Fc fragments that link to fcrn and methods of using them

Description

1 / 89 “FC FRAGMENTS THAT BIND TO FCRN AND METHODS OF USE” CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims priority over Provisional Application Serial No. US 63 / 492,170, filed March 24, 2023, which is incorporated herein by reference in its entirety.

[002] This application contains a Sequence Listing in XML file format which was submitted electronically and is incorporated herein by reference in its entirety. Said XML copy, created on March 22, 2024, is named VRD-018WO_SL.xml and is 29298 bytes in size. BACKGROUND

[003] Immunoglobulin gamma (IgG) antibodies play a fundamental role in the pathology of many disorders, such as autoimmune diseases, inflammatory diseases, and disorders in which the pathology is characterized by the overexpression of IgG antibodies (e.g., hypergammaglobulinemia) (see, for example, Junghans, Immunologic Research 16 (1): 29 (1997)).

[004] The serum half-life of IgG is prolonged relative to the serum half-life of other plasma proteins (Roopenian et al, J. Immunology 170:3528 (2003); Junghans and Anderson, Proc. Natl. Acad. Sci. USA 93:5512 (1996)). This long half-life is due, in part, to the binding of the Fc region of IgG to the Fc receptor, FcRn (which generally refers to the FcRn / b2m complex as its active form in this order, unless otherwise specified). Although FcRn was originally characterized as a neonatal transport receptor for maternal IgG, it also functions in adults to protect IgG from degradation. FcRn binds to pinocytosed IgG and protects the IgG from transport to degradative lysosomes, recycling it back to the extracellular compartment, where it is released from FcRn and can resume Petition 870250086042, dated 09 / 23 / 2025, p. 9 / 126 2 / 89 its biological function. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, where the IgG / FcRn interaction is strong at acidic endosomal pH, but weak or non-existent at physiological extracellular pH. Therefore, at physiological pH, IgG is released from its binding to FcRn and the antibody is recycled, thus prolonging its half-life.

[005] In certain cases, it is desirable to prevent IgG recycling, for example, in autoimmune or inflammatory diseases. Prevention of IgG recycling has already been achieved by means of agents that reduce or block IgG binding to FcRn or that increase IgG binding to FcRn at physiological extracellular pH. An example of such agents are antibodies against FcRn (see, for example, WO2002 / 43658) that block IgG binding. Peptides that bind to and antagonize FcRn function have also been described in the art (see, for example, US 6,212,022 and US 8,101,186). In addition, IgG molecules comprising variant Fc receptors with increased FcRn binding and decreased pH-dependent release have been identified (see, for example, US patent no. 8,163,881). These IgG molecules occupy the FcRn receptors, making them unavailable for binding and recycling of other IgG antibodies.Fc fragments comprising two Fc regions that form a homodimer and occupy FcRn receptors have also been developed and exhibit increased FcRn binding and decreased pH-dependent release (see, for example, US 10,316,073). However, there is a need in the art for additional and / or improved agents that reduce or block FcRn binding to IgG from intact antibodies for use in the treatment of antibody-mediated disorders caused by such intact antibodies. SUMMARY

[006] The present invention provides, among other things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn) with Petition 870250086042, dated 09 / 23 / 2025, p. 10 / 126 3 / 89 higher affinity to FcRn at endosomal pH (e.g., pH 6.0) and at physiological pH (e.g., pH 7.4) compared to a wild-type Fc fragment. As described herein, the present invention is, in part, based on the identification of novel sets of Fc mutations that are significantly effective in inhibiting the binding of IgGs to FcRn. In particular, the Fc fragment variants of the present invention are characterized by low IC50 values ​​(e.g., < 2.5 nM) for blocking IgG binding to FcRn and high affinity to FcRn at endosomal and physiological pHs (e.g., < 10 nM and < 300 nM, respectively). This is significant because Fc fragment variants of the present invention can be used at a lower dose and / or less frequently administered to achieve a therapeutic effect compared to other Fc fragments.The inventive variants of the Fc fragment of the present invention promise a more potent treatment of diseases associated with pathogenic IgGs, including autoimmune diseases, myasthenia gravis, and thyroid eye disease (TOD).

[007] In certain aspects, an isolated Fc fragment is described herein that binds to the neonatal Fc receptor (FcRn) of humans, dogs, mice, or rats, wherein the Fc fragment comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises at least one amino acid substitution selected from M428L, H433R, and N434Y. In some embodiments, the isolated Fc fragment comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, and 256 of SEQ ID NO: 1. In some embodiments, the additional amino acid substitutions are M252Y, S254T, and / or T256E.

[008] In certain respects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse or rat is described herein, with the Fc fragment comprising: a vari Petition 870250086042, dated 09 / 23 / 2025, p. 11 / 126 4 / 89 before the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an amino acid substitution at position 428. In some embodiments, the amino acid substitution is M428L. In some embodiments, the Fc fragment comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 433, and 434 of SEQ ID NO:1. In some embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, H433K, H433R, N434F, and / or N434Y.

[009] In certain aspects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse, or rat is described herein, with the Fc fragment comprising: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an H433R amino acid substitution. In some embodiments, the additional amino acid substitutions are at one or more of the amino acid positions 252, 254, 256, 428, and 434 of SEQ ID NO: 1. In some embodiments, the one or more additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F, and / or N434Y.

[0010] In certain aspects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse, or rat is described herein, with the Fc fragment comprising: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an amino acid substitution N434Y. In some embodiments, the Fc fragment comprises an additional amino acid substitution at one or more of the amino acid positions 252, 254, 256, 428, and 433 of SEQ ID NO:1. In some embodiments, the amino acid substitutions are M252Y, S254T, T256E, M428L, H433K and / or H433R.

[0011] In certain aspects, an isolated Fc fragment that binds to the human neonatal Fc receptor (FcRn) of humans, canine distemper, Petition 870250086042, dated 09 / 23 / 2025, p. 12 / 126 5 / 89 mice or rats, wherein the Fc fragment comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an H433K amino acid substitution and additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 428, and 434. In certain embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F, and / or N434Y.

[0012] In some embodiments, the isolated Fc fragment described here comprises a sequence selected from any of the SEQ ID NOs: 3-9.

[0013] The amino acid substitutions described herein result in an Fc fragment with a lower Kd for FcRn at pH 6.0 and a measurable Kd for FcRn at pH 7.4, compared to an IgG comprising a wild-type Fc region. The Fc region of a wild-type IgG has a Kd of approximately 8 x 10⁻⁷ M for FcRn at pH 6.0 and no detectable binding to FcRn at pH 7.4. The higher affinity for FcRn at pH 6.0 and / or the ability to remain bound to FcRn at pH 7.4 results in greater occupancy of FcRn by the Fc fragments present, thus reducing the amount of FcRn available to bind to an IgG comprising a wild-type Fc region. As a result, an IgG comprising a wild-type Fc region is more susceptible to degradation in the lysosome, effectively reducing its half-life.

[0014] In some embodiments, amino acid substitution results in an increased half-life of the Fc fragment compared to an Fc fragment comprising a wild-type human IgG1 Fc region. In some embodiments, the Fc fragment blocks or reduces the natural recycling of IgG antibodies. In some embodiments, the Fc fragment results in increased catabolism of a pathogenic IgG antibody. In some embodiments, the pa IgG antibody Petition 870250086042, dated 09 / 23 / 2025, p. 13 / 126 6 / 89 togenic is an antibody that is associated with an autoimmune disease.

[0015] In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10-17 with a Kd less than or equal to about 1 x 10-8M or less than or equal to about 1 x 10-9M, 2 x 10-9M, 3 x 10-9M, 4 x 10-9M, 5 x 10-9M, 6 x 10-9M, 7 x 10-9M, 8 x 10-9M or 9 x 10-9M, at pH 6.0, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10 or 11 with a Kd less than or equal to about 1 x 10-8M, or less than or equal to about 1 x 10-9M, 2 x 10-9M, 3 x 10-9M, 4 x 10-9M, 5 x 10-9M, 6 x 10-9M, 7 x 10-9M, 8 x 10-9M or 9 x 10-9M, at pH 6.0, as measured by surface plasmon resonance (SPR).In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 16 or 17 with a Kd less than or equal to approximately 1 x 10⁻⁸ M, or less than or equal to approximately 1 x 10⁻⁹ M, 2 x 10⁻⁹ M, 3 x 10⁻⁹ M, 4 x 10⁻⁹ M, 5 x 10⁻⁹ M, 6 x 10⁻⁹ M, 7 x 10⁻⁹ M, 8 x 10⁻⁹ M, or 9 x 10⁻⁹ M, at pH 6.0, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10-17 with a Kd less than or equal to approximately 1 x 10-8M, 2 x 10-8M, 3 x 10-8M, 4 x 10-8M, 5 x 10-8M, 6 x 10-8M, 7 x 10-8M, 8 x 10-8M, or 9 x 10-8M at approximately pH 6.0, as measured by surface plasmon resonance (SPR).In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 12 or 13 with a Kd less than or equal to approximately 1 x 10⁻⁸ M, 2 x 10⁻⁸ M, 3 x 10⁻⁸ M, 4 x 10⁻⁸ M, 5 x 10⁻⁸ M, 6 x 10⁻⁸ M, 7 x 10⁻⁸ M, 8 x 10⁻⁸ M, or 9 x 10⁻⁸ M at pH 6.0, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10⁻¹⁷ with a Kd less than or equal to approximately 1, 2, 3, 4, 5, 6, 7, 8, or 9 x 10⁻¹⁰ M at approximately pH 6.0, as measured by surface plasmon resonance (SPR). Petition 870250086042, dated 09 / 23 / 2025, page 14 / 126 7 / 89 form measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 14 or 15 with a Kd less than or equal to approximately 1 x 10-10M, 2 x 10-10M, 3 x 10-10M, 4 x 10-10M, 5 x 10-10M, 6 x 10-10M, 7 x 10-10M, 8 x 10-10M, or 9 x 10-10M, at pH 6.0, as measured by surface plasmon resonance (SPR).

[0016] In some forms, the Fc fragment exhibits a melting temperature greater than 55 °C, measured by Differential Scanning Fluorometry (DSF).

[0017] In some embodiments, the human Fc fragment exhibits an aggregation temperature equal to or greater than about 65 °C, or greater than about 70 °C, as measured by static light scattering (SLS).

[0018] In certain respects, the isolated human Fc fragments described herein are used in the treatment of an antibody-related disorder or disease, for example, an autoimmune disease or a disorder associated with an undesirable side effect of a therapeutic antibody.In some embodiments, the isolated human Fc fragments described herein are used in the treatment of a selected disease or disorder from the group consisting of: generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorders (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris, and cutaneous lupus erythematosus.

[0019] In some modalities, the isolated Fc fragments described here are used in the treatment of generalized myasthenia gravis. Petition 870250086042, dated 09 / 23 / 2025, page 15 / 126 8 / 89 (gMG). In some modalities, the isolated Fc fragments described here are used in the treatment of immune thrombocytopenia (ITP). In some modalities, treatment reduces disease severity in a patient, and disease severity is assessed by a gMG Disease Severity Outcome Measure.

[0020] In certain respects, a single polynucleotide or a set of polynucleotides is described herein for expression of the isolated Fc fragment of any of the embodiments described herein. Thus, single polynucleotides or sets of polynucleotides encoding the isolated Fc fragment of any of the embodiments described herein are described herein, and optionally, the polynucleotide or set of polynucleotides comprises mRNA or cDNA.

[0021] In certain aspects, a vector or set of vectors for expressing the isolated Fc fragment of any of the embodiments described herein comprising the polynucleotide or set of polynucleotides described herein is described herein.

[0022] In certain respects, a host cell comprising the polynucleotide or set of polynucleotides or the vector or set of vectors described herein is described herein.

[0023] In certain respects, a method for producing an Fc fragment is described herein, wherein the method comprises expressing the Fc fragment within the host cell described herein and isolating the expressed Fc fragment.

[0024] In certain respects, a pharmaceutical composition is described herein comprising the isolated Fc fragment of any of the embodiments described herein and a pharmaceutically acceptable excipient.

[0025] In certain aspects, a kit comprising the isolated Fc fragment of any of the embodiments described herein or a pharmaceutical composition described herein and instructions for is described herein. Petition 870250086042, dated 09 / 23 / 2025, page 16 / 126 9 / 89 usage.

[0026] In certain aspects, described herein is a method for treating or preventing a disorder or disease associated with an antibody, for example, an autoimmune disease or a disorder associated with an undesirable side effect of a therapeutic antibody in a mammalian individual in need thereof, the method comprising administering to the mammalian individual a therapeutically effective amount of the Fc fragment isolated from any of the modalities described herein or a pharmaceutical composition described herein.In some modalities, the disease or disorder is selected from the group consisting of: generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorders (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris, and cutaneous lupus erythematosus. In some modalities, the inflammatory disorder or disease is an autoimmune disease. In some modalities, the inflammatory disorder or disease is gMG. In some modalities, the method reduces the severity of the disease in a patient, and the severity of the disease is assessed by a gMG Disease Severity Outcome Measure.

[0027] In certain aspects, a method is described here for treating a pathology associated with elevated levels of an IgG in a mammalian individual who requires it, the method comprising administering to the mammalian individual a therapeutically effective amount of the Fc fragment of any of the modalities described herein or of a pharmaceutical composition described herein. Petition 870250086042, dated 09 / 23 / 2025, page 17 / 126 10 / 89

[0028] In certain aspects, a method of reducing the biological activity of an IgG in a mammalian individual in need thereof is described herein, wherein the method comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment of any of the modalities described herein or of a pharmaceutical composition described herein. In certain modalities, the disease is an autoimmune disease.

[0029] In certain aspects, a method of preventing a disorder in a mammalian individual requiring it is described herein, wherein the method comprises administering to the mammalian individual a therapeutically effective amount of the isolated Fc fragment or of a pharmaceutical composition described herein, wherein the disorder is an undesirable side effect of a therapeutic antibody.

[0030] In one aspect, the present embodiments provide, among other things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), wherein the variant of the Fc fragment comprises M428L and N434F amino acid substitutions compared to an amino acid sequence established in SEQ ID NO: 1.

[0031] In some embodiments, the Fc fragment variant further comprises an amino acid substitution at position 433 compared to an amino acid sequence established in SEQ ID NO: 1. In some embodiments, the Fc fragment comprises an amino acid substitution of H433K or H433R compared to an amino acid sequence established in SEQ ID NO: 1. In some embodiments, the Fc fragment comprises an amino acid substitution of N434F compared to an amino acid sequence established in SEQ ID NO: 1. In some embodiments, the Fc fragment comprises amino acid substitutions of H433K and N434F compared to an amino acid sequence established in SEQ ID NO: 1. In some embodiments, the Fc fragment comprises Petition 870250086042, dated 09 / 23 / 2025, p. 18 / 126 11 / 89 ende amino acid substitutions of H433R and N434F compared to an established amino acid sequence in SEQ ID NO: 1.

[0032] In one aspect, the present invention provides, among other things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), wherein the variant of the Fc fragment comprises amino acid substitutions (i) N434Y and (ii) H433R or H433K compared to an amino acid sequence established in SEQ ID NO: 1.

[0033] In some embodiments, the Fc fragment comprises amino acid substitutions of H433K and N434Y compared to an amino acid sequence established in SEQ ID NO: 1. In some embodiments, the Fc fragment comprises amino acid substitutions of H433R and N434Y compared to an amino acid sequence established in SEQ ID NO: 1.

[0034] In one aspect, the present invention provides, among other things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), wherein the variant of the Fc fragment comprises M428L and N434Y amino acid substitutions compared to an amino acid sequence established in SEQ ID NO: 1.

[0035] In some embodiments, an Fc fragment further comprises an amino acid substitution of H433K.

[0036] In one aspect, the present invention provides, among other things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), wherein the variant of the Fc fragment comprises M428L and H433R amino acid substitutions compared to an amino acid sequence established in SEQ ID NO: 1.

[0037] In some embodiments, the Fc fragment further comprises an amino acid substitution of N434Y.

[0038] In one aspect, the present invention provides, among other things Petition 870250086042, dated 09 / 23 / 2025, p. 19 / 126 12 / 89 things, a variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), wherein the variant of the Fc fragment comprises H433R and H434F amino acid substitutions compared to an established amino acid sequence in SEQ ID NO: 1.

[0039] In some embodiments, an Fc fragment further comprises amino acid substitutions of M252Y, S254T and T256E.

[0040] In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433K, and N434F. In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433K, and N434Y. In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, H433K, and N434Y. In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, and N434F. In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, H433R, and N434F. In some embodiments, the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433R, and N434F.

[0041] In some embodiments, the Fc fragment variant does not comprise an amino acid substitution of L309D.

[0042] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 3. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 3.

[0043] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 4. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 4. Petition 870250086042, dated 09 / 23 / 2025, p. 20 / 126 13 / 89

[0044] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 5. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 5.

[0045] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 6. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 6.

[0046] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 7. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 7.

[0047] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 8. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 8.

[0048] In some embodiments, the Fc fragment comprises an amino acid sequence that is at least 80%, 83%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, and 99% identical to SEQ ID NO: 9. In some embodiments, the Fc fragment comprises an amino acid sequence of SEQ ID NO: 9.

[0049] In some embodiments, a variant of the Fc fragment inhibits the binding of an IgG to human FcRn with an IC50 value less than 2.6 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value less than 2.5 nM. In some embodiments, a variant of Petition 870250086042, dated 09 / 23 / 2025, p. 21 / 126 14 / 89 Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 2.3 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 2.2 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 2.0 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.9 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.8 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.7 nM. In some forms, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value less than 1.6 nM.In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.5 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.4 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.3 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.2 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.1 nM. In some embodiments, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value less than 1.0 nM. In some forms, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value less than 0.9 nM.In some forms, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value less than 0.8 nM. Petition 870250086042, dated 09 / 23 / 2025, p. 22 / 126 15 / 89

[0050] In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.5 to 2.2 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value between 0.7 and 2.0 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.8 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.6 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.5 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.4 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.3 nM.In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.2 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.2 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of approximately 0.7 to 1.0 nM.

[0051] In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 2.0 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 1.9 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 1.8 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 1.7 nM. In some Petition 870250086042, dated 09 / 23 / 2025, p. 23 / 126 In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.5 nM. In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.4 nM. In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.3 nM. In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.2 nM. In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.1 nM. In some modalities, a variant of the Fc fragment inhibits IgG from binding to human FcRn with an IC50 value of 1.0 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 0.9 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 0.8 nM.In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 0.7 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn with an IC50 value of 0.6 nM.

[0052] In some embodiments, a variant of the Fc fragment effectively inhibits an IgG from binding to human FcRn at pHs of about 5.8 to 7.5. In some embodiments, a variant of the Fc fragment effectively inhibits an IgG from binding to human FcRn at pHs of about 6.0 to 7.4.

[0053] In some embodiments, a variant of the Fc fragment effectively inhibits an IgG from binding to human FcRn at pH 6.0. In some embodiments, a variant of the Fc fragment effectively inhibits an IgG from binding to human FcRn at pH 7.0. In some embodiments, a variant of the Fc fragment effectively inhibits an IgG of Petition 870250086042, dated 09 / 23 / 2025, p. 24 / 126 17 / 89 binds to human FcRn at pH 7.4.

[0054] In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn at pH 6.0 with an IC50 value of approximately 0.7 to 2.2 nM. In some embodiments, a variant of the Fc fragment inhibits an IgG from binding to human FcRn at pH 7.4 with an IC50 value of approximately 0.7 to 2.2 nM.

[0055] In some embodiments, an Fc fragment is fused or complexed to a half-life extension domain. In some embodiments, a half-life extension domain is a protein. In some embodiments, a half-life extension domain is a polypeptide. In some embodiments, a half-life extension domain is a peptide. In some embodiments, a half-life extension domain is an antibody. In some embodiments, a half-life extension domain is an antibody fragment. In some embodiments, a half-life extension domain is an scFv. In some embodiments, a half-life extension domain is an sdAb. In some embodiments, a half-life extension domain is a Fab. In some embodiments, a half-life extension domain is a VHH. In some embodiments, a half-life extension domain is one or more variable antigen receptors (VNARs).

[0056] In some embodiments, a half-life extension domain is an albumin. In some embodiments, a half-life extension domain is an albumin-binding domain. In some embodiments, a half-life extension domain is an HSA-binding domain.

[0057] In one aspect, the present invention provides, among other things, a method of inhibiting IgG binding to FcRn by administering a variant of the Fc fragment described herein. DETAILED DESCRIPTION Petition 870250086042, dated 09 / 23 / 2025, page 25 / 126 18 / 89 Definitions

[0058] Unless otherwise defined, all technical terms, notations, and other scientific terminology used herein shall have the meanings commonly understood by experts in the field. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ready reference, and the inclusion of such definitions herein should not necessarily be interpreted as a difference from what is generally understood in the field. The techniques and procedures described or referenced herein are generally well understood and commonly used using conventional methodologies by experts in the field, such as, for example, the widely used molecular cloning methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 4th ed. (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York.As appropriate, procedures involving the use of commercially available kits and reagents are generally performed in accordance with the protocols and conditions defined by the manufacturer, unless otherwise indicated.

[0059] As used in this document, the singular forms um, uma and o(a) include references to the plural, unless otherwise indicated.

[0060] It is understood that the aspects and embodiments of the invention described in this document include comprising, consisting of and essentially consisting of aspects and embodiments.

[0061] For all compositions described herein, and all methods that use a composition described herein, the compositions may comprise the listed components or steps, or may “consist essentially of” the listed components or steps. When a composition is described as “consisting essentially of” the listed components, the composition contains the components Petition 870250086042, dated 09 / 23 / 2025, p. 26 / 126 19 / 89 listed and may contain other components that do not substantially affect the condition being treated, but does not contain any other components that substantially affect the condition being treated beyond those expressly listed; or, if the composition contains extra components beyond those listed that substantially affect the condition being treated, the composition does not contain a sufficient concentration or quantity of the extra components to substantially affect the condition being treated. When a method is described as “essentially consisting of” the listed steps, the method contains the listed steps and may contain other steps that do not substantially affect the condition being treated, but the method does not contain any other steps that substantially affect the condition being treated beyond those expressly listed.As a specific, but not limiting, example, when a composition is described as consisting essentially of one component, the composition may additionally contain any amount of pharmaceutically acceptable vehicles, diluents or carriers and other components that do not substantially affect the condition being treated.

[0062] The term vector, as used in this document, refers to a nucleic acid molecule capable of propagating or to the nucleic acid to which it is attached. The term includes the vector as a self-replicating nucleic acid structure, as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operationally attached. Such vectors are referred to in this document as expression vectors.

[0063] The terms “host cell”, “host cell line” and “host cell culture” are used interchangeably and refer to cells into which an exogenous nucleic acid has been introduced. Petition 870250086042, dated 09 / 23 / 2025, page 27 / 126 20 / 89 and the progeny of these cells. Host cells include “transforming cells” (or “transformed cells”) and “transfecting cells” (or “transfected cells”), each of which includes the primary transformed or transfected cell and its derived progeny. This progeny may not be completely identical in nucleic acid content to the mother cell and may contain mutations. A “recombinant host cell” or “host cell” refers to a cell that includes an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells.

[0064] As used herein, the term “eukaryote” refers to organisms belonging to the phylogenetic domain Eucarya, such as animals (including, but not limited to, mammals, insects, reptiles, birds, etc.), ciliates, plants (including, but not limited to, monocots, dicots, algae, etc.), fungi, yeasts, flagellates, microsporidia, protists, etc.

[0065] As used herein, the term “prokaryote” refers to prokaryotic organisms. For example, a non-eukaryotic organism may belong to the phylogenetic domain Eubacteria (including, but not limited to, Escherichia coli, Thermus thermophilus, Bacillus stearothermophilus, Pseudomonas fluorescens, Pseudomonas aeruginosa, Pseudomonas putida, etc.) or to the phylogenetic domain Archaea (including, but not limited to, Methanococcus jannaschii, Methanobacterium thermotrofium, Halobacterium such as Haloferax volcanii and Halobacterium species NRC-1, Archaeoglobus fulgidus, Pyrococcus furiosus, Pyrococcus horikoshii, Aeropyrum pernix, etc.).

[0066] An “effective amount” or “therapeutically effective amount,” as used herein, refers to a quantity of a therapeutic compound, such as an Fc fragment, administered to an individual, Petition 870250086042, dated 09 / 23 / 2025, page 28 / 126 21 / 89, whether as a single dose or as part of a series of doses, is effective in producing or contributing to a desired therapeutic effect, alone or in combination with another therapeutic modality. Examples of a desired therapeutic effect are a reduction in IgG levels and improvement of one or more symptoms. An effective amount may be administered in one or more doses.

[0067] The term “treat” (and variations thereof, such as “treating” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in an individual who needs it. Treatment may be carried out during the course of the clinical pathology. The desirable effects of treatment include preventing disease recurrence, relieving symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, improving or palliating the disease state, and achieving remission or improved prognosis.

[0068] The term “sufficient quantity” means a quantity sufficient to produce a desired effect, for example, a quantity sufficient to modulate an immune response in an individual.

[0069] As used herein, the term “subject” or “individual” means an individual mammal. Examples of individuals include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, and sheep. In specific modalities, the individual is a human being.

[0070] The term “in vitro” refers to processes that occur in a living cell that grows separately from a living organism, for example, growing in tissue culture.

[0071] The term “in vivo” refers to processes that occur in a living organism.

[0072] The term “leaflet” is used to refer to the instructions for use in the product information leaflet. Petition 870250086042, dated 09 / 23 / 2025, page 29 / 126 22 / 89 usually included in commercial packaging of therapeutic or diagnostic products (e.g., kits) that contain information on the indications, use, dosage, administration, combination therapy, contraindications and / or warnings regarding the use of such therapeutic or diagnostic products.

[0073] The term “pharmaceutical composition” refers to a preparation that is in such a form that allows the biological activity of an active ingredient contained therein to be effective in the treatment of an individual, and that does not contain additional components that are unacceptably toxic to the individual in the quantities provided in the pharmaceutical composition.

[0074] The terms “co-administration,” “co-administer,” and “in combination with” include the administration of two or more therapeutic agents simultaneously, concomitantly, or sequentially, without specific time limits. In one embodiment, the agents are present in the individual’s cell or body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In other embodiments, the therapeutic agents are in separate compositions or unit dosage forms. In certain embodiments, a first agent may be administered before the administration of a second therapeutic agent.

[0075] The terms “modulate” and “modulation” refer to the reduction or inhibition or, alternatively, the activation or increase of a recited variable.

[0076] The terms “increase” and “activate” refer to an increase of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more in a recited variable.

[0077] The terms “reduce” and “inhibit” refer to a decrease Petition 870250086042, dated 09 / 23 / 2025, p. 30 / 126 23 / 89 of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 2 times, 3 times, 4 times, 5 times, 10 times, 20 times, 50 times, 100 times or more in a recited variable.

[0078] The term “about” indicates and encompasses a stated value and an interval above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, when applicable, the term “about” indicates the designated value(s) ± one standard deviation of that value(s).

[0079] For any of the structural and functional features described herein, methods for determining those features are known in the art.

[0080] The term “optionally” means, when used sequentially, to include from one to all of the enumerated combinations and encompasses all subcombinations.

[0081] The term “amino acid” refers to the twenty common amino acids that occur naturally. Natural amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine ​​(Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V).

[0082] The term “affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an Fc fragment) and its binding partner (e.g., FcRn). Unless otherwise indicated, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an Fc fragment and FcRn). Affinity is inversely proportional to KD. Petition 870250086042, dated 09 / 23 / 2025, p. 31 / 126 24 / 89

[0083] The term “variant”, as used herein when referring to an amino acid sequence, refers to an amino acid sequence comprising one or more sequence alterations compared to a reference amino acid sequence, including one or more substitutions compared to a reference amino acid sequence.

[0084] The term “kd” (s-1), as used herein, refers to the dissociation rate constant of a specific antibody-antigen or protein-protein interaction. This value is also called the koff value.

[0085] The term “ka” (M-1*s-1), as used herein, refers to the association rate constant of a specific antibody-antigen or protein-protein interaction. This value is also called the kon value.

[0086] The term “KD” or “Kd”) (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen or protein-protein interaction. KD = kd / ka. In some embodiments, the affinity of a protein is described in terms of the KD for an interaction between such protein and its binding partner. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0087] The term “measurable KD” or “KDmeasurable”, as used herein, means a value of KD that is less than 1 M, less than 0.1 M, less than 0.01 M, less than 0.001 M, less than 1 x 10-4 M, less than 1 x 10-5 M, or less than 1 x 10-6 M.

[0088] The term “KA” (M-1), as used herein, refers to the association equilibrium constant of a particular antibody-antigen or protein-protein interaction. KA = ka / kd.

[0089] The term “antibody” is used here in its broadest sense. Petition 870250086042, dated 09 / 23 / 2025, p. 32 / 126 25 / 89 plo and includes certain types of immunoglobulin molecules comprising one or more antigen-binding domains that bind specifically to an antigen or epitope. An antibody specifically includes intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multispecific antibodies.

[0090] The terms “full-length antibody”, “intact antibody”, and “whole antibody” are used herein interchangeably to refer to an antibody that has a structure substantially similar to a natural antibody structure and that has heavy chains comprising an Fc region. For example, when used to refer to an IgG molecule, a “full-length antibody” is an antibody comprising two heavy chains and two light chains.

[0091] The term “Fc domain” or “Fc region” or “Fc fragment” is used here to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.

[0092] An “Fc fragment”, as provided herein, refers to a fragment of the Fc domain that specifically binds to the target protein FcRn. In some embodiments, an Fc fragment is a variant of SEQ ID NO:1.

[0093] The term “human Fc fragment” refers to a fragment Fc having an amino acid sequence corresponding to that of an Fc region of an antibody produced by a human being or a human cell, or derived from a non-human source that utilizes a repertoire of human antibodies or human antibody-coding sequences (e.g., obtained from human sources or designed de novo).

[0094] The term “substantially purified” refers to a cons Petition 870250086042, dated 09 / 23 / 2025, p. 33 / 126 26 / 89 truto described herein, or a variant thereof, which may be substantially or essentially free of components that normally accompany or interact with the protein as found in its natural environment, i.e., a native cell or host cell in the case of recombinantly produced protein which, in certain embodiments, is substantially free of cellular material, including protein preparations having less than about 30%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2% or less than about 1% (by dry weight) of contaminating protein.

[0095] The intervals mentioned here are understood as an abbreviation of all values ​​within the interval, including the mentioned endpoints. For example, an interval from 1 to 50 is understood as including any number, combination of numbers, or subinterval of the group consisting of 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, and 50.

[0096] It should be noted that, as used in this descriptive report and the attached claims, the singular forms a and the include plural referents, unless the context clearly dictates otherwise. Fc Fragments Structure of the Fc Fragment

[0097] Fc fragments may include those described herein, such as the amino acid sequences shown in the tables. In some embodiments, the Fc fragment is a subclass of IgG IgG1, IgG2, or IgG4.

[0098] In certain embodiments, Fc fragments are produced by recombinant cells engineered to express the domains Petition 870250086042, dated 09 / 23 / 2025, p. 34 / 126 27 / 89 desired constants. Fc fragment sequences binding to FcRn

[0099] In certain aspects, an isolated Fc fragment is described herein that binds to the neonatal Fc receptor (FcRn) of humans, dogs, mice, or rats, wherein the Fc fragment comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises at least one amino acid substitution selected from M428L, H433R, and N434Y. In some embodiments, the isolated Fc fragment comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, and 256 of SEQ ID NO: 1. In some embodiments, the additional amino acid substitutions are M252Y, S254T, and / or T256E.

[00100] In certain aspects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse, or rat is described herein, with the Fc fragment comprising: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an amino acid substitution at position 428. In some embodiments, the amino acid substitution is M428L. In some embodiments, the Fc fragment comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 433, and 434 of SEQ ID NO: 1. In some embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, H433K, H433R, N434F, and / or N434Y.

[00101] In certain aspects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse, or rat is described herein, with the Fc fragment comprising: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an H433R amino acid substitution. In some embodiments, the additional amino acid substitutions are at one or more of the amino acid positions 252, 254, 256, 428 Petition 870250086042, dated 09 / 23 / 2025, p. 35 / 126 28 / 89 and 434 of SEQ ID NO: 1. In some embodiments, one or more additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F and / or N434Y.

[00102] In certain aspects, an isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of human, canine, mouse, or rat is described herein, with the Fc fragment comprising: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an amino acid substitution N434Y. In some embodiments, the Fc fragment comprises an additional amino acid substitution at one or more of the amino acid positions 252, 254, 256, 428, and 433 of SEQ ID NO:1. In some embodiments, the amino acid substitutions are M252Y, S254T, T256E, M428L, H433K and / or H433R.

[00103] In certain aspects, an isolated Fc fragment is described herein that binds to the neonatal Fc receptor (FcRn) of humans, canine distemper, mice or rats, wherein the Fc fragment comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an H433K amino acid substitution and additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 428 and 434. In certain embodiments, the additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F and / or N434Y.

[00104] In certain embodiments, the Fc fragment comprises a sequence selected from the sequences set out in SEQ ID Nos: 3-9.

[00105] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 3, provided that such fragment comprises the M252Y, S254T, T256E, M428L, H433K and mutations. Petition 870250086042, dated 09 / 23 / 2025, p. 36 / 126 29 / 89 N434F.

[00106] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 3.In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 3. In some embodiments... Petition 870250086042, dated 09 / 23 / 2025, p. 37 / 126 30 / 89 fads, a variant of the Fc fragment comprises an amino acid sequence that is 100% identical to SEQ ID NO: 3. In some embodiments, for each of the previous variants that have percentage identity with SEQ ID NO: 3, the variant comprises the mutations M252Y, S254T, T256E, M428L, H433K, and N434F.

[00107] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 4, provided that such fragment comprises the M252Y, S254T, T256E, M428L, H433K and N434Y mutations.

[00108] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 4.In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 4. In some embodiments, a variant of the Fc fragment comprises a sequence of... Petition 870250086042, dated 09 / 23 / 2025, p. 38 / 126 31 / 89 amino acids that are at least 95% identical to SEQ ID NO: 4. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 4. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 4. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 4. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 4. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is 100% identical to SEQ ID NO: 4. In some embodiments, for each of the preceding variants that have percent identity with SEQ ID NO: 4, the variant comprises the M252Y mutations, S254T, T256E, M428L, H433K and N434Y.

[00109] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 5, provided that such fragment comprises the M252Y, S254T, T256E, H433K and N434Y mutations.

[00110] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3. In some embodiments, a variant of the Fc fragment comprises Petition 870250086042, dated 09 / 23 / 2025, p. 39 / 126 32 / 89 an amino acid sequence that is at least 91% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 5. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 5.In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 5. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 5. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is 100% identical to SEQ ID NO: 5. In some embodiments, for each of the above variants that have percentage identity with SEQ ID NO: 5, the variant comprises the M252Y, S254T, T256E, H433K, and N434Y mutations.

[00111] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 6, provided that such fragment comprises the M252Y, S254T, T256E, M428L and N434F mutations.

[00112] In some forms, a variant of the Fc fragment Petition 870250086042, dated 09 / 23 / 2025, p. 40 / 126 33 / 89 comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 36. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 6.In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 6. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is 100% identical to SEQ ID NO: 6. NO: 6. In some fashion. Petition 870250086042, dated 09 / 23 / 2025, page 41 / 126 34 / 89 lidades, for each of the previous variants that have a percentage of identity with SEQ ID NO: 6, the variant comprises the mutations of M252Y, S254T, T256E, M428L and N434F.

[00113] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 7, provided that such fragment comprises the M252Y, S254T, T256E, H433R and N434Y mutations.

[00114] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 7.In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID. Petition 870250086042, dated 09 / 23 / 2025, p. 42 / 126 35 / 89 In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO:7. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO:7. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO:7. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is 100% identical to SEQ ID NO:7. In some embodiments, for each of the above variants that have percentage identity with SEQ ID NO:7, the variant comprises the M252Y, S254T, T256E, H433R, and N434Y mutations.

[00115] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 8, provided that such fragment comprises the M252Y, S254T, T256E, H433R and N434F mutations.

[00116] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 8. Petition 870250086042, dated 09 / 23 / 2025, p. 43 / 126 36 / 89 tica to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 8. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 8.In some embodiments, an Fc fragment variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 8. In some embodiments, an Fc fragment variant comprises an amino acid sequence that is 100% identical to SEQ ID NO: 8. In some embodiments, for each of the above variants that have percentage identity with SEQ ID NO: 8, the variant comprises the M252Y, S254T, T256E, H433R, and N434F mutations.

[00117] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 9, provided that such fragment comprises the M252Y, S254T, T256E, M428L, H433R and N434F mutations.

[00118] In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 9. In some embodiments, a variant of Petition 870250086042, dated 09 / 23 / 2025, p. 44 / 126 37 / 89 Fc fragment comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 88% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 9. NO: 9.In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 9. In some embodiments, a variant of the Fc fragment comprises an amino acid sequence that is 100% identical to SEQ ID NO: 9. In some embodiments, for each of the preceding variants that possess percentage identity with SEQ ID NO: 9, the variant comprises the... Petition 870250086042, dated 09 / 23 / 2025, p. 45 / 126 38 / 89 mutations of M252Y, S254T, T256E, M428L, H433R and N434F.

[00119] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 18, provided that such fragment comprises the M252Y, S254T, T256E, L309D, H433K and N434F mutations.

[00120] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 19, provided that such fragment comprises the M252Y, S254T, T256E, L309D, H433K and N434Y mutations.

[00121] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 20, provided that such fragment comprises the mutations M252Y, S254T, T256E, L309D, M428L, H433K and N434F.

[00122] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 21, provided that such fragment comprises the mutations M252Y, S254T, T256E, L309D, M428L, H433K and N434Y.

[00123] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 22, provided that such fragment comprises the mutations M252Y, S254T, T256E, L309D, Q311K, Petition 870250086042, dated 09 / 23 / 2025, p. 46 / 126 39 / 89 H433K and N434F.

[00124] In certain embodiments, the Fc fragment comprises a sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence comprising SEQ ID NO: 23, provided that such fragment comprises the mutations M252Y, S254T, T256E, L309D, Q311K, H433K and N434Y.

[00125] For sequence comparison, one sequence usually acts as a reference sequence, to which a second sequence is compared. When using a sequence comparison algorithm, test and reference sequences can be entered into a computer, subsequent coordinates can be assigned if necessary, and program parameters of the sequence algorithm can be assigned. Any suitable algorithm can be used, including but not limited to SmithWaterman alignment algorithm, Viterbi, Bayesian, Hidden Markov, and similar algorithms. Standard program parameters can be used, or alternative parameters can be assigned. The sequence comparison algorithm can then be used to calculate the percent identities of the test sequences with respect to the reference sequence, based on the program parameters. Any suitable algorithm can be used by which a percent identity is calculated.Some programs, for example, calculate the percentage of identity as the number of aligned positions that have identical residues, divided by the total number of aligned positions.

[00126] Sequence alignment methods for comparison are well known in the field. Optimal sequence alignment for comparison can be conducted, for example, by the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482 (1981), by the homology alignment algorithm of Needleman and Wunsch, Petition 870250086042, dated 09 / 23 / 2025, p. 47 / 126 40 / 89 J. Mol. Biol. 48:443 (1970), by the Pearson and Lipman similarity search method, Proc. USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, for example, Current Protocols in Molecular Biology (Ausubel et al., Eds. 1995 supplement)), each of which is incorporated herein by reference in its entirety. Exemplary computer software for determining the identity between two sequences includes, but is not limited to, the GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN and FASTA Altschul, SF et al., J Molec. Biol., 215, 403 (1990)), each of which is incorporated herein by reference in its entirety.

[00127] In some embodiments, the Fc fragment comprises additional amino acid residues at the N-terminus or C-terminus. In some embodiments, the Fc fragments provided herein comprise a C-terminus lysine residue. In some embodiments, the Fc fragment has 1, 2, 3, 4, or 5 additional amino acid residues at the N-terminus and / or C-terminus. Region FC

[00128] Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is in accordance with the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. An “Fc polypeptide” of an Fc dimeric domain, as used herein, refers to one of the two polypeptides that form the Fc dimeric domain, that is, a polypeptide comprising C-terminal constant regions of a heavy chain of Petition 870250086042, dated 09 / 23 / 2025, page 48 / 126 41 / 89 immunoglobulin, capable of stable self-association. For example, an Fc polypeptide of a dimeric IgG Fc comprises a constant domain sequence CH2 of IgG and CH3 of IgG. In certain respects, the Fc fragments described here comprise the 226 C-terminal amino acids of the complete human IgG Fc region. An Fc can be of the IgG class and can be divided into subclasses (isotypes), for example, IgG1, IgG2, IgGa, and IgG4. In certain respects, the Fc fragments described here are of the IgG1 subclass. In certain respects, the Fc fragments described here are variants of the human IgG1 Fc region established in SEQ ID NO: 1. In certain respects, the Fc fragments described here are of the IgG2 subclass. In certain respects, the Fc fragments described here are of the IgG4 subclass.

[00129] The terms “Fc receptor” and “FcR” are used to describe a receptor that binds to the Fc region of an antibody. For example, an FcR may be a native human sequence FcR. Generally, an FcR is one that binds to an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Immunoglobulins of other isotypes may also be bound by certain FcRs (see, for example, Janeway et al., Immuno Biology: the immune system in health and disease, (Elsevier Science Ltd., NY) (4th ed., 1999)). The term also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol.117:587 (1976); and Kim et al., J. Immunol. 24:249 (1994)). The Fc fragments described here bind selectively to FcRn. In certain respects, the Fc fragments bind selectively to a mammalian FcRn, including canine FcRn. Petition 870250086042, dated 09 / 23 / 2025, p. 49 / 126 42 / 89 rat and / or mouse.

[00130] The activating FcyRIIA receptor contains an immunoreceptor tyrosine-based activating motif (ITAM) in its cytoplasmic domain. The inhibitory FcyRIIB receptor contains an immunoreceptor tyrosine-based inhibiting motif (ITIM) in its cytoplasmic domain (reviewed in Daèron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term FcR here.

[00131] Modifications in the CH2 domain can affect the binding of FcRs to Fc. Several amino acid modifications in the Fc region are known in the art to selectively alter the affinity of Fc for different Fc gamma receptors.

[00132] Exemplary mutations that alter the binding of FcRs to FCs are listed below:

[00133] S298A / E333A / K334A, S298A / E333A / K334A / K326A (Lu Y, Vernes JM, Chiang N, et al. J Immunol Methods. February 28, 2011; 365 (1-2): 132-41);

[00134] F243L / R292P / Y300L / V305I / P396L, F243L / R292P / Y300L / L2 35V / P396L (Stavenhagen JB, Gorlatov S, Tuaillon N, et al. Cancer Res. 2007 Sep 15;67(18):8882-90; Nordstrom JL, Gorlatov S, Zhang W, et al. Breast Cancer Res. 2011 Nov 30;13(6):R123);

[00135] F243L (Stewart R, Thom G, Levens M, et al. Protein Eng Des Sel. September 2011; 24 (9): 671-8.), S298A / E333A / K334A (Shields RL, Namenuk AK, Hong K, et al. J Biol Chem. 2 March 2001; 276 (9): 6591-604);

[00136] S239D / I332E / A330L, S239D / I332E (Lazar GA, Dang W, Petition: 870250086042, on September 23, 2025, page. 50 / 126 43 / 89 Karki S, et al. Proc Natl Acad Sci US A. March 14, 2006; 103 (11): 4005-10);

[00137] S239D / S267E, S267E / L328F (Chu SY, Vostiar I, Karki S, et al. Mol Immunol. Setembro de 2008; 45(15): 3926-33);

[00138] S239D / D265S / S298A / I332E, S239E / S298A / K326A / A327H, G237F / S298A / A330L / I332E, S239D / I332E / S298A, S239D / K326E / A330L / I332E / S298A, G236A / S239D / D270L / I332E, S239E / S267E / H268D, L234F / S267E / N325L, G237F / V266L / S267D and other mutations listed in WO2011 / 120134 and WO2011 / 120135, incorporated herein by reference. Therapeutic Antibody Engineering (by William R. Strohl and Lila M. Strohl, Woodhead Publishing series in Biomedicine No. 11, ISBN 1 907568 37 9, October 2012) lists mutations on page 283.

[00139] In certain embodiments, the Fc fragments described herein are variants of (e.g., comprising one or more amino acid substitutions compared with) SEQ ID NO:1, wherein one or more substitutions result in a measurable KD at pH 7.4 compared with an Fc fragment of SEQ ID NO:1, which does not detectably bind to FcRn at pH 7.4 without one or more substitutions.

[00140] In certain embodiments, one or more amino acid substitutions result in an increased half-life of the Fc fragment at pH 6.0 compared to an Fc fragment comprising a wild-type Fc region. Connection

[00141] The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, including Petition 870250086042, dated 09 / 23 / 2025, page 51 / 126 44 / 89 of those described herein, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[00142] With respect to the binding of an Fc fragment to a target molecule, the terms “bind”, “specific binding”, “binds specifically to”, “specific to”, “binds selectively”, and “selective to” a specific target (e.g., a polypeptide target such as FcRn) mean a binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule (e.g., FcRn) and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the target molecule. In this case, specific binding is indicated if the binding of the Fc fragment to the target molecule is competitively inhibited by the control molecule.In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 50% of the affinity for FcRn (i.e., the Kd for FcRn is twice as small as the KD for a non-target molecule). In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 40% of the affinity for FcRn. In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 30% of the affinity for FcRn. In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 20% of the affinity for FcRn. In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 10% of the affinity for FcRn. In some embodiments, the affinity of an Fc fragment for a non-target molecule is less than about 1% of the affinity for FcRn. In some embodiments, the affinity of an Fc fragment for a non-target molecule is... Petition 870250086042, dated 09 / 23 / 2025, p. 52 / 126 45 / 89 less than approximately 0.1% of the affinity for FcRn.

[00143] When used here in the context of a first Fc fragment and a second Fc fragment or a wild-type IgG (the “second molecule”), the term “competes with” or “cross-competes with” indicates that the first Fc fragment and the second molecule compete for binding to a target (e.g., FcRn). In an exemplary assay, FcRn is coated onto a surface and brought into contact with a first Fc fragment, after which a second molecule is added. In another exemplary assay, a first Fc fragment is coated onto a surface and brought into contact with FcRn, and then a second molecule is added. If the presence of the first Fc fragment reduces the binding of the second molecule, in either assay, the Fc fragment competes with the second molecule.The term “competes with” also includes combinations where the first Fc fragment reduces the binding of the second molecule, but where no competition is observed when the first Fc fragment and the second molecule are added in reverse order. However, in some embodiments, the first Fc fragment and the second molecule inhibit each other's binding to FcRn, regardless of the order in which they are added. In some embodiments, the first Fc fragment reduces the binding of the second molecule to its receptor by at least 25%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%, as measured in a competitive binding assay. A skilled individual can select the concentrations of the first Fc fragments and the second molecules used in the competitive assays based on the affinities of the Fc fragment and the second molecule for FcRn.The tests described in this definition are illustrative, and a qualified professional may use any appropriate test to determine whether the Fc fragments compete with each other. Petition 870250086042, dated 09 / 23 / 2025, page 53 / 126 46 / 89 suitable assays are described, for example, in Cox et al., “Immunoassay Methods”, in Assay Guidance Manual [Internet], updated December 24, 2014 (ncbi.nlm.nih.gov / books / NBK92434 / ; accessed September 29, 2015); Silman et al., Cytometry, 2001, 44:30-37; and Finco et al., J. Pharm. Biomed. Anal., 2011, 54:351-358; each of which is incorporated by reference in its entirety.

[00144] A test (or first) Fc fragment competes with a second molecule (e.g., a reference Fc fragment) if an excess of a test Fc fragment (e.g., at least 2x, 5x, 10x, 20x, or 100x) inhibits or blocks the binding of the second molecule by, for example, at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, as measured in a competitive binding assay. For example, a second competing Fc fragment can be identified by its ability to compete for binding to FcRn with a first Fc fragment described herein. In certain cases, the second molecule may block or inhibit the binding of the first Fc fragment by, for example, at least 50%, 60%, 70%, 75%, 80%, 80%, 90%, 95%, or 99%, as measured in a competitive binding assay. %, 85%, 90%, 95%, or 99%, as measured in a competitive binding assay. In certain cases, the second molecule may displace the first Fc fragment by more than 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

[00145] In certain embodiments, the Fc fragment binds to an established FcRn sequence in SEQ ID NO:10-17.

[00146] In certain embodiments, the Fc fragment binds to an established FcRn sequence in SEQ ID NO: 10-17 with a Kd less than or equal to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 x 10-8M at pH 6.0, as measured by surface plasmon resonance (SPR). In certain embodiments, the Fc fragment binds to human FcRn with a Kd less than or equal to approximately 1 x 10-8M at pH 6.0, as measured Petition 870250086042, dated 09 / 23 / 2025, page 54 / 126 47 / 89 by surface plasmon resonance (SPR). In certain embodiments, the Fc fragment binds to an established FcRn sequence in SEQ ID NO: 10-17 with a Kd less than or equal to approximately 1 x 10-9M at pH 6.0, as measured by surface plasmon resonance (SPR). I

[00147] In certain embodiments, the Fc fragment binds to an FcRn with a lower Kd at pH 6.0 compared to an Fc fragment comprising a wild-type Fc region at the same pH.

[00148] In some embodiments, an Fc fragment provided herein binds FcRn at a pH of 6.0 with a Kd less than or equal to approximately 1 x 10⁻⁸, 1.1 x 10⁻⁸, 1.2 x 10⁻⁸, 1.3 x 10⁻⁸, 1.4 x 10⁻⁸, 1.5 x 10⁻⁸, 1.6 x 10⁻⁸, 1.7 x 10⁻⁸, 1.8 x 10⁻⁸, 1.9 x 10⁻⁸, 1.95 x 10⁻⁸, 2 x 10⁻⁸, 2.5 x 10⁻⁸, 3 x 10⁻⁸, 3.5 x 10⁻⁸, 4 x 10⁻⁸, 4.5 x 10⁻⁸, 5 x 10⁻⁸, 6 x 10⁻⁸, 7 x 10-8, 8 x 10-8, 9 x 0-8, 1 x 10-9, 1.1 x 10-9, 1.2 x 10-9, 1.3 x 10-9, 1.4 x 10-9, 1.5 x 10-9, 1.6 x 10-9, 1.7 x 10-9, 1.8 x 10-9, 1.9 x 10-9, 1.95 x 10-9, 2 x 10-9, 2.5 x 10-9, 3 x 10-9, 3.5 x 10-9, 4 x 10-9, 4.5 x 10-9, 5 x 10-9, 6 x 10-9, 7 x 10-9, 8 x 10-9, x 10-9, 1 10-10, 1.1x 10-10, 1.2 x 10-10, 1.3 x 10-10, 1.4 x 10-10, 1.5 x 10-10, 1.6 x 10-10, 1.7 x 10-10, 1.8 x 10-10, 1.9 x 10-10, 1.95 x 10-10, 2 x 10-10, 2.5 x 10-10, 3 x 10-10, 3.5 x 10-10, 4 x 10-10, 4.5 x 10-10, 5 x 10-10, 6 x 10-10, 7 x 10-10, 8 x 10-10 or 9 x 10-10 as measured by ELISA or any other suitable method known in technique.

[00149] In some embodiments, the Kd of the Fc fragment provided here for FcRn binding at a pH of 6.0 is approximately 1.0-1.1 x 10⁻⁸ M, 1.1-1.2 x 10⁻⁸ M, 1.2-1.3 x 10⁻⁸ M, 1.3-1.4 x 10⁻⁸ M, 1.4-1.5 x 10⁻⁸ M, 1.5-1.6 x 10⁻⁸ M, 1.6-1.7 x 10⁻⁸ M, 1.7-1.8 x 10⁻⁸ M, 1.8-1.9 x 10⁻⁸ M, 1.9-2 x 10⁻⁸ M, 1-2 x 10⁻⁸ M, 1-5 x 10⁻⁸ M, 2-7 x 10⁻⁸ M, 3-8 x 10-8M, 3-5 x 10-8M, 4-6 x 10-8M, 5-7 x 10-8M, 6-8 x 10-8M, 7-9 x 10-8M, 7-9.9 x 10-8M, 5-9.9 x 10-8M, 1.0-1.1 x 10-9M, 1.1-1.2 x 10-9M, 1.2-1.3 x 10-9M, 1.3-1.4 x 10-9M, 1.4-1.5 x 10-9M, 1.5-1.6 x 10-9M, 1.6-1.7 x 10-9M, 1.7-1.8 x 10-9M, 1.8-1.9 x 10-9M, 1.9-2 x 10-9M, 1-2 x 10-9M, 1-5 x Petition 870250086042, dated 09 / 23 / 2025, page 55 / 126 48 / 89 10-9M, 2-7 x 10-9M, 3-8 x 10-9M, 3-5 x 10-9M, 4-6 x 10-9M, 5-7 x 10-9M, 6-8 x 10-9M, 7-9 x 10-9M, 7-9.9 x 10-9M or 5-9.9 x 10-9M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an Fc fragment provided herein binds to FcRn at pH 6.0 with a Kd less than or equal to about 1 x 10-8M, or less than or equal to about 1 x 10-9M, as measured by ELISA or any other suitable method known in the art.

[00150] In some embodiments, an Fc fragment provided herein binds to FcRn at a pH of 7.4 with a KD greater than or equal to approximately 1 x 10⁻⁵, 1.1 x 10⁻⁵, 1.2 x 10⁻⁵, 1.3 x 10⁻⁵, 1.4 x 10⁻⁵, 1.5 x 10⁻⁵, 1.6 x 10⁻⁵, 1.7 x 10⁻⁵, 1.8 x 10⁻⁵, 1.9 x 10⁻⁵, 1.95 x 10⁻⁵, 2 x 10⁻⁵, 2.5 x 10⁻⁵, 3 x 10⁻⁵, 3.5 x 10⁻⁵, 4 x 10⁻⁵, 4.5 x 10⁻⁵, 5 x 10⁻⁵, 6 x 10⁻⁵, 7 x 10-5, 8 x 10-5, 9 x 10-5, 1 x 10-6, 1.1 x 10-6, 1.2 x 10-6, 1.3 x 10-6, 1.4 x 10-6, 1.5 x 10-6, 1.6 x 10-6, 1.7 x 10-6, 1.8 x 10-6, 1.9 x 10-6, 1.95 x 10-6, 2 x 10-6, 2.5 x 10-6, 3 x 10-6, 3.5 x 10-6, 4 x 10-6, 4.5 x 10-6, 5 x 10-6, 6 x 10-6, 7 x 10-6, 8 x 10-6.9 x 10-6, 1 x 10-7, 1.1 x 10-7, 1.2 x 10-7, 1.3 x 10-7, 1.4 x 10-7, 1.5 x 10-7, 1.6 x 10-7, 1.7 x 10-7, 1.8 x 10-7, 1.9 x 10-7, 1.95 x 10-7, 2 x 10-7, 2.5 x 10-7, 3 x 10-7, 3.5 x 10-7, 4 x 10-7, 4.5 x 10-7, 5 x 10-7, 6 x 10-7, 7 x 10-7, 8 x 10-7, 9 x 10-7, as measured by ELISA or any other suitable method known in the art.

[00151] In some embodiments, the KD of the Fc fragment provided here for FcRn binding at a pH of 6.0 is approximately 1.0-1.1 x 10⁻⁵M, 1.1-1.2 x 10⁻⁵M, 1.2-1.3 x 10⁻⁵M, 1.3-1.4 x 10⁻⁵M, 1.4-1.5 x 10⁻⁵M, 1.5-1.6 x 10⁻⁵M, 1.6-1.7 x 10⁻⁵M, 1.7-1.8 x 10⁻⁵M, 1.8-1.9 x 10⁻⁵M, 1.9-2 x 10⁻⁵M, 1-2 x 10⁻⁵M, 1-5 x 10⁻⁵M, 2-7 x 10⁻⁵M, 3-8 x 10-5M, 3-5 x 10-5M, 4-6 x 10-5M, 5-7 x 10-5M, 6-8 x 10-5M, 7-9 x 10-5M, 7-9.9 x 10-5M, 5-9.9 x 10-5M, 1.0-1.1 x 10-6M, 1.1-1.2 x 10-6M, 1.2-1.3 x 10-6M, 1.3-1.4 x 10-6M, 1.4-1.5 x 10-6M, 1.5-1.6 x 10-6M, 1.6-1.7 x 10-6M, 1.7-1.8 x 10-6M, 1.8-1.9 x 10-6M, 1.9-2 x 10-6M, 1-2 x 10-6M, 1-5 x 10-6M, 2-7 x 10-6M, 3-8 x 10-6M, 3-5 x 10-6M, 4-6 x 10-6M, 5-7 x 10-6 Petition 870250086042, dated 09 / 23 / 2025, page 56 / 126 49 / 89 M, 6-8 x 10 6 M, 7-9 x 106M, 7-9.9 x 10 6 M, 5-9.9 x 10 6 M, 1.0-1.1 x 10 7 M, 1.1-1.2 x 10-7M, 1.2-1.3 x 10-7M, 1.3-1.4 x 10-7M, 1.4-1.5 x 10-7M, 1.5-1.6 x 10-7M, 1.6-1.7 x 10-7M, 1.7-1.8 x 10-7M, 1.8-1.9 x 10-7M, 1.9-2 x 10-7M, 1-2 x 10-7M, 1-5 x 10-7M, 2-7 x 10-7M, 3-8 x 10-7M, 3-5 x 10-7M, 4-6 x 10-7M, 5-7 x 10-7M, 6-8 x 10-7M, 7-9 x 10-7M, 7-9.9 x 10-7M, 5-9.9 x 10-7M, as measured by ELISA or any other suitable method known in the art. In some embodiments, an Fc fragment provided herein binds to FcRn at a pH of 7.4 with a Kd greater than or equal to about 1 x 10-5M, or greater than or equal to about 1 x 10-6M, as measured by ELISA or any other suitable method known in the art.

[00152] In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10 or 11 with a Kd less than or equal to approximately 1 x 10⁻⁸ M, 2 x 10⁻⁸ M, 3 x 10⁻⁸ M, 4 x 10⁻⁸ M, 5 x 10⁻⁸ M, 6 x 10⁻⁸ M, 7 x 10⁻⁸ M, 8 x 10⁻⁸ M, 9 x 10⁻⁸ M, 1 x 10⁻⁹ M, 2 x 10⁻⁹ M, 3 x 10⁻⁹ M, 4 x 10⁻⁹ M, 5 x 10⁻⁹ M, 6 x 10⁻⁹ M, 7 x 10⁻⁹ M, 8 x 10⁻⁹ M, or 9 x 10⁻⁹ M, at a pH of 6.0, as measured by plasmon resonance. surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 12 or 13 with a Kd less than or equal to approximately 1 x 10-8M, 2 x 10-8M, 3 x 10-8M, 4 x 10-8M, 5 x 10-8M, 6 x 10-8M, 7 x 10-8M, 8 x 10-8M, 9 x 10-8M, at a pH of 6.0, as measured by surface plasmon resonance (SPR).In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 14 or 15 with a Kd less than or equal to approximately 1 x 10⁻¹⁰M, 2 x 10⁻¹⁰M, 3 x 10⁻¹⁰M, 4 x 10⁻¹⁰M, 5 x 10⁻¹⁰M, 6 x 10⁻¹⁰M, 7 x 10⁻¹⁰M, 8 x 10⁻¹⁰M, or 9 x 10⁻¹⁰M at pH 6.0, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 16 or 17 with a Kd less than or equal to approximately 1 x 10-9M, 2 x 10-9M, 3 x 10-9M, 4 x 10-9M. Petition 870250086042, dated 09 / 23 / 2025, page 57 / 126 50 / 89 x 1091M, 6 x 1091M, 7 x 109M, 8 x 109M or 9 x 109M, at a pH of 6.0, as measured by surface plasmon resonance (SPR).

[00153] In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 10 or 11 with a Kd greater than or equal to about 1 x 10-7M, 2 x 10-7M, 3 x 10-7M, 4 x 10-7M, 5 x 10-7M, 6 x 10-7M, 7 x 10-7M, 8 x 10-7M or 9 x 10-7M at a pH of 7.4, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 12 or 13 with a Kd greater than or equal to approximately 1 x 10-7M, 2 x 10-7M, 3 x 10-7M, 4 x 10-7M, 5 x 10-7M, 6 x 10-7M, 7 x 10-7M, 8 x 10-7M, 9 x 10-7M, 1 x 10-6M, 2 x 10-6M, 3 x 10-6M, 4 x 10-6M, 5 x 10-6M, 6 x 10-6M, 7 x 10-6M, 8 x 10-6M, or 9 x 10-6M, at a pH of 7.4, as measured by surface plasmon resonance (SPR).In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 14 or 15 with a Kd greater than or equal to approximately 1 x 10-9M, 2 x 10-9M, 3 x 10-9M, 4 x 10-9M, 5 x 10-9M, 6 x 10-9M, 7 x 10-9M, 8 x 10-9M, or 9 x 10-9M, at a pH of 7.4, as measured by surface plasmon resonance (SPR). In some embodiments, the Fc fragment binds to an established FcRn sequence at SEQ ID NO: 16 or 17 with a Kd greater than or equal to approximately 1 x 10-8M, 2 x 10-8M, 3 x 10-8M, 4 x 10-8M, 5 x 10-8M, 6 x 10-8M, 7 x 10-8M, 8 x 10-8M, or 9 x 10-8M, at a pH of 7.4, as measured by surface plasmon resonance (SPR). Fc fragment variant fusion proteins

[00154] In some embodiments, variants of the Fc fragment of the present invention are fused or complexed to various protein, peptide, and antibody fragments.

[00155] In some modalities, a variant of the Fc fragment is fused or complexed to a Fab. In some modalities, a variant of the Fc fragment is merged or complexed to an scFv. In some Petition 870250086042, dated 09 / 23 / 2025, p. 58 / 126 51 / 89 but modalities, a variant of the Fc fragment is fused or complexed to an sdAb. In some modalities, a variant of the Fc fragment is fused or complexed to a VHH. In some modalities, a variant of the Fc fragment is fused or complexed to a VNAR.

[00156] In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding domain. In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding Fab. In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding scFv. In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding sdAb. In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding VHH. In some embodiments, a variant of the Fc fragment is fused or complexed with an albumin-binding VNAR.

[00157] In some forms, a variant of the Fc fragment is fused or complexed with an albumin or its variants.

[00158] In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding domain. In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding Fab. In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding scFv. In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding sdAb. In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding VHH. In some embodiments, a variant of the Fc fragment is fused or complexed with an HSA-binding VNAR. Pharmaceutical Compositions

[00159] The present invention provides compositions comprising Petition 870250086042, dated 09 / 23 / 2025, page 59 / 126 52 / 89 dem the Fc fragments, including pharmaceutical compositions comprising one or more of the Fc fragments described herein with one or more pharmaceutically acceptable excipients. In some embodiments, the composition is sterile. The pharmaceutical compositions generally comprise an effective amount of an Fc fragment.

[00160] These compositions may comprise, in addition to one or more of the Fc fragments described herein, an excipient, carrier, buffer, stabilizer or other pharmaceutically acceptable materials well known to experts in the field. Such materials must be non-toxic and must not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material may depend on the route of administration, for example, oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal.

[00161] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powder or liquid. A tablet may include a solid carrier, such as gelatin, or an excipient. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solutions or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

[00162] For intravenous, cutaneous or subcutaneous injection, or injection at the site of affliction, the active ingredient may be in the form of a parenterally acceptable aqueous solution, free of pyrogens and with adequate pH, isotonicity and stability. Those skilled in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Ringer's Lactate Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included as necessary. Petition 870250086042, dated 09 / 23 / 2025, page 60 / 126 53 / 89

[00163] An Fc fragment intended for administration to an individual may be administered in a therapeutically effective amount or a prophylactically effective amount (as appropriate, although prophylaxis may be considered therapy), sufficient to demonstrate benefit to the individual. The amount actually administered, the rate and timing of administration will depend on the nature and severity of the protein aggregation disease being treated. Prescribing treatment, for example, dosage decisions, etc., is the responsibility of general practitioners and other physicians and normally takes into account the disorder being treated, the individual patient's condition, the site of administration, the method of administration, and other factors known to the professionals. Examples of the techniques and protocols mentioned above can be found in Remington's Pharmaceutical Sciences, 16th edition, Osol, A. (ed), 1980.

[00164] In certain embodiments, the pharmaceutical compositions described herein are formulated for intravenous injection.

[00165] A composition may be administered alone or in combination with other treatments, simultaneously or sequentially, depending on the condition being treated. Methods Preparation Methods

[00166] The Fc fragments described herein can be produced using recombinant methods and compositions, for example, as described in U.S. Patent No. 4,816,567. In one embodiment, an isolated nucleic acid encoding an Fc fragment described herein is provided. This nucleic acid may encode an amino acid sequence comprising an Fc fragment that binds to the FcRn described herein. In a further embodiment, one or more vectors (e.g., expression vectors) comprising these nucleic acids Petition 870250086042, dated 09 / 23 / 2025, page 61 / 126 54 / 89 cos are provided. In one embodiment, the nucleic acid is provided in a multicistronic vector. In a further embodiment, a host cell comprising that nucleic acid is provided. In one of these embodiments, a host cell comprises (e.g., has been transformed with): a vector comprising a nucleic acid encoding an amino acid sequence comprising an Fc fragment described herein. In one embodiment, the host cell is eukaryotic, for example, a Chinese hamster ovary (CHO) cell, or a human embryonic kidney (HEK) cell, or a lymphoid cell (e.g., Y0, NS0, Sp20 cell).In one embodiment, a method is provided for producing an Fc fragment, wherein the method comprises culturing a host cell comprising nucleic acid encoding the Fc fragment, as provided above, under conditions suitable for expression of the Fc fragment and, optionally, recovering the Fc fragment from the host cell (or host cell culture medium).

[00167] For recombinant production of the Fc fragment, the nucleic acid encoding an Fc fragment, for example, as described above, is isolated and inserted into one or more vectors for cloning and / or further expression in a host cell. This nucleic acid can be easily isolated and sequenced using conventional procedures (e.g., using oligonucleotide probes that are capable of specifically binding to genes encoding the Fc fragment).

[00168] When an Fc fragment is recombinantly produced by host cells, the protein in certain embodiments is present in about 30%, about 25%, about 20%, about 15%, about 10%, about 5%, about 4%, about 3%, about 2%, or about 1% or less of the dry weight of the cells. When the Fc fragment is recombinantly produced by the cells Petition 870250086042, dated 09 / 23 / 2025, p. 62 / 126 55 / 89 host squid, the protein, in certain embodiments, is present in the culture medium at about 5 g / l, about 4 g / l, about 3 g / l, about 2 g / l, about 1 g / l, about 750 mg / l, about 500 mg / l, about 250 mg / l, about 100 mg / l, about 50 mg / l, about 10 mg / l or about 1 mg / l or less of the dry weight of the cells.In certain embodiments, the “substantially purified” Fc fragment produced by the methods described herein has a purity level of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, specifically, a purity level of at least about 75%, 80%, 85%, and more specifically, a purity level of at least about 90%, a purity level of at least about 95%, a purity level of at least about 99% or higher, as determined by appropriate methods such as SDS / PAGE analysis, RP-HPLC, SEC, and capillary electrophoresis.

[00169] Suitable host cells for cloning or expression of Fc fragment-encoding vectors include prokaryotic or eukaryotic cells described herein.

[00170] Recombinant host cells, or host cells, are cells that include an exogenous polynucleotide, regardless of the method used for insertion, for example, direct uptake, transduction, f-mating, or other methods known in the art to create recombinant host cells. The exogenous polynucleotide may be maintained as a non-integrated vector, for example, a plasmid, or alternatively, it may be integrated into the host genome. Host cells may include CHO, CHO derivatives, NS0, Sp2O, CV-1, VERO-76, HeLa, HepG2, Per.C6, or BHK.

[00171] For example, Fc fragments can be produced in bac Petition 870250086042, dated 09 / 23 / 2025, page 63 / 126 56 / 89 saturates, particularly when glycosylation and Fc effector function are not required. For expression of Fc fragments and polypeptides in bacteria, see, for example, US Patents Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pages 245-254, describing the expression of Fc fragments in E. coli.) After expression, the Fc fragment can be isolated from the bacterial cell paste in a soluble fraction and can be subsequently purified.

[00172] In addition to prokaryotes, eukaryotic microbes, such as filamentous fungi or yeasts, are suitable hosts for cloning or expression of Fc fragment-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been “humanized,” resulting in the production of an Fc fragment with a partially or fully human glycosylation pattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[00173] Suitable host cells for the expression of glycosylated Fc fragments are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculovirus strains have been identified, which can be used in conjunction with insect cells, particularly for the transfection of Spodoptera frugiperda cells.

[00174] Plant cell cultures can also be used as hosts. See, for example, US Patents Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978 and 6,417,429 (which describe the PLANTIBODIES™ technology for antibody production in transgenic plants).

[00175] Vertebrate cells can also be used as Petition 870250086042, dated 09 / 23 / 2025, page 64 / 126 57 / 89 host cells. For example, mammalian cell lines that are adapted to grow in suspension can be useful. Other examples of useful mammalian host cell lines are SV40-transformed monkey kidney CV1 cell line (COS-7); human embryonic kidney cell line (293 or 293 cells as described, for example, in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM4 cells as described, for example, in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); Canine renal cells (MDCK); buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, for example, in Mather et al., Annals NY Acad. Sci.383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines, such as Y0, NS0, and Sp2 / 0. For a review of specific mammalian host cell lines suitable for production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pages 255-268 (2003).

[00176] In one embodiment, the Fc fragments described herein are produced in stable mammalian cells by a method comprising: transfecting at least one stable mammalian cell with: nucleic acid encoding the Fc fragment, at a predetermined ratio; and expressing the nucleic acid in at least one mammalian cell. In some embodiments, the predetermined nucleic acid ratio is determined in transient transfection experiments. Petition 870250086042, dated 09 / 23 / 2025, page 65 / 126 58 / 89 to determine the relative ratio of input nucleic acids that results in the highest percentage of the Fc fragment in the expressed product.

[00177] In some embodiments, the method for producing a glycosylated Fc fragment in stable mammalian cells is described herein, the method comprising the identification and purification of the desired glycosylated Fc fragment. In certain embodiments, the mammalian cell is selected and cultured under conditions to produce higher percentages of desired glycosylated Fc fragments. In some embodiments, the identification of the desired glycosylated Fc fragment is performed by one or both liquid chromatography and mass spectrometry techniques.

[00178] If necessary, the Fc fragment can be purified or isolated after expression. Proteins can be isolated or purified in various ways known to those skilled in the art. Standard purification methods include chromatographic techniques, including ion exchange, hydrophobic interaction, affinity, scaling or gel filtration, and reverse phase, performed at atmospheric pressure or at high pressure using systems such as FPLC and HPLC. Purification methods also include electrophoretic, immunological, precipitation, dialysis, and chromatography techniques. Ultrafiltration and diafiltration techniques, in conjunction with protein concentration, are also useful. As is well known in the art, a variety of natural proteins bind to Fc, and these proteins can find use in the present invention for the purification of Fc fragments. For example, bacterial proteins A and G bind to the Fc region.Purification can often be made possible by a specific fusion partner. For example, antibodies can be purified using glutathione resin if a GST fusion is used, Ni+2 affinity chromatography if a His tag is used, or immobilized anti-flag antibody if a... Petition 870250086042, dated 09 / 23 / 2025, page 66 / 126 59 / 89 label flag for use. For general guidance on proper purification techniques, see, for example, Protein Purification: Principles and Practice, 3rd Ed., Scopes, Springer-Verlag, NY, 1994, incorporated entirely by reference.

[00179] In certain embodiments, the Fc fragment is purified using anion exchange chromatography, including, but not limited to, Q-sepharose, DEAE sepharose, pore HQ, pore DEAF, Toyopearl Q, Toyopearl QAE, Toyopearl DEAE, Resource / Source Q and DEAE, Fractogel Q and DEAE column chromatography.

[00180] In specific embodiments, the proteins described herein are purified using cation exchange chromatography including, but not limited to, SP-sepharose, CM sepharose, HS pores, CM pores, Toyopearl SP, Toyopearl CM, Resource / Source S and CM, Fractogel S and CM columns and their equivalents and comparables.

[00181] Furthermore, the Fc fragments described herein can be chemically synthesized using techniques known in the art (e.g., see Creighton, 1983, Proteins: Structures and Molecular Principles, WH Freeman & Co., NY and Hunkapiller et al., Nature, 310:105111 (1984)). For example, a polypeptide corresponds to a fragment of a polypeptide and can be synthesized using a peptide synthesizer. Additionally, if desired, non-classical amino acids or chemical amino acid analogs can be introduced as a substitution or addition to the polypeptide sequence.Non-classical amino acids include, but are not limited to, the disomers of common amino acids: 2,4-diaminobutyric acid, alpha-aminoisobutyric acid, 4-aminobutyric acid, Abu, 2-aminobutyric acid, γ-Abu, ε-Ahx, 6-aminohexanoic acid, Aib, 2-aminoisobutyric acid, 3-aminopropionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, homocitrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, alanine, fluorine. Petition 870250086042, dated 09 / 23 / 2025, p. 67 / 126 60 / 89 amino acids, synthetic amino acids, such as methyl amino acids, C-methyl amino acids, N-methyl amino acids, and amino acid analogs in general. Furthermore, the amino acid can be D (dextrorotatory) or L (levorotatory). Methods of Use

[00182] In one aspect, the present application provides methods of contacting FcRn with an Fc fragment as described herein, for example, contacting a contemplated Fc fragment in vivo or ex vivo, which results in the inhibition of IgG binding to the FcRn receptor. In some embodiments, FcRn is expressed on the cell surface.

[00183] In one aspect, the present application provides methods of using the isolated Fc fragment described herein for the treatment of a disorder or disease in an individual. In certain aspects, described herein is a method for treating an individual in need thereof with an Fc fragment as described herein, wherein the method comprises administering to a mammalian individual a therapeutically effective amount of an Fc fragment or pharmaceutical composition comprising an Fc fragment described herein. In certain embodiments, the present application provides methods of treating a disorder or disease associated with elevated IgG levels in an individual by administering a described Fc fragment.

[00184] In certain respects, described herein are methods for treating a pathology associated with IgG activity, wherein the method comprises administering to a mammalian individual a therapeutically effective amount of an isolated Fc fragment or a pharmaceutical composition comprising an isolated Fc fragment described herein.

[00185] In certain aspects, described here are methods for treating a pathology associated with elevated FcRn levels in a mammalian individual requiring it, the method comprising admi Petition 870250086042, dated 09 / 23 / 2025, page 68 / 126 61 / 89 administer to the mammalian individual a therapeutically effective amount of an Fc fragment or a pharmaceutical composition described herein.

[00186] In certain aspects, a method is described herein for treating or preventing an antibody-related disorder or disease (for example, an autoimmune disease or a disorder related to an undesirable side effect of a therapeutic antibody) in a mammalian individual in need thereof, wherein the method comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment of any of the embodiments described herein or a pharmaceutical composition described herein. In some embodiments, the inflammatory disorder or disease is an autoimmune disease. In some embodiments, the inflammatory disorder or disease is myasthenia gravis (gMG). In some embodiments, the inflammatory disorder or disease is immune thrombocytopenia (ITP).

[00187] In certain aspects, a method is described here for treating a pathology associated with elevated levels of an IgG in a mammalian individual who requires it, the method comprising administering to the mammalian individual a therapeutically effective amount of the Fc fragment of any of the modalities described herein or of a pharmaceutical composition described herein.

[00188] In certain aspects, a method is described here for reducing the biological activity of an IgG in a mammalian individual who needs it, the method comprising administering to the mammalian individual a therapeutically effective amount of the Fc fragment isolated from any of the modalities described herein or from a pharmaceutical composition described herein.

[00189] In certain aspects, a method of treatment or prevention of autoimmune diseases is described here. In certain modalities, the autoimmune disease is caused by self-reactive antibodies.

[00190] In some modalities, the autoimmune disease is selected Petition 870250086042, dated 09 / 23 / 2025, p. 69 / 126 62 / 89 none of the group consisting of allogeneic islet graft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune adrenal gland diseases, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, autoimmune thrombocytopenia, autoimmune urticaria, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman syndrome, celiac dermatitis, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dermatomyositis, dilated cardiomyopathy, discoid lupus, acquired epidermolysis bullosa, essential mixed cryoglobulinemia, factor VIII deficiency, fibromyalgia, fibromyositis, glomerulonephritis,Graves' disease, Guillain-Barré syndrome, Goodpasture syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura (ITP), IgA neuropathy, IgM polyneuropathies, immune-mediated thrombocytopenia, juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, Ménière's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes mellitus, multifocal motor neuropathy (MMN), myasthenia gravis, paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigus vulgaris, pemphigus foliaceus, pernicious anemia, polyarteritis nodosa, polychondritis, syndromes Polyglandular disorders, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis.sarcoidosis, scleroderma, Sjögren's syndrome, organ transplant rejection, Petition 870250086042, dated 09 / 23 / 2025, page 70 / 126 63 / 89 solid, stiff man syndrome, systemic lupus erythematosus, Takayasu arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, vasculitis due to dermatitis herpetiformis, vasculitis associated with antineutrophil cytoplasmic antibodies, vitiligo, and Wegener's disease granulomatosis. Management and Manufacturing Methods

[00191] In some embodiments, the methods provided herein are useful for the treatment of a disease or disorder in an individual. In one embodiment, the individual is a human and the treatment comprises the administration of an Fc fragment described herein.

[00192] In some modalities, an Fc fragment is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In certain modalities, an Fc fragment is administered intravenously. An effective amount of an Fc fragment can be administered for the treatment of a disease or disorder. The appropriate dosage of the Fc fragment can be determined based on the type of disease or disorder being treated, the type of Fc fragment, the severity and course of the disease or disorder, the individual's clinical condition, medical history, and response to treatment, and at the discretion of the attending physician. EXAMPLES

[00193] Examples of specific embodiments for carrying out the present invention are described below. The examples are presented for illustrative purposes only and are not intended to impose limitations on the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to the numbers used (e.g., quantities, temperature, etc.). Petition 870250086042, dated 09 / 23 / 2025, page 71 / 126 64 / 89 but some experimental errors and deviations must, of course, be taken into account.

[00194] The practice of the present invention will use, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology, within the scope of technical competence. Such techniques are explained in detail in the literature. See, for example, T.E. Creighton, Proteins: Structures and Molecular Properties (W.H. Freeman and Company, 1993); A.L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Sambrook, et al., Molecular Cloning: A Laboratory Manual (2nd edition, 1989); Methods In Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.); Remington's Pharmaceutical Sciences, 18th edition (Easton, Pennsylvania: Mack Publishing Company, 1990); Carey and Sundberg Advanced Organic Chemistry 3rd edition (Plenum Press) Volumes A and B (1992). Methods Gene synthesis and plasmid construction

[00195] The coding sequences for the Fc fragments were generated by DNA synthesis and PCR, subsequently subcloned into a pcDNA3.1-based plasmid for protein expression in mammalian cell systems. The genetic sequences in the expression vectors were confirmed by DNA sequencing. Expression of fragments Fc

[00196] Transient antibody expression was performed using the ExpiCHO™ Expression System (ThermoFisher, Cat. No. A29133). ExpiCHO-S cells were expanded from a working cell bank and passed through ExpiCHO expression medium according to the manufacturer's instructions. Transfection mixtures were prepared following the protocol instructions described in the ExpiCHO-S system manual. (Catalog number A29133, Publication number MAN0014337, Revision D.0). ExpiCHO cells were cultured Petition 870250086042, dated 09 / 23 / 2025, page 72 / 126 65 / 89 for 14 days and harvesting was performed by filtration using 0.22 μm filtration units and DE as a filtration aid (Sartorius, Cat. n° SDLV-0150-05E0-2), after which they were processed immediately. The conditioned medium was harvested for protein purification. Fc fragment purification

[00197] The produced antibodies were captured from clarified supernatants using a 25 ml HiTrap MabSelect PrismA column (Cytiva, Cat. No. 17-5498-54) in an AKTA Pure 25 FPLC system. Column equilibration and protein binding were performed using 20 mM sodium phosphate with 150 mM NaCl at pH 7.4, and protein elution was performed using 100 mM sodium citrate with 150 mM NaCl at pH 3.5. After elution, the peak corresponding to the affinity-purified antibodies was immediately neutralized with 30% 1 M Tris at pH 8.0. To polish the sample and achieve a high-purity monomeric form >95%, protein samples were loaded onto a HiLoad 26 / 600 Superdex 200 pg (Cytiva, Cat. No. 28-9893-36) in an AKTA Pure 25 FPLC system. The fractions corresponding to the monomeric antibody form were collected from a 96-well deep plate into a 50 ml Falcon tube and filtered through a 0.22 μm PES membrane (Fisher brand, Cat.No. 15206869, lot No. 2103171806) in a laminar flow chamber. Protein samples were transferred to 50 kDa MWCO spin concentrators (Amicon 50K Cat. No. UFC905024; lot No. 0000187574) for concentration, and each centrifugation round was 10 minutes at 4000xg, and was repeated until the desired concentration was reached. SEC-HPLC analysis of Fc fragments.

[00198] Analytical SEC-HPLC was performed using the Thermo Vanquish Flex UHPLC system (Thermo Fisher) using a TSKgel Super SW mAb HTP column (4.6 mm x 15.0 cm) (Tosoh Bioscience, Cat. No. 00228559). Approximately 10 μg of sample were carried Petition 870250086042, dated 09 / 23 / 2025, page 73 / 126 66 / 89 cattle. The mobile phase was 200 mM sodium phosphate, 0.05% sodium azide, pH 6.7 with a flow rate of 0.35 ml / min for 10 min, 25 °C. Thermal stability test of proteins by differential scanning fluorimetry (DSF).

[00199] Fc fragments in 20 mM sodium acetate pH 5.5 were loaded into a UNi (Unchained Labs). Samples were subjected to a temperature ramp from 20-95 °C, with a ramp rate of 0.3 °C / minute, and the fluorescence intensity ratio at 330 / 350 nm and SLS at 266 nm as a function of temperature were collected. UNCLE software was used to measure the peak of the 2-derivatives of the fluorescence ratio for the inflection points (Tm) of the transition curves, and the SLS signal at 266 nm as a function of temperature was used to determine Tagg. HIC-HPLC analysis of Fc fragments

[00200] HIC-HPLC was performed using a Proteomix HIC Butyl column with a Proteomix HIC Butyl precolumn, in a Vanquish Flex UHPLC system (ThermoFisher Scientific, MA), using a salt gradient with a flow rate of 0.8 ml / min for 15 min. Detection was performed using a wavelength of 220 nm. Species eluted before the main peak were designated as species with lower hydrophobicity, while species eluted after the main peak were designated as species with higher hydrophobicity. Dynamic Light Scattering (DLS)

[00201] Protein size distribution and molecular size were monitored by dynamic light scattering (DLS) using UNCLE (Unchained Labs), 9 pl of each sample were loaded in triplicate onto the UNI sample holder, and the intensity of the scattered light was measured at 20 °C, 10 acquisitions of 10 s each. Reducing and non-reducing capillary electrophoresis with sodium dodecyl sulfate Petition 870250086042, dated 09 / 23 / 2025, page 74 / 126 67 / 89 (nrCE-SDS and rCE-SDS)

[00202] CE-SDS was performed using LabChip (Perkin Elmer) or Maurice (ProteinSimple, CA). For CE-SDS using LabChip, approximately 2.5 μg of each sample were analyzed using a Protein clear HT chip (cat. no. CLS1486695) under non-reducing and reducing conditions, following the manufacturer's instructions. Reduced samples were treated with β-Mercaptoethanol and non-reduced samples were treated with iodoacetamide (IAM) before analysis. For CE-SDS using Maurice, 25 μg of each sample were analyzed using a CE-SDS cartridge (ProteinSimple, cat. no. PS-MC02-SP) following the manufacturer's instructions. Reduced samples were treated with β-Mercaptoethanol. Differential Scanning Calorimetry (DSC)

[00203] DSC experiments were performed using an automated differential scanning microcalorimeter Microcal PEAQ DSC-DSC (Malvern Panalytical). All solutions and samples used for DSC were filtered using a 0.22 μm filter and degassed before being loaded into the calorimeter. The antibodies used in the DSC studies were >95% monomeric, as assessed by analytical gel filtration chromatography. Prior to DSC analysis, all samples were exhaustively dialyzed (at least three buffer changes) in 20 mM sodium acetate (pH 5.5). The buffer from this dialysis was then used as a reference buffer for subsequent DSC experiments. Before sample measurement, baseline measurements (buffer versus buffer) were obtained to be subtracted from the sample measurement.325 μL of each dialyzed sample (at a concentration of 0.5 mg / ml) were added to the sample well in duplicate, and DSC measurements were performed at a scan rate of 1.5 °C / min. Data analysis and deconvolution were performed using the DSC software provided by fabriPetição 870250086042, dated 23 / 09 / 2025, page 75 / 126. 68 / 89 sing. PEG precipitation test

[00204] PEG precipitation assays were performed similarly to Gibson et al., J. Pharm. 100: 1009-1021 (2011). The addition of increasing amounts of PEG 4000 was used to precipitate the antibody. A 40% PEG stock solution in test buffer was prepared; from this, eight solutions, varying the final percentage of PEG (from 20% to 0%), were prepared in a 96-well plate by 1:1 dilution of the protein samples in a total volume of 100 µl per well. The 96-well plates were incubated overnight at room temperature and then read using a microplate reader measuring the optical density at 320 nm. Capillary isoelectric focusing (clEF)

[00205] This work was conducted on a Maurice system (ProteinSimple, CA), using a clEF ProteinSimple cartridge, cat n° PSMC02-C), according to the manufacturer's instructions. Prior to analysis, samples were diluted in a master mix solution containing a mixture of ampholytes, pl markers, 1% methylcellulose, 12.5% ​​arginine, and 4 M urea. Example 1: Measurement of antibody-FcRn fragment binding kinetics using surface plasmon resonance. A Biacore 8K SPR system (GE Healthcare) equipped with a CM5 sensor chip (Cytiva, Cat. No. 29149603) immobilized with an amine-coupled anti-human Fc-specific antibody was used to determine the binding kinetic rate and affinity constants at 25 °C in a 1xHBS-EP+ pH 6.0 or pH 7.4 running buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% P20 surfactant) (Cytiva, Cat. BR100669).After a stabilization period in running buffer, 20 nM anti-FcRn mAb constructs were captured in flow cell 2 (active) for 60 seconds at a flow rate of 30 µl / min. The recombinant human FcRn protein... Petition 870250086042, dated 09 / 23 / 2025, page 76 / 126 69 / 89 nante, produced internally, was prepared at concentrations of 0, 26, 25, 52.5, 125, 250, and 500 nM and injected into flow cell 1 (reference) and flow cell 2 (active) for 120 seconds at a flow rate of 30 μL / min. Recombinant cynomolgus FcRn protein (Immunitrack, Cat. ITF06-400) was prepared at concentrations of 0, 25, 50, 100, 200, and 400 nM and injected into flow cell 1 (reference) and flow cell 2 (active) for 120 seconds at a flow rate of 30 μL / min. Samples were injected in multiple cycles onto freshly captured mAb, regenerating the capture surfaces with injection of 10 mM glycine pH 1.5 for 30 seconds at a flow rate of 30 μL / min. Data were processed and analyzed using Biacore Insight Evaluation Software version 2.0.15.12933 (GE Healthcare) as follows. Responses from flow cell 1 (reference) were subtracted from responses from flow cell 2 (active).The responses from the two blank buffer injections were then subtracted from the subtracted reference data (2-1) to produce doubly referenced data, which were fitted to a 1:1 linkage model to determine the apparent association constant (ka) and dissociation rate constant (kd). The ratio of these provided the apparent equilibrium dissociation constant or affinity constant (KD = kd / ka). Table 1. Binding kinetics of FcRn from different species and variants of Fc fragments at pH 6 and pH 7.4 mAb ID HuFcRn KD (M) cinoFcRn KD (M) mouse KD_FcRn (M) rat KD_FcRn (M) pH 6.0 pH 7.4 pH 6.0 pH 7.4 pH 6 pH 7.4 pH 6 pH 7.4 hIgG1 wt Control PAL020002 7.4E7* 3.3E7* 7.2E-8* 6.8E8* 8.80 E-09 2.39E07 3.97E08 1.37E06 2.69E- 10 2.80E09 3.71E- 09 1.23 E-08 Petition 870250086042, dated 09 / 23 / 2025, page 77 / 126 70 / 89 mAb ID HuFcRn KD (M) cinoFcRn KD (M) mouse FcRn KD (M) rat_FcRn KD (M) pH 6.0 pH 7.4 pH 6.0 pH 7.4 pH 6 pH 7.4 pH 6 pH 7.4 Construct 1 PAL020195 8.05 E-09 2.59E07 3.62E08 1.54E06 1.82E- 10 2.55E09 3.50E09 1.18 E-08 Construct 2 PAL020196 6.62 E-09 1.69E- 07 2.86E08 7.25E07 1.43E- 10 1.53E- 09 3.49E09 1.15 E-08 Construction 3 PAL020197 6.74 E-09 2.10E-07 2.89E08 9.48E07 1.72E-10 2.38E09 4.25E09 1.49 E-08 Construction 4 PAL020198 8.41 E-09 2.69E07 3.86E08 1.70E-06 2.48E-10 4.05E09 2.90E09 1.47 E-08 Construction 5 PAL020200 7.15 E-09 1.66E-07 3.01E-08 9.00E07 1.94E-10 2.83E09 5.41E-09 1.73 E-08 Construct 6 PAL020202 9.53 E-09 2.48E07 4.17E-08 1.37E-06 2.00E-10 2.73E09 4.33E09 1.62 E-08 Construct 7 PAL020203 8.26 E-09 2.49E07 3.61E-08 1.60E-06 2.88E-10 2.34E09 3.94E09 1.24 E-08 PAL020204 7.64 E-08 2.91E-07 6.08E08 1.43E-06 ndPAL020205 5.31 E-08 3.71E-07 4.72E08 1.68E-06 PAL020206 6.83 E-08 2.93E07 6.21E-08 2.19E-06 PAL020207 5.87 E-08 2.62E07 5.12E-08 2.11E-06 PAL020208 8.04 E-08 2.52E07 1.25E-06 1.43E-06. Petition 870250086042, dated 09 / 23 / 2025, p. 78 / 126 71 / 89 mAb id 3.72E07 1.55E- 06 *The kinetic values ​​were adapted from a reference doi.org / 10.1080 / 19420862.2015.1008353 Example 2: Blocking the binding of IgG and PAL02-0002 to human FcRn by ELISA.

[00206] The ability of the 7 constructs to block the binding of IgG and PAL02-0002, which is Efgartigimod without the C-terminal lysine, to human FcRn was measured by an ELISA assay. A competitive binding ELISA assay was used to screen molecules that prevent IgG binding to the internal recombinant human FcRn protein at pH 6.0. Candidate therapies prevent FcRn from binding to IgG antibodies in the acidic endosomal environment of pH 6.0. In this assay, functional huFcRn were coated at 2.0 pg / ml in 1xPBS in 96-well microtiter plates and then used in an ELISA assay to determine the IC50 concentrations of triple-serial diluted test articles, starting at 100 nM down to 0.002 nM at pH 6.0 in the presence of 0.568 nM of biotinylated human IgG1. The binding of biotinylated human IgG1 was revealed using ExtrAvidin-HRP (Sigma, Cat n° E2886-1ML) at a dilution of 1:5000.IC50 values ​​were calculated using GraphPad Prism 7 software applying a non-linear regression (curve fitting) of log(antagonist) vs. response - variable slope (four parameters). The Fc fragments that were therapeutic candidates were expected to efficiently inhibit the ability of human IgG1 to bind to FcRn. A similar procedure using biotinylated PAL02-0002 to replace biotinylated human IgG1 was performed to block PAL02-0002. Petition 870250086042, dated 09 / 23 / 2025, page 79 / 126 72 / 89

[00207] As shown in Table 2, constructs 1-7 were particularly effective in blocking IgG binding to FcRn. Notably, constructs 1-6 had IC50 values ​​that are half the EC50 value of Efigartigimod and, in particular, construct 3 had an IC50 value >3.5 times lower than that of Efigartigimod. Table 2. Blocking of IgG and PAL02-0002 binding to human FcRn by ELISA. IC50 construct for IgG blockade in triplicate (nM) IC50 for Egartigimod inhibition (nM) Wild-type Fc (PAL02-0001) ND ND Control (PAL02-0002) 2.85 4.82 Construct 1 (PAL020195) 1.31 4.09 Construct 2 (PAL020196) 1.48 5.03 Construct 3 (PAL020197) 0.77 4.59 Construct 4 (PAL020198) 1.51 6.47 Construct 5 (PAL020200) 1.41 3.73 Construct 6 (PAL020202) 1.13 4.71 Construct 7 (PAL020203) 2.09 3.85 PAL02-0204 30.31 nd PAL02-0205 8.45 PAL02-0206 10.21 PAL02-0207 6.91 PAL02-0208 7.98 PAL02-0209 5.18 Example 3. Characterization of variants of the Fc fragment that are Petition 870250086042, dated 09 / 23 / 2025, page 80 / 126 73 / 89 connect to FcRn

[00208] SEC-HPLC, HIC-HPLC analyses and thermostability measurements of the FcRn constructions were performed as described in the Method section described herein.

[00209] Dynamic light scattering (DLS), non-reducing capillary electrophoresis of sodium dodecyl sulfate (nrCE-SDS) and reducing capillary electrophoresis of sodium dodecyl sulfate (rCE-SDS) were performed as described in the Method section described herein. Table 3. Characterization of variants of the Fc fragment that binds gamma to FcRn. Sample ID Title Size Hydrophobicity Thermostability Size SEC-HPLC HICHPLC DSF / SLS DLS NR CESDS R CESDS (mg / l) TA (min) Peak Width (min) TA (min) Tm (°C) Tagg (°C) PDI Diameter Mode (nm) % of peak mass Monomer (%) Purity (%) PAL02-0001 of wild type 72.93 10.09 0.22 4.77 68.2 79.4 0.04 6.4 100 98.35 98.8 7 Control (PAL020002) 155.6 4 10.07 0.21 7.97 59.4 76.9 0.03 6.6 100 98.77 98.3 7 Construct 1 (PAL020195) 133.8 3 10.07 0.24 8.49 58.4 74.5 0.02 6.6 100 98.67 98.0 2 Construct 2 (PAL020196) 130.8 3 9.92 0.26 8.77 58.9 74 0.06 7.4 100 98.54 98.1 7 Petition 870250086042, dated 09 / 23 / 2025, page 81 / 126 74 / 89 Sample ID Title Size Hydrophobicity Thermostability Size SEC-HPLC HICHPLC DSF / SLS DLS NR CESDS R CESDS (mg / l) TA (min) Peak Width (min) TA (min) Tm (°C) Tagg (°C) PDI Diameter Mode (nm) Peak mass % Monomer (%) Purity (%) Construct 3 (PAL020197) 112.7 8 10.05 0.24 7.86 59.7 76.6 0.03 6.4 100 98.78 98.6 7 Construct 4 (PAL020198) 71.43 9.99 0.22 9.08 57.8 70.9 0.08 6.6 100 98.82 99.6 Construct 5 (PAL020200) 86.47 10.16 0.25 8.24 59.6 72.7 0.07 6.6 100 99.23 98.8 9 Construct 6 (PAL020202) 168.4 2 10.09 0.22 8.38 59.2 74.7 0.04 6.7 100 98.88 98.7 6 Construct 7 (PAL020203) 70.68 10.04 0.23 9.04 58.5 72.1 0.05 6.8 100 100 100 Range 70.7 168.4 9.9 10.2 0.2 0.3 4.8 - 9.1 57.8 - 68.2 70.9 79.4 6.4 - 7.4 98.4 100.0 98.0 100.0 Example 4. Summary of Fc variants Development study

[00210] The SEC-HPLC analysis was performed as described in the Method section described here.

[00211] Dynamic light scattering (DLS), differential scanning calorimetry (DSC) and PEG precipitation assay were performed as described in the Method section described herein. Petition 870250086042, dated 09 / 23 / 2025, page 82 / 126 75 / 89

[00212] All samples showed high monomer purity (>99%) before and after 3 freeze / thaw cycles. DLS analysis showed the expected hydrodynamic diameter and low to intermediate polydispersity (PDI <0.2) for all samples. Only the wild type (PAL02-0001) showed a TM value above 65 °C. Most of the remaining samples showed a TM between 60-63 °C. Table 4. Characterization of FcRn constructs SEC-HPLC DLS DSC Precipitation assay PEG Sample ID Concentration (mg / ml) % Monomer % HMWS Average Diameter Z (nm) Diameter of Peak Mode 1 (nm) PDI Peak Mass 1 (%) Tmi (°C) CH2 Tm2 (°C) CH3 % PEG resulting in increase of A320n m T0 3xFT T0 3xF T T0 3xF T T0 3xF T T0 3xF T T0 3xF T Wild type PAL020001 2.0 100.0 100.0 0.0 0.0 6.4 6.5 6.5 6.3 0.09 0.14 100. 0 100. 0 68.5 84.8 20 Control (PAL020002) 2.0 99.0 99.0 1.0 1.0 6.6 6.5 6.8 0.04 0.07 100.0 100, 0 60.7 83.5 20 Construct 1 (PAL020195) 2.0 99.1 99.1 0.9 0.9 6.6 6.6 6.8 6.4 0.04 0.08 100.0 100.0 60.0 80.8 18 Construct 2 (PAL020196) 2.0 100.0 99.5 0.0 0.5 6.9 7.0 6.8 6.8 0.14 0.08 100.0 100.0 59.9 81.1 16 Construct 3 (PAL020197) 2.0 99.5 99.5 0.5 0.5 6.5 6.2 6.5 6.3 0.07 0.06 100.0 100.0 60.6 83.8 18 Construct 4 (PAL020198) 2.0 99.5 99.6 0.5 0.4 6.8 6.2 6.8 6.3 0.05 0.09 100.0 100.0 59.5 80.5 16 Construct 5 (PAL020200) 2.0 100.0 100.0 0.0 0.0 6.6 6.4 6.7 6.0 0.06 0.15 100.0 100.0 60.5 83.3 16 Petition 870250086042, dated 09 / 23 / 2025, page 83 / 126 76 / 89 SEC-HPLC DLS DSC Precipitation assay PEG Sample ID Concentration (mg / ml) % Monomer % HMWS Average Diameter Z (nm) Diameter Peak Mode 1 (nm) PDI Peak Mass 1 (%) Tmi (°C) CH2 Tm2 (°C) CH3 % of PEG resulting in an increase in A320n m T0 3xFT T0 3xF T T0 3xF T T0 3xF T T0 3xF T T0 3xF T Construct 6 (PAL020202) 2.0 99.6 99.6 0.4 0.4 6.6 6.4 6.5 6.3 0.05 0.11 100.0 100.0 60.5 83.2 16 Construct 7 (PAL020203) 2.0 100.0 100.0 0.0 0.0 6.4 6.5 6.8 6.4 0.16 0.11 99.9 100.0 59.7 80.5 16 Example 5. Short-term stability of Fc variants

[00213] The short-term stability of Constructs 1-7 was tested in comparison with wild-type Fc and PAL02-0002 at a concentration of 10 mg / ml, at 40 °C, in 20 mM sodium acetate pH 5.5. SEC-HPLC analysis was performed as described in the Method section described here. Dynamic light scattering (DLS), non-reducing capillary electrophoresis of sodium dodecyl sulfate (nrCE-SDS), reducing capillary electrophoresis of sodium dodecyl sulfate (nrCE-SDS), and capillary isoelectric focusing (cIEF) were performed as described in the Method section described here. Table 5. Short-term stability of Fc variants Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF % Monomer % Monomer % HC % Main Peak Average Diameter Z (nm) Mode Diameter Peak 1 (nm) Mass of Peak 1 (%) PDI % Main Peak % Acid Species % Basic Species % Main Peak Decrease Petition 870250086042, dated 09 / 23 / 2025, page 84 / 126 77 / 89 Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF Wild type T0 100 97.5 97.9 6.5 6.4 100 0.0 7 70 24.5 5.5 -12.6 Wild type _T3days 100 97.7 97.9 6.4 6.3 99.9 0.0 7 69.4 24.7 5.9 Wild type T1week 100 97.4 97.7 6.4 6.5 100 0.0 3 66.8 26.6 6.6 Wild type T2week s 100 97.6 97.5 6.5 6.7 100 0.0 2 57.4 34 8.6 PAL020002 _T0 99.22 98.2 97.5 7.2 7.2 100 0.0 5 69.5 23.6 6.9 -13.3 PAL020002 _T3days 99.17 98.2 97.5 7.2 7.4 100 0.0 7 68.5 24.3 7.2 PAL020002 T1week 99.14 97.8 97.4 7.1 7.4 100 0.0 5 62.9 28 9.1 PAL020002 T2week s 99.06 97.9 97.3 7.2 7.1 100 0.0 8 56.2 33.9 9.9 Construct 1 PAL02- 0195_T0 99.26 97.8 97.1 6.8 6.8 100 0.0 3 63.8 30.4 5.8 -10.5 Construct 1 PAL020195_T3 days 99.16 97.4 96.8 6.9 6.7 100 0.0 7 61.9 32 6.1 Construct 1 PAL020195_T1 week 99.15 97.5 96.9 7 6.9 100 0.0 5 57.7 34 8.3 Petition 870250086042, dated 09 / 23 / 2025, p. 85 / 126 78 / 89 Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF Construct 1 PAL020195_T2 weeks 99.06 97 96.3 7.1 7.3 100 0.0 3 53.3 39.4 7.3 Construct 2 PAL02-0196_T0 99.46 98.1 97.3 10.1 10.7 100 0.0 9 74.9 18.8 6.3 -14.9 Construct 2 PAL020196_T3 days 99.39 98 97.3 10.1 10.2 100 0.0 9 73.9 19 7.1 Construct 2 PAL020196_T1 week 99.3 97.7 97.2 10.4 11.5 100 0.0 9 66.8 23.9 9.3 Constructor 2 PAL020196_T2 weeks 99.23 97.5 96.8 10.2 10.8 100 0.0 9 60 30.3 9.7 Constructor 3 PAL02-0197_T0 99.7 98 97.6 6.9 6.7 100 0.0 5 70.7 23.4 5.9 -13.8 Constructor 3 PAL020197_T3 days 99.54 98 97.5 6.7 6.9 100 0.0 3 68 25.7 6.3 Constructor 3 PAL020197_T1 week 99.76 97.8 97.4 6.6 6.8 100 0.0 4 65.3 26.9 7.8 Petition 870250086042, dated 09 / 23 / 2025, page 86 / 126 79 / 89 Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF Construct 3 PAL020197_T2 weeks 99.34 97.8 97.2 6.7 6.8 100 0.0 4 56.9 34.5 8.6 Construct 4 PAL02- 0198_T0 100 98.2 98.3 6.9 7.2 100 0.0 4 72.8 24.5 2.7 -13.2 Construct 4 PAL020198_T3 days 99.33 97.7 98.2 7 6.9 100 0.0 4 70.3 26.1 3.6 Construct 4 PAL020198_T1 week 99.03 97.7 96.8 7 7.1 100 0.0 5 66.8 29.6 3.6 Construct 4 PAL020198_T2 weeks 98.85 97.7 97.7 6.9 7.1 100 0.0 5 59.6 36.1 4.3 Construct 5 PAL02-0200_T0 99.62 98.6 97.7 6.7 6.8 100 0.0 6 68.5 25.9 5.6 -12 Construct 5 PAL020200_T3 days 99.57 95.9 97.7 6.7 6.9 100 0.0 3 67.2 27.1 5.7 Construct 5 PAL020200_T1 week 99.62 98.2 97.5 6.9 7.2 100 0.0 3 63.3 30.5 6.2 Petition 870250086042, dated 09 / 23 / 2025, page 87 / 126 80 / 89 Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF Construct 5 PAL020200_T2 weeks 99.57 98.2 97.2 7 7.2 100 0.0 4 56.5 35.3 8.2 Construct 6 PAL02- 0202_T0 99.72 98.3 98 6.9 7 100 0.0 4 72.2 22.3 5.5 -12.9 Construct 6 PAL020202_T3 days 99.71 98 97.9 6.8 7.1 100 0.0 4 70.9 22.5 6.6 Construct 6 PAL020202_T1 week 99.71 98.1 96.8 7 7 100 0.0 6 66.3 26.2 7.5 Construct 6 PAL020202_T2 weeks 99.46 97.8 97.7 7.3 7.6 100 0.0 5 59.3 32 8.7 Construct 7 PAL02-0203_T0 100 98.2 97.7 7.7 7.6 100 0.0 8 66.5 27.7 5.8 -11.8 Construct 7 PAL020203_T3 days 100 98.3 97.9 7.6 7.8 100 0.0 5 64.2 29.2 6.6 Construct 7 PAL020203_T1 week 99.66 98.1 97.6 7.7 7.8 100 0.0 6 59.9 32.2 7.9 Petition 870250086042, dated 09 / 23 / 2025, page 88 / 126 81 / 89 Sample ID SECHPLC NR CESDS R CE- SDS DLS cIEF Construct 7 PAL020203_T2 weeks 99.63 98 97.4 7.7 8 100 0.0 5 54.7 36.3 9 INFORMAL LISTING OF SEQUENCES Identifier Description Amino acid sequence Fc of human IgG1 WT (PAL020001) (SEQ ID NO: 1) Human IGH1 (221-446) DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG Fc of human IgG2 WT (SEQ ID NO: 24) Human IGHG2 (222-446) VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG WT human IgG4 Fc (SEQ ID NO: 25) human IGHG4 (224-446) PPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEK TISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG Petition 870250086042, dated 09 / 23 / 2025, page 89 / 126 82 / 89 Identifier Description Amino acid sequence Control PAL020002 (SEQ ID NO: 2) hIgG1_Fc_ M252Y / S2 54T / T256E / H433K / N4 34F DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG Construct 1 PAL020195 (SEQ ID NO: 3) Fc_M252Y / S254T / T2 56E / M428 L / H433K / N 434F of IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALKFHYTQKSLSLSPG Construct 2 PAL020196 (SEQ ID NO: 4) Fc_M252Y / S254T / T2 56E / M428 L / H433K / N 434Y of IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSSCSVLHEALKYHYTQKSLSLSLSPG Petition 870250086042, dated 09 / 23 / 2025, pp. 90 / 126 83 / 89 Identifier Description Amino acid sequence Construct 3 PAL020197 (SEQ ID NO: 5) Fc_M252Y / S254T / T2 56E / H433 K / N434Y of IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKYHYTQKSLSLSPG Construct 4 PAL020198 (SEQ ID NO: 6) Fc_M252Y / S254T / T2 IgG1 56E / M428 L / N434F DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHFHYTQKSLSLSPG Construct 5 PAL020200 (SEQ ID NO: 7) IgG1 Fc_M252Y / S254T / T2 56E / H433 R / N434Y DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALRYHYTQKSLSLSPG Petition 870250086042, dated 09 / 23 / 2025, pp. 91 / 126 84 / 89 Identifier Description Amino acid sequence Construct 6 PAL020202 (SEQ ID NO: 8) Fc_M252Y / S254T / T2 56E / H433 R / N434F of IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALRFHYTQKSLSLSPG Construct 7 PAL020203 (SEQ ID NO: 9) Fc_M252Y / S254T / T2 IgG1 56E / M428 L / H433R / N 434F DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALRFHYTQKSLSLSPG PAL020204 (SEQ ID NO: 18) IgG1 Fc_M252Y / S254T / T2 56E / L309D / H433K / N4 34F DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG Petition 870250086042, dated 09 / 23 / 2025, pp. 92 / 126 85 / 89 Identificador Descripción Sequência de aminoacidos PAL020205 (SEQ ID NO: 19) Fc_M252Y / S254T / T2 56E / L309D / H433K / N4 34Y de IgG1 DKTHTCPPCPAPELLGGPSVFLFPPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKYHYTQKSLSLSPG PAL020206 (SEQ ID NO: 20) Fc_M252Y / S254T / T2 56E / L309D / M428L / H4 33K / N434F de IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALKFHYTQKSLSLSPG PAL020207 (SEQ ID NO: 21) Fc_M252Y / S254T / T2 56E / L309D / M428L / H4 33K / N434 Y de IgG1 DKTHTCPPCPAPELLGGPSVFLFPKPKPDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALKYHYTQKSLSLSPG Petition 870250086042, dated 09 / 23 / 2025, pp. 93 / 126 86 / 89 Identificador Descrição Sequência de aminoácidos PAL020208 (SEQ ID NO: 22) Fc_M252Y / S254T / T2 56E / L309D / Q311K / H4 33K / N434F de IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHKDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG PAL020209 (SEQ ID NO: 23) Fc_M252Y / S254T / T2 56E / L309D / Q311K / H4 33K / N434 Y de IgG1 DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVDHKDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKYHYTQKSLSLSPG Sequência de Antígenos (SEQ ID NO: 10) P55899 Receptor FcRn de subunidade grande p51 de IgG humana FCGRNMGVPRPQPWALGLLLFLLPGSLGAESHLSLLYHLTAVSSPAPGTPAFWVSGWLGPQQYLSYNSLRGEAEPCGAWVWENQVSWYWEKETTDLRIKEKLFLEAFKALGGKGPYTLQGLLGCELGPDNTSVPTAKFALNGEEFMNFDLKQGTWGGDWPEALAISQRWQQQDKAANKELTFLLFSC PHRLREHLERGRGNLEWKEPPSMRLKARPSSPGFSVLTCSAFSFYPPELQLRFLRNGLAAGTGQGDFGPNSDGSFHASSSLTVKSGDEHHYCCIVQHAGLAQPLRVELESPAKSSVLVVGIVIGVLLLTAAAVGGALLWRRMRSGLPAPWISLRGDDTGVLLPTPGEAQDADLKDVNVIPATA Petition 870250086042, dated 09 / 23 / 2025, pp. 94 / 126 87 / 89 Identifier Description Amino acid sequence Antigen sequence (SEQ ID NO: 11) P61769 B2MG_HU MAN Beta-2 microglobulin MSRSVALAVLALLSLSGLEAIQRTPKIQVYSRHPAENGKSNFLNCYVSGFHPSDIEVDLLKNGERIEKVEHSDLSFSKDWSFYLLYYTEFTPTEKDEYACRVNHVTLSQPKIVKWDRDM Antigen sequence (SEQ ID NO: 12) Q8SPV9 IgG p51 large subunit FcRN receptor FCGRN_M ACFA MRVPRPQPWALGLLLFLLPGSLGAESHLSLLYHLTAVSSPAPGTPAFWVSGWLGPQQYLSYDSLRGQAEPCGAWVWENQVSWYWEKETTDLRIKEKLFLEAFKALGGKGPYTLQGLLGCELSPDNTSVPTAKFALNGEEFMNFDLKQGTWGGDWPEALAISQRWQQQDKAANKELTFLLFSCPHRLREHLERGRGNLEWKEPPSMRLKARPGNPGFSVLTCSAFSFYPPELQLRFLRNGMAAGTGQGDFGPNSDGSFHASSSLTVKSGDEHHYCCIVQHAGLAQPLRVELETPAKSSVLVVGIVIGVLLLTAAAVGGALLWRRMRSGLPAPWISLRGDDTGSLLPTPGEAQDADSKDINVIPATA Antigen Sequence (SEQ ID NO: 13) Q8SPW0 Beta-2 microglobulin B2MG_MA CFA MSPSVALAVLALLSLSGLEAIQRTPKIQVYSRHPPENGKPNFLNCYVSGFHPSDIEVDLLKNGEKMGKVEHSDLSFSKDWSFYLLYYTEFTPNEKDEYACRVNHVTLSGPRTVKWDRDM Petition 870250086042, dated 09 / 23 / 2025, pp. 95 / 126 88 / 89 Identifier Description Amino acid sequence Antigen sequence (SEQ ID NO: 14) Q61559 IgG p51 large subunit FcRN receptor FCGRN_M OUSE MGMPLPWALSLLLVLLPQTWGSETRPPLMYHLTAVSNPSTGLPSFWATGWLGPQQYLTYNSLRQEADPCGAWMWENQVSWYWEKETTDLKSKEQLFLEALKTLEKILNGTYTLQGLLGCELASDNSSVPTAVFALNGEEFMKFNPRIGNWTGEWPETEIVANLWMKQPDAARKESEFLLNSC PERLLGHLERGRRNLEWKEPPSMRLKARPGNSGSSVLTCAAFSFYPPELKFRFLRNGLASGSGNCSTGPNGDGSFHAWSLLEVKRGDEHHYQCQVEHEGLAQPLTVDLDSSARSSVPVVGIVLGLLLVVVAIAGGVLLWGRMRSGLPAPWLSLSGDDSGDLLPGGNLPPEAEPQGANAFPATS Antigen Sequence (SEQ ID NO: 15) P01887 Beta-2microglobulin B2MG_MO USE MARSVTLVFLVLVSLTGLYAIQKTPQIQVYSRHPPENGKPNILNCYVTQFHPPHIEIQMLKNGKKIPKVEMSDMSFSKDWSFYILAHTEFTPTETDTYACRVKHASMAEPKTVYWDRDM Petition 870250086042, dated 09 / 23 / 2025, pp. 96 / 126 89 / 89 Identifier Description Amino acid sequence Antigen sequence (SEQ ID NO: 16) P13599.1 FcRn receptor large subunit p51 of Fc FCGRN_R AT MGMSQPGVLLSLLLVLLPQTWGAEPRLPLMYHLAAVSDLSTGLPSFWATGWLGAQQYLTYNNLRQEADPCGAWIWENQVSWYWEKETTDLKSKEQLFLAIRTLENQINGTFTLQGLLGCELAPDNSSLPTAV FALNGEEFMRFNPRTGNWSGEWPETDIVGNLWMKQPEAARKESEFLLTSCPERLLGHLERGRQNLEWKEPPSMRLKARPGNSSVLTCAAFSFYPPELKFRFLRNGLASGNCSTGPNGDGSFHAWSLLE- VKRGDEHHYQCQVEHEGLAQPLTVDLDSPARSSVPVVGIILGLLVVVAIAGGVLLWNRMRSGLPAPWLSSGDDSGDLLPGGNLPPEAEPQGVNAFPATS Antigen Sequence (SEQ ID NO: 17) P07151 Beta-2microglo Bulina B2MGRA T MARSVTVIFLVLVSLAVVLAIQKTPQIQVYSRHPPENGKPNFLNCYVSQFHPPQIEIELLKNGKKIPNIEMSDLSFSKDWSFYILAHTEFTPTETDVYACRVKHVTLKEPKTVTWDRDM Efgartigimode (SEQ ID NO: 26) hIg_F MG25_G25 / SYc 54T / T256E / H433K / N4 34F DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEWKFNWYVDGVEVHNACTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPPGK. Petition 870250086042, of 23 / 09 / 2025, p. 97 / 126

Claims

1 / 13 CLAIMS 1. Isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of humans, cynomolgus, mice or rats, characterized in that it comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises at least one amino acid substitution selected from M428L, H433R, H433K and N434Y.

2. Isolated Fc fragment, according to claim 1, characterized in that it comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254 and 256 of SEQ ID NO:

1.

3. Isolated Fc fragment, according to claim 2, characterized in that the additional amino acid substitutions are M252Y, S254T and / or T256E.

4. Isolated Fc fragment, according to claim 1, characterized in that the variant comprises amino acid substitutions of M252Y, S254T, T256E, M428L, H433K and N434F or M252Y, S254T, T256E, H433K and N434Y.

5. Isolated Fc fragment, according to claim 4, characterized in that the variant comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433K and N434F.

6. Isolated Fc fragment, according to claim 5, characterized in that the variant comprises the amino acid sequence of SEQ ID NO:

3.

7. Isolated Fc fragment, according to claim 4, characterized in that the variant comprises amino acid substitutions of M252Y, S254T, T256E, H433K and N434Y.

8. Isolated Fc fragment, according to claim 7, characterized in that the variant comprises the amino acid sequence of Petition 870250086042, dated 09 / 23 / 2025, page 98 / 126 2 / 13 SEQ ID NO:

5.

9. Isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of humans, cynomolgus, mice or rats, characterized in that it comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an amino acid substitution at position 428.

10. Isolated Fc fragment, according to claim 9, characterized in that the amino acid substitution is M428L.

11. Isolated Fc fragment, according to claim 9 or 10, characterized in that it comprises additional amino acid substitutions at one or more of the positions of amino acids 252, 254, 256, 433 and 434 of SEQ ID NO:

1.

12. Isolated Fc fragment, according to claim 11, characterized in that the additional amino acid substitutions are M252Y, S254T, T256E, H433K, H433R, N434F and / or N434Y.

13. Isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of humans, cynomolgus, mice or rats, characterized in that it comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an H433R amino acid substitution.

14. Isolated Fc fragment, according to claim 13, characterized in that it comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 428 and 434 of SEQ ID NO:

1.

15. Isolated Fc fragment, according to claim 14, characterized in that one or more additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F and / or N434Y.

16. Isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of humans, cynomolgus, mice or rats, characterized in that it comprises: a variant of the amino acid sequence established in SEQ ID NO: 1, wherein the variant comprises an N434Y amino acid substitution.

17. Isolated Fc fragment, according to claim 16, characterized in that it comprises additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 428 and 433 of SEQ ID NO:

1.

18. Isolated Fc fragment, according to claim 17, characterized in that additional amino acid substitutions are M252Y, S254T, T256E, M428L, H433K and / or H433R.

19. Isolated Fc fragment that binds to the neonatal Fc receptor (FcRn) of humans, cynomolgus, mice or rats, characterized in that it comprises: a variant of the amino acid sequence presented in SEQ ID NO: 1, wherein the variant comprises an H433K amino acid substitution and additional amino acid substitutions at one or more of the amino acid positions 252, 254, 256, 428 and 434.

20. Isolated Fc fragment, according to claim 19, characterized in that additional amino acid substitutions are M252Y, S254T, T256E, M428L, N434F and / or N434Y.

21. Isolated Fc fragment, according to any of the preceding claims, characterized in that it comprises a sequence selected from any of the SEQ ID Nos: 3-9.

22. Isolated Fc fragment, according to any one of claims 1 to 16, characterized in that it blocks or reduces the natural recycling of antibodies.

23. Isolated Fc fragment, according to claim 22, characterized in that it results in increased catabolism of a pathogenic antibody.

24. Isolated Fc fragment, according to claim 23, characterized in that the pathogenic antibody is an antibody that is associated with an autoimmune disease.

25. Isolated Fc fragment, according to any one of claims 1 to 24, characterized in that it binds to a human, cynomolgus, mouse or rat FcRn with a lower KD at pH 6.0 compared to an Fc fragment comprising a wild-type Fc region and a measurable KD at pH 7.

4.

26. Isolated Fc fragment, according to any one of claims 1 to 25, characterized in that it binds to an established FcRn sequence in SEQ ID NOs: 10-17 with a Kd less than or equal to about 1 x 10-8 M, at a pH of 6.0, as measured by surface plasmon resonance (SPR).

27. Isolated Fc fragment, according to claim 26, characterized in that it binds to an established FcRn sequence in SEQ ID NOs: 10-17 with a Kd less than or equal to about 1, 2, 3, 4, 5, 6, 7, 8 or 9 x 10-9 M at about a pH 6.0, as measured by surface plasmon resonance (SPR).

28. Isolated Fc fragment, according to any one of claims 1 to 27, characterized in that it exhibits a melting temperature greater than 55 °C, measured by Differential Scanning Fluorometry (DSF).

29. Isolated Fc fragment, according to any one of claims 1 to 28, characterized in that it exhibits an aggregation temperature equal to or greater than 70 °C, measured by Differential Scanning Fluorometry (DSF).

30. Isolated Fc fragment, according to any one of claims 1 to 29, characterized in that it is for use in the treatment of a disorder or disease related to an antibody.

31. Isolated Fc fragment, according to claim 30, characterized in that it is for use in the treatment of an autoimmune disease.

32. Isolated Fc fragment, according to claim 30 or 31, characterized in that it is for use in the treatment of a disease or disorder selected from the group consisting of: generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorders (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris and cutaneous lupus erythematosus.

33. Isolated Fc fragment, according to claim 32, characterized in that the treatment reduces disease severity in a patient and in that disease severity is assessed by a gMG disease severity outcome measure.

34. Isolated polynucleotide or polynucleotide set, characterized in that they encode the isolated Fc fragment, as defined in any of the preceding claims, and optionally, wherein the polynucleotide or polynucleotide set comprises mRNA or cDNA.

35. Vector or set of vectors, characterized in that it comprises the polynucleotide or set of polynucleotides, Petition 870250086042, dated 09 / 23 / 2025, page 102 / 126 6 / 13 as defined in claim 34.

36. Host cell, characterized in that it comprises the polynucleotide or set of polynucleotides, as defined in claim 34, or the vector or set of vectors, as defined in claim 35.

37. Method for producing an Fc fragment, characterized in that it comprises expressing the Fc fragment within the host cell, as defined in claim 36, and isolating the expressed Fc fragment.

38. Pharmaceutical composition, characterized in that it comprises the isolated Fc fragment, as defined in any one of claims 1 to 33, and a pharmaceutically acceptable excipient.

39. A method for treating a disorder or disease in a mammalian individual requiring such treatment, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the isolated Fc fragment, as defined in any one of claims 1 to 33, or a pharmaceutical composition, as defined in claim 33.

40. Method according to claim 39, characterized in that the disease or disorder is selected from the group consisting of: generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorders (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris, and cutaneous lupus erythematosus. Petition 870250086042, dated 09 / 23 / 2025, p. 103 / 126 7 / 13 41. Method according to claim 40, characterized in that the disorder or disease is gMG.

42. A method according to claim 41, characterized in that it reduces the severity of the disease in a patient and in that the severity of the disease is assessed by a gMG disease severity outcome measure.

43. A method for treating a pathology associated with elevated levels of an IgG in a mammalian individual in need thereof, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the isolated Fc fragment, as defined in any one of claims 1 to 33, or a pharmaceutical composition, as defined in claim 38.

44. Method for reducing the biological activity of an IgG in a mammalian individual in need thereof, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the isolated Fc fragment, as defined in any one of claims 1 to 33, or a pharmaceutical composition, as defined in claim 38.

45. Method, according to claim 44, characterized in that the disease is an autoimmune disease.

46. ​​Method for preventing a disorder in a mammalian individual requiring the same, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the isolated Fc fragment, as defined in any one of claims 1 to 33, or a pharmaceutical composition, as defined in claim 38; wherein the disorder is an undesirable side effect of a therapeutic antibody.

47. Variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), characterized by the fact that it comprises the substitution of amino acids M428L and N434F compared to an amino acid sequence established in SEQ ID NO:

1.

48. Variant of the Fc fragment, according to claim 47, characterized in that the Fc fragment further comprises an amino acid substitution of H433K or H433R.

49. Variant of the Fc fragment, according to claim 47, characterized in that the Fc fragment further comprises amino acid substitutions of H433K and N434F.

50. Variant of the Fc fragment, according to claim 47, characterized in that the Fc fragment further comprises amino acid substitutions of H433R and N434F.

51. Variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), characterized in that it comprises amino acid substitutions (i) N434Y and (ii) H433R or H433K compared to an amino acid sequence established in SEQ ID NO:

1.

52. Variant of the Fc fragment, according to claim 51, characterized in that the Fc fragment comprises amino acid substitutions of H433K and N434Y.

53. Variant of the Fc fragment, according to claim 51, characterized in that the Fc fragment comprises amino acid substitutions of H433R and N434Y.

54. Variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), characterized by the fact that it comprises M428L and N434Y amino acid substitutions compared to an amino acid sequence established in SEQ ID NO:

1.

55. Variant of the Fc fragment, according to claim 54, characterized in that the Fc fragment further comprises an amino acid substitution of H433K.

56. Variant of the Fc fragment that binds to the Fc receptor (FcRn), characterized in that it comprises M428L and H433R amino acid substitutions compared to an amino acid sequence established in SEQ ID NO:

1.

57. Variant of the Fc fragment, according to claim 56, characterized in that the Fc fragment further comprises an N434Y amino acid substitution.

58. Variant of the Fc fragment that binds to the neonatal Fc receptor (FcRn), characterized by the fact that it comprises H433R and H434F amino acid substitutions compared to an amino acid sequence established in SEQ ID NO:

1.

59. Variant of the Fc fragment, according to any one of claims 47 to 58, characterized in that the Fc fragment further comprises amino acid substitutions of M252Y, S254T and T256E.

60. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433K and N434F.

61. Variant of the Fc fragment, according to claim 60, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

3.

62. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433K and N434Y.

63. Variant of the Fc fragment, according to claim 62, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

4.

64. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises M252Y, S254T, T256E, H433K and N434Y amino acid substitutions.

65. Variant of the Fc fragment, according to claim 64, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

5.

66. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L and N434F.

67. Variant of the Fc fragment, according to claim 66, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

6.

68. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, H433R and N434Y.

69. Variant of the Fc fragment, according to claim 68, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

7.

70. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, H433R and N434F.

71. Variant of the Fc fragment, according to claim 70, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

8.

72. Variant of the Fc fragment, according to claim 59, characterized in that the Fc fragment comprises amino acid substitutions M252Y, S254T, T256E, M428L, H433R and N434F.

73. Variant of the Fc fragment, according to claim 72, characterized in that the Fc fragment comprises an amino acid sequence of SEQ ID NO:

9. Petition 870250086042, dated 09 / 23 / 2025, pp. 107 / 126 11 / 13 74. Variant of the Fc fragment, according to any one of claims 47 to 73, characterized in that it does not comprise an amino substitution of L309D.

75. Variant of the Fc fragment, characterized in that it is at least 85%, 90%, 93%, 95%, 97% or 99% identical to: SEQ ID NO: 3, provided that such variant comprises the amino acid substitutions of M252Y, S254T, T256E, M428L, H433K and N434F; SEQ ID NO: 4 provided that such variant comprises the amino acid substitutions of M252Y, S254T, T256E, M428L, H433K and N434Y; SEQ ID NO: 5 provided that such variant comprises the amino acid substitutions of M252Y, S254T, T256E, H433K and N434Y; SEQ ID NO: 6 provided that such variant includes amino acid substitutions of S254T, T256E, M428L and N434F; SEQ ID NO: 7 provided that such variant includes amino acid substitutions of M252Y, S254T, T256E, H433R and N434Y; SEQ ID NO: 8 provided that such variant includes amino acid substitutions of M252Y, S254T, T256E, H433R and N434F; or SEQ ID NO: 9, provided that such variant includes amino acid substitutions of M252Y, S254T, T256E, M428L, H433R and N434F.

76. Variant of the Fc fragment, according to claim 75, characterized in that it inhibits an IgG from binding to human FcRn with an IC50 value less than 2.5 nM, 2.0 nM, 1.5 nM or 1.0 nM.

77. Variant of the Fc fragment, according to claim 76, characterized in that it inhibits an IgG from binding to human FcRn at pH 6.

0. Petition 870250086042, dated 09 / 23 / 2025, pp. 108 / 126 12 / 13 78. Variant of the Fc fragment, according to any one of claims 47 to 77, characterized in that the Fc fragment is fused or complexed to a half-life extension domain.

79. Variant of the Fc fragment, according to claim 78, characterized in that the half-length domain is an albumin, an albumin-binding domain, or an HSA-binding domain.

80. Method for inhibiting the binding of an IgG to FcRn, characterized in that it comprises administering the variant of the Fc fragment, as defined in any one of claims 47 to 79.

81. A method for treating a disorder or disease in a mammalian individual requiring such treatment, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment variant, as defined in any one of claims 47 to 79.

82. Method according to claim 81, characterized in that the disease or disorder is selected from the group consisting of: generalized myasthenia gravis (gMG), chronic inflammatory demyelinating polyneuropathy, myositis, autoimmune encephalitis, myelin oligodendrocyte glycoprotein antibody disorders (MOG antibody disorder), membranous nephropathy, lupus nephritis, thyroid eye disease, warm autoimmune hemolytic anemia, hemolytic disease of the fetus and newborn, idiopathic thrombocytopenic purpura, primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, bullous pemphigoid, pemphigus foliaceus, pemphigus vulgaris, and cutaneous lupus erythematosus.

83. Method according to claim 82, characterized in that the disease or disorder is gMG.

84. The method, according to claim 83, is characterized by the fact that it reduces the severity of the disease in a patient and in that the severity of the disease is assessed by a gMG disease severity outcome measure.

85. Method for treating a pathology associated with elevated levels of an IgG in a mammalian individual in need thereof, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment variant, as defined in any one of claims 47 to 79.

86. Method for reducing the biological activity of an IgG in a mammalian individual in need thereof, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment variant, as defined in any one of claims 47 to 79.

87. Method, according to claim 86, characterized in that the disease is an autoimmune disease.

88. Method for preventing a disorder in a mammalian individual requiring the same, characterized in that it comprises administering to the mammalian individual a therapeutically effective amount of the Fc fragment variant, as defined in any one of claims 47 to 79; wherein the disorder is an undesirable side effect of a therapeutic antibody. Petition 870250086042, dated 23 / 09 / 2025, pp. 110 / 126