 15%, 20% or more), where the number of substitutions, deletions, or insertions changes 5%, 10%, 15%, 20% or more of the amino acids in the total sequence.

[0030] In some embodiments, the Fc domain of the antibody is afucosylated. In some embodiments, the Fc domain of the antibody is aglycosylated. In some embodiments, the antibody lacks effector function. In some embodiments of all of the methods described herein, the antibody is an IgG1 antibody.

[0031] 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 International Publication No. 2020 / 097099, rozanolixizumab is described in International Publication No. 2014 / 019727, and efgartigimod (ARGX-113) is described in International Publication No. 2015 / 100299, each of which is incorporated herein by reference in its entirety. In some embodiments, the anti-FcRn antibody is a biosimilar of any of the anti-FcRn antibodies provided herein. In some embodiments, the anti-FcRn antibody comprises the heavy and light chain CDRs of nipocalimab. In 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.

[0032] In some embodiments, the methods described herein comprise administering an anti-FcRn antibody to a pregnant woman carrying a 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 antibody is administered based on the weight of the pregnant subject. In some embodiments, the antibody is administered at a dose of 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. In some 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. A dosage of 45 mg / kg may be preferred.

[0033] In some embodiments, the maximum dose can be 5,400 mg. For example, the pharmaceutical composition can be administered at a dose of 45 mg / kg, provided that the dose does not exceed 5,400 mg.

[0034] In some embodiments, the calculated dose may be rounded to the nearest 0.1 kg.

[0035] In some embodiments, the antibody is administered weekly, every two weeks, or monthly. Weekly administration may be preferred. In some embodiments, the antibody is administered for at least 20 weeks. In some embodiments, the antibody is administered for up to 23 weeks. In some embodiments, the antibody is administered starting at gestation week (GW) 13, GW 14, GW 15, or GW 16. In some embodiments, the antibody is administered until GW 35. In some embodiments, the antibody is administered weekly from GW 13 to GW 35. In some embodiments, the antibody is administered weekly from GW 14 to GW 35. In some embodiments, the antibody is administered weekly from GW 15 to GW 35. In some embodiments, the antibody is administered weekly from GW 16 to GW 35. As used herein, the terms "weekly" or "weekly" refer to every 7 days (± 1 day), and the terms "biweekly" or "every two weeks" refer to every 14 days (± 1 day).

[0036] In some embodiments, the antibody is administered as part of a pharmaceutical composition, and about 15 mg / kg to 60 mg / kg of antibody is administered based on the weight of the pregnant woman. 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 first administration is based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration is based on the weight of the pregnant woman assessed one week prior to the subsequent administration. In some embodiments, the first administration is based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration is based on the weight of the pregnant woman assessed one week prior to the subsequent administration. In some embodiments, the first administration is based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration is based on the weight of the pregnant woman assessed two weeks prior to the subsequent administration. In some embodiments, the first administration is based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration is based on the weight of the pregnant woman assessed two weeks prior to the subsequent administration. In some embodiments, the administration occurs within about 15 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[0037] In some embodiments, the dose for the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses for subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediately preceding administration. In some embodiments, the dose for the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose for each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediately preceding administration. As used herein, the "immediately preceding administration" refers to the administration of the composition or anti-FcRn antibody administered immediately before the subsequent administration for which the dose is determined (e.g., in the case of weekly administration, the administration of the composition or anti-FcRn antibody administered one week prior).

[0038] In some embodiments, the dose for the first administration is based on the weight of the pregnant woman on the day of the first administration, and the doses for subsequent administrations are based on the weight of the pregnant woman assessed on the day of the immediately preceding administration. In some embodiments, the dose for the first administration is based on the weight of the pregnant woman on the day of the first administration, and the dose for each subsequent administration is based on the weight of the pregnant woman assessed on the day of the immediately preceding administration. As used herein, the "immediately preceding administration" refers to the administration of the composition or anti-FcRn antibody administered immediately before the subsequent administration for which the dose is determined (e.g., in the case of weekly administration, the administration of the composition or anti-FcRn antibody administered one week prior).

[0039] In some embodiments, the composition is administered weekly for at least 20 weeks, and the pregnant woman has an FcRn receptor occupancy rate of at least 90% after the first administration of the composition, and the pregnant woman maintains an FcRn receptor occupancy rate of at least 90% until after the last administration of the composition. The FcRn receptor occupancy rate can reach 90% or more at any time after the first administration and before the second administration. For example, the FcRn receptor occupancy rate can reach 90% or more within 1, 2, 3, 4, 5, or 6 days after the first administration. An FcRn receptor occupancy rate of 90% or more is considered full receptor occupancy in the art. FcRn receptor occupancy can be measured using flow cytometry.

[0040] The composition may be administered by any suitable route. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered by intravenous infusion.

[0041] In some embodiments, the pharmaceutical composition comprises one or more of sodium phosphate, sodium chloride, trehalose, or polysorbate.

[0042] As used herein, the term "pharmaceutical composition" refers to a pharmaceutical or pharmaceutical preparation containing an active ingredient and one or more excipients and diluents to make the active ingredient suitable for the administration method. The pharmaceutical composition of the present disclosure contains, for example, pharmaceutically acceptable components that are compatible with an anti-FcRn antibody. The pharmaceutical composition may be in aqueous form for intravenous administration.

[0043] In some embodiments, pharmaceutical compositions comprising anti-FcRn antibodies as therapeutic agents may be formulated for intravenous administration.

[0044] As used herein, the term "pharmaceutically acceptable carrier" refers to an excipient or diluent in a pharmaceutical composition. A pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. In the present disclosure, a pharmaceutically acceptable carrier must provide adequate pharmaceutical stability for the Fc construct. The nature of the carrier will vary depending on the mode of administration. For example, for intravenous administration, aqueous solution carriers are generally used, while for oral administration, solid carriers are preferred.

[0045] As used herein, the term "therapeutically effective amount" refers to an amount (e.g., a pharmaceutical dose) effective in inducing a desired biological effect in a subject or patient, or in treating a patient having a condition or disorder described herein. It is also understood that, as used herein, a "therapeutically effective amount" may be interpreted as an amount that provides the desired therapeutic effect, either taken in a single dose alone or in combination with other therapeutic agents, or taken in any dosage or route.

[0046] As used herein, the term "no more than" refers to an amount equal to or less than. This may be an integer amount. For example, no more than two substitutions can refer to 0, 1, or 2 substitutions.

[0047] As used herein, the terms "treat," "treatment," or "treating" refer to reducing, decreasing, reducing the risk of, or reducing the side effects of a particular disease or condition. The reducing, decreasing, reducing the risk, or reducing the side effects is compared to a subject not receiving the treatment, e.g., a control, baseline, or known control level or measurement.

[0048] In some embodiments, methods of treating hemolytic disease of the newborn (HDFN) in a fetal subject are provided. In some embodiments, the fetal subject has or is at risk for HDFN. In some embodiments, the HDFN is severe HDFN. In some embodiments, the fetal subject with or at risk for HDFN is an antigen-positive fetus. In some embodiments, the fetal subject with or at risk for HDFN is an antigen-positive fetus, where the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the fetal subject with or at risk for HDFN is an antigen-positive fetus, where the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof, and 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, and the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the fetal subject having or at risk for HDFN is an antigen positive fetus, and the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof, and the pregnant woman carrying the fetal subject is antigen negative, and the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the fetal subject having or at risk for HDFN is positive for an antigen selected from the group consisting of RhD, Kell, Rhc, RhE, RhC, or any combination thereof, and the pregnant woman carrying the fetal subject is negative for the same antigen. In some embodiments, a fetal subject having or at risk for HDFN is a subject whose pregnant mother has alloantibodies to an antigen, where the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, a fetal subject having or at risk for HDFN is positive for an antigen selected from the group consisting of RhD, Kell, Rhc, RhE, RhC, or any combination thereof, and the pregnant woman carrying the fetal subject has maternal alloantibodies to the same antigen.In some embodiments, the maternal alloantibodies are maternal alloantibodies of an isotype selected from IgG1, IgG2, IgG3, or IgG4. In some embodiments, the maternal alloantibodies have a titer selected from: anti-Kell 4 or greater, anti-RhD 16 or greater, anti-Rhc 16 or greater, anti-RhE 16 or greater, anti-RhC 16 or greater, or any combination thereof.

[0049] In some embodiments, the pregnant woman carrying the fetal subject has an obstetric history, which in some embodiments includes a previous pregnancy in which the fetus carried a fetus with fetal anemia requiring IUT, fetus with hydrops fetalis with an MCA-PSV MoM of 1.5 or greater, or fetus with HDFN-associated stillbirth at 25 weeks gestation or less, and / or maternal alloantibody titers for RhD, Kell, Rhc, RhE, or RhC antigens above critical levels (anti-Kell > 4, others > 16). In some embodiments, the pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus, wherein i) the woman underwent one or more intrauterine transfusions (IUT) to treat fetal anemia during the previous pregnancy, ii) the previous fetus suffered from fetal anemia, and / or iii) the previous pregnancy resulted in fetal death, and the woman had detectable maternal alloantibody titers to one or more of the RhD, Kell, Rhc, RhE, or RhC antigens above a critical level during the previous pregnancy, wherein the above-mentioned critical level for the anti-Kell maternal alloantibody titer is 4 or greater, the above-mentioned critical level for the anti-RhD maternal alloantibody titer is 16 or greater, the above-mentioned critical level for the anti-RhC maternal alloantibody titer is 16 or greater, the above-mentioned critical level for the anti-RhE maternal alloantibody titer is 16 or greater, and the above-mentioned critical level for the anti-RhC maternal alloantibody titer is 16 or greater. In some embodiments, the pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus, wherein i) the woman underwent one or more intrauterine transfusions (IUT) to treat fetal anemia during the previous pregnancy, ii) the previous fetus suffered from fetal anemia, and iii) the previous pregnancy resulted in fetal death, and the woman had a detectable maternal alloantibody titer to one or more RhD, Kell, Rhc, RhE, or RhC antigens above a critical level during the previous pregnancy, wherein the above-mentioned critical level for the anti-Kell maternal alloantibody titer is 4 or greater, the above-mentioned critical level for the anti-RhD maternal alloantibody titer is 16 or greater, the above-mentioned critical level for the anti-RhC maternal alloantibody titer is 16 or greater, the above-mentioned critical level for the anti-RhE maternal alloantibody titer is 16 or greater, and the above-mentioned critical level for the anti-RhC maternal alloantibody titer is 16 or greater.In some embodiments, the pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus, and i) the woman underwent one or more intrauterine transfusions (IUT) to treat fetal anemia during the previous pregnancy, ii) the previous fetus suffered from fetal anemia, or iii) the previous pregnancy resulted in fetal death, and the woman had a detectable maternal alloantibody titer to one or more RhD, Kell, Rhc, RhE, or RhC antigens above a critical level during the previous pregnancy, wherein the above-mentioned critical level for the anti-Kell maternal alloantibody titer was 4 or greater, the above-mentioned critical level for the anti-RhD maternal alloantibody titer was 16 or greater, the above-mentioned critical level for the anti-RhC maternal alloantibody titer was 16 or greater, the above-mentioned critical level for the anti-RhE maternal alloantibody titer was 16 or greater, and the above-mentioned critical level for the anti-RhC maternal alloantibody titer was 16 or greater.

[0050] In some embodiments, the method comprises administering to a pregnant woman a pharmaceutical composition comprising an anti-FcRn antibody to treat HDFN. In some embodiments, the anti-FcRn antibody is nipocalimab, RVT-1401 (HL161), rozanolixizumab (UCB7665), ALXN1830, ABY-039, or efgartigimod. In some embodiments, the antibody is nipocalimab. In some embodiments, the antibody is RVT-1401 (HL161). In some embodiments, the antibody is rozanolixizumab (UCB7665). In some embodiments, the antibody is ALXN1830. In some embodiments, the antibody is ABY-039. In some embodiments, the antibody is efgartigimod. In some embodiments, the anti-FcRn antibody is as provided herein. In some embodiments, the methods involve administering a pharmaceutical composition comprising an anti-FcRn antibody to a pregnant woman having or at risk of HDFN to treat a fetal subject carried by the pregnant woman.

[0051] In some embodiments, a pregnant woman carrying a fetal subject being treated for HDFN exhibits improvement in one or more of the following assays, scores, or criteria, which can be used to assess the improvement or condition of a pregnant woman carrying a fetal subject with HDFN: In some embodiments, a pregnant woman carrying a fetal subject exhibits improvement in one or more of a Generalized Anxiety Disorder 7-item (GAD-7) score, a 36-Item Short Form Health Survey version 2 Acute (SF-36 v2 Acute) score, a EuroQoL five-dimension questionnaire (EQ-5D-5L) score, or a combination thereof. In some embodiments, a pregnant woman carrying a fetal subject has an obstetric history that includes a previous pregnancy carrying a previous fetus, and the fetal subject exhibits a reduction in the severity of HDFN compared to the previous fetus, and / or the fetal subject exhibits an improvement in an MCA-PSV MoM score compared to the previous fetus.

[0052] In some embodiments, a pregnant woman carrying a fetal subject being treated for HDFN has or exhibits a reduction in one or more immunoglobulin isotypes or total IgG. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%. In some embodiments, the reduced immunoglobulin isotype is IgG1, IgG2, IgG3, IgG4, or any combination thereof.

[0053] In some embodiments, a pregnant woman carrying a fetal subject treated for HDFN has or exhibits a reduction in pathogenic alloantibodies. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the pathogenic alloantibody that is reduced is selected from the group including anti-RhD alloantibody, anti-Kell alloantibody, anti-Rhc alloantibody, anti-Rhe alloantibody, anti-RhC alloantibody, or any combination thereof.

[0054] In some embodiments, methods are provided for treating or ameliorating anemia (e.g., mild anemia or severe anemia), severe anemia with liver and spleen enlargement, hyperbilirubinemia, jaundice, fetal hydrops, severe hyperbilirubinemia, and / or kernicterus in a fetal subject. In some embodiments, the method comprises administering a pharmaceutical composition comprising administering an anti-FcRn antibody to a pregnant woman carrying the fetal subject. In some embodiments, the anti-FcRn antibody is nipocalimab, RVT-1401 (HL161), rozanolixizumab (UCB7665), ALXN1830, ABY-039, or efgartigimod. In some embodiments, the antibody is nipocalimab. In some embodiments, the antibody is RVT-1401 (HL161). In some embodiments, the antibody is rozanolixizumab (UCB7665). In some embodiments, the antibody is ALXN1830. In some embodiments, the antibody is ABY-039. In some embodiments, the antibody is efgartigimod. In some embodiments, the anti-FcRN antibody is as provided herein. In some embodiments, the fetal subject has or is at risk of having hemolytic disease of the fetus of the newborn.

[0055] In some embodiments, a fetal subject being treated for HDFN achieves a change in the severity of HDFN after administering an anti-FcRn antibody to a pregnant woman carrying the fetal subject. The severity of HDFN is classified as follows: i) severe: HDFN results in fetal and neonatal death, fetal hydrops, or the need for IUT during pregnancy; ii) moderate: HDFN results in the need for exchange transfusion of the neonate, but no prenatal treatment for HDFN is required; iii) mild: HDFN results in the need for simple transfusion of the neonate with or without phototherapy within 12 weeks of birth, but no exchange transfusion or prenatal treatment for HDFN is required; iv) self-limited: no treatment is required for HDFN, or hemolysis requires only phototherapy treatment, and / or HDFN is treated with recombinant EPO / iron supplements; and v) absent: in pregnancies not affected by HDFN, neonates have hemoglobin above the lower limit of the age-appropriate normal reference range and bilirubin below the upper limit of the age-appropriate normal reference range at birth and within 12 weeks after birth.

[0056] In some embodiments, the fetal subject achieves a change in the severity of HDFN after treatment with an anti-FcRn antibody. In some embodiments, the change in the severity of HDFN is from more severe to milder HDFN. In some embodiments, the severity of HDFN is classified as severe, moderate, mild, self-limiting, or none. In some embodiments, the change in the severity of HDFN is from severe to moderate. In some embodiments, the change in the severity of HDFN is from severe to mild. In some embodiments, the change in the severity of HDFN is from severe to self-limiting. In some embodiments, the change in the severity of HDFN is from severe to none. In some embodiments, the change in the severity of HDFN is from moderate to mild. In some embodiments, the change in the severity of HDFN is from moderate to self-limiting. In some embodiments, the change in the severity of HDFN is from moderate to none. In some embodiments, the change in severity of HDFN is from mild to self-limiting. In some embodiments, the change in severity of HDFN is from mild to none. In some embodiments, the change in severity of HDFN is from self-limiting to none. In some embodiments, the fetal subject achieves a change in severity of HDFN from severe to moderate after administration of a composition comprising an anti-FcRn antibody. In some embodiments, the fetal subject achieves a change in severity of HDFN from severe to mild after administration of a composition comprising an anti-FcRn antibody. In some embodiments, the fetal subject achieves a change in severity of HDFN from severe to self-limiting after administration of a composition comprising an anti-FcRn antibody. In some embodiments, the fetal subject achieves a change in severity of HDFN from severe to none after administration of a composition comprising an anti-FcRn antibody. In some embodiments, the fetal subject achieves a change in the severity of HDFN after administration of a composition comprising an anti-FcRn antibody, where the severity of HDFN is changed from moderate to mild.In some embodiments, a fetal subject achieves a change in the severity of HDFN from moderate to self-limited after administration of a composition comprising an anti-FcRn antibody. In some embodiments, a fetal subject achieves a change in the severity of HDFN from moderate to none after administration of a composition comprising an anti-FcRn antibody. In some embodiments, a fetal subject achieves a change in the severity of HDFN from mild to self-limited after administration of a composition comprising an anti-FcRn antibody. In some embodiments, a fetal subject achieves a change in the severity of HDFN from mild to none after administration of a composition comprising an anti-FcRn antibody. In some embodiments, a fetal subject achieves a change in the severity of HDFN from self-limited to none after administration of a composition comprising an anti-FcRn antibody.

[0057] As used herein, "severe HDFN" is defined as fetal anemia requiring intrauterine transfusion (IUT), or fetal death or hydrops fetalis as a result of HDFN.

[0058] In some embodiments, a pregnant woman carrying a fetal subject treated for HDFN does not require intrauterine transfusion (IUT) during pregnancy after being treated with the antibody. In some embodiments, treatment of HDFN in a fetal subject does not cause IUT during pregnancy. In some embodiments, a pregnant woman carrying a fetal subject treated for HDFN does not experience fetal loss due to HDFN after being treated with the antibody. In some embodiments, treatment of HDFN in a fetal subject does not cause fetal loss due to HDFN. In some embodiments, treatment of HDFN in a fetal subject results in a live birth in the fetal subject. In some embodiments, the fetal subject is live born and the pregnant woman did not undergo IUT before GW24. In some embodiments, the fetal subject is live born at or after GW32. In some embodiments, the fetal subject is live born at or after GW32 and the pregnant woman did not undergo IUT during the fetal subject's pregnancy. In some embodiments, treatment of HDFN in a fetal subject does not cause neonatal postpartum death due to HDFN. In some embodiments, treating HDFN in a fetal subject results in the live birth of a newborn. In some embodiments, treating HDFN in a fetal subject results in the live birth of the fetal subject. In some embodiments, the fetal subject survives for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 weeks after delivery. In some embodiments, the fetal subject survives for at least 24 weeks after delivery. In some embodiments, a pregnant woman carrying a fetal subject treated for fetal hemolytic disease of the newborn does not experience complications due to fetal hydrops during pregnancy after treatment with the antibody. In some embodiments, the fetal subject does not have fetal hydrops. In some embodiments, treating HDFN in a fetal subject does not cause complications due to fetal hydrops during pregnancy. In some embodiments, the treatment prevents complications due to fetal hydrops during pregnancy / gestation.In some embodiments, a pregnant woman carrying a fetal subject treated for hemolytic disease of the fetus of the newborn does not experience fetal loss due to HDFN, complications due to fetal hydrops during pregnancy, or intrauterine transfusions during pregnancy after being treated with the antibody. In some embodiments, treating HDFN in a fetal subject does not cause fetal loss due to HDFN, or neonatal postpartum death due to HDFN, or complications due to fetal hydrops during pregnancy, or intrauterine transfusions during pregnancy, or postpartum exchange transfusions of the newborn. In some embodiments, a pregnant woman carrying a fetal subject treated for hemolytic disease of the newborn experiences a reduced incidence of IUT after being treated with the antibody. In some embodiments, treating HDFN reduces the incidence of hydrops fetalis. In some embodiments, the pregnant woman has an obstetric history including a previous pregnancy with a previous fetus, and the pregnant woman experiences fewer IUTs compared to the previous pregnancy. In some embodiments, the fetal subject does not receive an exchange transfusion within 12 weeks of birth. In some embodiments, the fetal subject does not receive a simple blood transfusion within 12 weeks of birth.

[0059] In some embodiments, the pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus. In some embodiments, the fetus had or was diagnosed with HDFN. In some embodiments, the HFDN was severe HDFN.

[0060] In some embodiments, pregnant women carrying fetal subjects treated for HDFN achieve a change from baseline in GAD-7 on the GAD-7 scale after treatment with the antibody. The GAD-7 scale is a self-administered questionnaire designed to measure anxiety (Spitzer et al., "A brief measure for assessing generalized anxiety disorder: the GAD-7," Arch Intern Med. 2006 May 22;166(10):1092-7; Lowe et al., "Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population," Med Care. 2008 Mar;46(3):266-74, the contents of which are incorporated herein by reference). The recall period for all items is the past two weeks. Responses to all items are rated on a 4-point Likert scale ranging from 0 ("never") to 3 ("almost every day"). Total scores range from 0 to 21, with higher scores indicating more severe anxiety symptoms. The GAD-7 can generally be completed in 2-3 minutes.

[0061] In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in GAD-7 score on the GAD-7 scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, the change from baseline in GAD-7 score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0062] In some embodiments, pregnant women carrying fetal subjects treated for HDFN achieve a change from baseline in the SF-36 v2 Acute scale after treatment with the antibody. The SF-36 Health Survey version 2 is a self-administered 36-item questionnaire that measures health-related quality of life (HRQOL) (Maruish ME (Ed.) (2011): User's Manual for the SF-36v2 Health Survey. QualityMetric Inc. 3rd ed. Lincoln, RI: QualityMetric Inc., the contents of which are incorporated herein by reference). The recall period for all items is the past week. The SF-36 version 2 Acute includes eight domains measuring physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. The eight domains can be aggregated into two summary scales reflecting physical and mental health: a physical summary and a mental summary. Responses to all items are ranked on a 3-, 5-, or 6-point Likert scale, with higher scores indicating better health. The SF-36 version 2 Acute can generally be completed in 5–10 minutes.

[0063] In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in the SF-36 v2 Acute score on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in the SF-36 v2 Acute score of the physical component summary (PCS) on the SF-36 v2 Acute scale over time. In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in the SF-36 v2 Acute score of the mental component summary (MCS) on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in the SF-36 v2 Acute score of the Physical Component Summary (PCS) and Mental Component Summary (MCS) on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in the SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the PCS SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the MCS SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the PCS and MCS SF-36 v2 Acute scores indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0064] In some embodiments, pregnant women carrying fetal subjects treated for HDFN achieve a change from baseline in EQ-5D-5L scores on the EQ-5D-5L scale after treatment with an anti-FcRn antibody. The EQ-5D-5L Descriptive System is a self-administered, standardized measure of a wide range of health conditions and treatments (Herdman et al., "Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L)," Qual Life Res. 2011 December;20(10):1727-36; Janssen et al., "Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study," Qual Life Res. 2013 September;22(7):1717-27, the contents of which are incorporated herein by reference). It provides a descriptive profile of health status and a single index value for health conditions that can be used in clinical and economic evaluations of healthcare. The recall period for all items is "today." The EQ-5D-5L consists of the EQ-5D descriptive system (EQ-5D descriptive system) and the EQ visual analogue scale (EQ-VAS). The EQ-5D descriptive system consists of five items across five dimensions, including mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. The EQ-5D-5L uses a 5-point Likert response scale ranging from "no problem" to "extreme problem," with higher scores indicating better quality of life. The EQ-5D health status defined by the EQ-5D descriptive system can be converted into a single index value using country-specific value sets. The index value facilitates the calculation of quality-adjusted life years, which can be used to inform economic evaluations of healthcare interventions.The EQ-5D also includes a VAS with endpoints labeled "best imaginable health state" and "worst imaginable health state," anchored at 100 and 0, respectively. Participants are asked to indicate how they rank their health by indicating the point on the EQ-VAS that best describes their health for that day. The EQ-5D-5L generally takes 2–3 minutes to complete.

[0065] In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in EQ-5D-5L on the EQ-5D-5L scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in EQ-5D on the EQ-5D scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in VAS score on the VAS scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in EQ-5D-5L score indicates an improvement. In some embodiments, a change from baseline in EQ-5D score indicates an improvement. In some embodiments, a change from baseline in VAS score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0066] In some embodiments, pregnant women carrying fetal subjects treated for HDFN achieve a change from baseline in the multiple of the median peak systolic velocity of the middle cerebral artery on the MCA-PSV MoM scale (MCA-PSV MoM) score after treatment with an anti-FcRn antibody. The fetal subjects are monitored for anemia via weekly assessment of MCA PSV via Doppler ultrasound from screening to birth according to Mari (Mari et al., "Noninvasive Diagnosis by Doppler Ultrasonography of Fetal Anemia Due to Maternal Red-Cell Alloimmunization," The New England Journal of Medicine, 342:9-14, 2000, the contents of which are incorporated herein by reference). According to current standard of care, if the MCA PSV is 1.5 MoM or greater for the fetal subject's estimated GA, cordocentesis to confirm fetal anemia should be completed using the following guidelines: i) If the MCA PSV is 1.8 MoM or greater, cordocentesis should be performed within 24 hours of the measurement. ii) If the MCA PSV is 1.5–1.8 MoM, the investigator may choose to perform cordocentesis within 24 hours of the initial measurement based on other clinical considerations, or may choose to repeat the MCA PSV within 48 hours of the initial measurement to confirm the result. If the repeated MCA PSV is 1.5 or greater, cordocentesis should be performed within 24 hours of the repeat measurement. If the repeated MCA PSV is less than 1.5, cordocentesis is not necessary. Weekly MCA PSV measurements are resumed, but the investigator may choose to monitor MCA PSV more frequently than weekly and proceed with cordocentesis if any repeated MCA PSV is 1.5 or greater. iii) Because other aspects of clinical decision-making regarding cordocentesis criteria cannot be fully standardized, if the investigator does not specifically follow the above criteria regarding the timing of cordocentesis, the reasons for any deviation from the criteria should be explained in detail in the electronic case report form (eCRF).

[0067] In some embodiments, a pregnant woman carrying a fetal subject achieves a change from baseline in MCA-PSV MoM score on the MCA-PSV MoM scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, the change from baseline in MCA-PSV MoM score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0068] In some embodiments, treatment of HDFN in fetal subjects results in newborns achieving improved IQI scores on the IQI scale after administration of a composition containing an anti-FcRN antibody. The IQI is a seven-item, proxy-reported (often by parents or caregivers) mobile questionnaire designed to assess HRQOL by measuring an infant's health status during the first year of life (Krabbe 2020; Jabrayilov 2018). Parents and / or caregivers are asked to select whether the hypothetical child's health is better or worse than their own child's. The IQI consists of seven health attributes, including sleep, feeding, breathing, bowel movements / pooping, mood, skin, and interaction. Responses to all items are ranked on a four-point Likert scale, with higher scores indicating better quality of life. The IQI health status can be used to calculate a utility score. The IQI generally takes 2-3 minutes to complete.

[0069] In some embodiments, treatment of HDFN in a fetal subject results in the newborn achieving an improved IQI score on the IQI scale after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in IQI score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0070] In some embodiments, treating HDFN in a fetal subject does not cause neonatal death at birth of the newborn after 24 weeks of gestation or within 24 weeks of gestation. In some embodiments, treating HDFN in a fetal subject does not cause placental IgG transfer to the fetal subject. In some embodiments, treating HDFN in a fetal subject blocks placental IgG transfer to the fetal subject. In some embodiments, treating HDFN in a fetal subject results in a newborn that exhibits a reduction in maternal alloantibodies over time. In some embodiments, the maternal alloantibody is a pathogenic alloantibody. In some embodiments, the pathogenic alloantibody is against an antigen selected from RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the reduction is at least 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the reduction is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold. In some embodiments, the reduction is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, or 20-fold.

[0071] In some embodiments, after the first administration of the anti-FcRn antibody, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least eight-fold compared to before the first administration. This at least eight-fold reduction in the concentration of maternal alloantibodies in the pregnant woman can be achieved any time after the first administration and before the second administration, for example, within 1, 2, 3, 4, 5, or 6 days after the first administration. In some embodiments, after the first administration of the antibody, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least eight-fold compared to before the first administration of the antibody, and the pregnant woman maintains the reduced concentration of maternal alloantibodies until after the last administration of the composition. In some embodiments, after the first administration of the antibody, the concentration of serum IgG in the pregnant woman is reduced by at least 80% compared to before the first administration, and the pregnant woman maintains the reduced concentration of serum IgG until after the last administration of the composition. This at least 80% reduction in the concentration of serum IgG in the pregnant woman can be achieved any time after the first administration and before the second administration, for example, within 1, 2, 3, 4, 5, or 6 days after the first administration. The maintenance of the reduced concentration of serum IgG until after the last administration of the composition can be, for example, at least one day after the last administration of the composition.

[0072] In some embodiments, the pregnant woman has not received intravenous immune globulin (IVIG) prior to the last administration of the composition.

[0073] As provided herein, in some embodiments, a pharmaceutical composition comprising an anti-FcRn antibody is provided. In some embodiments, a pharmaceutical composition comprising an anti-FcRn antibody for administration to a pregnant woman who is pregnant with a fetal subject suffering from or at risk of hemolytic disease of the newborn, wherein the anti-FcRn antibody is administered to the pregnant woman in a therapeutically effective amount of about 15 mg / kg to about 60 mg / kg weekly, is provided. In some embodiments, the pharmaceutical composition is administered to the pregnant woman who is pregnant with the fetal subject in a therapeutically effective amount of about 45 mg / kg weekly. In some embodiments, the pregnant woman is carrying an antigen-positive fetus. In some embodiments, the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the pregnant woman who is pregnant with the fetal subject has an alloantibody against the antigen. In some embodiments, the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the alloantibody titers are 4 or greater for anti-Kell, 16 or greater for anti-RhD, 16 or greater for anti-Rhc, 16 or greater for anti-RhE, 16 or greater for anti-RhC, or any combination thereof. In some embodiments, the pregnant woman carrying the fetal subject has an obstetric history. In some embodiments, the obstetric history includes a previous pregnancy in which the fetus carried a fetus with fetal anemia requiring IUT, fetus with hydrops fetalis with an MCA-PSV MoM of 1.5 or greater, or fetus with HDFN-associated stillbirth at 25 weeks gestation or less, and / or a fetus with maternal alloantibody titers for RhD, Kell, Rhc, RhE, or RhC antigens above critical levels (anti-Kell ≧4, others ≧16). In some embodiments, the pregnant woman did not undergo IUT during the pregnancy in which the fetal subject was carried. In some embodiments, the fetal subject carried by the pregnant woman is a fetal subject with or at risk for severe HDFN.

[0074] In some embodiments, a method of treating or reducing the severity of HDFN in a fetal subject is provided, the method comprising administering to a pregnant woman carrying the fetal subject a composition comprising nipocalimab, wherein nipocalimab is administered at about 45 mg / kg based on the woman's weight, and the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration, and each subsequent administration being based on the woman's weight assessed one week or two weeks prior to the subsequent administration. In some embodiments, a method of treating or reducing the severity of HDFN in a fetal subject is provided, the method comprising administering to a pregnant woman carrying the fetal subject a composition comprising nipocalimab, wherein nipocalimab is administered at about 45 mg / kg based on the woman's weight, and the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration, and each subsequent administration being based on the woman's weight assessed one week or two weeks prior to the subsequent administration.

[0075] In some embodiments, administration of a pharmaceutical composition to a pregnant woman to treat HDFN results in the pregnant woman showing an improvement in the severity of HDFN, a Generalized Anxiety Disorder 7-item (GAD-7) score, a 36-item Short-Form Health Survey version 2 Acute (SF-36 v2 Acute) score, a EuroQoL 5-dimensional questionnaire (EQ-5D-5L) score, or a combination thereof. In some embodiments, administration of a pharmaceutical composition to a pregnant woman to treat hemolytic disease of the fetus reduces the severity of HDFN.

[0076] In some embodiments, administration of a pharmaceutical composition to a pregnant woman to treat HDFN in a fetal subject results in the newborn achieving an improvement in one or more of the following assays, scores, or criteria, which can be used to assess the improvement or condition of the newborn: In some embodiments, the newborn demonstrates an improvement in Infant Health-Related Quality of Life Instrument (IQI) score.

[0077] In some embodiments, administration of the pharmaceutical composition to a pregnant woman carrying a fetal subject results in a reduction of one or more immunoglobulin isotypes or total IgG in the pregnant woman. In some embodiments, the isotype is IgG1, IgG2, IgG3, or IgG4. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or 80%.

[0078] In some embodiments, administration of the pharmaceutical composition to a pregnant woman carrying a fetal subject results in a reduction in pathogenic alloantibodies. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the pathogenic alloantibodies that are reduced are selected from the group including RhD, Kell, Rhc, RhE, RhC, or any combination thereof.

[0079] In some embodiments, administration of the pharmaceutical composition to a pregnant woman carrying a fetal subject treats or ameliorates anemia (e.g., mild anemia or severe anemia), severe anemia with enlarged liver and spleen, hyperbilirubinemia, jaundice, hydrops fetalis, severe hyperbilirubinemia, or kernicterus, or a combination thereof.

[0080] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN following administration of a composition comprising an anti-FcRN antibody. In some embodiments, the change in severity of HDFN is from more severe to milder HDFN. In some embodiments, the severity of HDFN is classified as severe, moderate, mild, self-limiting, or none. In some embodiments, the change in severity of HDFN is from severe to moderate. In some embodiments, the change in severity of HDFN is from severe to mild. In some embodiments, the change in severity of HDFN is from severe to self-limiting. In some embodiments, the change in severity of HDFN is from severe to none. In some embodiments, the change in severity of HDFN is from moderate to mild. In some embodiments, the change in severity of HDFN is from moderate to self-limiting. In some embodiments, the change in severity of HDFN is from moderate to none. In some embodiments, the change in severity of HDFN is from mild to self-limiting. In some embodiments, the change in severity of HDFN is from mild to none. In some embodiments, the change in severity of HDFN is from self-limiting to none. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in severity of HDFN from severe to moderate after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in severity of HDFN from severe to mild after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in severity of HDFN from severe to self-limiting after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of the pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN is changed from severe to none after administration of the composition comprising an anti-FcRN antibody.In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN is changed from moderate to mild, after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN is changed from moderate to self-limited, after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN is changed from moderate to none, after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN is changed from mild to self-limited, after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN changes from mild to none, after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject achieves a change in the severity of HDFN, where the severity of HDFN changes from self-limited to none, after administration of a composition comprising an anti-FcRN antibody.

[0081] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for hemolytic disease of the fetus of the newborn results in the pregnant woman not requiring intrauterine transfusions during pregnancy after treatment with the pharmaceutical composition. In some embodiments, administration of a pharmaceutical composition for treating HDFN in a fetal subject does not result in intrauterine transfusions during pregnancy. In some embodiments, administration of a pharmaceutical composition for treating HDFN in a fetal subject does not result in exchange transfusion of the newborn after delivery. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for HDFN results in the pregnant woman not experiencing fetal loss due to HDFN after treatment with the antibody. In some embodiments, administration of a pharmaceutical composition for treating HDFN in a fetal subject does not result in fetal loss due to HDFN. In some embodiments, administration of a pharmaceutical composition for treating HDFN in a fetal subject does not result in neonatal postpartum death due to HDFN. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for HDFN results in the pregnant woman not experiencing complications due to fetal hydrops during pregnancy after being treated with the antibody. In some embodiments, administration of a pharmaceutical composition to treat HDFN in a fetal subject does not cause complications due to fetal hydrops during pregnancy. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for HDFN results in the pregnant woman not experiencing fetal loss due to HDFN, complications due to fetal hydrops during pregnancy, and intrauterine transfusions during pregnancy after being treated with the antibody. In some embodiments, treatment of HDFN in a fetal subject does not cause fetal loss due to HDFN or neonatal postpartum death due to HDFN, does not cause complications due to fetal hydrops during pregnancy, does not cause intrauterine transfusions during pregnancy, or does not cause neonatal exchange transfusions after delivery. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for HDFN results in the pregnant woman experiencing a reduced incidence of intrauterine transfusions after being treated with an anti-FcRn antibody. In some embodiments, administration of a pharmaceutical composition to treat HDFN reduces the incidence of intrauterine transfusions.In some embodiments, administration of a pharmaceutical composition for treating HDFN reduces the occurrence of fetal hydrops. In some embodiments, administration of a pharmaceutical composition for treating HDFN reduces the occurrence of exchange transfusion in newborns. In some embodiments, administration of a pharmaceutical composition for treating HDFN reduces the occurrence of simple transfusion within 12 weeks of birth.

[0082] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for hemolytic disease of the newborn achieves a change from baseline in GAD-7 score on the GAD-7 scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, the change from baseline in GAD-7 score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0083] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for hemolytic disease of the newborn achieves a change from baseline in the SF-36 v2 Acute score on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for HDFN achieves a change from baseline in the SF-36 v2 Acute score of the Physical Component Summary (PCS) on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for HDFN achieves a change from baseline in the SF-36 v2 Acute score of the Mental Component Summary (MCS) on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject to be treated for HDFN achieves a change from baseline in the SF-36 v2 Acute scores of the Physical Component Summary (PCS) and Mental Component Summary (MCS) on the SF-36 v2 Acute scale over time after administration of a composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in the SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the PCS SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the MCS SF-36 v2 Acute score indicates an improvement. In some embodiments, a change from baseline in the PCS and MCS SF-36 v2 Acute scores indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0084] In some embodiments, administration of a pharmaceutical composition to a pregnant woman pregnant with a fetal subject being treated for fetal hemolytic disease of the newborn achieves a change from baseline in the EQ-5D-5L score on the EQ-5D-5L scale over time after administration of the composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman pregnant with a fetal subject being treated for HDFN achieves a change from baseline in the EQ-5D score on the EQ-5D scale over time after administration of the composition comprising an anti-FcRN antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman pregnant with a fetal subject being treated for HDFN achieves a change from baseline in the VAS score on the VAS scale over time after administration of the composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in the EQ-5D-5L score indicates an improvement. In some embodiments, a change from baseline in the EQ-5D score indicates an improvement. In some embodiments, a change from baseline in the VAS score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0085] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for hemolytic disease of the newborn achieves a change from baseline in the MCA-PSV MoM score on the MCA-PSV MoM scale over time after administration of the composition comprising an anti-FcRN antibody. In some embodiments, the change from baseline in the MCA-PSV MoM score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0086] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject being treated for hemolytic disease of the newborn achieves an improved IQI score on the IQI scale over time after administration of the composition comprising an anti-FcRN antibody. In some embodiments, a change from baseline in the IQI score indicates an improvement. In some embodiments, the improvement is at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, or 300% compared to baseline.

[0087] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for hemolytic disease of the newborn does not result in neonatal death at birth of the newborn after 24 weeks of gestation or within 24 weeks of gestation. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for HDFN does not result in placental transfer of IgG to the fetus. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for HDFN blocks placental transfer of IgG to the fetus. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject treated for HDFN results in the newborn exhibiting a reduction in maternal alloantibodies over time. In some embodiments, the maternal alloantibody is a pathogenic alloantibody. In some embodiments, the pathogenic alloantibody is directed against an antigen selected from RhD, Kell, Rhc, RhE, RhC, or any combination thereof. In some embodiments, the reduction is about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1-20%, 5-20%, 5-25%, 10-30%, 15-35%, 20-40%, 40-60%, or about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 95%.

[0088] As used herein, the term "change" with respect to baseline refers to an improvement in a subject compared to the subject's condition, score, symptom, etc. before being treated with an anti-FcRn antibody provided herein.

[0089] "Baseline" refers to a subject before being treated with a therapeutic agent such as an anti-FcRn antibody, including those provided herein.

[0090] As provided herein, in some embodiments, maternal / fetal improvement of symptoms or conditions is said to occur 22 weeks after initiation of treatment. As provided herein, in some embodiments, maternal improvement of symptoms or conditions is said to occur 22 weeks after initiation of treatment and 24 weeks postpartum. As provided herein, in some embodiments, neonatal / infant / child improvement of symptoms or conditions is said to occur 96 weeks after initiation of treatment. Although reference is made to determining whether these improvements are measurable at 22, 24, and 96 weeks, in some embodiments, the improvements or changes described herein are measured at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, , 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, and 96 weeks. In some embodiments, the change or improvement is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 21, Lasts 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, and 96 weeks.

[0091] In some embodiments, a pregnant woman who is pregnant with a fetal subject being treated for hemolytic disease of the newborn with an anti-FcRn antibody is receiving concurrent or prophylactic treatment including: i) previously received nipocalimab; ii) previously received batoclimab, efgartigimod, rozanolixizumab, or other anti-FcRn investigational agents; iii) currently receiving systemic corticosteroids or other immunosuppressants for a disorder unrelated to pregnancy (Note: use of low-potency topical corticosteroids, nasal / inhaled corticosteroids, or intra-articular corticosteroids is permitted); iv) received or will receive plasmapheresis, immunoadsorption therapy, IVIg, or any IgG Fc-related protein therapeutic during the current pregnancy; v) received a live vaccine within 3 months prior to screening or is known to need to receive a live vaccine within at least 3 months after the last dose of the study intervention on or in this study; or vi) previously received rituximab or eculizumab within 6 months prior to screening.

[0092] In some embodiments, the pregnant woman carrying the fetal subject has been previously treated with nipocalimab, batoclimab, efgartigimod, rozanolixizumab, corticosteroids, immunosuppressants, plasmapheresis, immunoadsorption therapy, IVIG, rituximab, eculizumab, RhoGAM, blood transfusion, intravenous infusion, exchange transfusion, intrauterine transfusion, or any combination thereof. In some embodiments, the pregnant woman carrying the fetal subject has been previously treated with a first anti-FcRn antibody and is then switched to a different anti-FcRn antibody. In some embodiments, the pregnant woman carrying the fetal subject has been previously treated with a therapeutic agent for treating HDFN that is not nipocalimab.

[0093] In some embodiments, a pregnant woman carrying a fetal subject is treated with an additional therapeutic agent or therapy in addition to an anti-FcRn antibody. In some embodiments, the additional therapeutic agent or therapy is RhoGAM, blood transfusion, intravenous infusion, exchange transfusion, intrauterine transfusion, IVIG, plasmapheresis, immunoadsorption therapy, or any combination thereof. In some embodiments, the additional therapeutic agent or therapy is RhoGAM. In some embodiments, the additional therapeutic agent or therapy is blood transfusion. In some embodiments, the additional therapeutic agent or therapy is intravenous infusion. In some embodiments, the additional therapeutic agent or therapy is exchange transfusion. In some embodiments, the additional therapeutic agent or therapy is intrauterine transfusion. In some embodiments, the additional therapeutic agent or therapy is IVIG. In some embodiments, the additional therapeutic agent or therapy is plasmapheresis. In some embodiments, the additional therapeutic agent or therapy is immunoadsorption therapy. In some embodiments, the additional therapeutic agent is administered simultaneously or sequentially (before or after) the anti-FcRn antibody.

[0094] In some embodiments, the pharmaceutical composition is co-administered with at least one additional therapeutic agent or therapy. In some embodiments, the additional therapeutic agent or therapy is RhoGAM, blood transfusion, intravenous infusion, exchange transfusion, intrauterine transfusion, IVIG, plasmapheresis, immunoadsorption therapy, or any combination thereof. In some embodiments, the additional therapeutic agent or therapy is RhoGAM. In some embodiments, the additional therapeutic agent or therapy is blood transfusion. In some embodiments, the additional therapeutic agent or therapy is intravenous infusion. In some embodiments, the additional therapeutic agent or therapy is exchange transfusion. In some embodiments, the additional therapeutic agent or therapy is intrauterine transfusion. In some embodiments, the additional therapeutic agent or therapy is IVIG. In some embodiments, the additional therapeutic agent or therapy is plasmapheresis. In some embodiments, the additional therapeutic agent or therapy is immunoadsorption therapy. In some embodiments, the additional therapeutic agent is administered simultaneously or sequentially (before or after) with the anti-FcRn antibody.

[0095] In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglyceride levels after treatment with the antibody. In some embodiments, the antibody is M281 (nipocalimab). In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in total cholesterol levels after treatment with the antibody. In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in high-density lipoprotein (HDL) levels after treatment with the antibody. In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in calculated low-density lipoprotein (LDL) levels after treatment with the antibody. In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in triglyceride levels after treatment with the antibody. In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in total cholesterol levels after treatment with M281 (nipocalimab). In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in high-density lipoprotein (HDL) levels after treatment with M281 (nipocalimab). In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in calculated low-density lipoprotein (LDL) levels after treatment with M281 (nipocalimab). In some embodiments, pregnant women carrying fetal subjects treated for HDFN with an anti-FcRn antibody do not experience a significant increase in triglyceride levels after treatment with M281 (nipocalimab).

[0096] In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the levels of total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), and triglycerides after administration of the pharmaceutical composition comprising the antibody. In some embodiments, the antibody is M281 (nipocalimab). In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of total cholesterol after administration of the pharmaceutical composition comprising the antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of high-density lipoprotein (HDL) after administration of the pharmaceutical composition comprising the antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of calculated low-density lipoprotein (LDL) after administration of the pharmaceutical composition comprising the antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of triglycerides after administration of the pharmaceutical composition comprising the antibody. In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of total cholesterol after administration of a pharmaceutical composition comprising M281 (nipocalimab). In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of high-density lipoprotein (HDL) after administration of a pharmaceutical composition comprising M281 (nipocalimab). In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of calculated low-density lipoprotein (LDL) after administration of a pharmaceutical composition comprising M281 (nipocalimab). In some embodiments, administration of a pharmaceutical composition to a pregnant woman carrying a fetal subject does not significantly increase the level of triglycerides after administration of a pharmaceutical composition comprising M281 (nipocalimab).

[0097] As used herein, the phrase "not significantly increase," when used in reference to total cholesterol, high-density lipoprotein (HDL), calculated low-density lipoprotein (LDL), or triglyceride levels (measurements), means that any increase is less than 25% compared to the level before administration of an antibody or composition provided herein (baseline). 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 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%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, or about 25% or less. In some embodiments, the subject being treated for HDFN is a subject in need thereof.

[0098] The present invention 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 invention provides a composition comprising an anti-FcRn antibody for use in a method for treating or reducing the severity of hemolytic disease of the fetal newborn (HDFN) in a fetal subject, the method comprising administering the composition to a pregnant woman carrying the fetal subject. The present invention also provides a composition comprising nipocalimab for use in a method for treating or reducing the severity of HDFN in a fetal subject, the method comprising administering the composition to a pregnant woman carrying the fetal subject, wherein nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman, and the composition is administered weekly for at least 20 weeks, the first administration being based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration. The invention also provides the use of a composition comprising an anti-FcRn antibody in the manufacture of a medicament for treating or lessening the severity of hemolytic disease of the fetus or newborn (HDFN) in a fetal subject.

[0099] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0100] As used herein, the term "about" means that a numerical value is approximate and that small variations do not significantly affect the practice of the disclosed embodiments. When numerical limitations are used, unless otherwise indicated by context, "about" means that the numerical value can vary ±10% and remain within the scope of the disclosed embodiments.

[0101] As used herein, "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") is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. Any composition or method reciting the term "comprising" should be understood to also describe such a composition consisting of, consisting of, or consisting essentially of the recited components or elements.

[0102] As used herein, the terms "individual," "subject," or "patient" can be used interchangeably and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, such as humans. As used herein, the term "mammal" refers to a rodent (i.e., a mouse, rat, or guinea pig), monkey, cat, dog, cow, horse, pig, or human. In some embodiments, the mammal is a human.

[0103] As used herein, the phrase "in need thereof" means that a subject has been identified as having need of a particular method or treatment. In some embodiments, identification can be by any diagnostic means. A subject may be in need of any of the methods and treatments described herein. In some embodiments, a subject is in or moves to an environment where a particular disease, disorder, or condition is prevalent.

[0104] As used herein, the phrase "an integer from X to Y" means any integer, including the endpoints. For example, the phrase "an integer from 1 to 5" means 1, 2, 3, 4, or 5.

[0105] 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.

[0106] Enumerated Embodiments 1. A composition comprising an anti-FcRn antibody for use in treating or reducing the severity of hemolytic disease of the fetus or newborn (HDFN) in a fetal subject, wherein the composition is administered to a pregnant woman who is carrying the fetal subject. 2. The use of embodiment 1, wherein the fetal subject is antigen positive. 3. The use of embodiment 1 or 2, wherein the pregnant woman is antigen-negative. 4. The use of embodiment 2 or 3, wherein the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof. 5. The use according to embodiment 3 or 4, wherein the pregnant woman has maternal alloantibodies against the antigen. 6. The use according to embodiment 5, wherein the maternal alloantibody is of an isotype selected from IgG1, IgG2, IgG3, or IgG4. 7. Maternal alloantibodies Anti-Kell 4 or higher, ≥16 for anti-RhD; 16 or more for anti-Rhc; ≥16 for anti-RhE; Anti-RhC ≥ 16, or The use according to embodiment 5 or 6, having a potency selected from any combination thereof. 8. The use of any one of the preceding embodiments, wherein the fetal subject has a decrease in maternal alloantibodies or total immunoglobulin (IgG) after administration of the composition. 9. The pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus, i) the woman has had one or more intrauterine transfusions (IUT) to treat fetal anemia during a previous pregnancy; ii) the previous fetus had fetal anemia, and / or iii) The use according to any one of the preceding embodiments, wherein a previous pregnancy resulted in fetal death and the woman had detectable maternal alloantibody titers to one or more of the RhD, Kell, Rhc, RhE or RhC antigens above a critical level during the previous pregnancy, wherein the said critical level of the anti-Kell maternal alloantibody titer is 4 or more, the said critical level of the anti-RhD maternal alloantibody titer is 16 or more, the said critical level of the anti-RhC maternal alloantibody titer is 16 or more, the said critical level of the anti-RhE maternal alloantibody titer is 16 or more, and the said critical level of the anti-RhC maternal alloantibody titer is 16 or more. 10. The use of any one of the preceding embodiments, wherein the fetal subject is a fetus having or at risk for severe HDFN. 11. The use of any one of the preceding embodiments, 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. 12. The use of embodiment 11, wherein the anti-FcRn antibody is administered 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. 13. The use of embodiment 11 or 12, wherein the anti-FcRn antibody is administered at about 45 mg / kg, based on the weight of the pregnant woman. 14. The use of any one of embodiments 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration, and each subsequent administration being based on the woman's weight assessed one week prior to the subsequent administration. 15. The use of any one of embodiments 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed one week prior to each subsequent administration. 16. The use of any one of embodiments 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration, and each subsequent administration being based on the woman's weight assessed two weeks prior to the subsequent administration. 17. The use of any one of embodiments 11-13, wherein the composition is administered weekly for at least 20 weeks, the first dose being based on the woman's weight on the day of the first dose and each subsequent dose being based on the woman's weight assessed two weeks prior to each subsequent dose. 18. The use of any one of the preceding embodiments, wherein the composition is administered weekly for a minimum of 20 weeks and a maximum of 23 weeks. 19. The use of any one of the preceding embodiments, wherein the composition is administered weekly from 13, 14, or 15 weeks of gestation. 20. The use of any one of the preceding embodiments, wherein the composition is administered weekly until 35 weeks gestation. 21. The use of any one of the preceding embodiments, wherein the composition is administered weekly until parturition. 22. The use of any one of the preceding embodiments, wherein the composition is administered weekly for at least 20 weeks, and wherein the pregnant woman has at least 90% FcRn receptor occupancy after the first administration of the composition, and wherein the pregnant woman maintains at least 90% FcRn receptor occupancy until after the last administration of the composition. 23. The use of any one of the preceding embodiments, wherein the pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus. 24. The use of any one of the preceding embodiments, wherein the pregnant woman has an obstetric history including a previous pregnancy in which she carried a previous fetus, and the fetal subject exhibits reduced severity of HDFN compared to the previous fetus. 25. The use of any one of the preceding embodiments, wherein the pregnant woman has an obstetric history including a previous pregnancy in which she carried a previous fetus, and the fetal subject exhibits an improved MCA-PSV MoM score compared to the previous fetus. 26. The use of any one of the preceding embodiments, wherein a pregnant woman carrying a fetal subject exhibits improvement in one or more assessments selected from a Generalized Anxiety Disorder 7-item (GAD-7) score, a 36-item Short-Form Health Survey version 2 Acute (SF-36 v2 Acute) score, a EuroQoL 5-dimensional questionnaire (EQ-5D-5L) score, or a combination thereof. 27. The use of any one of the preceding embodiments, wherein the use is to treat or ameliorate one or more symptoms in a fetal subject selected from mild anemia, severe anemia, severe anemia with liver and spleen enlargement, hyperbilirubinemia, jaundice, hydrops fetalis, severe hyperbilirubinemia, kernicterus, or a combination thereof. 28. The use of any one of the preceding embodiments, wherein the pregnant woman has not undergone intrauterine transfusion (IUT) during the pregnancy of the fetal subject. 29. The use of any one of the preceding embodiments, wherein the fetal subject is live-born. 30. The use of any one of the preceding embodiments, wherein the fetal subject was live-born and the pregnant woman has not undergone IUT before 24 weeks gestation. 31. The use of any one of the preceding embodiments, wherein the fetal subject was live-born at or after 32 weeks gestation, and the pregnant woman did not undergo IUT during the fetal subject's pregnancy. 32. The use of any one of the preceding embodiments, wherein the fetal subject is live-born at or after 34 weeks of gestation. 33. The use of any one of the preceding embodiments, wherein the use reduces the severity of HDFN in a fetal subject following administration of the composition. 34. The use of any one of the preceding embodiments, wherein the fetal subject does not have hydrops fetalis. 35. The use of any one of the preceding embodiments, wherein the pregnant woman has an obstetric history that includes a previous pregnancy carrying a previous fetus, and the pregnant woman underwent fewer IUTs compared to the previous pregnancy. 36. The use of any one of the preceding embodiments, wherein the fetal subject does not receive an exchange transfusion within 12 weeks of birth. 37. The use of any one of the preceding embodiments, wherein the fetal subject does not receive an uncomplicated blood transfusion within 12 weeks of birth. 38. The use of any one of embodiments 5 to 37, wherein the composition is administered weekly for at least 20 weeks, and wherein after the first administration, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least 8-fold compared to before the first administration of the composition, and optionally the pregnant woman maintains the reduced concentration of maternal alloantibodies until after the last administration of the composition. 39. The use of any one of the preceding embodiments, wherein the composition is administered weekly for at least 20 weeks, and wherein after the first administration, the concentration of serum IgG in the pregnant woman is reduced by at least 80% compared to before the first administration of the composition, and the pregnant woman maintains the reduced concentration of serum IgG until after the last administration of the composition. 40. The use of any one of the preceding embodiments, wherein the use does not significantly increase total cholesterol, HDL, calculated LDL, and triglyceride levels in the pregnant woman compared to levels before administration of the composition. 41. The use according to embodiment 40, wherein the use does not significantly increase the level of total cholesterol in pregnant women. 42. The use according to embodiment 40, wherein the use does not significantly increase the level of total HDL in pregnant women. 43. The use according to embodiment 40, wherein the use does not significantly increase the level of calculated LDL in pregnant women. 44. The use according to embodiment 40, wherein the use does not significantly increase the level of triglycerides in pregnant women. 45. The use of any one of the preceding embodiments, wherein the composition is administered intravenously. 46. ​​The use of any one of the preceding embodiments, wherein the composition is administered by intravenous infusion. 47. The use of any one of the preceding embodiments, wherein the pregnant woman has not received intravenous immunoglobulin (IVIG) prior to the last administration of the composition. 48. The use of any one of the preceding embodiments, wherein the use further comprises administering an additional therapeutic agent or therapy to the pregnant woman, optionally wherein the additional therapeutic agent or therapy is selected from RhoGAM, blood transfusion, intravenous fluid infusion, exchange transfusion, intrauterine transfusion, IVIG, plasmapheresis, immunoadsorption therapy, or any combination thereof. 49. The use according to embodiment 47 or 48, wherein the additional therapeutic agent or therapy is administered simultaneously with or sequentially (before or after) the composition. 50. Anti-FcRn antibodies (a) a light chain in which CDR L1 comprises the sequence TGTGSDVGSYNLVS (SEQ ID NO: 3), CDR L2 comprises the sequence GDSERPS (SEQ ID NO: 4), and CDR L3 comprises the sequence SSYAGSGIYV (SEQ ID NO: 5); (b) a heavy chain, wherein CDR H1 comprises the sequence of TYAMG (SEQ ID NO: 6), CDR H2 comprises the sequence of SIGASGSQTRYADS (SEQ ID NO: 7), and CDR H3 comprises the sequence of LAIGDSY (SEQ ID NO: 8). 51. The use of any one of the preceding embodiments, wherein the anti-FcRn antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 9. 52. The use of any one of the preceding embodiments, wherein the anti-FcRn antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10. 53. Anti-FcRn antibodies a light chain comprising the sequence of SEQ ID NO: 1; 2. The use of any one of the preceding embodiments, comprising: a heavy chain comprising the sequence of SEQ ID NO:2. 54. The use according to any one of embodiments 1 to 53, wherein the anti-FcRn antibody is nipocalimab. 55. Anti-FcRn antibodies (a) a light chain at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, wherein CDR L1 comprises the sequence of SEQ ID NO: 3, CDR L2 comprises the sequence of SEQ ID NO: 4, and CDR L3 comprises the sequence of SEQ ID NO: 5; (b) a heavy chain at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 2, wherein CDR H1 comprises the sequence of SEQ ID NO: 6, CDR H2 comprises the sequence of SEQ ID NO: 7, and CDR H3 comprises the sequence of SEQ ID NO: 8. 56. The use of any one of the preceding embodiments, wherein the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of SEQ ID NO:9. 57. The use according to embodiment 56, wherein the light chain variable region contains CDR L1 having the sequence of SEQ ID NO: 3, CDR L2 having the sequence of SEQ ID NO: 4, and CDR L3 having the sequence of SEQ ID NO: 5. 58. The use of any one of the preceding embodiments, wherein the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of SEQ ID NO: 10. 59. The use according to embodiment 58, wherein the heavy chain variable region contains CDR H1 having the sequence of SEQ ID NO: 6, CDR H2 having the sequence of SEQ ID NO: 7, and CDR H3 having the sequence of SEQ ID NO: 8. 60. A composition comprising nipocalimab for use in treating or reducing the severity of HDFN in a fetal subject, wherein the composition is administered intravenously to a pregnant woman carrying the fetal subject; Nipocalimab was administered at approximately 45 mg / kg based on maternal weight; The composition is administered weekly for at least 20 weeks, the first administration being based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration. 61. A composition comprising nipocalimab for use in treating or reducing the severity of HDFN in a fetal subject, the method comprising administering to a pregnant woman who is carrying the fetal subject a composition comprising nipocalimab; Nipocalimab was administered intravenously at approximately 45 mg / kg based on the maternal weight. The composition is administered weekly for at least 20 weeks, with the first administration being based on the weight of the pregnant woman on the day of the first administration and subsequent administrations being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration. 62. The use of embodiment 60 or 61, wherein the composition is administered weekly from the 13th, 14th, or 15th week of gestation. 63. The use of any one of embodiments 60-62, wherein the composition is administered weekly for up to 23 weeks. 64. The use according to any one of embodiments 60 to 63, wherein the pregnant woman has maternal alloantibodies against one or more antigens, wherein the antigens are RhD, Kell, Rhc, RhE, RhC, or any combination thereof. 65. The use of embodiment 64, wherein the composition is administered weekly for at least 20 weeks, and after the first administration, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least 8-fold compared to before the first administration of the composition, and the pregnant woman maintains the reduced concentration of maternal alloantibodies until after the last administration of the composition. 66. The use of any one of embodiments 60-65, wherein the composition is administered weekly for at least 20 weeks, and the pregnant woman has at least 90% FcRn receptor occupancy after the first administration of the composition, and the pregnant woman maintains at least 90% FcRn receptor occupancy until after the last administration of the composition. 67. The use of any one of the preceding embodiments, wherein the composition is administered weekly for at least 20 weeks, and wherein after the first administration, the concentration of serum IgG in the pregnant woman is reduced by at least 80% compared to before the first administration of the composition, and the pregnant woman maintains the reduced concentration of serum IgG until after the last administration of the composition. 68. The use of any one of embodiments 60-67, wherein the fetal subject is live-born at or after 32 weeks of gestation and the pregnant woman has not undergone IUT during the pregnancy of the fetal subject. 69. The use of any one of embodiments 60 to 68, wherein the fetal subject is live-born. 70. The use of any one of embodiments 60-69, wherein the fetal subject is a live-born fetus and the pregnant woman has not undergone IUT before 24 weeks of gestation. 71. The use of any one of embodiments 60-70, wherein the fetal subject does not have hydrops fetalis. 72. The use of any one of embodiments 60-71, wherein the pregnant woman has not received intravenous immunoglobulin (IVIG) before the last administration of the composition. 73. The pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus; i) the woman has had one or more intrauterine transfusions (IUT) to treat fetal anemia during a previous pregnancy; ii) the previous fetus had fetal anemia, and / or iii) Use according to any one of embodiments 60 to 72, wherein a previous pregnancy has resulted in fetal death and the woman has had detectable maternal alloantibody titers against one or more of the RhD, Kell, Rhc, RhE or RhC antigens during the previous pregnancy that exceed a critical level, wherein the above-mentioned critical level of the anti-Kell maternal alloantibody titer is 4 or more, the above-mentioned critical level of the anti-RhD maternal alloantibody titer is 16 or more, the above-mentioned critical level of the anti-RhC maternal alloantibody titer is 16 or more, the above-mentioned critical level of the anti-RhE maternal alloantibody titer is 16 or more, and the above-mentioned critical level of the anti-RhC maternal alloantibody titer is 16 or more. 74. A composition comprising an anti-FcRn antibody for use in a method of treating or reducing the severity of hemolytic disease of the fetus or newborn (HDFN) in a fetal subject, the method comprising administering the composition to a pregnant woman who is carrying the fetal subject. 75. The composition for use according to embodiment 74, wherein the method is as defined in any one of embodiments 1 to 59. 76. A composition comprising nipocalimab for use in a method for treating or reducing the severity of HDFN in a fetal subject, the method comprising administering the composition to a pregnant woman who is carrying the fetal subject; Nipocalimab was administered intravenously at approximately 45 mg / kg based on the maternal weight. The composition is administered weekly for at least 20 weeks, the first administration being based on the weight of the pregnant woman on the day of the first administration, and each subsequent administration being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration. 77. A composition comprising nipocalimab for use in a method for treating, reducing the severity of, or preventing HDFN in a fetal subject, the method comprising administering the composition to a pregnant woman who is carrying the fetal subject; Nipocalimab was administered intravenously at approximately 45 mg / kg based on the maternal weight. The composition is administered weekly for at least 20 weeks, with the first administration being based on the weight of the pregnant woman on the day of the first administration and subsequent administrations being based on the weight of the pregnant woman assessed one week or two weeks prior to the subsequent administration. 77. The composition for use according to embodiment 76 or 77, wherein the method is as defined in any one of embodiments 62 to 73. [Example]

[0107] Example 1. Study Design to Evaluate the Safety and Efficacy of Nipocalimab in Pregnant Women at High Risk for Early-Onset Severe Hemolytic Disease of the Fetus and the Newborn: UNITY. This was a Phase 2, multicenter, open-label study (UNITY, ClinicalTrials.gov Identifier: NCT03842189) in pregnant women at high risk for early-onset severe HDFN (EOS-HDFN) based on their obstetric history. For this study and the following CLARITY study, EOS-HDFN was defined as HDFN disease onset at 24 weeks gestational age or less. The EOS-HDFN population is at highest risk for severe HDFN. A sample size of approximately 15 pregnant women was planned, with enrollment occurring at multiple study centers worldwide specializing in maternal-fetal medicine and HDFN treatment. The total duration of the study was approximately 50 weeks for each pregnant woman participating in the study and 96 weeks for each child born during the study. The study included a maternal screening period of approximately 6 weeks, a treatment period of approximately 20 weeks, a 24-week postnatal follow-up period for mothers, and a 96-week follow-up period for all newborns / infants. Nipocalimab was initiated at 14 weeks GA to ensure placental FcRn blockade before accelerated placental transfer of maternal alloantibodies through the second trimester. Four nipocalimab dosing regimens were evaluated during the study: 30 mg / kg IV weekly (QW), 30–45 mg / kg IV QW, and 45 mg / kg IV QW based on baseline body weight (BLW), and 45 mg / kg IV QW based on time-adjusted body weight (TAW). Two participants switched from 30 mg / kg BLW to 45 mg / kg BLW during the study, and two participants switched from 45 mg / kg BLW to 45 mg / kg TAW. Participants otherwise remained in the same dose group throughout the study. Time-adjusted weight-based doses were recalculated every 2 weeks according to maternal weight. Nipocalimab administration was weekly until GA 35 weeks or delivery of the infant, whichever occurred first. If delivery did not occur before 35 weeks, the infant was delivered at 37 weeks. If an IUT was required, nipocalimab was continued until fetal blood analysis at the subsequent IUT revealed primarily donor adult cells.Pregnant women received IVIG at a dose of 500 mg / kg 48 to 72 hours before delivery, unless contraindicated, as prophylaxis against maternal infection and to allow placental transfer of IgG. However, if delivery was urgent or critical, IVIG was given to the mother after delivery or to the newborn as soon as possible after delivery.

[0108] During the follow-up period, neonates / infants who were at risk for infection and had a cord blood total IgG concentration <500 mg / dL or who had no risk factors for infection and a cord blood total IgG concentration <200 mg / dL were administered IVIG 500 mg / kg. Risk factors for infection in the neonate included maternal fever (>38°C) or clinical signs of chorioamnionitis during labor, spontaneous premature rupture of membranes, maternal group B streptococcus (GBS) colonization, bacteriuria, or UTI, invasive GBS infection in a previous child or neonate requiring umbilical artery catheterization, a central line, or other risk factors for infection identified by the investigator or study personnel. The primary safety endpoint was the maternal and neonatal safety of nipocalimab, including treatment-emergent AEs, serious AEs, AEs of particular interest (i.e., infections requiring oral / IV anti-infectives and maternal Grade 3 or greater hypoalbuminemia), need for concomitant therapy, ECG changes, vital signs, and laboratory parameters monitored up to 24 weeks postpartum. Fetal safety outcomes included signs of potential fetal growth restriction and changes in fetal heart rate during the infusion. For neonates, AEs, unexpected / abnormal child illnesses, IgG levels, and neurodevelopment were monitored through 24 weeks or through 96 weeks. The primary efficacy endpoint was the proportion of patients with live births at 32 weeks gestational age or later without IUT throughout pregnancy. Secondary efficacy endpoints included the rate of live births, the rate of patients with GA 24 weeks without IUT, GA at first IUT, number of IUTs required, GA at delivery, the rate of patients with hydrops fetalis, the rate of neonates requiring phototherapy, the rate of neonates requiring exchange transfusion, the rate of neonates requiring simple transfusion within 12 weeks of life, and the number of simple transfusions required by neonates within 12 weeks of life. Other secondary outcomes included PD outcomes (i.e., rate of maternal FcRn RO, and maternal IgG and alloantibody levels) and PK outcomes (i.e., serum concentrations of nipocalimab).

[0109] Using PK / PD modeling and leveraging data from a completed Phase 1 study (ClinicalTrials.gov Identifier: NCT02828046), the inventors selected a nipocalimab dose of 45 mg / kg QW as the maximum dose for this study. PK / PD modeling results indicate that 45 mg / kg with time-adjusted weight-based dosing was able to maintain more than 90% of participants with complete RO (defined as RO ≥ 90%) for more than one day and longer than one week, ensuring that drug holidays or other unexpected interruptions in the scheduled infusion would not cause loss of RO or IgG rebound, while nipocalimab doses less than 45 mg / kg did not maintain complete RO. Given the increase in maternal weight and corresponding blood volume and rate of IgG placental transfer during pregnancy, a time-adjusted weight-based dosing approach was designed for this study. IgG placental transfer was GA-dependent and significantly higher in the third trimester compared with the first trimester. Based on the same PK / PD modeling, mean predose nipocalimab exposure after a time-adjusted weight-based dosing approach would be approximately 14.4% and 22.6% higher at GA weeks 29 and 36, respectively. Therefore, time-adjusted weight-based dosing, in which the nipocalimab dose is recalculated every 2 weeks from baseline based on maternal weight, was considered necessary to maintain adequate nipocalimab exposure during pregnancy, although a <25% increase in mean exposure would not raise safety concerns.

[0110] The following inclusion criteria were followed: 1. Able to understand and voluntarily provide written, signed informed consent to participate in the study. 2. Female and 18 years of age or older. 3. Pregnant from 8 weeks up to an estimated GA of 14 weeks. 4. A previous pregnancy at 24 weeks gestation or less that included at least one of the following: (a) Severe fetal anemia defined as hemoglobin <0.55MoM for GA (see table below)

[0111] [Table 1] (b) MCA-PSV MoM ≥ 4 fetal hydrops (ascites) (c) stillbirth with fetal or placental pathology indicative of HDFN; 5. Maternal alloantibody titer for anti-D ≥ 32 or anti-Kell titer ≥ 4. 6. Free fetal DNA was matched with antigen-positive fetuses (blood samples taken from the mother). 7. Maternal evidence of immunity to measles, mumps, rubella, and chickenpox, documented by serology performed during screening. If the initial serology test is borderline or negative, the serology test may be repeated in a second laboratory. Alternatively, vaccination records may be used to support evidence of immunity. 8. Screening laboratory IgG and albumin levels within normal range. 9. Willingness to undergo standard treatment with IUT if clinically indicated. 10. Agree to receive recommended vaccinations in accordance with local standard of care for both mother and child throughout the course of the study. 11. Willing to forgo cord blood collection for stem cell banking or other non-experimental purposes. 12. For the mother and neonate, be willing to refrain from participating in other clinical trials of the investigational therapy for the duration of participation in the current study. 13. Willing to agree to a 24-week safety follow-up period for patients and a 96-week safety follow-up period for neonates / infants. 14. Patients are encouraged to receive their most current age-appropriate vaccinations prior to screening, in accordance with usual local medical guidelines. For study patients who received a locally approved (and emergency use authorized) COVID-19 vaccine immediately prior to study entry, follow applicable local vaccine labeling, guidelines, and standards of care for pregnant women receiving immune-targeted therapies when determining the appropriate interval between vaccination and study enrollment.

[0112] This open-label, multicenter study enrolled 13 maternal participants at risk for early-onset, severe HDFN. One maternal participant was enrolled twice, across two consecutive pregnancies. The first pregnancy was electively terminated at 17 weeks gestational age due to a fetal familial genetic disorder unrelated to HDFN. For this participant, data from the first pregnancy were not considered in efficacy analyses but were considered for exposure, AEs, and clinical abnormalities, and data from the second pregnancy were included in all applicable analyses. The majority of subjects were Caucasian (92%) and not Hispanic or Latino (92%). The mean age was 35.8 years, ranging from 28 to 43 years. In total, 6 of the 13 maternal participants (46%) completed treatment with nipocalimab. Four (31%) maternal participants discontinued nipocalimab due to adverse events (AEs) (1 [33%] in the 30 mg / kg BLW group, 1 [25%] in the 45 mg / kg BLW group, and 2 [50%] in the 45 mg / kg TAW group).

[0113] Primary efficacy endpoint: Analysis of the primary efficacy endpoint estimated based on treatment policy showed that a statistically significantly higher proportion of maternal participants (53.8% [7 / 13]; 95% CI: 25.1%, 80.8%; p<0.001) achieved treatment success (live birth at 32 weeks gestational age or greater without IUT throughout pregnancy) compared with the historical benchmark of 10% (p<0.001). A higher proportion of participants in the 45 mg / kg dose group (BLW and TAW) met the primary efficacy endpoint (5 of 8) than in the 30 or 30-45 mg / kg BLW dose groups (2 of 5).

[0114] Secondary efficacy endpoints: Based on FAS analysis (N=13): Twelve (92.3%) maternal participants had a live birth at any time (95% CI: 64.0%, 99.8%) Twelve (92.3%) maternal participants had a live birth without IUT before 24 weeks GA (95% CI: 64.0%, 99.8%) · The mean GA at any birth outcome (live birth or fetal loss) with or without IUT was 6 / 7 at 34 weeks (range: 6 / 7 at 23 weeks to 3 / 7 at 37 weeks), with 6 (46.2%) maternal participants having a birth outcome at GA ≥ 37 weeks. For the five maternal participants with a live birth following an IUT, the median GA at first IUT was 3 / 7 at 28 weeks (range, 1 / 7 at 24 weeks to 5 / 7 at 31 weeks). Regardless of pregnancy outcome (live birth or fetal death [n=6]), the median GA at first IUT was 1 / 7 at 27 weeks (range, 5 / 7 at 22 weeks to 5 / 7 at 31 weeks). No maternal participants had a fetus with hydrops fetalis (95% CI: 0.0%, 26.5%). Comparing study pregnancies with eligible pregnancies, study pregnancies resulted in a higher rate of live births (92.3% vs. 38.5%), fewer participants required IUT (46.2% vs. 84.6%), a later median age at first IUT (1 / 7 at 27 weeks GA vs. 4 / 7 at 20 weeks GA), and a later median GA at delivery (4 / 7 at 36 weeks GA vs. 6 / 7 at 23 weeks GA). Of the eligible pregnancies, seven participants carried a fetus with hydrops. In a post hoc analysis pooling the number of IUTs among all participants with a live birth, the mean (SD) number of IUTs was 1.4 (2.0) in the study pregnancy. The mean (SD) number of IUTs was 5.6 (3.3) among all live births in the most recent eligible pregnancy. The median number of IUTs was 0 (range, 0-5) in the study pregnancy. The median number of IUTs was 5 (range, 2-11) among all live births in the most recent eligible pregnancy.

[0115] Based on the neonatal / infant (N=12) analysis, 11 (91.7%) newborns / infants had at least one phototherapy session During the first 12 weeks, 6 (50.0%) neonates / infants received at least one simple blood transfusion. During the first 12 weeks, 1 (8.3%) neonate / infant underwent an exchange transfusion (in the 45 mg / kg TAW group) Eleven of the 12 neonates required hospitalization, of which nine required NICU care for EOS HDFN-related care, with a median length of hospital stay of 7.0 days (range, 3-64 days). The reason for hospitalization (treatment of HDFN-related AEs for SOC phototherapy or feeding problems [one neonate]) resolved in each neonate. No formal hypothesis testing was performed for these endpoints.

[0116] Further analysis was performed comparing each regimen group. Figure 1A shows the percentage of participants who had a live birth after GA 32 weeks and did not undergo IUT throughout pregnancy. As demonstrated herein, among the different regimen groups, the 30 mg / kg BLW regimen group had a lower percentage of participants with live births (33.3%) compared to the other regimen groups. Figure 1B shows that the 45 mg / kg dose group (BLW and TAW) had the highest percentage (62.5%) of maternal subjects who had a live birth after GA 32 weeks and did not undergo IUT throughout pregnancy. Figure 2 shows that the 45 mg / kg BLW and 45 mg / kg TAW doses showed a trend toward higher median serum nipocalimab concentrations with reduced variability toward the end of pregnancy (after GA 24 weeks), indicating that less variability and more consistent exposure was achieved using the 45 mg / kg dose compared to the 30 mg / kg IV weekly BLW dosing. Figures 3A-3D show neonatal outcomes between each regimen group. A) The proportion of newborns requiring phototherapy. B) The proportion of newborns and infants requiring simple transfusions. C) The mean number of simple transfusions required by newborns and infants, and D) The mean volume of simple transfusions required by newborns and infants. Here, it can be seen that the 30 mg / kg BLW group had the highest proportion of newborns and infants requiring simple transfusions, the highest mean number of simple transfusions, and the highest mean volume of simple transfusions compared to the other regimen groups.

[0117] Safety: SAEs were primarily related to HDFN or pregnancy and occurred without a discernible pattern or relationship to nipocalimab dose or pharmacological effect. All 13 maternal participants had one or more treatment-emergent AEs (TEAEs). Twelve (92.3%) maternal participants had TEAEs that were possibly, probably, or definitely related to nipocalimab. The most common TEAEs by preferred terminology occurring in four or more maternal participants across all dose levels were peripheral edema (46.2%), nausea (30.8%), back pain (30.8%), and hypoalbuminemia (30.8%). Four (30.8%) maternal participants permanently discontinued study medication due to a TEAE. The number of maternal participants with serious adverse events (SAEs) was five (38.5%). Of these, two (15.4%) maternal participants experienced serious AEs (SAEs) related to nipocalimab. Five maternal participants (38.5%) experienced AEs of special interest (AESIs). No maternal participants died during the study. One maternal participant experienced a fetal loss. All 12 neonates / infants had one or more AEs. Seven (58.3%) neonates / infants had AEs that were possibly, probably, or definitely related to maternal nipocalimab exposure. The most common AEs, by preferred term, occurring in four or more neonates / infants were neonatal anemia (58.3%), decreased blood immunoglobulin G (41.7%), neonatal hyperbilirubinemia (41.7%), and neonatal jaundice (33.3%). The number of neonates / infants with SAEs was five (41.7%). Of these, two (16.7%) neonates / infants had an SAE related to maternal nipocalimab exposure, and four (33.3%) neonates / infants experienced an AESI. No neonates / infants died during the study.

[0118] Pharmacokinetics: Maternal serum nipocalimab concentration was higher in the 45 mg / kg IV QW dosing group (BLW and TAW) compared to the 30 mg / kg IV QW BLW dosing group. Furthermore, the median serum nipocalimab concentration showed a tendency to decrease variability and increase towards the end of pregnancy (after GA week 24) with 45 mg / kg IV QW TAW dosing compared to BLW dosing. The median maternal serum nipocalimab level at birth was generally undetectable or near-undetectable, except for 1 maternal participant who delivered on the same day as receiving the morning dose. By 4 weeks postpartum, maternal serum levels of nipocalimab were undetectable across all dose groups. Neonatal serum nipocalimab concentration at birth (day 0) was detectable only 8 days after the last maternal dose in 1 neonate in the 30 - 45 mg / kg BLW maternal group at birth (0.7 μg / mL). Considering the absence of a complete RO (detectable serum nipocalimab time point) and IgG observations at birth as measured in this neonate being equivalent to those of other neonates, the detectable nipocalimab in the serum at birth in this neonate was considered not clinically significant. Serum levels were undetectable in all other dose groups. Up to 4 weeks, neonatal serum levels of nipocalimab remained undetectable in all other maternal dose groups. Nipocalimab was undetectable in colostrum samples (n = 7) from 3 participants and breast milk samples (n = 9) from 7 participants. In 5 out of 6 samples with detectable nipocalimab in colostrum or breast milk, nipocalimab levels were lower than the threshold (10 μg / mL) required for PD effect. 1 maternal participant who delivered 1 day after nipocalimab dosing had a colostrum level of 68.4 μg / mL, which was considered not clinically significant based on the neonatal nipocalimab serum PK level (<LLOQ) in the breastfed neonate at week 1 and normal IgG levels for neonatal age at each measured time point. Overall, due to the small number of participants, the clinical impact of nipocalimab in colostrum and breast milk could not be reliably determined.

[0119] Pharmacodynamics: After the first dose of nipocalimab at the GA week 14 visit, receptor occupancy (RO) decreased from 100% unoccupied to a mean (SD) of 2.12 (4.103) percent unoccupied by GA week 16 in all maternal participants across all dose groups, indicating rapid full receptor occupancy. Full receptor occupancy was maintained throughout the treatment period until approximately 1 to 3 weeks after the last nipocalimab dose, when full receptor occupancy was rapidly lost (a mean unoccupied receptors of >60% at birth). On day 0 (birth), neonates had a mean (SD) of 80.70 (25.077) (range: 51.1–118.2) percent unoccupied FcRn receptors in monocytes due to nipocalimab (in seven neonates). Maternal alloantibody titers (a semiquantitative measure) decreased compared to baseline after dosing initiation in all subjects at all nipocalimab doses. Maximum titer reductions were observed, ranging from 8- to 32-fold lower than baseline. Decreased alloantibody titers generally remained below baseline values ​​and increased after the final dose. By week 4 or 24 postpartum, titers returned to values ​​near or above baseline. Starting at week 16 of GA, serum IgG decreased in maternal participants after the first nipocalimab dose, from a mean (SD) of 9.45 (2.035) g / L to approximately -80% to -85% change from baseline during subsequent visits during the treatment period. After the last dose of nipocalimab, maternal serum IgG recovery began to return toward baseline, with a mean (SD) change of -36 (4) percent from baseline at birth (measured only in participants treated with 45 mg / kg BLW or TAW). All maternal participants were observed with IgG levels similar to baseline values ​​by week 4 postpartum.

[0120] The high trough serum nipocalimab concentrations, complete RO, total IgG, alloantibody decline, and sustained neonatal outcomes observed in UNITY support testing of a 45 mg / kg IV weekly TAW dose in a Phase 3 study.

[0121] Additionally, for each of the 13 participants, the participant's on-study pregnancy was compared with their previous eligible pregnancy that met the criteria listed under item 4 of the inclusion criteria. As shown in Figure 5, in contrast to the on-study pregnancies, none of the eligible pregnancies had an outcome consistent with the primary endpoint (live birth at 32 weeks' GA or later without IUT throughout pregnancy). The proportion of participants with live births was 38% (5 / 13) in eligible pregnancies and 92% (12 / 13) in on-study pregnancies. IUT was required in 85% of eligible pregnancies (IUT per pregnancy range, 1-11) and 46% of on-study pregnancies (IUT per pregnancy range, 1-5). Among those undergoing IUT, the median GA at the first IUT was 4 / 7 of 20 weeks in eligible pregnancies and 1 / 7 of 27 weeks in on-study pregnancies. The median (range) number of IUTs per pregnancy resulting in a live birth was 5 (2-11) in eligible pregnancies and 3 (1-5) in study pregnancies. Fetal losses due to IUT complications were reported in 31% (4 / 13) of eligible pregnancies and 8% (1 / 13) of study pregnancies. Hydrops fetalis was observed in 54% (7 / 13) of eligible pregnancies and none in study pregnancies. The median GA at delivery with a live birth was 6 / 7 of 23 weeks in eligible pregnancies and 5 / 7 of 36 weeks in study pregnancies.

[0122] For postnatal outcomes, 80% (4 / 5) of neonates / infants from eligible pregnancies and 50% (6 / 12) from study pregnancies required simple RBC transfusions. One of the six neonates / infants from study pregnancies who received simple RBC transfusions also underwent a single exchange transfusion and achieved the primary endpoint. Of the seven study pregnancies that achieved the primary outcome, six neonates / infants did not require prenatal / postnatal transfusions, indicating that 46% (6 / 13) of study fetuses / neonates / infants did not undergo any invasive intervention.

[0123] Example 2. Prospective observational trial (CLARITY, ClinicalTrials.gov Identifier: NCT03755128) designed to collect medical and therapeutic information regarding the current treatment of EOS-HDFN in pregnant women and their offspring. The purpose of this study was to provide data on the natural history of a population similar to that studied in UNITY (Example 1). The CLARITY trial was conducted in parallel with the UNITY trial at overlapping clinical centers representing national and regional referral centers. CLARITY represents typical care at these referral centers for advanced monitoring and IUT to treat severe HDFN. Approximately 50% of CLARITY participants received IVIG (intravenous immunoglobulin) for the treatment of EOS-HDFN, corresponding to historical benchmark treatment. Of note, IVIG is not approved for the treatment of HDFN, and data are limited, including small randomized controlled trials (RCTs) or case series, and it is not included in ACOG or SMFM treatment guidelines. IVIG use was not permitted for most of the UNITY trial period, except immediately prior to fetal birth.

[0124] The total time on the study was approximately 48 months for each pregnant woman and each child born during the study, including enrollment and pregnancy, a 6-month follow-up period after birth for the mothers, and a 1-year follow-up period for all newborns / infants.

[0125] Primary efficacy variable / primary time point: At-risk pregnancies with a live birth at 32 weeks GA or greater and without intrauterine transfusion (IUT) throughout the at-risk pregnancy.

[0126] Selected secondary efficacy variables: Pregnancy at risk of live birth Maternal participants with live birth without IUT before 24 weeks GA ○ First IUT and GA at delivery ○IUT per parent participant Participants who are pregnant with a fetus with hydrops fetalis Neonatal outcomes (neonates requiring phototherapy, simple transfusions during the first 3 months, and / or exchange transfusions)

[0127] Fifteen pregnant women with the same primary inclusion criteria as the UNITY trial were enrolled in this study. In total, 10 of the 15 maternal participants (66.7%) completed the study (i.e., did not discontinue early and completed the 6-month postpartum follow-up). Of the eight participants who received IVIG, two achieved the primary outcome, while six participants did not. Of the seven participants who did not receive IVIG during pregnancy, none achieved the primary outcome.

[0128] Based on analysis of the primary efficacy variable, 13.3% (2 / 15) (95% CI: 1.7%, 40.5%) of maternal participants achieved the primary endpoint (live birth at GA ≥ 32 weeks without IUT throughout pregnancy). This 13.3% rate is consistent with the historical benchmark of 10% and is much lower than the 53.8% rate achieved in the UNITY trial in which nipocalimab was administered.

[0129] Based on the maternal subject (N=15) analysis, Fourteen (93.3%) maternal participants had a live birth at any time (95% CI: 68.1%, 99.8%). Nine (60.0%) maternal participants had a live birth without IUT before GA 24 weeks (95% CI: 32.3%, 83.7%). Of these nine, seven (46.7%) maternal participants had an IUT after GA 24 weeks. The mean GA for any delivery outcome (live birth or fetal loss) with or without IUT was 2 / 7 at 34 weeks (range: 5 / 7 at 16 weeks to 0 / 7 at 38 weeks), with 7 (46.7%) maternal participants having a delivery outcome at GA ≥ 37 weeks. For the 12 maternal participants (80.0%) with a live birth involving an IUT, the mean GA at first IUT was <5 / 7 at 22 weeks (range: 1 / 7 at 17 weeks to 2 / 7 at 28 weeks). One (6.7%) maternal participant was pregnant with a fetus with hydrops fetalis.

[0130] Based on the neonatal / infant (N=14) analysis, Fourteen (100%) newborns / infants had at least one phototherapy session. Eight (57.1%) neonates / infants had at least one uncomplicated blood transfusion during the first 3 months. Three (21.4%) neonates / infants had exchange transfusions.

[0131] Safety: Two (13.3%) maternal participants had one or more serious adverse events (SAEs). These SAEs were classified by system organ class (SOC) and preferred terminology as pregnancy, postpartum, perinatal conditions (spontaneous abortion), and skin and subcutaneous tissue disorders (scar pain). Maternal participants (38.5%) did not experience any adverse events of special interest (AESIs). No maternal participants died during the study, however, one maternal participant experienced fetal loss. One (7.1%) newborn / infant had one or more SAEs. The SAE by SOC and preferred term was investigational (increased blood bilirubin). One (7.1%) newborn / infant experienced an AESI. No newborns / infants died during the study.

[0132] As shown in Figure 4, in the UNITY trial, 54% (7 / 13) of participants met the primary efficacy endpoint (live birth at GA ≥ 32 weeks without IUT throughout pregnancy), while in the CLARITY trial, only 13% of participants met the primary efficacy endpoint. In the CLARITY trial, no participants (0 / 7) met the primary efficacy endpoint in the non-IVIG group.

[0133] Example 3. Phase 3 Study Design. This is a phase 3, randomized, placebo-controlled, double-blind, multicenter study to evaluate the efficacy and safety of nipocalimab in pregnancies at risk for severe HDFN. A summary of the objectives (primary and secondary) and endpoints is shown in Table 1 below.

[0134] [Table 2-1]

[0135] [Table 2-2]

[0136] [Table 2-3]

[0137] The total duration of the study will be up to 135 weeks and will consist of four study periods: a screening period of approximately 9 weeks, a double-blind treatment period of up to 23 weeks, and a safety follow-up period of 24 weeks postpartum for the mother and 104 weeks from delivery for the neonate / infant. The timing of delivery will depend on the investigator's discretion and is expected at 37 or 38 weeks GA, which is standard practice for pregnancies with severe HDFN.

[0138] Screening procedures will be completed between Day 0 / 7 of GA week 8 (i.e., week 8, the earliest time the maternal participant consents) and before randomization (Day 1 / Baseline). The randomization period will be from Day 0 / 7 of GA week 13 (i.e., week 13) to Day 3 / 7 of GA week 16 (i.e., week 16 and day 3). Day 1 dosing should occur between Day 0 / 7 and Day 3 / 7 of GA week 16 (i.e., GA week 13–16) during the randomization period. On Day 1, an ultrasound will be performed to confirm the absence of signs of fetal anemia or hydrops and an MCA-PSV <1.5 MoM before randomization. The timing of screening procedures must take into account the turnaround time for the availability of laboratory tests required for eligibility assessment, including cffDNA testing. The optimal timing for cffDNA sample collection is ≥10 weeks GA, with a maximum turnaround time for results availability of 2 weeks from the date of sample collection. Study intervention administration will occur on Day 1 after eligibility is confirmed. Body weight measured on Day 1 will be used to calculate study intervention dose. At subsequent visits, body weight measured during the previous week will be used to calculate study intervention dose.

[0139] Up to approximately 120 eligible pregnant women will be randomized in a 2:1 ratio (nipocalimab vs. placebo) to receive nipocalimab 45 mg / kg weekly intravenously or matching placebo from randomization through 35 weeks GA. A permuted block randomization will be used. The target study population will be pregnant women currently carrying an antigen-positive fetus with an obstetric history of HDFN-associated fetal anemia with IUT, hydrops fetalis, fetal loss, or neonatal death in a previous pregnancy who have not received and are not planning to receive IVIg / plasmapheresis.

[0140] In both treatment groups, participants are monitored weekly by MCA Doppler and an IUT is performed if the PSV of blood flow in the MCA is 1.5 MoM or greater for GA or hydrops and fetal blood sampling confirms anemia.

[0141] During postnatal follow-up, neonatal / infant monitoring includes hyperbilirubinemia, anemia, and IgG levels. Although there are no universally accepted international guidelines for the management of anemia and hyperbilirubinemia in neonates / infants, guidance for management is provided for this study.

[0142] Efficacy, safety, PK, immunogenicity, PD (e.g., FcRn RO and IgG), and biomarkers will be assessed according to a schedule.

[0143] Efficacy assessments include weekly MCA Doppler to assess fetal anemia and IUT during the antenatal period, phototherapy or exchange transfusion and / or simple transfusion to manage neonatal / infant anemia and hyperbilirubinemia, modified neonatal mortality and morbidity index, and other neonatal outcomes. Additionally, fetal / neonatal hemoglobin, hematocrit, and total bilirubin will be assessed. Patient-reported outcomes for the mother include GAD-7, SF-36v2 Acute, and EQ-5D-5L. Caregiver-reported health-related quality of life outcomes for the neonate / infant will be assessed by IQI.

[0144] Safety assessments will include AEs, infusion reactions, concomitant medications, laboratory tests (hematology, chemistry [including lipid panel and urinalysis]), ECG, vital signs, maternal and neonatal / infant weights, physical examination, ultrasound monitoring of fetal growth and development, newborn hearing screening, Bayley Scales of Infant Development (3rd Edition), and neonatal / infant immune development (Ig profile, lymphocyte phenotyping, vaccine response to tetanus). Regional and central placental pathology will be performed.

[0145] Study Population: The target study population is currently pregnant women with an antigen-positive fetus who have an obstetric history of HDFN-associated fetal anemia with IUT, hydrops fetalis, fetal loss, or neonatal death in a previous pregnancy and who have not received or are not planning to receive IVIg / plasmapheresis. These pregnancies are at risk for severe HDFN with fetal anemia during the current pregnancy and are considered appropriate to provide relevant efficacy and safety information for nipocalimab using a randomized, double-blind, placebo-controlled design for its intended use if approved for severe HDFN. Maternal alloimmunization against the RBC antigens most commonly implicated in severe HDFN (RhD, Kell, Rhc, RhE, and RhC) allows for testing of efficacy across different RBC antigens.

[0146] Blinded, Controlled, Study Phase / Duration, Intervention Group: A placebo control will be used to establish the frequency and magnitude of changes in clinical endpoints that may occur in the absence of active treatment. A placebo control is considered appropriate for this target population because all participants have standard treatment available. Participants will be closely monitored for fetal anemia via weekly assessment of MCA-PSV by Doppler ultrasound and will undergo IUT if fetal anemia is detected.

[0147] The nipocalimab dosing regimen selected for evaluation in this study in pregnant women at risk for severe HDFN was as follows: IV nipocalimab at 45 mg / kg given qw, initiated between 0 / 7 of GA week 13 and 3 / 7 of GA week 16 and continued until GA week 35 (i.e., approximately 23 weeks before planned delivery at GA week 37 or 38), based on weight measurements during pregnancy to account for weight gain during pregnancy.

[0148] This dosing regimen was selected based on available data (using baseline body weight and time-adjusted body weight-based dosing) from completed and ongoing clinical trials of nipocalimab, including PK, PD, efficacy, and safety data from: 1) the Phase 1 FIH SAD / MAD study in healthy participants (MOM-M281-001), which evaluated single doses of nipocalimab up to 60 mg / kg and multiple weekly doses up to 30 mg / kg; 2) the Phase 2 study in gMG (MOM-M281-004), which evaluated doses up to 60 mg / kg every 2 weeks for 8 weeks; and 3) the ongoing open-label study in HDFN (MOM-M281-003) with weekly dosing of 30 mg / kg or 45 mg / kg. Additionally, simulations based on PK / PD models (including FcRn receptor occupancy and IgG) using FIH data contributed to dose selection for this Phase 3 HDFN study.

[0149] Participants will be randomized in a 2:1 (nipocalimab vs. placebo) ratio to one of two treatment arms, each as described below.

[0150] Group 1: Nipocalimab 45mg / kg IV QW: Participants will receive nipocalimab 45mg / kg IV QW until GA 35 weeks. Group 2: Placebo IV QW: Participants receive placebo IV QW until GA 35 weeks.

[0151] The study intervention will be administered weekly via IV infusion at a dose of 45 mg / kg based on the participant's body weight (rounded to the nearest 0.1 kg) starting on randomization day 1 and continuing through GA week 35. Body weight measurements will be used to calculate the study intervention dose as follows: On Day 1, the body weight measured at the Day 1 visit will be used to calculate the dose of study intervention to be administered at that visit. For subsequent visits, the weight measured in the previous week is used to calculate the study intervention dose to be administered. If a weight measurement in the previous week is not available or if the last dose is more than 9 days old, the weight measured on the same day as the study intervention infusion is used. Adjusting the composition dose according to the participant's weight measured in the previous week is intended to provide more effective treatment and improve patient outcomes compared to embodiments in which the composition dose is based solely on the participant's weight at the start of the study. Determining the composition dose based on the participant's weight in the week prior to administration also allows for the composition to be prepared prior to the day of administration.

[0152] The maximum dose given to any participant at any dosing visit will not exceed 5.4 grams, regardless of the participant's weight. Day 1 (first administration of study intervention) will occur on days 0 / 7 to 3 / 7 of GA week (i.e., GA weeks 13-16) during the randomization period. All weekly study intervention infusions after Day 1 will occur every 7 days (±1 day) counting from Day 1. "QW" stands for weekly. The minimum interval between two administrations is 6 days, and the maximum interval between two administrations will not exceed 8 days. Each participant will receive study intervention for a minimum of 20 weeks (GA weeks 16-35) and a maximum of 23 weeks (GA weeks 13-35) unless discontinuation criteria are met. In the event of an unplanned (e.g., emergency or crisis) delivery, study intervention administration will be stopped as soon as the decision to deliver early is made. If dosing is delayed or interrupted (e.g., more than 9 days since the most recent dose), subsequent weekly study drug doses and study visits will occur every 7 days (± 1 day) from the date study intervention dosing is resumed. Study intervention management, including start and stop dates and times (including delay and / or interruption events), will be captured in source documents and eCRFs.

[0153] When screening participants, the following inclusion and exclusion criteria will be followed:

[0154] Inclusion criteria included the following: 1. Female, aged 18 years (or legal age of consent in the local territory if over 18 years) to 45 years (inclusive) at the time of informed consent. 2. Pregnancy and estimated GA (based on ultrasound age measurement) between 0 / 7 at 13 weeks and 3 / 7 at 16 weeks (i.e., 13 weeks to 16 weeks and 3 days) at the time of randomization. 3. History of severe HDFN in a previous pregnancy defined as: a) documented fetal anemia (defined as fetal hemoglobin level <0.84 MoM; fetal hemoglobin (g / dL) can be calculated using hematocrit (%) / 3) or receipt of one or more IUTs as a result of HDFN; or b) maternal alloantibody titers to RhD, Kell, Rhc, RhE, or RhC antigens above critical levels (anti-Kell ≥ 4, others ≥ 16), fetal loss or neonatal death as a result of HDFN, and evidence of an antigen-positive fetus. 4. Presence of maternal alloantibody titers to RhD, Kell, Rhc, RhE, or RhC antigens during the current pregnancy, with titers above critical levels (anti-Kell ≥ 4, other ≥ 16) based on results from a designated central laboratory at the time of screening. 5. Evidence of an antigen-positive (RhD, Kell, Rhc, RhE, or RhC) fetus corresponding to historical maternal alloantibodies, confirmed by non-invasive cffDNA performed in a central laboratory. 6. Based on central laboratory results, screen laboratory results within the following parameters: a. Albumin ≥ 2.6 g / dL (International System of Units [SI]: > 26 g / L), f. Aspartate aminotransferase (AST) ≤ 2 × upper limit of normal (ULN). * c. Alanine aminotransferase (ALT) ≤ 2 × ULN * d. Creatinine ≦0.8 mg / dL (SI: ≦70.7 μmol / L), e. Serum total IgG ≧600 mg / dL (SIL ≧6 g / L), *NOTE: ULN values ​​are based on normal reference ranges for appropriate gestational ages (Abbassi-Ghanavati M (2009), Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table for clinicians [published qualitatively in Obstet Gynecol. 2010 Feb;115(2 Pt 1):387]. Obstet Gynecol. 2009;114(6):1326-1331). 7. Otherwise healthy based on physical examination, medical history, vital signs, 12-lead ECG, and clinical laboratory tests performed at screening. 8. Willingness to be treated with standard of care with IUT if clinically indicated. 9. Agree to receive recommended vaccinations for both mother and infant throughout the course of the study, in accordance with local standard of care. 10. Stem Cell Preservation or Other Willingness to refrain from collecting cord blood for non-study purposes. 11. For the mother and neonate, willingness to refrain from participation in other clinical trials of the investigational therapy for the duration of participation in the current study. 12. Each individual must sign an ICF indicating that they understand the purpose and procedures of the study, are willing to participate in the study, and consent to a 24-week safety follow-up period. Additional consents may be obtained if necessary per local requirements. The newborn / infant's parents / guardians must also sign an ICF to allow 104 weeks of follow-up of the newborn / infant and agree to complete caregiver-reported outcomes for the infant. 14. Must be able to read and write. 15. Must agree not to donate blood through the final follow-up visit at 24 weeks postpartum.

[0155] Exclusion criteria included: 1. Currently pregnant with multiple pregnancies (twins or more), 2. Evidence of fetal anemia by pre-randomization ultrasound or repeated MCA-PSV > 1.5MoM in the current pregnancy 3. History of severe early-onset preeclampsia before 34 weeks GA or severe FGR (EFW < 3rd percentile) in a previous pregnancy, 4. Current unstable hypertension, 5. History of myocardial infarction, unstable ischemic heart disease, or stroke, 6. Has a history of severe and / or uncontrolled hepatitis (e.g., viral / alcoholic / autoimmune hepatitis / cirrhosis, and / or metabolic liver disease), gastrointestinal disorder, renal disorder, pulmonary disorder, cardiovascular disease, psychiatric disorder, neurological disorder, musculoskeletal disorder, hypertension, and / or any other medical or uncontrolled autoimmune disorder (e.g., diabetes mellitus) that may prevent the participant's full participation in the study and / or jeopardize the participant's safety. (Note: Any condition (e.g., COVID-19) where, in the investigator's opinion, participation would not be in the participant's best interest (e.g., compromising their health) or which may prevent, limit, or disrupt the protocol-specified assessments.) 7. Have any confirmed or suspected clinical immunodeficiency syndrome or a family history of congenital or inherited immunodeficiency unless confirmed to be absent in the participant; 8. History of solid organ or bone marrow transplant (excluding corneal transplant performed more than 12 weeks prior to screening), 9.Having an inflammatory or autoimmune disease requiring immunosuppressive therapy that may jeopardize the participant's safety; 10. Currently have a malignancy or have a history of a malignancy within the 3 years prior to screening (excluding localized basal cell and / or squamous cell skin cancer that has been adequately treated and has had no evidence of recurrence for at least 3 months (defined as a minimum of 12 weeks) prior to the first study intervention, or in situ cervical intraepithelial neoplasia that has been treated and has had no evidence of recurrence for at least 3 months prior to the first study intervention). 11. Known allergy, hypersensitivity, or intolerance to any excipient in the study intervention, 12. Previous severe immediate hypersensitivity reaction, such as anaphylaxis, to therapeutic proteins (e.g., mAbs), 13. Previously received nipocalimab or was enrolled in this study and received the study intervention in a previous pregnancy. 14. Previously received batoclimab, efgartigimod, rozanolixizumab, or other anti-FcRn investigational agents. 15. Currently receiving systemic corticosteroids or other immunosuppressants for disorders unrelated to pregnancy (Note: Use of low-potency topical corticosteroids, nasal / inhaled corticosteroids, or intra-articular corticosteroids is acceptable; use of systemic corticosteroids prior to delivery is acceptable, if needed, for lung maturation). 16. Have received or plan to receive plasmapheresis, immunoadsorption therapy, IVIg, or any IgG Fc-related protein therapeutic during the current pregnancy; 17. Previously received rituximab or eculizumab within 6 months prior to screening. 18. Have received a live virus vaccination during the current pregnancy or are known to be required to receive a live virus vaccination during the study while receiving the study intervention or within at least 8 weeks after the last dose of the study intervention in this study. 19. Have received, or are currently enrolled in, or plan to enroll in an investigational intervention (including an investigational vaccine other than a COVID-19 vaccine authorized for emergency use) within 3 months or 5 half-lives (whichever is longer) prior to the first dose of the investigational intervention; 20. Have a severe infection, including opportunistic infections (e.g., pneumonia, biliary tract infection, diverticulitis, Clostridium difficile infection, cytomegalovirus, pneumocystis, aspergillosis, etc.) requiring parenteral anti-infectives and / or hospitalization, and / or are assessed by the investigator as severe / clinically significant during the current pregnancy. 21. History of active granulomatous infection (e.g., histoplasmosis or coctidioidomycosis) before screening, 22. Active infection during screening or on Day 1 (prior to participant randomization) with coxsackie, syphilis, cytomegalovirus, toxoplasmosis, or herpes simplex type 1 or 2, as evidenced by clinical signs and symptoms and serology results from a central laboratory (Note: Patients with serologic evidence of prior infection or exposure but without clinical signs and symptoms of active infection may be considered for participation). 23. History of severe or recurrent pyelonephritis or 4 or more lower urinary tract infections in the past year or in any previous pregnancy; 24. Have a chronic infection (e.g., bronchiectasis, chronic osteomyelitis) or require chronic treatment with anti-infectives (e.g., antibiotics, antivirals), 25. History of atypical mycobacterial disease or varicella zoster infection within the last 6 months. 26. Test positive for hepatitis B virus (HBV) infection. 27. Seropositive for antibodies to hepatitis C virus (HCV) unless one of the following conditions is met: a) Have a history of successful treatment defined as being negative for HCV ribonucleic acid (RNA) at least 24 weeks after completing antiviral treatment and have a negative HCV RNA test result at screening, or b) Are seropositive but have a negative HCV RNA test result at least 24 weeks prior to screening and have a negative HCV RNA test result at screening. 28. History of human immunodeficiency virus (HIV) 1 or HIV2 antibody positivity or positive HIV test at screening. 29. COVID-19 infection (tested positive for or exposed to COVID-19 within 4 weeks prior to the first dose of study intervention). Exception: Participants who have tested positive for or been exposed to COVID-19 may participate if they have both the absence of symptoms and a negative validated COVID-19 test obtained at least 2 weeks after the onset of symptoms (or first positive test for asymptomatic infection) or exposure, in accordance with local regulations / guidelines for validated COVID-19 testing procedures and standard definitions of COVID-19 exposure. 30. History of drug or alcohol abuse according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-V) within one year prior to screening. 31. Has any condition (including known genetic defects in the fetus or umbilical cord abnormalities) where, in the opinion of the investigator, participation would not be in the best interest of the participant or fetus / newborn / infant (e.g., would compromise their health) or which could prevent, limit, or confound the evaluations specified in the protocol. 32. Have received BCG vaccination within 1 year prior to the first dose of study intervention or are known to be required to receive BCG vaccination during the study or within at least 8 weeks after the last dose of study intervention. 33. Presence of abnormal hematological test values ​​during screening: Hemoglobin <8.0g / dL SI:<80g / L b.WBC <3.0x103 / μL SI:<3.0GI / L c. Neutrophil <1.5x103 / μL SI:<1.5GI / L d. Platelets <100x103 / μL SI:<100GI / L (Note: Inclusion of any participant with a hemoglobin level between 8.0 and 9.0 g / dL must be discussed with the sponsor to determine whether the participant can be included in the study).

[0156] Example 4. Treatment of Hemolytic Disease of the Fetus with Nipocalimab Does Not Elevate Cholesterol. Elevations of total cholesterol and low-density lipoprotein (LDL) were recently reported with another experimental anti-FcRN antibody, other than nipocalimab, in the same pharmacological class of FcRn antagonists. This finding prompted a review of lipid data in sponsor-completed, ongoing nipocalimab trials. In the phase 1 healthy volunteer study MOM-M281-001 and the phase 2 generalized myasthenia gravis study MOM-M281-004, asymptomatic, dose-dependent, reversible increases in non-fasting mean total cholesterol were observed up to 25% of baseline. In the MOM-M281-004 study, at the highest dose of 60 mg / kg every 2 weeks (Q2W), the mean percent change in total cholesterol increased to a stable maximum of 21% to 23% above baseline within 1 month of starting dosing and decreased to near baseline levels 1 to 2 months after the last dose. As a result of these findings, the following will be evaluated: 1) assessment of lipids (total cholesterol, HDL, calculated LDL, and triglycerides) in fasting and non-fasting states at multiple time points during and off treatment, 2) exclusion criteria for patients with recent significant cardiovascular events, and 3) recommendations for lipid dyslipidemia management according to local health guidelines.

[0157] This list of therapies is not all-inclusive, and consultation with a sponsor is recommended before initiating any biologic, non-biologic, or other advanced therapy.

[0158] The embodiments and examples provided herein demonstrate that anti-FcRn antibodies, such as, but not limited to, nipocalimab, are effective in treating hemolytic disease of the fetus and newborn, as measured by one or more of the indicators and outcomes provided herein.

[0159] The disclosures of any and all patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. While various embodiments have been disclosed with reference to certain aspects, it will be apparent that other aspects and modifications of these embodiments may be devised by those skilled in the art without departing from the true spirit and scope of the embodiments. It is intended that the appended claims be construed to include all such aspects and equivalent modifications.

Claims

1. 1. A method of treating or reducing the severity of hemolytic disease of the newborn (HDFN) in a fetal subject, said method comprising administering a composition comprising an anti-FcRn antibody to a pregnant woman carrying said fetal subject.

2. 10. The method of claim 1, wherein the fetal subject is antigen positive.

3. The method of claim 1 or 2, wherein the pregnant woman is antigen-negative.

4. 4. The method of claim 2 or 3, wherein the antigen is RhD, Kell, Rhc, RhE, RhC, or any combination thereof.

5. 5. The method of claim 3 or 4, wherein the pregnant woman has maternal alloantibodies against the antigen.

6. 6. The method of claim 5, wherein the maternal alloantibody is a maternal alloantibody of an isotype selected from IgG1, IgG2, IgG3, or IgG4.

7. The maternal alloantibody is Anti-Kell 4 or higher 16 or more for anti-RhD; 16 or more for anti-Rhc; 16 or more for anti-RhE; ≥ 16 for anti-RhC, or The method of claim 5 or 6, having a potency selected from any combination thereof.

8. 8. The method of any one of claims 1 to 7, wherein the fetal subject has a decrease in maternal alloantibodies or total immunoglobulin (IgG) after administration of the composition.

9. the pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus; i) the pregnant woman has received one or more intrauterine transfusions (IUTs) to treat fetal anemia during the previous pregnancy; ii) the previous fetus suffered from fetal anemia, and / or 9. The method of claim 1, wherein the previous pregnancy resulted in fetal death and the pregnant woman had detectable maternal alloantibody titers to one or more of RhD, Kell, Rhc, RhE and RhC antigens above a critical level during the previous pregnancy, wherein the critical level of anti-Kell maternal alloantibody titer is 4 or greater, the critical level of anti-RhD maternal alloantibody titer is 16 or greater, the critical level of anti-RhC maternal alloantibody titer is 16 or greater, the critical level of anti-RhE maternal alloantibody titer is 16 or greater, and the critical level of anti-RhC maternal alloantibody titer is 16 or greater.

10. 10. The method of any one of claims 1 to 9, wherein the fetal subject is a fetus having or at risk of having severe HDFN.

11. The method of any one of claims 1 to 10, wherein the anti-FcRn antibody is administered at about 15 mg / kg to about 60 mg / kg of the pregnant woman's body weight.

12. 12. The method of claim 11, wherein the anti-FcRn antibody is administered 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 body weight of the pregnant woman.

13. 13. The method of claim 11 or 12, wherein the anti-FcRn antibody is administered at about 45 mg / kg based on the weight of the pregnant woman.

14. 14. The method of any one of claims 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed one week prior to the subsequent administration.

15. 14. The method of any one of claims 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed one week prior to each subsequent administration.

16. 14. The method of any one of claims 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed two weeks prior to the subsequent administration.

17. 14. The method of any one of claims 11-13, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed two weeks prior to each subsequent administration.

18. 18. The method of any one of claims 1 to 17, wherein the composition is administered weekly for a minimum of 20 weeks and a maximum of 23 weeks.

19. 19. The method of any one of claims 1 to 18, wherein the composition is administered weekly from 13, 14, or 15 weeks of gestation.

20. 20. The method of any one of claims 1-19, wherein the composition is administered weekly up to 35 weeks gestation.

21. 21. The method of any one of claims 1 to 20, wherein the composition is administered weekly until parturition.

22. 22. The method of any one of claims 1-21, wherein the composition is administered weekly for at least 20 weeks, wherein the pregnant woman has an FcRn receptor occupancy of at least 90% after the first administration of the composition, and wherein the pregnant woman maintains an FcRn receptor occupancy of at least 90% after the last administration of the composition.

23. 23. The method of any one of claims 1 to 22, wherein the pregnant woman has an obstetric history including a previous pregnancy in which she was carrying a previous fetus.

24. 24. The method of any one of claims 1-23, wherein the pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus, and the fetal subject exhibits reduced severity of HDFN compared to the previous fetus.

25. 25. The method of any one of claims 1-24, wherein the pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus, and the fetal subject exhibits an improved MCA-PSV MoM score compared to the previous fetus.

26. 26. The method of any one of claims 1-25, wherein the pregnant woman shows improvement in one or more assessments selected from Generalized Anxiety Disorder 7-item (GAD-7) score, Short-Form 36-item Health Survey version 2 Acute (SF-36 v2 Acute) score, EuroQoL 5 Dimension Questionnaire (EQ-5D-5L) score, or a combination thereof.

27. 27. The method of any one of claims 1-26, wherein the method treats or ameliorates one or more symptoms in the fetal subject selected from mild anemia, severe anemia, severe anemia with liver and spleen enlargement, hyperbilirubinemia, jaundice, hydrops fetalis, severe hyperbilirubinemia, kernicterus, or a combination thereof.

28. 28. The method of any one of claims 1-27, wherein the pregnant woman did not undergo intrauterine transfusion (IUT) during the pregnancy in which she was carrying the fetal subject.

29. 29. The method of any one of claims 1 to 28, wherein the fetal subject is live-born.

30. 30. The method of any one of claims 1-29, wherein the fetal subject was live-born and the pregnant woman did not undergo IUT before 24 weeks gestation.

31. 31. The method of any one of claims 1-30, wherein the fetal subject was live-born at or after 32 weeks gestation, and the pregnant woman did not undergo IUT during the pregnancy in which she was carrying the fetal subject.

32. 32. The method of any one of claims 1-31, wherein the fetal subject is live-born at or after 34 weeks gestation.

33. 33. The method of any one of claims 1-32, wherein said method reduces the severity of HDFN in said fetal subject following administration of said composition.

34. 34. The method of any one of claims 1 to 33, wherein the fetal subject does not have hydrops fetalis.

35. 35. The method of any one of claims 1-34, wherein the pregnant woman has an obstetric history that includes a previous pregnancy carrying a previous fetus, and wherein the pregnant woman underwent fewer IUTs compared to the previous pregnancy.

36. 36. The method of any one of claims 1-35, wherein the fetal subject does not undergo an exchange transfusion within 12 weeks of birth.

37. 37. The method of any one of claims 1 to 36, wherein the fetal subject does not receive a simple blood transfusion within 12 weeks of birth.

38. 38. The method of any one of claims 5-37, wherein the composition is administered weekly for at least 20 weeks, and wherein after a first administration of the composition, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least 8-fold compared to before the first administration, and optionally the pregnant woman maintains the reduced concentration of maternal alloantibodies until after a final administration of the composition.

39. 39. The method of any one of claims 1-38, wherein the composition is administered weekly for at least 20 weeks, and wherein after a first administration of the composition, the concentration of serum IgG in the pregnant woman is reduced by at least 80% compared to before the first administration, and the pregnant woman maintains the reduced concentration of serum IgG until after a final administration of the composition.

40. 40. The method of any one of claims 1-39, wherein the method does not significantly increase total cholesterol, HDL, calculated LDL, and triglyceride levels in the pregnant woman compared to levels before administration of the composition.

41. 41. The method of claim 40, wherein the method does not significantly increase the level of total cholesterol in the pregnant woman.

42. 41. The method of claim 40, wherein the method does not significantly increase the level of total HDL in the pregnant woman.

43. 41. The method of claim 40, wherein the method does not significantly increase calculated LDL levels in the pregnant woman.

44. 41. The method of claim 40, wherein the method does not significantly increase triglyceride levels in the pregnant woman.

45. 45. The method of any one of claims 1 to 44, wherein the composition is administered intravenously.

46. 46. ​​The method of any one of claims 1 to 45, wherein the composition is administered by intravenous infusion.

47. 47. The method of any one of claims 1 to 46, wherein the pregnant woman has not received intravenous immunoglobulin (IVIG) prior to the last administration of the composition.

48. 48. The method of any one of claims 1 to 47, wherein the method further comprises administering an additional therapeutic agent or therapy to the pregnant woman, optionally wherein the additional therapeutic agent or therapy is selected from RhoGAM, blood transfusion, intravenous fluid infusion, exchange transfusion, intrauterine transfusion, IVIG, plasmapheresis, immunoadsorption therapy, or any combination thereof.

49. 49. The method of claim 47 or 48, wherein the additional therapeutic agent or therapy is administered simultaneously with or sequentially (before or after) the composition.

50. The anti-FcRn antibody (a) a light chain, wherein CDR L1 comprises the sequence of SEQ ID NO: 3, CDR L2 comprises the sequence of SEQ ID NO: 4, and CDR L3 comprises the sequence of SEQ ID NO: 5; (b) a heavy chain wherein CDR H1 comprises the sequence of SEQ ID NO: 6, CDR H2 comprises the sequence of SEQ ID NO: 7, and CDR H3 comprises the sequence of SEQ ID NO: 8; 50. The method of any one of claims 1 to 49, comprising:

51. The method of any one of claims 1 to 50, wherein the anti-FcRn antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:

9.

52. The method of any one of claims 1 to 51, wherein the anti-FcRn antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

10.

53. The anti-FcRn antibody a light chain comprising the sequence of SEQ ID NO: 1; a heavy chain comprising the sequence of SEQ ID NO: 2; 53. The method of any one of claims 1 to 52, comprising:

54. The method of any one of claims 1 to 53, wherein the anti-FcRn antibody is nipocalimab.

55. The anti-FcRn antibody (a) a light chain at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, wherein CDR L1 comprises the sequence of SEQ ID NO: 3, CDR L2 comprises the sequence of SEQ ID NO: 4, and CDR L3 comprises the sequence of SEQ ID NO: 5; (b) a heavy chain at least 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2, wherein CDR H1 comprises the sequence of SEQ ID NO:6, CDR H2 comprises the sequence of SEQ ID NO:7, and CDR H3 comprises the sequence of SEQ ID NO:8; 55. The method of any one of claims 1 to 54, comprising:

56. 56. The method of any one of claims 1 to 55, wherein the anti-FcRn antibody comprises a light chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of SEQ ID NO:

9.

57. 57. The method of claim 56, wherein the light chain variable region comprises a CDR L1 having the sequence of SEQ ID NO:3, a CDR L2 having the sequence of SEQ ID NO:4, and a CDR L3 having the sequence of SEQ ID NO:

5.

58. 58. The method of any one of claims 1 to 57, wherein the anti-FcRn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 95%, 97%, 99%, or 100% identical to the sequence of SEQ ID NO:

10.

59. 59. The method of claim 58, wherein the heavy chain variable region comprises a CDR H1 having the sequence of SEQ ID NO:6, a CDR H2 having the sequence of SEQ ID NO:7, and a CDR H3 having the sequence of SEQ ID NO:

8.

60. 1. A method of treating or reducing the severity of HDFN in a fetal subject, said method comprising administering a composition comprising nipocalimab to a pregnant woman carrying said fetal subject; Nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman; The method, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and each subsequent administration being based on the woman's weight assessed one week or two weeks prior to the subsequent administration.

61. 1. A method of treating or reducing the severity of HDFN in a fetal subject, said method comprising administering a composition comprising nipocalimab to a pregnant woman carrying said fetal subject; Nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman; The method, wherein the composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration and subsequent administrations being based on the woman's weight assessed one week or two weeks prior to the subsequent administration.

62. 62. The method of claim 60 or 61, wherein the composition is administered weekly starting at 13, 14, or 15 weeks of gestation.

63. 63. The method of any one of claims 60-62, wherein the composition is administered weekly for up to 23 weeks.

64. 64. The method of any one of claims 60 to 63, wherein the pregnant woman has maternal alloantibodies to one or more antigens, wherein the antigens are RhD, Kell, Rhc, RhE, RhC, or any combination thereof.

65. 65. The method of claim 64, wherein the composition is administered weekly for at least 20 weeks, and after the first administration of the composition, the concentration of maternal alloantibodies in the pregnant woman is reduced by at least 8-fold compared to before the first administration, and the pregnant woman maintains the reduced concentration of maternal alloantibodies until after the last administration of the composition.

66. 66. The method of any one of claims 60-65, wherein the composition is administered weekly for at least 20 weeks, wherein the pregnant woman has an FcRn receptor occupancy of at least 90% after the first administration of the composition, and wherein the pregnant woman maintains an FcRn receptor occupancy of at least 90% after the last administration of the composition.

67. 67. The method of any one of claims 1-66, wherein the composition is administered weekly for at least 20 weeks, and wherein after a first administration, the concentration of serum IgG in the pregnant woman is reduced by at least 80% compared to before the first administration of the composition, and the pregnant woman maintains the reduced concentration of serum IgG until after the last administration of the composition.

68. 68. The method of any one of claims 60-67, wherein the fetal subject was live-born at or after 32 weeks gestation, and the pregnant woman did not undergo IUT during the pregnancy in which she was carrying the fetal subject.

69. 69. The method of any one of claims 60-68, wherein the fetal subject is live-born.

70. 70. The method of any one of claims 60-69, wherein the fetal subject is live-born and the pregnant woman has not undergone IUT before 24 weeks gestation.

71. 71. The method of any one of claims 60 to 70, wherein the fetal subject does not have hydrops fetalis.

72. 72. The method of any one of claims 60-71, wherein the pregnant woman has not received intravenous immunoglobulin (IVIG) prior to the last administration of the composition.

73. the pregnant woman has an obstetric history including a previous pregnancy carrying a previous fetus; i) the pregnant woman has received one or more intrauterine transfusions (IUTs) to treat fetal anemia during the previous pregnancy; ii) the previous fetus suffered from fetal anemia, and / or 73. The method of any one of claims 60 to 72, wherein the previous pregnancy resulted in fetal death and the pregnant woman had detectable maternal alloantibody titres to one or more of RhD, Kell, Rhc, RhE and RhC antigens above a critical level during the previous pregnancy, wherein the critical level of anti-Kell maternal alloantibody titre is 4 or greater, the critical level of anti-RhD maternal alloantibody titre is 16 or greater, the critical level of anti-RhC maternal alloantibody titre is 16 or greater, the critical level of anti-RhE maternal alloantibody titre is 16 or greater, and the critical level of anti-RhC maternal alloantibody titre is 16 or greater.

74. 1. A composition comprising an anti-FcRn antibody for use in a method of treating or reducing the severity of hemolytic disease of the newborn (HDFN) in a fetal subject, the method comprising administering the composition to a pregnant woman who is carrying the fetal subject.

75. 75. The composition for use according to claim 74, wherein the method is as defined in any one of claims 1 to 59.

76. 1. A composition comprising nipocalimab for use in a method of treating or reducing the severity of HDFN in a fetal subject, said method comprising administering said composition to a pregnant woman who is carrying said fetal subject; Nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman; The composition is administered weekly for at least 20 weeks, the first administration being based on the woman's weight on the day of the first administration, and each subsequent administration being based on the woman's weight assessed one week or two weeks prior to the subsequent administration.

77. 1. A composition comprising nipocalimab for use in a method of treating or reducing the severity of HDFN in a fetal subject, said method comprising administering said composition to a pregnant woman who is carrying said fetal subject; Nipocalimab is administered intravenously at about 45 mg / kg based on the weight of the pregnant woman; The composition is administered weekly for at least 20 weeks, with the first administration being based on the woman's weight on the day of the first administration and subsequent administrations being based on the woman's weight assessed one week or two weeks prior to the subsequent administration.

78. A composition for use according to claim 76 or 77, wherein the method is as defined in any one of claims 62 to 73.

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