MULTIFUNCTIONAL FcRn ANTAGONISTS AND USES THEREOF

Abstract

The present disclosure provides a protein comprising a target binding domain that specifically binds to a soluble molecule associated with inflammation; and a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

Description

[0001] MULTIFUNCTIONAL FcRn ANTAGONISTS AND USES THEREOF

[0002] RELATED APPLICATION DATA

[0003] The present application claims priority from Australian Provisional Patent Application No. 2024901841 filed 17 June 2024, entitled “Multifunctional FcRn antagonists and uses thereof’. The entire contents of this application are hereby incorporated by reference.

[0004] SEQUENCE LISTING

[0005] The present application is filed together with a Sequence Listing in electronic form. The entire contents of the Sequence Listing is hereby incorporated by reference.

[0006] FIELD

[0007] The present disclosure provides a protein comprising a target binding domain that specifically binds to a soluble molecule associated with inflammation; and a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

[0008] BACKGROUND

[0009] Inflammation is initiated as a defensive response by the host triggered by injury, infection and / or other inflammatory stimuli.

[0010] Autoimmune diseases result when the immune system reacts to one or more self antigens often resulting in inflammation and damage to the body’s own tissues. A hallmark of many autoimmune diseases is the generation of pathogenic self-reactive antibodies or autoantibodies. Currently, some autoimmune diseases are treated with an intravenous infusion of pooled IgG (IVIg) from human donors. As many of these autoimmune diseases are chronic, afflicted individuals may require repeated administrations of IVIg and / or other suitable therapies in order to manage their disease. Alternatively, patients are treated with antibodies directed towards a specific inflammatory target. For example, adalimumab (sold as Humira®) is one of the top selling anti-TNFa therapeutics currently used to treat autoimmune and inflammatory conditions, such as rheumatoid arthritis and uveitis.

[0011] However, a common side effect of therapies targeting the immune system is the generation of anti-drug antibodies. The formation of anti-drug antibodies against a biotherapeutic can result in adverse effects during a patient’s treatment, such as an increased clearance rate and hypersensitivity to the drug. In addition, anti-drug antibodies can impact the pharmacodynamics and pharmacokinetics of the target drug, thereby reducing the drug’s efficacy.

[0012] Another setting in which inflammation and unwanted antibodies are generated is the transplant setting where the transplant recipient generates an anti-donor inflammatory response, including the development of anti-donor antibodies, which can lead to the rejection of the transplanted donor tissue.

[0013] Thus, there is a need in the art for the development of improved therapeutics for use in treating inflammatory, autoimmune conditions, transplant indications and for patients who have developed anti-drug antibodies.

[0014] SUMMARY

[0015] In work leading up to the present disclosure, the inventors recognized the need for improved therapies for inflammatory and autoimmune diseases. In producing the present invention, the inventors sought to develop multifunctional antagonists that antagonize the binding of IgG to FcRn and a soluble mediator of inflammatory disease. The inventors modified the Fc domain of an immunoglobulin (e.g., an IgGl or IgG4) with ‘YPY’ or ‘YEY’ mutations to enhance binding to FcRn both at neutral and acidic pH, thereby acting to block and antagonise recycling of endogenous IgG, including that of autoantibodies. The inventors found that by conjugating the modified Fc with a target binding domain of soluble mediators of inflammation or autoimmunity (including Factor XU / XIIa, complement C2 / C2b and Interleukin 6), a reduction in both autoantibodies and the activity of inflammatory mediators is achieved.

[0016] Based on the foregoing, the present disclosure provides a multifunctional FcRn antagonist. For example, the present disclosure provides a protein comprising a target binding domain and a modified Fc domain from an immunoglobulin.

[0017] Accordingly, the present disclosure provides a protein comprising:

[0018] (i) a target binding domain, wherein the target binding domain specifically binds to a soluble molecule associated with inflammation; and

[0019] (ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

[0020] In one example, the target binding domain containing protein is: (i) a single chain Fv fragment (scFv);

[0021] (ii) a dimeric scFv (di-scFv);

[0022] (iii) a nanobody;

[0023] (iv) a minibody;

[0024] (v) a diabody;

[0025] (vi) a triabody;

[0026] (vii) a tetrabody;

[0027] (viii) a Fab;

[0028] (ix) a F(ab’)2;

[0029] (x) a Fv

[0030] (xi) a lipocalin;

[0031] (xii) an anticalin;

[0032] (xiii)a soluble receptor;

[0033] (xiv)a T-cell receptor;

[0034] (xv) an adnectin;

[0035] (xvi)an affibody;

[0036] (xvii) an avimer; or

[0037] (xviii) a designed ankyrin repeat protein (DARPin).

[0038] In one example, the soluble receptor comprises or consists of an extracellular domain of a cell surface receptor. For example, a cytokine receptor extracellular domain.

[0039] In one example, the target binding domain is a target binding domain containing protein. In one example, the target binding domain is an antigen binding domain of an antibody.

[0040] In one example, the target binding domain comprises at least a VH and a VL, wherein the VH and VL bind to form a Fv comprising a target binding domain. For example, the target binding domain is:

[0041] (i) a single chain Fv fragment (scFv);

[0042] (ii) a dimeric scFv (di-scFv).

[0043] (iii) a diabody;

[0044] (iv) a triabody;

[0045] (v) a tetrabody;

[0046] (vi) a Fab;

[0047] (vii) a F(ab’)2; or

[0048] (viii) a Fv.

[0049] In one example, the protein is an antibody, for example, a monoclonal antibody. In one example, the antibody is a naked antibody. In one example, a protein (or antibody) is chimeric, de-immunized, humanized, human or primatized.

[0050] In one example, the protein or antibody is human.

[0051] The present disclosure provides an antibody comprising:

[0052] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0053] (ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

[0054] In one example, on administering the protein or antibody to a subject, binding of the target binding domain to the soluble molecule causes a reduction in a level of the soluble molecule in circulation of the subject and / or binding of the modified IgG Fc to FcRn causes reduced circulating Fc-containing proteins and / or antibodies in the subject.

[0055] It will be apparent to the skilled person from the disclosure herein that the protein or antibody of the disclosure is a multifunctional FcRn antagonist.

[0056] In one example, the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of

[0057] (i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system;

[0058] (ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system;

[0059] (iii) alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system;

[0060] (iv) tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system,

[0061] (v) glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system;

[0062] (vi) proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system;

[0063] (vii) glycine substituted for proline at a position corresponding to amino acid 329 according to the EU numbering system;

[0064] (viii) tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and

[0065] (ix) combinations thereof. In one example, the modified Fc region comprises alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system.

[0066] In one example, the modified Fc region comprises alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system.

[0067] In one example, the modified Fc region comprises alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

[0068] In one example, the modified Fc region comprises tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system.

[0069] In one example, the modified Fc region comprises glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system.

[0070] In one example, the modified Fc region comprises proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system.

[0071] In one example, the modified Fc region comprises glycine substituted for proline at a position corresponding to amino acid 329 according to the EU numbering system.

[0072] In one example, the modified Fc region comprises tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0073] In one example, the modified Fc region comprises:

[0074] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0075] (ii) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0076] In one example, the modified Fc region additionally comprises:

[0077] (i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system; or (ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

[0078] In one example, the modified Fc region comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0079] In one example, the modified Fc region comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0080] In one example, the modified Fc region additionally comprises alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

[0081] In one example, the modified Fc region additionally comprises alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

[0082] The present disclosure provides an antibody comprising:

[0083] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0084] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0085] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0086] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0087] The present disclosure provides an antibody comprising:

[0088] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0089] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0090] The present disclosure provides an antibody comprising:

[0091] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0092] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0093] In one example of any protein or antibody described herein, the target binding domain specifically binds to the soluble molecule at neutral and acidic pH.

[0094] In one example of any protein or antibody described herein, the target binding domain specifically binds and inhibits the soluble molecule.

[0095] In one example of any protein or antibody described herein, the soluble molecule is selected from the group consisting of a B-lymphocyte stimulator (BLyS), a complement component, a cytokine, a chemokine, an enzyme, a coagulation factor and combinations thereof.

[0096] In one example, the soluble molecule is a BLyS. In one example, the soluble molecule is a complement component. For example, a complement C2 and / or C2b, complement C5, albumin and / or complement Clq. In one example, the complement component is a complement C2 and / or C2b.

[0097] In one example, the soluble molecule is a cytokine. For example, a tumor necrosis factor (TNF), such as TNF-alpha, interleukin 6 (IL-6), IL-13, IL-5, IL-33, IL-17, IL- Ibeta, IL-23 and / or interferon beta. In one example, the cytokine is IL-6.

[0098] In one example, the soluble molecule is a chemokine.

[0099] In one example, the soluble molecule is an enzyme. For example, the enzyme is a protease. In one example, the protease is urokinase-type plasminogen activator (uPA).

[0100] In one example, the soluble molecule is a coagulation factor. In one example, the coagulation factor is Factor XI or Factor XII, or an activated form thereof. For example, the coagulation factor is Factor XII (FXII) or an activated form thereof (i.e., FXIIa).

[0101] In one example, the soluble molecule is a human soluble molecule.

[0102] In one example, the antibody is a monospecific or a multispecific antibody. For example, the antibody is a monospecific antibody. In another example, the antibody is a multispecific antibody. For example, the multispecific antibody is a bispecific antibody.

[0103] In one example, the target binding domain corresponds to, or is derived from, an antigen binding domain of an antibody selected from the group consisting of adalimumab, belimumab, bimekizumab, golimumab, guselkumab, infliximab, ixekizumab, lebrikizumab, mirikizumab, netakimab, olokizumab, ozoralizumab, risankizumab, secukinumab, siltuximab, sutimlimab, tezepelumab, tildrakizumab, tralokinumab, ustekinumab, vunakizumab, ebdarokimab, xeligekimab, garadacimab, abelacimab, cendakimab, clazakizumab, dazukibart, depemokimab, garetosmab, gefurulimab, itepekimab, pamrevlumab, picankibart, sibeprenlimab, tozorakimab, gumokimab, ziltivekimab, suvemcitug and combinations thereof.

[0104] In one example, the target binding domain comprises the six complementarity determining regions (CDRs) of an antibody selected from the group consisting of adalimumab, belimumab, bimekizumab, golimumab, guselkumab, infliximab, ixekizumab, lebrikizumab, mirikizumab, netakimab, olokizumab, ozoralizumab, risankizumab, secukinumab, siltuximab, sutimlimab, tezepelumab, tildrakizumab, tralokinumab, ustekinumab, vunakizumab, ebdarokimab, xeligekimab, garadacimab, abelacimab, cendakimab, clazakizumab, dazukibart, depemokimab, garetosmab, gefurulimab, itepekimab, pamrevlumab, picankibart, sibeprenlimab, tozorakimab, gumokimab, ziltivekimab, suvemcitug and combinations thereof.

[0105] Methods of determining the CDRs of the above antibodies will be apparent to the skilled person. In one example, the target binding domain corresponds to, or is derived from, a soluble receptor domain of a molecule selected from the group consisting of atacicept, afhbercept, briobacept, conbercept, etanercept, dalantercept, inbakicept, lenercept, luspatercept, olamkicept, opinercept, povetacicept, ramatercept, sotatercept, sozinibercept, telitacicept, tulinercept.

[0106] The present disclosure provides an antibody comprising:

[0107] (i) a target binding domain that specifically binds to a blood soluble molecule selected from the group consisting of: complement component C2 / C2b, Factor Xll / XIIa, urokinase-type plasminogen activator (uPA), interleukin 6 and combinations thereof; and

[0108] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0109] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0110] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0111] The present disclosure provides an antibody comprising:

[0112] (i) a target binding domain that specifically binds to a blood soluble molecule selected from the group consisting of: complement component C2 / C2b, Factor XH / XIIa, urokinase-type plasminogen activator (uPA), interleukin 6 and combinations thereof; and

[0113] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0114] The present disclosure provides an antibody comprising:

[0115] (i) a target binding domain that specifically binds to a blood soluble molecule selected from the group consisting of: complement component C2 / C2b, Factor XH / XIIa, urokinase-type plasminogen activator (uPA), interleukin 6 and combinations thereof; and

[0116] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0117] The present disclosure provides an antibody comprising:

[0118] (i) a target binding domain that specifically binds to a complement component C2 / C2b; and

[0119] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0120] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0121] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0122] The present disclosure provides an antibody comprising:

[0123] (i) a target binding domain that specifically binds to a complement component C2 / C2b; and (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0124] The present disclosure provides an antibody comprising:

[0125] (i) a target binding domain that specifically binds to a complement component C2 / C2b; and

[0126] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0127] In one example, the target binding domain comprises: a light chain variable region (VL) comprising: i. a complementarity determining region (CDR)l comprising a sequence set forth in SEQ ID NO: 91; and ii. a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and iii. a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising: i. a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and ii. a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and iii. a CDR3 comprising a sequence set forth in SEQ ID NO: 96.

[0128] In one example, the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0129] The present disclosure provides an antibody comprising:

[0130] (i) a target binding domain that specifically binds to a Factor XH / XIIa; and

[0131] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0132] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0133] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0134] The present disclosure provides an antibody comprising:

[0135] (i) a target binding domain that specifically binds to a Factor XH / XIIa; and

[0136] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0137] The present disclosure provides an antibody comprising:

[0138] (i) a target binding domain that specifically binds to a Factor XH / XIIa; and

[0139] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0140] In one example, the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9.

[0141] In one example, the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10. In one example, the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0142] The present disclosure provides an antibody comprising:

[0143] (i) a target binding domain that specifically binds to a urokinase-type plasminogen activator (uPA); and

[0144] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0145] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0146] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0147] The present disclosure provides an antibody comprising:

[0148] (i) a target binding domain that specifically binds to a urokinase-type plasminogen activator (uPA); and

[0149] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0150] The present disclosure provides an antibody comprising:

[0151] (i) a target binding domain that specifically binds to a urokinase-type plasminogen activator (uPA); and

[0152] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0153] In one example, the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14.

[0154] In one example, the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0155] The present disclosure provides an antibody comprising:

[0156] (i) a target binding domain that specifically binds to a interleukin 6; and

[0157] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0158] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0159] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0160] The present disclosure provides an antibody comprising:

[0161] (i) a target binding domain that specifically binds to a interleukin 6; and

[0162] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system. The present disclosure provides an antibody comprising:

[0163] (i) a target binding domain that specifically binds to a interleukin 6; and

[0164] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0165] In one example, the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12.

[0166] In one example, the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0167] The present disclosure provides an antibody comprising:

[0168] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0169] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0170] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0171] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0172] (A) a light chain variable region (VL) comprising:

[0173] (i) a complementarity determining region (CDR)l comprising a sequence set forth in SEQ ID NO: 91; and (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and

[0174] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0175] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0176] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0177] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96; or

[0178] (B) a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0179] The present disclosure provides an antibody comprising:

[0180] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0181] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0182] (A) a light chain variable region (VL) comprising:

[0183] (i) a complementarity determining region (CDR)1 comprising a sequence set forth in SEQ ID NO: 91; and

[0184] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and

[0185] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0186] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0187] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0188] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96; or

[0189] (B) a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0190] The present disclosure provides an antibody comprising:

[0191] (i) a target binding domain that specifically binds to complement component C2 / C2b; and (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0192] (A) a light chain variable region (VL) comprising:

[0193] (i) a complementarity determining region (CDR)1 comprising a sequence set forth in SEQ ID NO: 91; and

[0194] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and

[0195] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0196] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0197] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0198] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96; or

[0199] (B) a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0200] The present disclosure provides an antibody comprising:

[0201] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0202] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises: a light chain variable region (VL) comprising:

[0203] (i) a complementarity determining region (CDR)1 comprising a sequence set forth in SEQ ID NO: 91; and

[0204] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and (iii)a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0205] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0206] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0207] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96.

[0208] The present disclosure provides an antibody comprising:

[0209] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0210] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises: a light chain variable region (VL) comprising:

[0211] (i) a complementarity determining region (CDR)1 comprising a sequence set forth in SEQ ID NO: 91; and

[0212] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and

[0213] (iii)a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0214] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0215] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0216] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96.

[0217] The present disclosure provides an antibody comprising:

[0218] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0219] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0220] The present disclosure provides an antibody comprising:

[0221] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0222] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0223] The present disclosure provides an antibody comprising:

[0224] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0225] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0226] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0227] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0228] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9; or (ii) a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10; or

[0229] (iii)a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0230] The present disclosure provides an antibody comprising:

[0231] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0232] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0233] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9; or

[0234] (ii) a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10; or

[0235] (iii)a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0236] The present disclosure provides an antibody comprising:

[0237] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0238] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0239] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9; or (ii) a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10; or

[0240] (iii)a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0241] The present disclosure provides an antibody comprising:

[0242] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0243] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9.

[0244] The present disclosure provides an antibody comprising:

[0245] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0246] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9.

[0247] The present disclosure provides an antibody comprising:

[0248] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0249] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10.

[0250] The present disclosure provides an antibody comprising:

[0251] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0252] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10.

[0253] The present disclosure provides an antibody comprising:

[0254] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0255] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0256] The present disclosure provides an antibody comprising:

[0257] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0258] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0259] The present disclosure provides an antibody comprising:

[0260] (i) a target binding domain that specifically binds to interleukin 6; and

[0261] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0262] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0263] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0264] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12; or

[0265] (ii) a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0266] The present disclosure provides an antibody comprising:

[0267] (i) a target binding domain that specifically binds to interleukin 6; and

[0268] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0269] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12; or

[0270] (ii) a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0271] The present disclosure provides an antibody comprising:

[0272] (i) a target binding domain that specifically binds to interleukin 6; and

[0273] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0274] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12; or

[0275] (ii) a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0276] The present disclosure provides an antibody comprising:

[0277] (i) a target binding domain that specifically binds to interleukin 6; and

[0278] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0279] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12.

[0280] The present disclosure provides an antibody comprising:

[0281] (i) a target binding domain that specifically binds to interleukin 6; and

[0282] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12.

[0283] The present disclosure provides an antibody comprising:

[0284] (i) a target binding domain that specifically binds to interleukin 6; and

[0285] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12.

[0286] The present disclosure provides an antibody comprising:

[0287] (i) a target binding domain that specifically binds to interleukin 6; and (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0288] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0289] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0290] The present disclosure provides an antibody comprising:

[0291] (i) a target binding domain that specifically binds to interleukin 6; and

[0292] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0293] The present disclosure provides an antibody comprising:

[0294] (i) a target binding domain that specifically binds to interleukin 6; and

[0295] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0296] The present disclosure provides an antibody comprising:

[0297] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0298] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0299] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0300] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0301] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14; or

[0302] (ii) a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0303] The present disclosure provides an antibody comprising:

[0304] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0305] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0306] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14; or

[0307] (ii) a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0308] The present disclosure provides an antibody comprising:

[0309] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0310] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises:

[0311] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14; or

[0312] (ii) a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0313] The present disclosure provides an antibody comprising:

[0314] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0315] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0316] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0317] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14.

[0318] The present disclosure provides an antibody comprising:

[0319] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0320] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14.

[0321] The present disclosure provides an antibody comprising:

[0322] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0323] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14.

[0324] The present disclosure provides an antibody comprising:

[0325] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0326] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0327] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0328] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0329] The present disclosure provides an antibody comprising:

[0330] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0331] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0332] The present disclosure provides an antibody comprising: (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0333] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system and wherein the target binding domain comprises a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0334] In one example, the binding affinity of the target binding domain to the soluble molecule at acidic pH is substantially the same as binding at neutral pH or less than binding at neutral pH. In one example, the binding affinity of the target binding domain to the soluble molecule at acidic pH is about 10-, or about 9-, or about 8-, or about 7-, or about 6-, or about 5-, or about 4-, or about 3-, or about 2-fold less, or between 1-2 fold less than binding at neutral pH. In one example, the binding affinity of the target binding domain to the soluble molecule at acidic pH is substantially the same as binding at neutral pH.

[0335] In one example, the target binding domain does not necessarily have a faster dissociation rate from its soluble molecule at acidic pH compared to neutral pH.

[0336] In one example, the target binding domain optionally has a faster dissociation rate from its soluble molecule at acidic pH compared to neutral pH.

[0337] In one example, the modified immunoglobulin Fc region is from an IgGl or an IgG4 constant region. In one example, the modified immunoglobulin Fc region is from an IgGl constant region. For example, the modified immunoglobulin Fc region is a modified IgGl Fc region. In another example, the modified immunoglobulin Fc is from an IgG4 constant region. For example, the modified immunoglobulin Fc region is a modified IgG4 Fc region. In another example, the modified immunoglobulin Fc region is from a stabilized IgG4 constant region. For example, the modified immunoglobulin Fc region is a stabilized modified IgG4 Fc region.

[0338] In one example, the modified Fc has a reduced ability to induce effector function.

[0339] In one example, the binding affinity of the modified Fc to FcRn is measured at neutral and / or acidic pH. For example, the binding affinity of the modified Fc to FcRn is measured at neutral pH. In one example, the binding affinity of the modified Fc to FcRn is measured at acidic pH. In a further example, the binding affinity of the modified Fc to FcRn is measured at neutral and acidic pH.

[0340] In one example, the protein or antibody has a reduced circulating blood plasma half-life compared to a protein or antibody with an unmodified Fc domain. In one example, the protein or antibody does not have an increased circulating blood plasma half-life compared to a protein or antibody with an unmodified Fc domain. For example, protein or antibody has a half-life that is at least about two times or three times or four times or five times shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. For example, the protein or antibody has a half-life that is at least about two times shorter (i.e., half) compared to the half-life of the protein or antibody with an unmodified Fc domain. For example, the protein or antibody has a half-life that is at least about three times shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. For example, the protein or antibody has a half-life that is at least about four times shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. For example, the protein or antibody has a half-life that is at least about five times shorter compared to the half-life of the protein or antibody with an unmodified Fc domain.

[0341] In one example, the protein or antibody has a half-life that is at least 25 hours, 30 hours, 35 hours, 40 hours, 45 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, 75 hours or 80 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 25 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 30 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 35 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 40 hours shorter compared to the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 45 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 50 hours shorter compared to the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 55 hours shorter compared to the halflife of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 60 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 65 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 70 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 75 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has a half-life that is at least 80 hours shorter compared to the half-life of the protein or antibody with an unmodified Fc domain.

[0342] A protein or antibody of the disclosure inhibits or reduces binding of immunoglobulins, e.g., IgG, to a FcRn. For example, administration of the protein or antibody of the disclosure to a subject inhibits or reduces binding of immunoglobulin, e.g., IgG, to FcRn. Such inhibition can be determined using standard methods known in the art, for example, by administering an antibody (a ‘tracer antibody’) to the subject and measuring clearance of the tracer antibody from circulation, wherein increased clearance and / or more rapid clearance of the tracer antibody from circulation compared to the level or rate of clearance in a control subject is indicative of a FcRn antagonist.

[0343] In one example, the protein or antibody has prolonged and / or increased in vivo target inhibition and / or FcRn inhibition compared to a protein or antibody with an unmodified Fc domain. For example, the protein or antibody has prolonged and / or increased in vivo target inhibition compared to a protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has prolonged in vivo target inhibition. In another example, the protein or antibody has increased in vivo target inhibition. In another example, the protein or antibody has prolonged and / or increased in vivo FcRn inhibition compared to a protein or antibody with an unmodified Fc domain. In one example, the protein or antibody has prolonged in vivo FcRn inhibition. In another example, the protein or antibody has increased in vivo FcRn inhibition.

[0344] In one example, the modified Fc is an IgGl Fc further comprises the following amino acid substitutions:

[0345] (i) an alanine substituted for leucine at a position corresponding to amino acid 234 and an alanine substituted for leucine at a position corresponding to amino acid 235; and / or

[0346] (ii) a glycine substituted for a proline at a position corresponding to amino acid 329, wherein the amino acid substitutions are according to the EU numbering system.

[0347] In one example, the modified Fc is indirectly linked to the target binding domain of the antibody via a linker. In one example, the linker is a peptide or polypeptide. For example, the linker is a peptide linker comprising between 2 and 31 amino acids in length. For example, the linker comprises glycine or glycine and serine. For example, the linker comprises one or more repeats of Gly4Ser.

[0348] In one example, the modified Fc is directly linked to the target binding domain of the antibody, e.g., without an intervening linker.

[0349] The present disclosure additionally provides a composition comprising the protein or antibody of the disclosure and a pharmaceutically acceptable carrier.

[0350] The disclosure additionally provides a nucleic acid encoding the protein or antibody of the disclosure. In one example, the nucleic acid is DNA. In another example, the nucleic acid is RNA, including modified forms thereof. In one example, the nucleic acid is linked to nucleic acid required for expression of the protein or antibody.

[0351] The present disclosure provides the protein or antibody of the disclosure for use as a medicament.

[0352] The present disclosure further provides the protein or antibody or composition of the disclosure for use in treating or preventing an inflammatory mediated condition in a subject. The present disclosure further provides a method of treating or preventing an inflammatory mediated condition in a subject, the method comprising administering the protein, or the antibody or the composition of the disclosure. The present disclosure also provides use of the antibody, or the protein in the manufacture of a medicament for treating or preventing an inflammatory mediated condition in a subject.

[0353] The present disclosure further provides the protein or antibody or composition of the disclosure for use in reducing circulating Fc-containing proteins and / or antibodies in a subject in need thereof. The disclosure also provides a method of reducing circulating antibodies in a subject in need thereof, the method comprising administering the protein, or the antibody or the composition of the disclosure. The disclosure further provides use of the antibody or the protein in the manufacture of a medicament for reducing circulating antibodies in a subject in need thereof. In one example, the time over which the level of autoantibodies in the subject is reduced is longer compared to the time over which the level of autoantibodies is reduced in the subject if administered the protein or antibody comprising an unmodified Fc domain.

[0354] In one example, the circulating antibodies are unwanted circulating antibodies. For example, the circulating antibodies are anti-drug antibodies.

[0355] In one example, the subject is suffering from an autoimmune disease, is a transplant recipient and has developed or is at risk of developing anti-donor antibodies, or has developed anti-drug antibodies and / or is at risk of developing anti-drug antibodies.

[0356] In one example, the subject is suffering from an autoimmune disease.

[0357] In one example, the subject is a transplant recipient. In one example, the subject is at risk of developing anti-donor antibodies.

[0358] In one example, the subject has developed anti-drug antibodies.

[0359] In one example, the subject is at risk of developing anti-drug antibodies.

[0360] The disclosure additionally provides a method of reducing circulating anti-drug antibodies in a subject, the method comprising administering the protein or antibody or composition of the disclosure to the subject. In one example, the time over which the level of anti-drug antibodies in the subject is reduced is longer compared to the time over which the level of anti-drug antibodies is reduced in the subject if administered the protein or antibody comprising an unmodified Fc domain.

[0361] The present disclosure also provides the protein or antibody or composition of the disclosure for use in treating or preventing progression of an antibody-mediated disorder in a subject in need thereof. The present disclosure further provides a method of treating or preventing progression of an antibody-mediated disorder in a subject in need thereof, the method comprising administering the protein, or the antibody or the composition of the disclosure. The present disclosure also provides use of the protein or antibody of the disclosure in the manufacture of a medicament for treating or preventing progression of an antibody-mediated disorder in a subject in need thereof.

[0362] The present disclosure further provides a method of reducing anti-donor alloantibodies in a subject who has received a transplant, the method comprising administering the protein or antibody or composition of the disclosure to the subject. In one example, the time over which the level of anti -donor alloantibodies in the subject is reduced is longer compared to the time over which the level of anti-donor alloantibodies is reduced in the subject if administered the protein or antibody comprising an unmodified Fc domain.

[0363] In one example, the time over which the level of antibodies in the subject is reduced is longer compared to the time over which the level of antibodies is reduced in the subject if administered the protein or antibody with an unmodified Fc domain.

[0364] In one example, the subject is suffering from an autoimmune disease, has developed undesirable antibodies and / or is at risk of developing undesirable antibodies. For example, the undesirable antibodies are autoantibodies. In another example, the undesirable antibodies are anti-drug antibodies. In a further example, the undesirable antibodies are alloantibodies.

[0365] In one example, the subject has developed or is at risk of developing anti-drug antibodies.

[0366] In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. For example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% to about 80% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 20% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 30% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 50% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 60% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 70% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 80% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 90% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or antibody reduces endogenous IgG levels within at least 2 days, 3 days, 4, days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 1 day, 2 days, 3 days, 4, days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days of administration. For example, the protein or antibody reduces endogenous IgG levels within 1 to 9 days of administration. For example, the protein or antibody reduces endogenous IgG levels within 2 to 9 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 1 day of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 2 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 3 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 4 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 5 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 6 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 7 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 8 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 9 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 10 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 11 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 12 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 13 days of administration. In one example, the protein or antibody reduces endogenous IgG levels within at least 14 days of administration.

[0367] In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 10% or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%. For example, administration of the protein or antibody reduces endogenous IgG levels by at least about 50% to about 80%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 10% to about 90%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 10%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 20%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 30%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 40%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 50%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 60%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 70%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 80%. In one example, administration of the protein or antibody reduces endogenous IgG levels by at least about 90%.

[0368] In one example, the protein or antibody reduces endogenous IgG levels by at least about 10% or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. For example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% to about 80% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 20% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 30% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% for a period of at least

[0369] 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 50% for a period of at least 3, or at least

[0370] 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 60% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 70% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 80% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 90% for a period of at least 3, or at least 4, or at least 5 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0371] In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 20% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 30% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0372] In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels within at least 1 day of administration. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels within at least 2 days of administration.

[0373] In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduce endogenous IgG levels by at least about 10% or about 20%, or about 30%, for a period of at least 3, or at least 4, or at least 5 days, or 10 days, or 15 days compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduce endogenous IgG levels by at least about 10% for a period of at least 5 days. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of at least 10 days. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of at least 15 days. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least 3 days. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least 5 days. In one example, the target binding domain specifically binds complement component C2 / C2b and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least 2 days.

[0374] In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 20% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 30% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 50% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 60% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0375] In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels within at least 1 day of administration. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels within at least 2 days of administration.

[0376] In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduced endogenous IgG levels by at least about 10% or about 20%, or about 30%, or about 40%, or about 50%, or about 60% for a period of at least 3, or at least 4, or at least 5 days, or 10 days, compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of at least 5 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of about 8 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least 3 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least 4 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least 5 days. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least 3 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least 4 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least 5 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least 2 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least 3 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least 4 days. In one example, the target binding domain specifically binds Factor XH / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least 5 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least 2 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least 3 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least 4 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least 2 days. In one example, the target binding domain specifically binds Factor Xll / XIIa and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least 3 days.

[0377] In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 10% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 20% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 30% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 40% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL- 6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 50% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 60% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least about 70% compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0378] In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels within at least 1 day of administration. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels within at least 2 days of administration.

[0379] In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 10% or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70% for a period of at least 2, or at least 3, or at least 4, or at least 5 days, or 10 days, compared to the level observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of at least 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 10% for a period of about 8 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least

[0380] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 20% for a period of at least

[0381] 4 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduce endogenous IgG levels by at least about 20% for a period of at least

[0382] 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least

[0383] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least

[0384] 4 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 30% for a period of at least

[0385] 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least 2 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least

[0386] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least

[0387] 4 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 40% for a period of at least

[0388] 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0389] 2 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0390] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0391] 4 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0392] 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0393] 6 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0394] 7 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 50% for a period of at least

[0395] 8 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least

[0396] 2 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least

[0397] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least

[0398] 4 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 60% for a period of at least

[0399] 5 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 70% for a period of at least

[0400] 2 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 70% for a period of at least

[0401] 3 days. In one example, the target binding domain specifically binds IL-6 and the protein or antibody reduces endogenous IgG levels by at least about 70% for a period of at least

[0402] 4 days. In one example, the protein or antibody antagonizes IgG recycling. For example, the protein or antibody antagonizes IgG recycling, however, does not significantly, substantially or detectably reduce endogenous levels of the soluble molecule.

[0403] In one example, the protein or antibody does not antagonize albumin recycling.

[0404] In one example, administration of the protein or antibody reduces the volume of distribution (Vss) by a least about 40 mL, 50 mL, 60 mL, 70 mL or 80 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. For example, administration of the protein or antibody reduces the Vss by at least about 40 mL to 80 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the Vss by at least about 40 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the Vss by at least about 50 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the Vss by at least about 60 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the Vss by at least about 70 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the Vss by at least about 80 mL compared to the Vss observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0405] In one example, administration of the protein or antibody reduces the area under the curve (AUC) compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. For example, administration of the protein or antibody reduces the AUC by at least 250 pg / mL*h / mg, 300 pg / mL*h / mg, 350 pg / mL*h / mg, 400 pg / mL*h / mg, 450 pg / mL*h / mg, or 500 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 250 pg / mL*h / mg to 500 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 250 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 300 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 350 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 400 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 450 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain. In one example, administration of the protein or antibody reduces the AUC by at least 500 pg / mL*h / mg compared to the AUC observed following administration of a protein or antibody comprising an unmodified Fc domain.

[0406] In one example, the protein or antibody or the composition is administered at a dose in excess of the therapeutically effective dose. For example, the protein, the antibody or the composition is administered at a dose effective to saturate or block or completely antagonise FcRn.

[0407] In one example, the protein or the antibody is administered to the subject at a dose of at least 1 mg / kg. For example, the protein or antibody is administered to the subject at a dose of between about 1 mg / kg and 100 mg / kg. In one example, the protein or antibody is administered to the subject at a dose of between about 1 mg / kg and 10 mg / kg. In one example, the protein or antibody is administered to the subject at a dose of about 1 mg / kg, or about 2 mg / kg, or about 3 mg / kg, or about 4 mg / kg, or about 5 mg / kg, or about 6 mg / kg, or about 7 mg / kg, or about 8 mg / kg, or about 9 mg / kg, or about 10 mg / kg. In one example, the protein or the antibody is administered to the subject at a dose of at least 10 mg / kg. For example, the protein or antibody is administered to the subject at a dose of between 10 mg / kg and 100 mg / kg. In one example, the protein or antibody is administered to the subject at a dose of about 10 mg / kg, or about 20 mg / kg, or about 30 mg / kg, or about 40 mg / kg, or about 50 mg / kg, or about 60 mg / kg, or about 70 mg / kg, or about 80 mg / kg, or about 90 mg / kg, or about 100 mg / kg. In one example, the protein or antibody is administered to the subject at a dose of about 100 mg / kg.

[0408] In one example, the inflammatory-mediated disorder is selected from the group consisting of Achalasia, Addison’s disease, Adult Still’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, ANCA-associated vasculitis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, anti-phospholipid syndrome, antibody mediated rejection, Antiphospholipid syndrome, atypical haemolytic-uremic syndrome, autoimmune haemolytic anemia, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid (Mucous membrane pemphigoid), Bullous pemphigoid, C3- glomerulonephritis, Castleman disease (CD), Celiac disease, cerebral infarction, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy), Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, delayed graft function, Dense Deposit Disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, glomerulosclerosis, Goodpasture’s syndrome, Granulomatosis with polyangiitis, graft salvage, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis suppurativa (HS) (Acne inversa), Huntington’s disease, IgA nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), ischemia-reperfusion injury, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), motor neuron disease, Mucha-Habermann disease, Multifocal motor neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myelin oligodendrocyte glycoprotein antibody disorder, Myositis, Narcolepsy, Neonatal lupus, nephritides, Nephropathy, IgA nephropathy, Neuromyelitis optica / devic disease, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections), Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Pars planitis (peripheral uveitis), Parkinson’s disease,, Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cholangitis, Primary sclerosing cholangitis, Progesterone dermatitis, Progressive hemifacial atrophy (PHA) Parry romberg syndrome, Psoriasis, Psoriatic arthritis, Pulmonary Alveolar Proteinosis (PAP), Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive arthritis, Relapsing polychondritis, renal scarring, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome or Autoimmune poly endocrine syndrome type II, Scleritis, Scleroderma, Sjogren’s, Stiff person syndrome (SPS), ischemic stroke, somatic trauma, Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis / giant cell arteritis, Thrombocytopenic purpura (TTP), Thrombotic thrombocytopenic purpura (Ttp), Thyroid Eye Disease (TED), Tolosa-Hunt syndrome (THS), transplant rejection, antibody-mediated graft rejection, Transverse myelitis, traumatic brain injury, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt- Koyanagi-Harada disease, Warm autoimmune hemolytic anemia and combinations thereof.

[0409] In one example, the inflammatory-mediated disorder is selected from the group consisting of myasthenia gravis (MG), systemic lupus erythematosus (SLE), autoimmune hemolytic anemia (AIHA), warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), neuromyelitis optica spectrum disorder (NMOSD), neuromyelitis optica (NMO), membranous nephropathy (MN), primary membranous nephropathy (MN), antibody-mediated rejection (AMR), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), bullous pemphigoid (BP), Sjogren's syndrome (SjS), hidradenitis suppurativa (HS), chronic inflammatory demyelinating polyneuropathy (CIDP), immune-mediated necrotizing myopathy (IMNM), anti synthetase syndrome (ASyS), autoimmune myocarditis, multifocal motor neuropathy and combinations thereof.

[0410] In one example, the target binding domain specifically binds to complement component C2 / C2b and the inflammatory-mediated disorder is selected from the group consisting of myasthenia gravis (MG), systemic lupus erythematosus (SLE), autoimmune hemolytic anemia (AIHA), warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), neuromyelitis optica spectrum disorder (NMOSD), neuromyelitis optica (NMO), membranous nephropathy (MN), primary membranous nephropathy (MN), antibody-mediated rejection (AMR), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), bullous pemphigoid (BP), Sjogren's syndrome (SjS), hidradenitis suppurativa (HS), chronic inflammatory demyelinating polyneuropathy (CIDP), immune-mediated necrotizing myopathy (IMNM), anti synthetase syndrome (ASyS), autoimmune myocarditis, multifocal motor neuropathy and combinations thereof.

[0411] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of an inflammatory-mediated disorder selected from the group consisting of myasthenia gravis (MG), systemic lupus erythematosus (SLE), autoimmune hemolytic anemia (AIHA), warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), neuromyelitis optica spectrum disorder (NMOSD), neuromyelitis optica (NMO), membranous nephropathy (MN), primary membranous nephropathy (MN), antibody- mediated rejection (AMR), atypical hemolytic uremic syndrome (aHUS), paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), bullous pemphigoid (BP), Sjogren's syndrome (SjS), hidradenitis suppurativa (HS), chronic inflammatory demyelinating polyneuropathy (CIDP), immune-mediated necrotizing myopathy (IMNM), anti synthetase syndrome (ASyS), autoimmune myocarditis, multifocal motor neuropathy and combinations thereof.

[0412] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of myasthenia gravis (MG). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of systemic lupus erythematosus (SLE). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of autoimmune hemolytic anemia (AIHA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of warm autoimmune hemolytic anemia (wAIHA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of immune thrombocytopenia (ITP), neuromyelitis optica spectrum disorder (NMOSD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of neuromyelitis optica (NMO). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of membranous nephropathy (MN). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of primary membranous nephropathy (MN). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of antibody-mediated rejection (AMR). For example, antibody -mediated graft rejection. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of atypical hemolytic uremic syndrome (aHUS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of paroxysmal nocturnal hemoglobinuria (PNH). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of cold agglutinin disease (CAD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of anti-phospholipid syndrome (APS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of dermatomyositis (DM). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of inclusion body myositis (IBM). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of bullous pemphigoid (BP). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment of Sjogren's syndrome (SjS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of hidradenitis suppurativa (HS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of chronic inflammatory demyelinating polyneuropathy (CIDP). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of immune-mediated necrotizing myopathy (IMNM). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of anti synthetase syndrome (ASyS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of autoimmune myocarditis. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to C2 / C2b is useful in the treatment or prevention of multifocal motor neuropathy.

[0413] In one example, the inflammatory-mediated disorder is selected from the group consisting of systemic lupus erythematosus (SLE), myasthenia gravis (MG), hereditary angioedema (HAE), rheumatoid arthritis (RA), immune thrombocytopenia (ITP), multiple sclerosis (MS), Guillain-Barre syndrome (GBS), chronic spontaneous urticaria (CSU), Graves' disease (GD), Wegener's granulomatosis (WG), anti-phospholipid Syndrome (APS) and combinations thereof.

[0414] In one example, the target binding domain specifically binds to Factor XH / XIIa and the inflammatory-mediated disorder is selected from the group consisting of systemic lupus erythematosus (SLE), myasthenia gravis (MG), hereditary angioedema (HAE), rheumatoid arthritis (RA), immune thrombocytopenia (ITP), multiple sclerosis (MS), Guillain-Barre syndrome (GBS), chronic spontaneous urticaria (CSU), Graves' disease (GD), Wegener's granulomatosis (WG), anti-phospholipid Syndrome (APS) and combinations thereof.

[0415] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor XH / XIIa is useful in the treatment or prevention of an inflammatory-mediated disorder selected from the group consisting of systemic lupus erythematosus (SLE), myasthenia gravis (MG), hereditary angioedema (HAE), rheumatoid arthritis (RA), immune thrombocytopenia (ITP), multiple sclerosis (MS), Guillain-Barre syndrome (GBS), chronic spontaneous urticaria (CSU), Graves' disease (GD), Wegener's granulomatosis (WG), anti-phospholipid Syndrome (APS) and combinations thereof.

[0416] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor XH / XIIa is useful in the treatment or prevention of systemic lupus erythematosus (SLE). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor XH / XIIa is useful in the treatment or prevention of myasthenia gravis (MG). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor XH / XIIa is useful in the treatment or prevention of hereditary angioedema (HAE). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor XH / XIIa is useful in the treatment or prevention of rheumatoid arthritis (RA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of immune thrombocytopenia (ITP). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of multiple sclerosis (MS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of Guillain-Barre syndrome (GBS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of chronic spontaneous urticaria (CSU). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of Graves' disease (GD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of Wegener's granulomatosis (WG). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to Factor Xll / XIIa is useful in the treatment or prevention of anti-phospholipid Syndrome (APS).

[0417] In one example, the inflammatory-mediated disorder is selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), giant cell arteritis (GCA), myocarditis, uveitic macular edema, atherosclerotic cardiovascular disease, antibody -mediated graft rejection, chronic kidney disease (CKD), end stage kidney disease, Sjogren's syndrome (SjS), autoimmune myocarditis, anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), anti synthetase syndrome (ASyS), Warm autoimmune hemolytic anemia (wAIHA) and combinations thereof.

[0418] In one example, the target binding domain specifically binds to IL-6 and the inflammatory-mediated disorder is selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), giant cell arteritis (GCA), myocarditis, uveitic macular edema, atherosclerotic cardiovascular disease, antibody-mediated graft rejection, chronic kidney disease (CKD), end stage kidney disease, Sjogren's syndrome (SjS), autoimmune myocarditis, anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), anti synthetase syndrome (ASyS), Warm autoimmune hemolytic anemia (wAIHA) and combinations thereof. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of an inflammatory-mediated disorder selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), myasthenia gravis (MG), chronic inflammatory demyelinating polyneuropathy (CIDP), psoriasis, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), giant cell arteritis (GCA), myocarditis, uveitic macular edema, atherosclerotic cardiovascular disease, antibody-mediated graft rejection, chronic kidney disease (CKD), end stage kidney disease, Sjogren's syndrome (SjS), autoimmune myocarditis, anti-phospholipid syndrome (APS), dermatomyositis (DM), inclusion body myositis (IBM), anti synthetase syndrome (ASyS), Warm autoimmune hemolytic anemia (wAIHA) and combinations thereof.

[0419] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of rheumatoid arthritis (RA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of systemic lupus erythematosus (SLE). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of myasthenia gravis (MG). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of chronic inflammatory demyelinating polyneuropathy (CIDP). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of psoriasis. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of psoriatic arthritis (PsA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of ankylosing spondylitis (AS).

[0420] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of Crohn's disease (CD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of ulcerative colitis (UC). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of giant cell arteritis (GCA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of myocarditis. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of uveitic macular edema. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of atherosclerotic cardiovascular disease. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of antibody- mediated graft rejection. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of chronic kidney disease (CKD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of end stage kidney disease.

[0421] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of Sj ogren's syndrome (Sj S). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of autoimmune myocarditis. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of anti-phospholipid syndrome (APS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of dermatomyositis (DM). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of inclusion body myositis (IBM). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of anti synthetase syndrome (ASyS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to IL-6 is useful in the treatment or prevention of Warm autoimmune hemolytic anemia (wAIHA).

[0422] In one example, the inflammatory-mediated disorder is selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic pulmonary fibrosis (IPF), diabetic nephropathy (DN), asthma, cystic fibrosis (CF), psoriasis, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), autoimmune myocarditis and combinations thereof.

[0423] In one example, the target binding domain specifically binds to uPA and the inflammatory-mediated disorder is selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic pulmonary fibrosis (IPF), diabetic nephropathy (DN), asthma, cystic fibrosis (CF), psoriasis, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), autoimmune myocarditis and combinations thereof.

[0424] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of an inflammatory-mediated disorder selected from the group consisting of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), idiopathic pulmonary fibrosis (IPF), diabetic nephropathy (DN), asthma, cystic fibrosis (CF), psoriasis, inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), multiple sclerosis (MS), chronic obstructive pulmonary disease (COPD), autoimmune myocarditis and combinations thereof.

[0425] In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of rheumatoid arthritis (RA). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of systemic lupus erythematosus (SLE). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of idiopathic pulmonary fibrosis (IPF). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of diabetic nephropathy (DN). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of asthma. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of cystic fibrosis (CF). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of psoriasis. In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of inflammatory bowel disease (IBD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of Crohn's disease (CD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of ulcerative colitis (UC). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of multiple sclerosis (MS). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of chronic obstructive pulmonary disease (COPD). In one example, the multifunctional FcRn antagonist comprising a target binding domain that specifically binds to uPA is useful in the treatment or prevention of autoimmune myocarditis.

[0426] The disclosure additionally provides a kit for use in reducing circulating autoantibodies in a subject in need thereof, the kit comprising:

[0427] (i) at least one protein or antibody or composition of the disclosure;

[0428] (ii) instructions for using the kit in reducing circulating autoantibodies in the subject; and

[0429] (iii) optionally, at least one additional therapy.

[0430] The disclosure also provides a kit for treating or preventing progression of an antibody-mediated disorder in a subject in need thereof, the kit comprising:

[0431] (i) at least one protein or antibody or composition of the disclosure;

[0432] (ii) instructions for using the kit in treating or preventing progression of an antibody- mediated disorder in the subject; and

[0433] (iii) optionally, at least one additional therapy.

[0434] The disclosure additionally provides a kit for use in reducing anti-donor alloantibodies in a subject in need thereof, the kit comprising:

[0435] (i) at least one protein or antibody or composition of the disclosure;

[0436] (ii) instructions for using the kit in reducing anti-donor alloantibodies in the subject; and

[0437] (iii) optionally, at least one additional therapy.

[0438] In one example, the subject is a human.

[0439] BRIEF DESCRIPTION OF THE DRAWINGS

[0440] Figure 1 is a series of graphical representations showing binding of antibodies to (A) FXIIa, (B) murine IL-6, or (C) murine uPA by ELISA. Antibodies were tested in a 5-fold dilution series with the highest concentration at 200 nM (A) and (B) or 1000 nM (C).

[0441] Figure 2 is a graphical representation showing chromogenic assay showing inhibition of FXIIa activity by anti-FXII / FXIIa multifunctional FcRn antagonist antibodies. Antibodies were diluted in a 5-fold dilution series starting from the highest concentration of 500 nM. Figure 3 is a graphical representation showing anti-FXII / FXIIa multifunctional FcRn antagonist antibodies retain ability to inhibit coagulation. aPTT assays determining coagulation time was measured for human pooled plasma treated with 1 pM final concentration of various antibodies as indicated.

[0442] Figure 4 is a graphical representation showing dose-dependent inhibition of mouse tc-uPA activity. Each data point represents the area under the curve (AUC) for a single replicate reading (n=l). Data points were fitted to a 4-parameter logistic curve fit using GraphPad Prism.

[0443] Figure 5 is a graphical representation showing inhibition of B9 cell proliferation by ALD518-P18 against mouse IL-6 (1 ng / ml) stimulation. Each point represents technical replicates (n=2) and fit using a log(inhibitor) vs response - four parameter logistic (4PL).

[0444] Figure 6 is a graphical representation showing inhibition of human IL-6 stimulation using EEK-BLUE™ E-6 cells. Dose dependent inhibition of secreted embryonic alkaline phosphatase (SEAP) production was observed using the ALD518- P18 antibodies against human E-6 (0.1 ng / ml). Each point represents technical replicates (n=2) and fit using a log(inhibitor) vs response - 4PL.

[0445] Figure 7 is a series of graphical representations showing inhibition of the human complement molecule C2b by the anti-huC2 / C2b multifunctional FcRn antagonist and control antibodies in Wieslab complement assays. Dose dependent inhibition of huC2b was observed by 4D8LC05 both with the [YPY] Fc modification as well as with a WT Fc in (A) the classical and (B) the lectin complement pathway. The alternative pathway (C) was not affected by the addition of 4D8LC05.

[0446] Figure 8 is a graphical representation showing pharmacokinetics of anti- FXEFXIIa multifunctional FcRn antagonist antibodies and respective non- YPY controls and YPY-isotype control after dosing of wild type mice at 30 mg / kg i.v.. n=3 animals were used per timepoint, and the graph shows the geometric mean ± geometric SD.

[0447] Figure 9 is a graphical representation showing pharmacokinetics of the anti-E6 multifunctional FcRn antagonist antibody and its respective non- YPY control after dosing of wild type mice at 30 mg / kg i.v.. n=3 animals were used per timepoint, and the graph shows the geometric mean ± geometric SD.

[0448] Figure 10 is a graphical representation showing impact of anti-FXII / FXIIa multifunctional FcRn antagonist antibodies and respective non-YPY controls and YPY- isotype control on endogenous murine IgG levels after dosing WT mice at 30 mg / kg i.v.. n=3 animals were used per timepoint. Mouse IgG levels were normalised to baseline. Figure 11 is a graphical representation showing impact of anti-IL6 multifunctional FcRn antagonist antibody and respective non-YPY control on endogenous murine IgG levels after dosing WT mice at 30 mg / kg i.v.. n=3 animals were used per timepoint. Mouse IgG levels were normalised to baseline.

[0449] Figure 12 is a graphical representation showing pharmacokinetics of anti huC2 / C2b multifunctional FcRn antagonist antibody (4D8LC05_G4[YPY]) and respective non-YPY control (4D8LC05 G4) after a single intravenous bolus to wild type mice at indicated doses. n=3 animals were used per timepoint, and the graph shows the geometric mean ± geometric SD.

[0450] Figure 13 is a graphical representation showing impact of anti-huC2 / C2b multifunctional FcRn antagonist antibody and respective non-YPY control on endogenous murine IgG levels after dosing wild type mice at indicated concentrations. n=3 animals were used per timepoint. Mouse IgG levels were normalised to baseline.

[0451] Figure 14 is a graphical representation showing pharmacokinetics of anti- huC2 / C2b multifunctional FcRn antagonist antibody and respective non-YPY control after dosing of cynomolgus monkeys at indicated concentrations.

[0452] Figure 15 is a graphical representation showing impact of anti-huC2 / C2b multifunctional FcRn antagonist antibody and respective non-YPY control antibody on endogenous monkey IgG levels after dosing cynomolgus monkeys at indicated concentrations.

[0453] Figure 16 is a graphical representation showing free C2 concentrations after dosing anti-huC2 / C2b multifunctional FcRn antagonist antibody and respective non- YPY control in cynomolgus monkeys at indicated concentrations.

[0454] Figure 17 is a graphical representation Pharmacodynamic analysis of complement pathway inhibition (A) Wieslab assay classical pathway and (B) Wieslab assay lectin pathway, by anti-huC2 / C2b multifunctional FcRn antagonist antibody and respective non-YPY control ex vivo following dosing of cynomolgus monkeys at indicated concentrations.

[0455] Figure 18 is a graphical representation showing pharmacokinetic analysis of anti- uPA multifunctional FcRn antagonists (mUl_G4 and mUl_G4[YPY]) and control antibodies (BM4 G4 and BM4 G1 [YPY]) in wild-type mice by ELISA of human IgG levels after dosing of wild type mice at 30 mg / kg i.v.; n=3 animals were used per timepoint, and the graph shows the geometric mean ± geometric SD. Solid lines present connection of measured mean data, while dashed lines (in combination with an open symbol) are added for visualization of quick elimination of YPY variants, connecting the last measurable value with the first measure below the LLOQ, where a value of LLOQ / 2 was used.

[0456] Figure 19 is a graphical representation showing antagonism of FcRn recycling by anti-uPA multifunctional FcRn antagonists (mUl_G4 and mUl_G4[YPY]) and control antibodies (BM4 G4 and BM4 G1 [YPY]) in wild-type mice by ELISA of endogenous mouse plasma IgG levels after dosing WT mice at 30 mg / kg i.v.; n=3 animals were used per timepoint. Mouse IgG levels were normalised to baseline. The value as well as the error bar of the 240 h timepoint of sample mUl_G4 go beyond 300% (323% to be exact). For ease of visualization of all other data points the maximal value of the x-axis was chosen as 200% and hence 240 h data point of mUl_G4 is not visible.

[0457] Figure 20 is a graphical representation showing pharmacokinetic analysis of anti- FXII / XIIa multifunctional FcRn antagonists (3F7_G4[YEY], 3F7-VR112_G4[YEY]) and control antibodies (BM4_G4[YEY]) in wild-type mice by ELISA of human IgG levels after dosing of wild type mice at 30 mg / kg i.v.; n=3 animals were used per timepoint, and the graph shows the geometric mean ± geometric SDA non- YPY control was omitted as it was already assessed in earlier experiments (e.g. Figure 8). Solid lines present connection of measured mean data, while dashed lines (in combination with an open symbol) are added for visualization of quick elimination of YPY variants, connecting the last measurable value with the first measure below the LLOQ, where a value of LLOQ / 2 was used.

[0458] Figure 21 is a graphical representation showing antagonism of FcRn recycling by anti-FXn / XIIa multifunctional FcRn antagonists (3F7_G4[YEY], 3F7-

[0459] VR112_G4[YEY]) and control antibodies (BM4_G4[YEY]) in wild-type mice by ELISA of endogenous mouse plasma IgG levels after dosing WT mice at 30 mg / kg i.v.; n=3 animals were used per timepoint. Mouse IgG levels were normalised to baseline.. A non-YPY control was omitted as it was already assessed in earlier experiments (e.g. Figure 9).

[0460] Figure 22 is a series of graphical representations showing pharmacodynamic analysis of the Fab part of anti-FXII / XIIa multifunctional FcRn antagonists in wild-type mice by (A) inhibition of FXIIa activity by anti-FXH / FXHa multifunctional FcRn antagonist antibodies with [YPY] and [YEY] Fc modification and wt Fc controls (3F7_G4[YPY], 3F7_G4, 3F7-VR112_G4[YPY], 3F7-VR112_G4, 3F7_G4[YEY], 3F7-VR112_G4[YEY]) after dosing wt mice at 30 mg / kg i.v. and (B) the ability to inhibit coagulation in an aPTT assay.

[0461] Figure 23 is a series of graphical representations showing the impact of FcRn antagonist protein (4D8CL05_G4[YPY]) and control molecules on IgG and albumin recycling following macropinocytosis by BMDM from huFcRn transgenic mice. Data shows intensity for IgG-AF594 (A) or HSA-AF488 (B) signal at 0 and 15 min chase time points in the presence and absence of protease inhibitor (PI). Signal detected in the presence of protease inhibitor at 15 min chase (but not in absence of protease inhibitor) represents lysosomal rescue of protein destined for degradation. Graphs shown are representative of 3 independent experiments where an average fluorescent intensity value was determined from 5 images (each containing 8 or more cells) for each time point. Black line shows estimated mean fluorescence intensity of each FcRn antagonists at the respective timepoint and condition. Length of bar shows min and max values.

[0462] Figure 24 is a graphical representation showing the impact of FcRn antagonist proteins (3F7_G4[YEY] and 3F7_G4[YPY]) and control molecules on IgG recycling following macropinocytosis by BMDM from huFcRn Transgenic mice. Data shows intensity for IgG-AF568 signal at 0 and 15 min chase time points in the presence and absence of protease inhibitor. Signal detected in the presence of protease inhibitor at 15 min chase (but not in absence of protease inhibitor) represents lysosomal rescue of protein destined for degradation. Graphs shown are representative of 2 independent experiments where an average fluorescent intensity value was determined from 5 images (each containing 8 or more cells) for each time point. Black line shows estimated mean fluorescence intensity of each FcRn antagonists at respective timepoint and condition. Length of bar shows min and max values.

[0463] DETAILED DESCRIPTION

[0464] General

[0465] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter.

[0466] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features.

[0467] The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the present disclosure.

[0468] Any example of the present disclosure herein shall be taken to apply mutatis mutandis to any other example of the disclosure unless specifically stated otherwise. Stated another way, any specific example of the present disclosure may be combined with any other specific example of the disclosure (except where mutually exclusive).

[0469] Any example of the present disclosure disclosing a specific feature or group of features or method or method steps will be taken to provide explicit support for disclaiming the specific feature or group of features or method or method steps.

[0470] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for example, in cell culture, molecular genetics, immunology, immunohistochemistry, protein chemistry, and biochemistry).

[0471] Unless otherwise indicated, the recombinant protein, cell culture, and immunological techniques utilized in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al. Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present).

[0472] The description and definitions of variable regions and parts thereof, antibodies and fragments thereof herein may be further clarified by the discussion in Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991.

[0473] The term “EU numbering system of Kabat” will be understood to mean the numbering of an antibody heavy chain is according to the EU index as taught in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda. The EU index is based on the residue numbering of the human IgGl EU antibody. Any discussion of a protein or antibody herein will be understood to include any variants of the protein or antibody produced during manufacturing and / or storage. For example, during manufacturing or storage an antibody can be deamidated (e.g., at an asparagine or a glutamine residue) and / or have misincorporated amino acid residues (e.g., a serine misincorporated in place of an asparagine residue) and / or have altered glycosylation and / or have a glutamine residue converted to pyroglutamine and / or have a N-terminal or C-terminal residue removed or “clipped” and / or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody. It is understood that a composition comprising a particular amino acid sequence may be a heterogeneous mixture of the stated or encoded sequence and / or variants of that stated or encoded sequence.

[0474] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0475] Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0476] As used herein the term “derived from” shall be taken to indicate that a specified integer may be obtained from a particular source albeit not necessarily directly from that source.

[0477] The term “about”, unless stated to the contrary, refers to + / - 20%, more preferably + / - 10%, of the designated value. For the avoidance of doubt, the term “about” followed by a designated value is to be interpreted as also encompassing the exact designated value itself (for example, “about 10” also encompasses 10 exactly).

[0478] All publications cited herein are hereby incorporated by reference in their entirety. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0479] Any discussion of documents, acts, materials, devices, articles or the like that has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Selected Definitions

[0480] The term “recombinant” shall be understood to mean the product of artificial genetic recombination. Accordingly, in the context of a recombinant protein comprising an antibody antigen binding domain, this term does not encompass an antibody naturally- occurring within a subject’s body that is the product of natural recombination that occurs during B cell maturation. However, if such an antibody is isolated, it is to be considered an isolated protein comprising an antibody antigen binding domain. Similarly, if nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein comprising an antibody antigen binding domain. A recombinant protein also encompasses a protein expressed by artificial recombinant means when it is within a cell, tissue or subject, e.g., in which it is expressed.

[0481] The term “protein” shall be taken to include a single polypeptide chain, i.e., a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains covalently or non-covalently linked to one another (i.e., a polypeptide complex). For example, the series of polypeptide chains can be covalently linked using a suitable chemical linker or a disulphide bond, for example. Examples of non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.

[0482] The term “polypeptide” or “polypeptide chain” will be understood from the foregoing paragraph to mean a series of contiguous amino acids linked by peptide bonds.

[0483] As used herein, the term “antigen binding domain” shall be taken to mean a structure formed by a protein that is capable of binding or specifically binding to an antigen. The antigen binding site need not be a series of contiguous amino acids, or even amino acids in a single polypeptide chain. For example, in a Fv produced from two different polypeptide chains the antigen binding site is made up of a series of amino acids of a VL and a VH that interact with the antigen and that are generally, however not always in the one or more of the CDRs in each variable region. In some examples, an antigen binding site comprises a VH or a VL or a Fv.

[0484] The skilled artisan will be aware that an “antibody” is generally considered to be a protein that comprises a variable region made up of a plurality of polypeptide chains, e.g., a polypeptide comprising a VL and a polypeptide comprising a VH. An antibody also generally comprises constant domains, some of which can be arranged into a constant region, which includes a constant fragment or fragment crystallizable (Fc) region, in the case of a heavy chain. A VH and a VL interact to form a Fv comprising an antigen binding site that is capable of specifically binding to one or a few closely related antigens. Generally, a light chain from mammals is either a K light chain or a light chain and a heavy chain from mammals is a, 5, a, y, or p. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGi, IgG2, IgGs, IgG4, IgAi and IgA2) or subclass. The term “antibody” also encompasses humanized antibodies, primatized antibodies, human antibodies and chimeric antibodies.

[0485] The term “Fc” herein is used 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 Fes and Fc domain variants. In some examples, a human IgG heavy chain Fc domain region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, Fes produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Thus, a Fc domain may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447, numbering according to EU index). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc domain region may or may not be present. When specified herein, numbering of amino acid residues in the Fc domain region or constant region is according to 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.

[0486] For the purposes of nomenclature only and not limitation an exemplary sequence of a human IgGl Fc domain is provided in Uniprot Accession No: P01857.

[0487] As used herein the phrase “corresponding to” in reference to the position of an amino acid in SEQ ID NO: should be understood as reference to an amino acid residue or position within a polypeptide or protein (e.g., a Fc), and not necessarily a sequence comprising the recited SEQ ID NO.

[0488] The terms "full-length antibody," "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antigen binding fragment of an antibody. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be wildtype sequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants thereof.

[0489] As used herein, “variable region" refers to the portions of the light and / or heavy chains of an antibody as defined herein that is capable of specifically binding to an antigen and includes amino acid sequences of complementarity determining regions (CDRs); i.e., CDR1, CDR2, and CDR3, and framework regions (FRs). Exemplary variable regions comprise three or four FRs (e.g., FR1, FR2, FR3 and optionally FR4) together with three CDRs. In the case of a protein derived from an IgNAR, the protein may lack a CDR2. VH refers to the variable region of the heavy chain. VL refers to the variable region of the light chain.

[0490] As used herein, the term "complementarity determining regions” (syn. CDRs; i.e., CDR1, CDR2, and CDR3) refers to the amino acid residues of an antibody variable region the presence of which are necessary for antigen binding. Each variable region typically has three CDR regions identified as CDR1, CDR2 and CDR3. The amino acid positions assigned to CDRs and FRs can be defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 or other numbering systems in the performance of this disclosure, e.g., the canonical numbering system of Chothia and Lesk J. Mol Biol. 196'. 901-917, 1987; Chothia et al. Nature 342, 877-883, 1989; and / or Al-Lazikani et al, J Mol Biol 273: 927-948, 1997; the IMGT numbering system of Lefranc et al., Devel. And Compar. Immunol., 27'. 55- 77, 2003; or the AHO numbering system of Honnegher and Pliikthun J. Mol. BioL, 309: 657-670, 2001. For example, according to the numbering system of Kabat, VH framework regions (FRs) and CDRs are positioned as follows: residues 1-30 (FR1), 31- 35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3) and 103- 113 (FR4). According to the numbering system of Kabat, VL FRS and CDRs are positioned as follows: residues 1-23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3) and 98-107 (FR4). The present disclosure is not limited to FRs and CDRs as defined by the Kabat numbering system, but includes all numbering systems, including those discussed above. In one example, reference herein to a CDR (or a FR) is in respect of those regions according to the numbering system of Kabat.

[0491] "Framework regions" (FRs) are those variable region residues other than the CDR residues.

[0492] As used herein, the term “Fv” shall be taken to mean any protein, whether comprised of multiple polypeptides or a single polypeptide, in which a VL and a VH associate and form a complex having an antigen binding site, i.e., capable of specifically binding to an antigen. The VH and the VL which form the antigen binding site can be in a single polypeptide chain or in different polypeptide chains. Furthermore, an Fv of the disclosure (as well as any protein of the disclosure) may have multiple antigen binding sites which may or may not bind the same antigen. This term shall be understood to encompass fragments directly derived from an antibody as well as proteins corresponding to such a fragment produced using recombinant means. In some examples, the VH is not linked to a heavy chain constant domain (CH) 1 and / or the VL is not linked to a light chain constant domain (CL). Exemplary Fv containing polypeptides or proteins include a Fab fragment, a Fab’ fragment, aF(ab’) fragment, a scFv, a diabody, atriabody, a tetrabody or higher order complex, or any of the foregoing linked to a constant region or domain thereof, e.g., CH2 or CH3 domain, e.g., a minibody. A "Fab fragment" consists of a monovalent antigen-binding fragment of an immunoglobulin, and can be produced by digestion of a whole antibody with the enzyme papain, to yield a fragment consisting of an intact light chain and a portion of a heavy chain or can be produced using recombinant means. A "Fab1fragment" of an antibody can be obtained by treating a whole antibody with pepsin, followed by reduction, to yield a molecule consisting of an intact light chain and a portion of a heavy chain comprising a VH and a single constant domain. Two Fab' fragments are obtained per antibody treated in this manner. A Fab’ fragment can also be produced by recombinant means. A "F(ab')2 fragment” of an antibody consists of a dimer of two Fab' fragments held together by two disulfide bonds, and is obtained by treating a whole antibody molecule with the enzyme pepsin, without subsequent reduction. A “Fab2” fragment is a recombinant fragment comprising two Fab fragments linked using, for example a leucine zipper or a CH3 domain. A “single chain Fv” or “scFv” is a recombinant molecule containing the variable region fragment (Fv) of an antibody in which the variable region of the light chain and the variable region of the heavy chain are covalently linked by a suitable, flexible polypeptide linker.

[0493] As used herein, the term “specifically binds” or “binds specifically” shall be taken to mean that a protein of the disclosure reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular antigen or cell expressing same than it does with alternative antigens or cells. For example, a protein binds to a soluble molecule with materially greater affinity (e.g., 20 fold or 40 fold or 60 fold or 80 fold to 100 fold or 150 fold or 200 fold) than it does to other soluble molecules or to antigens commonly recognized by polyreactive natural antibodies (i.e., by naturally occurring antibodies known to bind a variety of antigens naturally found in humans). Generally, but not necessarily, reference to binding means specific binding, and each term shall be understood to provide explicit support for the other term.

[0494] As used herein, the term “FcRn” refers to the neonatal Fc receptor, also known as the Brambell receptor, and is a heterodimer of truncated heavy chain of the major histocompatibility complex class 1-like Fc receptor (FCGRT) and beta-2-microglobulin.

[0495] As used herein, the terms “half-life”, “serum half-life” or “plasma half-life” in the context of the present disclosure refers to the period of time required for the concentration or amount of Fc domain or FcRn antagonist in the body to be reduced by 50% (i.e., one half) for example due to degradation and / or clearance or sequestration by natural mechanisms. The skilled person will recognise that the serum half-life of proteins in a subject is dependent on various physiological conditions (e.g., health status, body size / weight). For example, in a healthy human subject, the serum half-life of IgGl is about 21 days. Methods for determining the serum half-life of protein are known in the art and include, for example, pharmacokinetic analysis.

[0496] For the purposes of clarification and as will be apparent to the skilled artisan based on the exemplified subject matter herein, reference to “affinity” herein is a reference to a level of binding which can be quantified using, for example, a dissociation constant (KD). Generally, reference to a level of affinity of a protein described herein is a reference to the protein’s KD for a particular antigen. Thus, as referred to herein, a protein that has an affinity for a soluble molecule of at least 15 nM, has a KD of at least 15 nM (15 nM or stronger), i.e., the numerical value of the dissociation constant is either 15 nM or lower (for example, 10 nM or 100 pM). In this regard, reference to a higher affinity is reference to KD having a lower numerical value and vice versa. The level of binding is detected using biosensor analysis (e.g. Biacore™) in which the protein is immobilized and contacted with an antigen, or vice versa.

[0497] As used herein, the phrase “neutral pH” refers to the approximate pH of blood in a healthy human individual (i.e., about pH 7.0 to about pH 7.5). Similarly, the phrase “acidic pH” refers to the approximate pH of an endosome (i.e., about pH 4.5 to about pH 6.5). In some examples, the acidic pH is the pH of an early endosome (i.e., about pH 5.5 to about pH 6.5). Also, any reference herein to an affinity at a particular pH, e.g., pH 6.0, encompasses an affinity at a pH within 0.2 units of the recited pH.

[0498] As used herein, the term “neutralize” shall be taken to mean that a binding protein is capable of blocking, reducing or preventing the soluble molecule-mediated signaling in a cell. Methods for determining neutralization are known in the art and / or described herein.

[0499] As used herein, the term “epitope” (syn. “antigenic determinant”) shall be understood to mean a region of soluble molecule to which a protein of the disclosure binds. This term is not necessarily limited to the specific residues or structure to which the protein makes contact. For example, this term includes the region spanning amino acids contacted by the protein and / or 5-10 or 2-5 or 1-3 amino acids outside of this region. In some examples, the epitope comprises a series of discontinuous amino acids that are positioned close to one another when the soluble molecule is folded, i.e., a “conformational epitope”. The skilled artisan will also be aware that the term "epitope" is not limited to peptides or polypeptides. For example, the term “epitope” includes chemically active surface groupings of molecules such as sugar side chains, phosphoryl side chains, or sulfonyl side chains, and, in certain examples, may have specific three dimensional structural characteristics, and / or specific charge characteristics.

[0500] As used herein, the term “disorder” refers to a disruption of or interference with normal function, and is not to be limited to any specific disorder, and will include diseases or conditions.

[0501] As used herein, the terms “preventing”, “prevent” or “prevention” include administering a protein of the disclosure to thereby stop or hinder the development of at least one symptom of a disorder.

[0502] As used herein, the terms “treating”, “treat” or “treatment” include administering a protein described herein to thereby reduce or eliminate at least one symptom of a specified disease or disorder.

[0503] As used herein, the term “subject” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and non-human primates. For example, the subject is a human.

[0504] Multifunctional FcRn Antagonists

[0505] In one example, the target binding domain as described herein according to any example is a target binding domain from a protein, antibody or other non-antibody comprising a target binding domain thereof.

[0506] Antibodies

[0507] In one example, the target binding domain as described herein according to any example is an antigen binding domain of an antibody. For example, the protein is an antibody.

[0508] Methods for generating antibodies are known in the art and / or described in Harlow and Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988). Generally, in such methods the soluble molecule or a region thereof (e.g., an extracellular domain) or immunogenic fragment or epitope thereof or a cell expressing and displaying same (i.e., an immunogen), optionally formulated with any suitable or desired carrier, adjuvant, or pharmaceutically acceptable excipient, is administered to a non-human animal, for example, a mouse, chicken, rat, rabbit, guinea pig, dog, horse, cow, goat or pig. The immunogen may be administered intranasally, intramuscularly, subcutaneously, intravenously, intradermally, intraperitoneally, or by other known routes.

[0509] Monoclonal antibodies are one exemplary form of an antibody contemplated by the present disclosure. The term “monoclonal antibody" or “mAb” refers to a homogeneous antibody population capable of binding to the same antigen(s), for example, to the same epitope within the antigen. This term is not intended to be limited as regards to the source of the antibody or the manner in which it is made.

[0510] For the production of mAbs any one of a number of known techniques may be used, such as, for example, the procedure exemplified in US4196265 or Harlow and Lane (1988), supra.

[0511] Alternatively, ABL-MYC technology (NeoClone, Madison WI 53713, USA) is used to produce cell lines secreting MAbs (e.g., as described in Largaespada et al, J. Immunol. Methods. 197'. 85-95, 1996).

[0512] Antibodies can also be produced or isolated by screening a display library, e.g., a phage display library, e.g., as described in US6300064 and / or US5885793.

[0513] In another example, a phage display library is screened or an animal is immunized with the soluble molecule, or a fragment thereof, and identified proteins and / or antibodies are screened to identify those that are cross-reactive with the soluble molecule and / or the fragment thereof.

[0514] The antibody of the present disclosure may be a synthetic antibody. For example, the antibody is a chimeric antibody, a humanized antibody, a human antibody or a deimmunized antibody.

[0515] In one example, an antibody described herein is a chimeric antibody. The term “chimeric antibody” refers to antibodies in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species (e.g., murine, such as mouse) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species (e.g., primate, such as human) or belonging to another antibody class or subclass. Methods for producing chimeric antibodies are described in, e.g., US4816567; and US5807715.

[0516] The antibodies of the present disclosure may be humanized or human.

[0517] The term "humanized antibody” shall be understood to refer to a subclass of chimeric antibodies having an antigen binding site or variable region derived from an antibody from a non-human species and the remaining antibody structure based upon the structure and / or sequence of a human antibody. In a humanized antibody, the antigenbinding site generally comprises the complementarity determining regions (CDRs) from the non-human antibody grafted onto appropriate FRs in the variable regions of a human antibody and the remaining regions from a human antibody. Antigen binding sites may be wild-type (i.e., identical to those of the non-human antibody) or modified by one or more amino acid substitutions. In some instances, FR residues of the human antibody are replaced by corresponding non-human residues.

[0518] Methods for humanizing non-human antibodies or parts thereof (e.g., variable regions) are known in the art. Humanization can be performed following the method of US5225539, or US5585089. Other methods for humanizing an antibody are not excluded.

[0519] The term "human antibody" as used herein refers to antibodies having variable regions (e.g. VH, VL) and, optionally constant regions derived from or corresponding to sequences found in humans, e.g. in the human germline or somatic cells.

[0520] The "human" antibodies can include amino acid residues not encoded by human sequences, e.g. mutations introduced by random or site directed mutations in vitro (in particular mutations which involve conservative substitutions or mutations in a small number of residues of the antibody, e.g. in 1, 2, 3, 4, 5 or 6 of the residues of the antibody, e.g. in 1, 2, 3, 4, 5 or 6 of the residues making up one or more of the CDRs of the antibody). These “human antibodies” do not actually need to be produced by a human, rather, they can be produced using recombinant means and / or isolated from a transgenic animal (e.g., mouse) comprising nucleic acid encoding human antibody constant and / or variable regions (e.g., as described above). Human antibodies can be produced using various techniques known in the art, including phage display libraries (e.g., as described in US5885793).

[0521] Human antibodies which recognize a selected epitope can also be generated using a technique referred to as "guided selection." In this approach a selected non-human monoclonal antibody, e.g., a mouse antibody, is used to guide the selection of a completely human antibody recognizing the same epitope (e.g., as described in US5565332).

[0522] Target Binding Domain Containing Proteins

[0523] Diabodies, Triabodies, Tetrabodies

[0524] In some examples, target binding domain of the disclosure is or comprises a diabody, triabody, tetrabody or higher order protein complex such as those described in W098 / 044001 and / or W094 / 007921.

[0525] For example, a diabody is a protein comprising two associated polypeptide chains, each polypeptide chain comprising the structure VL-X-VH or VH-X-VL, wherein VL is an antibody light chain variable region, VH is an antibody heavy chain variable region, X is a linker comprising insufficient residues to permit the VH and VL in a single polypeptide chain to associate (or form an Fv) or is absent, and wherein the VH of one polypeptide chain binds to a VL of the other polypeptide chain to form an antigen binding domain, i.e., to form a Fv molecule capable of specifically binding to one or more antigens. The VL and VH can be the same in each polypeptide chain or the VL and VH can be different in each polypeptide chain so as to form a bispecific diabody (i.e., comprising two Fvs having different specificity).

[0526] Single Chain Fv (scFv)

[0527] The target binding domain of the disclosure can be a scFv. The skilled artisan will be aware that scFvs comprise VH and VL regions in a single polypeptide chain and a polypeptide linker between the VH and VL which enables the scFv to form the desired structure for antigen binding (i.e., for the VH and VL of the single polypeptide chain to associate with one another to form a Fv). For example, the linker comprises in excess of 12 amino acid residues with (Gly4Ser)3 being one of the more favored linkers for a scFv.

[0528] The present disclosure also contemplates a disulfide stabilized Fv (or diFv or dsFv), in which a single cysteine residue is introduced into a FR of VH and a FR of VL and the cysteine residues linked by a disulfide bond to yield a stable Fv.

[0529] Alternatively, or in addition, the present disclosure encompasses a dimeric scFv, i.e., a protein comprising two scFv molecules linked by a non-covalent or covalent linkage, e.g., by a leucine zipper domain (e.g., derived from Fos or Jun). Alternatively, two scFvs are linked by a peptide linker of sufficient length to permit both scFvs to form and to bind to an antigen, e.g., as described in US20060263367.

[0530] V-Like Proteins

[0531] In one example, a target binding domain of a protein of the present disclosure comprises a T-cell receptor. T cell receptors have two V-domains that combine into a structure similar to the Fv module of an antibody. Novotny et al., 1991 describes how the two V-domains of the T-cell receptor (termed alpha and beta) can be fused and expressed as a single chain polypeptide and, further, how to alter surface residues to reduce the hydrophobicity directly analogous to an antibody scFv. Other publications describing production of single-chain T-cell receptors or multimeric T cell receptors comprising two V-alpha and V-beta domains include W01999045110 or WO201 1107595.

[0532] Other non-antibody proteins comprising antigen binding domains include proteins with V-like domains, which are generally monomeric. Examples of proteins comprising such V-like domains include CTLA-4, CD28 and ICOS. Further disclosure of proteins comprising such V-like domains is included in WO1999045110. Adnectins

[0533] In one example, a target binding domain of the present disclosure comprises an adnectin. Adnectins are based on the tenth fibronectin type III (10Fn3) domain of human fibronectin in which the loop regions are altered to confer antigen binding. For example, three loops at one end of the P-sandwich of the10Fn3 domain can be engineered to enable an Adnectin to specifically recognize an antigen. For further details see US20080139791 or W02005056764.

[0534] Anticalins

[0535] In a further example, a target binding domain of the disclosure comprises an anticalin. Anticalins are derived from lipocalins, which are a family of extracellular proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids and lipids. Lipocalins have a rigid P-sheet secondary structure with a plurality of loops at the open end of the conical structure which can be engineered to bind to an antigen. Such engineered lipocalins are known as anticalins. For further description of anticalins see US7250297 or US20070224633.

[0536] Affibodies

[0537] In a further example, a target binding domain of the disclosure comprises an affibody. An affibody is a scaffold derived from the Z domain (antigen binding domain) of Protein A of Staphylococcus aureus which can be engineered to bind to antigen. The Z domain consists of a three-helical bundle of approximately 58 amino acids. Libraries have been generated by randomization of surface residues. For further details see EP1641818.

[0538] Avimers

[0539] In a further example, a target binding domain of the disclosure comprises an Avimer. Avimers are multidomain proteins derived from the A-domain scaffold family. The native domains of approximately 35 amino acids adopt a defined disulphide bonded structure. Diversity is generated by shuffling of the natural variation exhibited by the family of A-domains. For further details see W02002088171.

[0540] DARPins

[0541] In a further example, a target binding domain of the disclosure comprises a Designed Ankyrin Repeat Protein (DARPin). DARPins are derived from Ankyrin which is a family of proteins that mediate attachment of integral membrane proteins to the cytoskeleton. A single ankyrin repeat is a 33 residue motif consisting of two a-helices and a P-tum. They can be engineered to bind different target antigens by randomizing residues in the first a-helix and a P-turn of each repeat. Their binding interface can be increased by increasing the number of modules (a method of affinity maturation). For further details see US20040132028.

[0542] Fc domain and fragments thereof

[0543] The present disclosure encompasses proteins and / or antibodies described herein comprising a constant region of an antibody. This includes antigen binding fragments of an antibody fused to a Fc.

[0544] As described herein, a protein of the disclosure comprises a modified IgG Fc domain or FcRn binding fragment thereof. The present disclosure provides a modified IgG Fc domain (i.e., Fc domain variant), or FcRn-binding fragment thereof, that binds specifically to FcRn with increased affinity compared to a Fc domain from an unmodified (i.e., a wild-type) human IgG.

[0545] In one example, the FcRn binding fragment of the Fc domain refers to the part of an immunoglobulin heavy chain, e.g., IgGl heavy chain, that extends approximately from EU position 243 to EU position 261 and approximately from EU position 275 to EU position 293 and approximately from EU position 302 to EU position 319 and approximately from EU position 336 to EU position 348 and approximately from EU position 367 to EU position 393 and EU position 408 and approximately from EU position 424 to EU position 440.

[0546] In one example, the variant Fc domain or fragment thereof has reduced pH dependence for binding to FcRn relative to a native Fc domain region. An exemplary Fc domain or fragments thereof inhibits or reduces the binding of immunoglobulins and / or other Fc-containing proteins (e.g. immunoadhesins and antibody-drug conjugates) to FcRn in vivo, which results in an increased rate of degradation of the immunoglobulin or Fc-containing proteins and, concomitantly, a reduced serum level of these immunoglobulins or Fc-containing proteins.

[0547] In one example, the Fc domain is from human IgG. For example, the Fc domain is from IgGl. For example, the Fc domain is from human IgGl. For example, the Fc domain is from IgG4. For example, the Fc domain is from human IgG4.

[0548] Any Fc domain region can be modified to produce a Fc domain variant of the disclosure. As discussed herein, generally a Fc domain is from a human immunoglobulin. However, the Fc domain may be derived from an immunoglobulin of any other mammalian species, including for example, a Camelid species, a rodent (e.g. a mouse, rat, rabbit, guinea pig) or non-human primate (e.g. chimpanzee, macaque) species. Moreover, the Fc domain may be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA and IgE, and any immunoglobulin isotype, including IgGl, IgG2, IgG3 and IgG4. In certain examples, the Fc domain is an IgG Fc domain (e.g., a human IgG region). In certain examples, the Fc domain is an IgGl Fc domain (e.g., a human IgGl). In certain examples, the Fc domain is a chimeric Fc domain comprising portions of several different Fc domain. Suitable examples of a chimeric Fc domain are set forth in US20110243966. It will be appreciated that the scope of the present disclosure encompasses alleles, variants and mutations of Fc domains.

[0549] In one example, the Fc region is an IgG4 Fc region (i.e., from an IgG4 constant region), e.g., a human IgG4 Fc region. Sequences of suitable IgG4 Fc regions will be apparent to the skilled person and / or available in publically available databases (e.g., available from National Center for Biotechnology Information).

[0550] In one example, the constant region is a stabilized IgG4 constant region. The term “stabilized IgG4 constant region” will be understood to mean an IgG4 constant region that has been modified to reduce Fab arm exchange or the propensity to undergo Fab arm exchange or formation of a half-antibody or a propensity to form a half antibody. “Fab arm exchange" refers to a type of protein modification for human IgG4, in which an IgG4 heavy chain and attached light chain (half-molecule) is swapped for a heavy-light chain pair from another IgG4 molecule. Thus, IgG4 molecules may acquire two distinct Fab arms recognizing two distinct antigens (resulting in bispecific molecules). Fab arm exchange occurs naturally in vivo and can be induced in vitro by purified blood cells or reducing agents such as reduced glutathione. A “half antibody” forms when an IgG4 antibody dissociates to form two molecules each containing a single heavy chain and a single light chain.

[0551] In one example, a stabilized IgG4 constant region comprises a proline at position 241 of the hinge region according to the system of KABAT (Kabat et al., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 1987 and / or 1991). This position corresponds to position 228 of the hinge region according to the EU numbering system (Kabat et al., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 2001 and Edelman etal., Proc. Natl. Acad. USA, 63, 78-85, 1969). In human IgG4, this residue is generally a serine. In one example, the stabilized IgG4 constant region comprises a S228P mutation according to the EU numbering system. Following substitution of the serine for proline, the IgG4 hinge region comprises a sequence CPPC. In this regard, the skilled person will be aware that the “hinge region” is a proline-rich portion of an antibody heavy chain constant region that links the Fc and Fab regions that confers mobility on the two Fab arms of an antibody. The hinge region includes cysteine residues which are involved in inter-heavy chain disulfide bonds. It is generally defined as stretching from Glu226 to Pro243 of human IgGl according to the numbering system of KABAT. Hinge regions of other IgG isotypes may be aligned with the IgGl sequence by placing the first and last cysteine residues forming inter-heavy chain disulphide (S-S) bonds in the same positions (see for example WO2010 / 080538).

[0552] Additional examples of stabilized IgG4 antibodies are antibodies in which arginine at position 409 in a heavy chain constant region of human IgG4 (according to the EU numbering system) is substituted with lysine, threonine, methionine, or leucine (e.g., as described in W02006 / 033386). The Fc region of the constant region may additionally or alternatively comprise a residue selected from the group consisting of: alanine, valine, glycine, isoleucine and leucine at the position corresponding to 405 (according to the EU numbering system). Optionally, the hinge region comprises a proline at position 241 (i.e., a CPPC sequence) (as described above).

[0553] In another example, the Fc region is a region modified to have reduced effector function, i.e., a “non-immunostimulatory Fc region”. For example, the Fc region of the constant region has a reduced ability to induce effector function, e.g., compared to a native or wild-type human IgGl or IgG3 Fc region. For example, the Fc region is an IgGl Fc region comprising a substitution at one or more positions selected from the group consisting of 268, 309, 330 and 331. In another example, the Fc region is an IgGl Fc region comprising one or more of the following changes E233P, L234V, L235A and deletion of G236 and / or one or more of the following changes A327G, A330S and P331 S (Armour et al., Eur J Immunol. 29:2613-2624, 1999; Shields et al, J Biol Chem. 276(9 / 6591-604, 2001). Additional examples of non-immunostimulatory Fc regions are described, for example, in Dall'Acqua et al., J Immunol. 177 : 1129-1138 2006; and / or Hezareh J Virol ;75 12161-12168, 2001). In one example, the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cell- mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC). Methods for assessing the level of effector function of an Fc region containing protein are known in the art and / or described herein.

[0554] To enhance the manufacturability of the FcRn antagonists disclosed herein, it is desirable that the constituent Fc domain does not comprise any non-disulphide bonded cysteine residues. Accordingly, in certain examples the Fc domains do not comprise a free cysteine residue. In one example, the modified Fc domain comprises an amino acid modification, e.g., substitution that enhances binding of the Fc domain to FcRn. In one example, the amino acid modification enhances binding of the modified Fc domain to FcRn at neutral pH and / or acidic pH. In one example, the amino acid modification enhances binding of the modified Fc domain to FcRn at neutral pH and acidic pH. For example, the Fc region has increased affinity for FcRn at lower pH, e.g., about pH 6.0, to facilitate Fc / FcRn binding in an endosome. In one example, the Fc region has increased affinity for FcRn at about pH 6 compared to its affinity at about pH 7.4, which facilitates the re-release of Fc into blood following cellular recycling. These amino acid substitutions are useful for extending the half life of a protein, by reducing clearance from the blood.

[0555] In some examples, the one or more amino acid substitutions are selected from S228P, M252Y, V308P, N286E, L234A, F234A, L235A, P329G and N434Y according to the EU numbering system. In some examples, the protein comprises one or more or all of the following amino acid substitutions in its Fc region: S228P, M252Y, V308P, N286E, L234A, F234A, L235A, P329G and N434Y (according to the EU numbering system).

[0556] In one example, the protein comprises a S228P mutation. In another example, the protein comprises S228P, M252Y, V308P and N434Y mutations. In one example, the protein comprises M252Y, V308P and N434Y (‘ YPY’) mutations. In one example, the protein comprises L234A and L235A (‘LALA’) mutations. In a further example, the protein comprises a P329G (‘PG’) mutation. In another example, the protein comprises L234A, L235A and P329G (‘LALA-PG’) mutations. In one example, the protein comprises F234A and L234A (‘FALA’) mutations. In another example, the protein comprises S228P, F234A and L234A mutations. In a further example, the protein comprises F234A, L234A and P329G (‘FALA-PG’) mutations. In one example, the protein comprises S228P, F234A, L234A and P329G mutations. In another example, the protein comprises M252Y and N286E, N434Y (‘YEY’) mutations.

[0557] In one example, the L234A / L235A or L234A / L235A / P329G mutations are introduced into an IgGl Fc. For example, the IgGl Fc comprises L234A and L235A mutations. In another example, the IgGl Fc comprises L234A, L235A and P329G mutations.

[0558] In one example, the F234A / L234A or S228P / F234A / L234A or F234A / L234A / P329G or S228P / F234A / L234A / P329G mutations are introduced into an IgG4 Fc. For example, the IgG4 Fc comprises F234A and L234A mutations. In another example, the IgG4 Fc comprises S228P, F234A and L234A mutations. In a further example, the IgG4 Fc comprises F234A, L234A and P329G mutations. In one example, the IgG4 Fc comprises S228P, F234A, L234A and P329G mutations.

[0559] The YPY and YEY modifications enhance binding of the antibodies to FcRn at both neutral and acidic pH potentially conferring ability to antagonise FcRn mediated recycling of endogenous IgG. The addition of the LALA modification, reduces effector function by reducing interaction with Fc gamma Receptors.

[0560] In one example, the protein or antibody of the disclosure comprises one or more variants. For example, the variant is a post-translationally modified variant.

[0561] In one example, the protein or antibody comprises a variant missing an encoded C -terminal lysine residue, a deamidated variant, a miscorporated amino acid residue, a glycosylated variant, a variant comprising a pyroglutamate, a variant lacking a N- terminal residue, and / or a variant comprising all or part of a secretion signal.

[0562] In one example, the protein or antibody comprises a variant missing an encoded C -terminal lysine residue.

[0563] In one example, the protein or antibody comprises a deamidated variant. Deamidated variants of encoded asparagine residues may result in isoaspartic acid and / or aspartic acid being generated or even a succinamide involving an adjacent amino acid residue. Deamidated variants of encoded glutamine residues may result in glutamic acid being formed. Compositions comprising a heterogeneous mixture of such sequences and variants are intended to be included when reference is made to a particular amino acid sequence.

[0564] In one example, the protein or antibody comprises a miscorporated amino acid residue. For example, methionine residues are substituted with nor-leucine, asparagine residues are substituted with serine and / or phenylalanine residues are substituted with tyrosine.

[0565] In one example, the protein or antibody comprises a variant comprising a pyroglutamate. For example, at the N-terminus of a protein.

[0566] In one example, the protein or antibody comprises a glycosylated variant.

[0567] In one example, the protein or antibody comprises a variant lacking a N-terminal residue. For example, a N-terminal glutamine in an antibody or V region.

[0568] In one example, the protein or antibody comprises a variant comprising all or part of a secretion signal.

[0569] Linkers

[0570] In some examples, components of the protein of the disclosure are indirectly linked, e.g., via a linker. In some examples, the linker is a polypeptide linker. In some examples, a polypeptide linker comprises or consists of a gly-ser linker. As used herein, the term “gly-ser linker” refers to a peptide that consists of glycine and serine residues. An exemplary gly / ser linker comprises an amino acid sequence of the formula (Gly4Ser)n, wherein n is a positive integer (e.g., 1, 2, 3, 4, or 5). In certain examples the gly / ser linker is (Gly4Ser)i. In some examples, the gly / ser linker is (Gly4Ser)2. In some examples the gly / ser linker is (Gly4Ser)3 or (Gly4Ser)4.

[0571] Other linkers that are suitable for use in the proteins of the disclosure are known in the art, for example, the serine-rich linkers disclosed in US 5525491, the helix forming peptide linkers (e.g., A(EAAAK)nA (n=2-5)) disclosed in Arai et al, Protein Eng 2001;14:529-32, or the stable linkers disclosed in Chen etal, MolPharm 2011;8:457-65.

[0572] Other exemplary linkers include GS linkers (i.e., (GS)n), GGSG linkers (i.e., (GGSG)n), GSAT linkers, SEG linkers, and GGS linkers (i.e., (GGSGGS)n), wherein n is a positive integer (e.g., 1, 2, 3, 4, or 5).

[0573] Polypeptide linkers of the disclosure are at least one amino acid in length and can be of varying lengths. In some examples, a polypeptide linker of the disclosure is from about 1 to about 50 amino acids in length. In another example, a polypeptide linker of the disclosure is from about 5-10 amino acids in length. In another example, a polypeptide linker of the disclosure is from about 10-20 amino acids in length. In another example, a polypeptide linker of the disclosure is from about 15 to about 50 amino acids in length.

[0574] In some examples, the linker comprises or is a chemical linker. In some examples, the linker is one or more ethylene glycol (EG) units, e.g., 2 or more EG units (i.e., polyethylene glycol (PEG)). In some examples, a linker comprises or consists of a polyethylene glycol (PEG) linker. Polyethylene glycol or PEG refers to a chemical compound composed of repeating ethylene glycol units. An exemplary “PEG linker” comprises a compound of the formula: H-(0-CH2-CH2)n-OH, wherein n is a positive integer (e.g., 1, 10, 20, 50, 100, 200, 300, 400, 500, 600). In some examples, the PEG linker is PEG1000. In some examples, the PEG linker is PEG2000. In some examples, the PEG linker is PEG3000.

[0575] Production of Multifunctional FcRn Antagonists

[0576] The disclosure provides polynucleotides, vectors and host cells encoding the proteins disclosed herein. Methods of making proteins of the disclosure comprising expressing these polynucleotides are also provided. In one example, a protein described herein according to any example is produced using methods that are known in the art, e.g., by culturing a hybridoma under conditions sufficient to produce the protein.

[0577] Recombinant Expression

[0578] In another example, a protein described herein according to any example is recombinant.

[0579] In the case of a recombinant protein, nucleic acid encoding same can be cloned into expression constructs or vectors, which are then transfected into host cells, such as E. coli cells, yeast cells, insect cells, or mammalian cells, such as simian COS cells, Chinese Hamster Ovary (CHO) cells, human embryonic kidney (HEK) cells, or myeloma cells that do not otherwise produce the protein. Exemplary cells used for expressing a protein are CHO cells, myeloma cells or HEK cells. Molecular cloning techniques to achieve these ends are known in the art and described, for example in Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley- Interscience (1988, including all updates until present) or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989). A wide variety of cloning and in vitro amplification methods are suitable for the construction of recombinant nucleic acids. Methods of producing recombinant antibodies are also known in the art, see, e.g., US4816567 or US5530101.

[0580] Following isolation, the nucleic acid is inserted operably linked to a promoter in an expression construct or expression vector for further cloning (amplification of the DNA) or for expression in a cell-free system or in cells.

[0581] The term “vector” or “expression vector” is used herein for the purposes of the specification and claims, to mean vectors used in accordance with the present disclosure as a vehicle for introducing into and expressing a desired gene in a cell. As known to those skilled in the art, such vectors may easily be selected from the group consisting of plasmids, phages, viruses and retroviruses.

[0582] As used herein, the term “promoter” is to be taken in its broadest context and includes the transcriptional regulatory sequences of a genomic gene, including the TATA box or initiator element, which is required for accurate transcription initiation, with or without additional regulatory elements (e.g., upstream activating sequences, transcription factor binding sites, enhancers and silencers) that alter expression of a nucleic acid, e.g., in response to a developmental and / or external stimulus, or in a tissue specific manner. In the present context, the term “promoter” is also used to describe a recombinant, synthetic or fusion nucleic acid, or derivative which confers, activates or enhances the expression of a nucleic acid to which it is operably linked. Exemplary promoters can contain additional copies of one or more specific regulatory elements to further enhance expression and / or alter the spatial expression and / or temporal expression of said nucleic acid.

[0583] As used herein, the term “operably linked to" means positioning a promoter relative to a nucleic acid such that expression of the nucleic acid is controlled by the promoter.

[0584] Many vectors for expression in cells are available. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, a sequence encoding a protein (e.g., from the information provided herein), an enhancer element, a promoter, and a transcription termination sequence. The skilled artisan will be aware of suitable sequences for expression of a protein. Exemplary signal sequences include prokaryotic secretion signals (e.g., pelB, alkaline phosphatase, penicillinase, Ipp, or heat-stable enterotoxin II), yeast secretion signals (e.g., invertase leader, a factor leader, or acid phosphatase leader) or mammalian secretion signals (e.g., herpes simplex gD signal).

[0585] Exemplary promoters active in mammalian cells include cytomegalovirus immediate early promoter (CMV-IE), human elongation factor 1-a promoter (EFl), small nuclear RNA promoters (Ula and Ulb), a-myosin heavy chain promoter, Simian virus 40 promoter (SV40), Rous sarcoma virus promoter (RSV), Adenovirus major late promoter, P-actin promoter; hybrid regulatory element comprising a CMV enhancer / P- actin promoter or an immunoglobulin promoter or active fragment thereof. Examples of useful mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or 293 cells subcloned for growth in suspension culture; baby hamster kidney cells (BHK, ATCC CCL 10); or Chinese hamster ovary cells (CHO).

[0586] Typical promoters suitable for expression in yeast cells such as for example a yeast cell selected from the group comprising Pichia pastoris, Saccharomyces cerevisiae and S. pombe. include, but are not limited to, the ADH1 promoter, the GALI promoter, the GAL4 promoter, the CUP1 promoter, the PHO 5 promoter, the nmt promoter, the RPR1 promoter, or the TEF1 promoter.

[0587] Means for introducing the isolated nucleic acid or expression construct comprising same into a cell for expression are known to those skilled in the art. The technique used for a given cell depends on the known successful techniques. Means for introducing recombinant DNA into cells include microinjection, transfection mediated by DEAE-dextran, transfection mediated by liposomes such as by using lipofectamine (Gibco™, MD, USA) and / or cellfectin (Gibco™, MD, USA), PEG-mediated DNA uptake, electroporation and microparticle bombardment such as by using DNA-coated tungsten or gold particles (Agracetus Inc., WI, USA) amongst others.

[0588] The host cells used to produce the protein may be cultured in a variety of media, depending on the cell type used. Commercially available media such as Ham's F10 (Sigma), Minimal Essential Medium ((MEM), (Sigma), RPM1-1640 (Sigma), and Dulbecco's Modified Eagle's Medium ((DMEM), Sigma) are suitable for culturing mammalian cells. Media for culturing other cell types discussed herein are known in the art.

[0589] Isolation of Proteins

[0590] Methods for isolating a protein are known in the art and / or described herein.

[0591] Where a protein is secreted into culture medium, supernatants from such expression systems can be first concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit. A protease inhibitor such as PMSF may be included in any of the foregoing steps to inhibit proteolysis and antibiotics may be included to prevent the growth of adventitious contaminants. Alternatively, or additionally, supernatants can be filtered and / or separated from cells expressing the protein, e.g., using continuous centrifugation.

[0592] The protein prepared from the cells can be purified using, for example, ion exchange, hydroxyapatite chromatography, hydrophobic interaction chromatography, gel electrophoresis, dialysis, affinity chromatography (e.g., protein A affinity chromatography or protein G chromatography), or any combination of the foregoing. These methods are known in the art and described, for example in WO99 / 57134 or Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, (1988).

[0593] The skilled artisan will also be aware that a protein can be modified to include a tag to facilitate purification or detection, e.g., a poly-histidine tag, e.g., a hexa-histidine tag, or an influenza virus hemagglutinin (HA) tag, or a Simian Virus 5 (V5) tag, or a FLAG tag, or a glutathione S-transferase (GST) tag. The resulting protein is then purified using methods known in the art, such as, affinity purification. For example, a protein comprising a hexa-his tag is purified by contacting a sample comprising the protein with nickel-nitrilotriacetic acid (Ni-NTA) that specifically binds a hexa-his tag immobilized on a solid or semi-solid support, washing the sample to remove unbound protein, and subsequently eluting the bound protein. Alternatively, or in addition a ligand or antibody that binds to a tag is used in an affinity purification method. Assaying Activity

[0594] Proteins of the present disclosure are readily screened for biological activity, e.g., as described below.

[0595] Binding to a soluble molecule, fragments and mutants thereof

[0596] Methods for assessing binding to a protein are known in the art, e.g., as described in Scopes (In: Protein purification: principles and practice, Third Edition, Springer Verlag, 1994). Such a method generally involves labeling the protein and contacting it with immobilized antigen or vice versa. Following washing to remove non-specific bound protein, the amount of label and, as a consequence, bound protein is detected. Of course, the protein can be immobilized and the antigen labeled. Panning-type assays can also be used. Alternatively, or additionally, surface plasmon resonance assays can be used. Thus, in one example, the affinity of a protein described herein is determined using a biosensor.

[0597] Affinity measurements can be determined by standard methodology, for example, immunoassays, surface plasmon resonance (SPR; e.g., using BIAcore™ surface plasmon resonance (BIAcore™, Inc., Piscataway, NJ) (Rich and Myszka Curr. Opin. Biotechnol 11: 54, 2000; Englebienne Analyst. 123'. 1599, 1998), isothermal titration calorimetry (ITC) or other kinetic interaction assays known in the art.

[0598] Optionally, the dissociation constant (Kd) of a protein for the soluble molecule is determined. The "Kd" or “KD” or "Kd value" for a protein of the disclosure is in one example measured by a radiolabeled or fluorescently-labeled binding assay. This assay equilibrates the protein with a minimal concentration of labeled soluble molecule (i.e., antigen) in the presence of a titration series of unlabeled soluble molecule. Following washing to remove unbound soluble molecule, the amount of label is determined, which is indicative of the Kd of the protein.

[0599] In some examples, the protein of the disclosure has a similar KD or an improved KD (i.e., a KD value lower than) for FcRn than a human IgGl Fc domain or a variant or fragment thereof.

[0600] Binding affinity for FcRn can also be determined non-quantitatively using flow cytometry. For example, CHO cells stably expressing the protein of the disclosure, are stained with alexa-488 labeled FcRn / p2m (to detect target binding) and anti-myc-alexa 647 (to detect expression) at acidic (pH 5.5) and neutral (pH 7.4) pH and analysed by flow cytometry. Relative binding to FcRn / p2m is determined, for example, by calculating mean fluorescence intensity relative to an unmodified human IgGl Fc domain or a variant or fragment thereof.

[0601] According to another example the Kd is measured by using surface plasmon resonance assays, e.g., using BIAcore surface plasmon resonance (BIAcore, Inc., Piscataway, NJ) with immobilized C2 or vice versa. Thus, in one example, the affinity of a protein is determined using a biosensor (e.g., by surface plasmon resonance) in an assay in which the protein is immobilized and C2 is contacted with the immobilized protein.

[0602] Determining Half-Life

[0603] Proteins encompassed by the present disclosure have a reduced half-life, e.g., are modified to reduce their half-life compared to a protein or antibody comprising an unmodified IgG Fc domain. Methods for determining half-life of a FcRn antagonist will be apparent to the skilled person.

[0604] For the purposes of clarification and as will be apparent to the skilled artisan based on the description herein, reference to “half-life” will be understood to refer to an increase in one or more of the following parameters: terminal half-life, mean residence time, area under the curve, decrease in volume of distribution and / or clearance rate.

[0605] The half-life of a FcRn antagonist of the disclosure can also be measured by pharmacokinetic studies, e.g., according to the method described by Kim et al, Eur J of Immunol 24:542, 1994. According to this method, protein is injected intravenously into mice and its plasma concentration is periodically measured as a function of time, for example at 3 minutes to 72 hours after the injection. The clearance curve thus obtained should be biphasic, that is, an alpha phase and beta phase. For the determination of the in vivo terminal half-life of the protein, the clearance rate in beta-phase is calculated and compared with that of a human IgGl Fc domain or a variant or fragment thereof.

[0606] In vitro Cellular Assays

[0607] Various in vitro assays are available to assess the ability of a protein of the disclosure, to treat a disease or condition described herein.

[0608] In one example, the uptake and recycling of the protein is tested in an in vitro cellular assay.

[0609] Methods of assessing cellular uptake and recycling are known in the art and / or exemplified herein. For example, fluorescently labelled protein is incubated with cells expressing the human FcRn receptor on the cell surface. After addition of the labelled protein the progress of the protein recycling can be tracked and compared to a human IgGl Fc domain or variant or fragment thereof by methods including flow cytometry and fluorescence microscopy (for example, confocal fluorescence microscopy). Changes to the normal recycling pathway for a particular protein can be identified and characterised.

[0610] Pharmacokinetic Analysis

[0611] In one example, the pharmacokinetic (PK) properties of the protein are assessed.

[0612] Methods of assessing the PK properties are known in the art and / or are exemplified herein. For example, the protein of the disclosure is injected into transgenic mice expressing human FcRn receptor or other suitable mammalian hosts (e.g. rats, cynomolgus monkeys). In one example, the transgenic mice expressing human FcRn receptor are “hFcRn Tg32” homozygous mice (i.e., B6.Cg-FcgrttmlDcr Tg(FCGRT)32Dcr / DcrJ; The Jackson Laboratory stock number 014565; or as described in Roopenian et al., J. Immunol 2003; 170:3528-3533). Plasma levels of protein are assessed using ELISA using commercially available methods.

[0613] Immunoglobulin clearance

[0614] In one example, the ability of a protein of the disclosure to reduce levels of circulating immunoglobulin is assessed.

[0615] For example, a known tracer antibody, e.g., IgGl antibody, is administered to a subject, e.g., a mouse. The protein of the disclosure is then administered and the level of the antibody is determined at various time points. A protein induces more rapid reduction in the level of the tracer antibody than is observed in the absence of the protein.

[0616] In another example, the level of endogenous immunoglobulin, e.g., IgG is determined in the presence or absence of the protein.

[0617] Compositions

[0618] In some examples, a protein as described herein can be administered orally, parenterally, by inhalation spray, adsorption, absorption, topically, rectally, nasally, bucally, vaginally, intraventricularly, via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, or by any other convenient dosage form. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrastemal, and intracranial injection or infusion techniques.

[0619] Methods for preparing a protein into a suitable form for administration to a subject (e.g. a pharmaceutical composition) are known in the art and include, for example, methods as described in Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Co., Easton, Pa., 1990) and U.S. Pharmacopeia: National Formulary (Mack Publishing Company, Easton, Pa., 1984).

[0620] The pharmaceutical compositions of this disclosure are particularly useful for parenteral administration, such as intravenous administration or administration into a body cavity or lumen of an organ or joint. The compositions for administration will commonly comprise a solution of protein dissolved in a pharmaceutically acceptable carrier, for example an aqueous carrier. A variety of aqueous carriers can be used, e.g., buffered saline and the like. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. The concentration of proteins of the present disclosure in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient's needs. Exemplary carriers include water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Nonaqueous vehicles such as mixed oils and ethyl oleate may also be used. Liposomes may also be used as carriers. The vehicles may contain minor amounts of additives that enhance isotonicity and chemical stability, e.g., buffers and preservatives.

[0621] Upon formulation, proteins of the present disclosure will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically / prophylactically effective. Formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but other pharmaceutically acceptable forms are also contemplated, e.g., tablets, pills, capsules or other solids for oral administration, suppositories, pessaries, nasal solutions or sprays, aerosols, inhalants, liposomal forms and the like. Pharmaceutical "slow release" capsules or compositions may also be used. Slow release formulations are generally designed to give a constant drug level over an extended period and may be used to deliver compounds of the present disclosure.

[0622] W02002 / 080967 describes compositions and methods for administering aerosolized compositions comprising antibodies for the treatment of, e.g., asthma, which are also suitable for administration of a protein of the present disclosure.

[0623] One skilled in the art would be able, by routine experimentation, to determine what an effective dose of the protein of the disclosure would be for the purpose of treating or preventing a disorder as described herein in a subject as described herein. For example, a therapeutically active amount of a protein may vary according to factors such as the disease stage, age, sex and weight of the subject, and the ability of the compound to elicit a desired response in the subject. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, the optimum therapeutic response may be a reduction in frequency of a symptom of a disorder as described herein. In one example, a method of the disclosure reduces the frequency of a symptom of a disorder as described herein.

[0624] In one example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Generally, however, an effective dosage is expected to be in the range of about 1 to 200 mg / kg body weight. Furthermore, an effective dosage is expected to be administered at least one or more times, such as every 7-30 days, such as every 10-22 days, for example, every 10-15 days.

[0625] Administration of a compound according to the methods of the present disclosure can be continuous or intermittent, depending, for example, on the subject’s physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. For example, the compound described herein may be administered prior to, during or after development of a disorder as described herein, or pro re nata. In one example, the compound is administered pro re nata. For example, the compound is administered at the onset of a disorder as described herein, or a symptom thereof.

[0626] Uses of the Multifunctional FcRn Antagonists

[0627] The protein compositions of the present disclosure are particularly useful for reducing the serum levels of immunoglobulin or other Fc-containing agents (e.g., antibody-drug conjugates and immunoadhesins). Accordingly, in one example the disclosure provides a method of inhibiting FcRn function in a subject, the method generally comprising administering to the subject an effective amount of a protein or pharmaceutical composition comprising the protein of the disclosure.

[0628] The reduction of serum levels of immunoglobulin or Fc-containing agents is applicable to the treatment of antibody-mediated disorders (e.g. autoimmune diseases). Accordingly, in one example the instant disclosure provides methods of treating antibody-mediated disorders (e.g. autoimmune diseases) using the protein and compositions disclosed herein.

[0629] Any antibody-mediated disorder can be treated using the protein and compositions disclosed herein. The proteins of the instant disclosure are suited to treating antibody-mediated disorders characterized by an over production of serum immunoglobulin. Accordingly, in some examples, the FcRn antagonist compositions are used to treat hypergammaglobulinemia.

[0630] The FcRn antagonists can also be used in combination with one or more additional therapeutic agents. For example, the additional therapeutic agent is the standard of care for the condition to be treated. In some examples, the additional therapeutic agent is an anti-inflammatory agent. In examples, the additional therapeutic agent is leucocyte depleting agent (e.g., B-cell or T-cell depleting agent). Any leucocyte depleting agent can be used in combination with the protein disclosed herein. In some examples, the leucocyte depleting agent is a B-cell depleting agent. In some examples, the leucocyte depleting agent is an antibody against a cell surface marker. Suitable cell surface markers include, without limitation, CD 10, CD 19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, or CD86. The protein of the disclosure and the additional therapeutic agent(s) can be administered to the subject simultaneously or sequentially, via the same or different route(s) of administration.

[0631] The proteins of the instant disclosure are also suited to reducing the serum levels of an Fc-containing agent in the subject. For example, wherein the Fc-containing agent is a labelled antibodies, antibody drug conjugates or non-human immunoglobulin or immunoadhesins. Such clearance is advantageous in cases where the Fc-containing agent is toxic (e.g., an antibody-drug conjugate or an agent that is immunogenic) because it reduces the exposure of the subject to the drug. Clearance is also advantageous in cases where the Fc-containing agent is an imaging agent that requires a low serum level of the agent to achieve better contrast imaging and / or minimise damage to normal tissue when the Fc-containing agent is radiolabelled. Accordingly, in some examples, the proteins of the disclosure are used to reduce the serum levels of an Fc-containing agent in a subject.

[0632] In one example, the proteins disclosed herein enhance the benefit of the target binding domain to the soluble molecule by reducing the levels of IgG, wherein IgG is responsible for the decreased bioavailability of protein.

[0633] In some examples the disclosure provides a method of reducing or preventing an immune response against the target binding domain.

[0634] One skilled in the art would be able, by routine experimentation, to determine what an effective, non-toxic amount of the protein of the disclosure would be for the purpose of treating a disorder described herein. For example, a therapeutically active amount of a polypeptide may vary according to factors such as the disease stage (, age, sex, medical complications (e.g., immunosuppressed conditions or diseases) and weight of the subject, and the ability of the antibody to elicit a desired response in the subject. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. Generally, however, an effective dosage is expected to be in the range of about 1 to 200 mg / kg body weight.

[0635] Kits and Other Compositions of Matter

[0636] Another example of the disclosure provides kits containing a protein of the present disclosure useful for the reducing circulating antibodies in a subject in need thereof, the kit comprising:

[0637] (i) at least one protein or pharmaceutical composition or nucleic acid of the disclosure; and

[0638] (ii) instructions for using the kit in reducing circulating antibodies in the subject.

[0639] The disclosure also provides a kit for treating or preventing progression of an antibody-mediated disorder in a subject in need thereof, the kit comprising:

[0640] (i) at least one protein or pharmaceutical composition or nucleic acid of the disclosure; and

[0641] (ii) instructions for using the kit in treating or preventing progression of an antibody- mediated disorder in the subject.

[0642] The disclosure also provides a kit for treating or preventing progression of an inflammatory -mediated disorder in a subject in need thereof, the kit comprising:

[0643] (i) at least one protein or pharmaceutical composition or nucleic acid of the disclosure; and

[0644] (ii) instructions for using the kit in treating or preventing progression of an inflammatory -mediated disorder in the subject.

[0645] In accordance with this example of the disclosure, the instructions (or package insert) is on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, etc. The containers may be formed from a variety of materials such as glass or plastic. The label or package insert indicates that the protein or composition thereof is used for treating a subject eligible for treatment, e.g., one having or predisposed to developing a condition described herein, with specific guidance regarding dosing amounts and intervals of the protein and any other medicament being provided. The kit may further comprise an additional container comprising a pharmaceutically acceptable diluent buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and / or dextrose solution. The kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0646] The present disclosure is further defined in the following numbered paragraphs. Unless this would result in a contradiction, the embodiments of the following paragraphs can be combined with any of the above examples and provide further details on certain aspects of the disclosure.

[0647] 1. A protein comprising:

[0648] (i) a target binding domain, wherein the target binding domain specifically binds to a soluble molecule associated with inflammation; and

[0649] (ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

[0650] 2. The protein of paragraph 1, wherein the target binding domain is:

[0651] (i) a Fv;

[0652] (ii) a single chain Fv fragment (scFv);

[0653] (iii) a dimeric scFv (di-scFv);

[0654] (iv) a nanobody;

[0655] (v) a minibody;

[0656] (vi) a diabody;

[0657] (vii) a triabody;

[0658] (viii) a tetrabody;

[0659] (ix) a Fab;

[0660] (x) a F(ab’)2;

[0661] (xi) a lipocalin;

[0662] (xii) an anticalin;

[0663] (xiii) a soluble receptor;

[0664] (xiv) a T-cell receptor;

[0665] (xv) an adnectin;

[0666] (xvi) an affibody;

[0667] (xvii) an avimer; or (xviii) a designed ankyrin repeat protein (DARPin).

[0668] 3. The protein of paragraph 1 or paragraph 2, wherein the target binding domain is an antigen binding domain of an antibody.

[0669] 4. An antibody comprising:

[0670] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0671] (ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

[0672] 5. The protein of any one of paragraphs 1 to 3, or the antibody of paragraph 4, wherein on administering the protein or antibody to a subject, binding of the target binding domain to the soluble molecule causes a reduction in a level of the soluble molecule in circulation of the subject and / or binding of the modified IgG Fc to FcRn causes reduced circulating Fc-containing proteins and / or antibodies in the subject.

[0673] 6. The protein of any one of paragraphs 1 to 3 or 5, or the antibody of paragraphs 4 or 5, wherein the modified Fc region comprises one or more amino acid substitutions selected from the group consisting of:

[0674] (i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system;

[0675] (ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system;

[0676] (iii) alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system;

[0677] (iv) tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system,

[0678] (v) glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system;

[0679] (vi) proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system; (vii) glycine substituted for proline at a position corresponding to amino acid 329 according to the EU numbering system;

[0680] (viii) tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and

[0681] (ix) combinations thereof.

[0682] 7. The protein or antibody of paragraph 6, wherein the modified Fc region comprises:

[0683] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0684] (ii) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0685] 8. The protein or antibody of paragraph 7, wherein the modified Fc region further comprises:

[0686] (i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system; or

[0687] (ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

[0688] 9. An antibody comprising:

[0689] (i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and

[0690] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0691] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0692] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0693] 10. The protein of any one of paragraphs 1 to 3, or 5 to 8, or the antibody of any one of paragraphs 4 to 9, wherein the target binding domain specifically binds to the soluble molecule at neutral and acidic pH.

[0694] 11. The protein of any one of paragraphs 1 to 3, 5 to 8 or 10, or the antibody of any one of paragraphs 4 to 10, wherein the target binding domain specifically binds and inhibits the soluble molecule.

[0695] 12. The protein of any one of paragraphs 1 to 3, 5 to 8 or 10 to 11, or the antibody of any one of paragraphs 3 to 11, wherein the soluble molecule is selected from the group consisting of a B-lymphocyte stimulator (BLyS), a complement component, a cytokine, a chemokine, an enzyme, a coagulation factor and combinations thereof.

[0696] 13. The protein or antibody of paragraph 12, wherein:

[0697] (i) the complement component is C2 and / or C2b,

[0698] (ii)the coagulation factor is Factor XII or an activated form thereof;

[0699] (iii)the enzyme is urokinase-type plasminogen activator (uPA);

[0700] (iv)the cytokine is interleukin 6.

[0701] 14. The protein or antibody of paragraphs 12 or 13, wherein the soluble molecule is a human soluble molecule. 15. The protein of any one of paragraphs 3, 5 to 8 or 10 to 14, or the antibody of any one of paragraphs 4 to 14, wherein the antibody is a monospecific or a multispecific antibody.

[0702] 16. The protein or antibody of paragraph 15, wherein the multispecific antibody is a bispecific antibody.

[0703] 17. The protein of any one of paragraphs 1 to 3, 5 to 8, or 10 to 16, or the antibody of any one of paragraphs 4 to 16, wherein the target binding domain corresponds to, or is derived from, an antigen binding domain of an antibody selected from the group consisting of adalimumab, belimumab, bimekizumab, golimumab, guselkumab, infliximab, ixekizumab, lebrikizumab, mirikizumab, netakimab, olokizumab, ozoralizumab, risankizumab, secukinumab, siltuximab, sutimlimab, tezepelumab, tildrakizumab, tralokinumab, ustekinumab, vunakizumab, ebdarokimab, xeligekimab, garadacimab, abelacimab, cendakimab, clazakizumab, dazukibart, depemokimab, garetosmab, gefurulimab, itepekimab, pamrevlumab, picankibart, sibeprenlimab, tozorakimab, gumokimab, ziltivekimab, suvemcitug, and combinations thereof.

[0704] 18. The protein of any one of paragraphs 1 to 3, 5 to 8, or 9 to 16, wherein the target binding domain corresponds to, or is derived from, a soluble receptor domain of a molecule selected from the group consisting of atacicept, aflibercept, briobacept, conbercept, etanercept, dalantercept, inbakicept, lenercept, luspatercept, olamkicept, opinercept, povetacicept, ramatercept, sotatercept, sozinibercept, telitacicept, tulinercept.

[0705] 19. An antibody comprising:

[0706] (i) a target binding domain that specifically binds to a blood soluble molecule selected from the group consisting of complement component C2 / C2b, Factor Xll / XIIa, urokinase-type plasminogen activator (uPA), interleukin 6 and combinations thereof; and

[0707] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0708] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0709] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

[0710] 20. An antibody comprising:

[0711] (i) a target binding domain that specifically binds to complement component C2 / C2b; and

[0712] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0713] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0714] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0715] (A) a light chain variable region (VL) comprising:

[0716] (i) a complementarity determining region (CDR)l comprising a sequence set forth in SEQ ID NO: 91; and

[0717] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 92; and

[0718] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 93; and a heavy chain variable region (VH) comprising:

[0719] (i) a CDR1 comprising a sequence set forth in SEQ ID NO: 94; and

[0720] (ii) a CDR2 comprising a sequence set forth in SEQ ID NO: 95; and

[0721] (iii) a CDR3 comprising a sequence set forth in SEQ ID NO: 96; or (B) a VL comprising a sequence set forth in SEQ ID NO: 7 and a VH comprising a sequence set forth in SEQ ID NO: 16.

[0722] 21. An antibody comprising:

[0723] (i) a target binding domain that specifically binds to Factor XH / XIIa; and

[0724] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0725] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0726] (ii) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0727] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 1 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 9; or

[0728] (ii) a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 10; or

[0729] (iii)a VL comprising a sequence set forth in SEQ ID NO: 2 and a VH comprising a sequence set forth in SEQ ID NO: 11.

[0730] 22. An antibody comprising:

[0731] (i) a target binding domain that specifically binds to interleukin 6; and

[0732] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0733] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0734] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0735] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 3 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 12; or

[0736] (ii) a VL comprising a sequence set forth in SEQ ID NO: 4 and a VH comprising a sequence set forth in SEQ ID NO: 13.

[0737] 23. An antibody comprising:

[0738] (i) a target binding domain that specifically binds to urokinase-type plasminogen activator (uPA); and

[0739] (ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:

[0740] (i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or

[0741] (ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and wherein the target binding domain comprises:

[0742] (i) a light chain variable region (VL) comprising a sequence set forth in SEQ ID NO: 5 and a heavy chain variable region (VH) comprising a sequence set forth in SEQ ID NO: 14; or (ii) a VL comprising a sequence set forth in SEQ ID NO: 6 and a VH comprising a sequence set forth in SEQ ID NO: 15.

[0743] 24. The protein of any one of paragraphs 1 to 3, 5 to 8 or 10 to 18, or the antibody of any one of paragraphs 4 to 23, wherein the modified Fc region is from an IgGl or an IgG4 constant region.

[0744] 25. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24, or the antibody of any one of paragraphs 4 to 24, wherein the modified Fc region is from a stabilized IgG4 constant region.

[0745] 26. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 25, or the antibody of any one of paragraphs 4 to 25, wherein the modified Fc has a reduced ability to induce effector function.

[0746] 27. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 26, or the antibody of any one of paragraphs 4 to 26, wherein the binding affinity of the Fc to FcRn is measured at neutral and / or acidic pH.

[0747] 28. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 27, or the antibody of any one of paragraphs 4 to 27, wherein the protein or antibody has a reduced circulating blood plasma half-life compared to a protein or antibody with an unmodified Fc domain.

[0748] 29. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 28, or the antibody of any one of paragraphs 4 to 28, wherein the protein or antibody has prolonged and / or increased in vivo target inhibition and / or FcRn inhibition compared to a protein or antibody with an unmodified Fc domain.

[0749] 30. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 29, or the antibody of any one of paragraphs 4 to 29, wherein the modified Fc is an IgGl Fc further comprises the following amino acid substitutions:

[0750] (i) an alanine substituted for leucine at a position corresponding to amino acid 234 and an alanine substituted for leucine at a position corresponding to amino acid 235; and / or

[0751] (ii) a glycine substituted for a proline at a position corresponding to amino acid 329, wherein the amino acid substitutions are according to the EU numbering system.

[0752] 31. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 30, or the antibody of any one of paragraphs 4 to 30, wherein the modified Fc is indirectly linked to the target-binding domain of the antibody via a linker.

[0753] 32. The protein or antibody of paragraph 31, wherein the linker is a peptide linker comprising between 2 and 31 amino acids in length.

[0754] 33. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 32, or the antibody of any one of paragraphs 4 to 32, wherein the modified Fc is directly linked to the target binding domain of the antibody.

[0755] 34. The protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 33, or the antibody of any one of paragraphs 4 to 33, for use as a medicament.

[0756] 35. A composition comprising the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, and a pharmaceutically acceptable carrier.

[0757] 36. The composition of paragraph 35, for use in treating or preventing an inflammatory mediated condition in a subject.

[0758] 37. The composition of paragraph 35, for use in reducing circulating Fc-containing proteins and / or antibodies in a subject in need thereof.

[0759] 38. The composition of paragraph 35, for use in treating or preventing progression of an antibody-mediated disorder in a subject in need thereof.

[0760] 39. The composition of paragraph 25, for use in reducing anti-donor alloantibodies in a subject in need thereof.

[0761] 40. A method of reducing circulating antibodies in a subject in need thereof, the method comprising administering the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, or the composition of paragraph 35 to the subject. 41. A method of treating or preventing progression of an antibody -mediated disorder in a subject in need thereof, the method comprising administering the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, or the composition of paragraph 35 to the subject.

[0762] 42. A method of treating or preventing an inflammatory mediated condition in a subject, the method comprising administering the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, or the composition of paragraph 35 to the subject.

[0763] 43. A method of reducing anti-donor alloantibodies in a subject in need thereof, method comprising administering the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, or the composition of paragraph 35 to the subject.

[0764] 44. Use of the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, in the manufacture of a medicament for reducing circulating antibodies in a subject in need thereof.

[0765] 45. Use of the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, in the manufacture of a medicament for treating or preventing progression of an antibody-mediated disorder in a subject in need thereof.

[0766] 46. Use of the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, in the manufacture of a medicament for treating or preventing an inflammatory mediated condition in a subject.

[0767] 47. Use of the protein of any one of paragraphs 1 to 3, 5 to 8, 10 to 18, or 24 to 34, or the antibody of any one of paragraphs 4 to 34, in the manufacture of a medicament for reducing anti-donor alloantibodies in a subject in need thereof.

[0768] 48. The composition for use of any one of paragraphs 36 to 39, or the method of any one of paragraphs 40 to 43, or the use of any one of paragraphs 44 to 47, wherein the subject is suffering from an autoimmune disease, is a transplant recipient and has developed or is at risk of developing anti-donor antibodies, or has developed anti-drug antibodies or is at risk of developing anti-drug antibodies.

[0769] 49. The composition for use, the method or the use of paragraph 48, wherein the protein or the antibody or the composition is administered in an amount effective to reduce endogenous IgG levels by at least 30% (compared to in the absence of protein or antibody administration).

[0770] 50. The composition for use, the method or the use of paragraph 48 or paragraph 49, wherein the protein, or the antibody, or the composition antagonizes IgG recycling.

[0771] 51. The composition for use of paragraph 36, or the method of paragraph 42 or the use of paragraph 46, wherein the inflammatory-mediated condition is selected from the group consisting of Achalasia, Addison’s disease, Adult Still’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, ANCA-associated vasculitis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, anti-phospholipid syndrome, antibody mediated rejection, Antiphospholipid syndrome, atypical haemolytic-uremic syndrome, autoimmune haemolytic anemia, Autoimmune angioedema, Autoimmune dysautonomia, Autoimmune encephalitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid (Mucous membrane pemphigoid), Bullous pemphigoid, C3- glomerulonephritis, Castleman disease (CD), Celiac disease, cerebral infarction, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy), Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, delayed graft function, Dense Deposit Disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, glomerulosclerosis, Goodpasture’s syndrome, Granulomatosis with polyangiitis, graft salvage, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis suppurativa (HS) (Acne inversa), Huntington’s disease, IgA nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), ischemia-reperfusion injury, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), motor neuron disease, Mucha-Habermann disease, Multifocal motor neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myelin oligodendrocyte glycoprotein antibody disorder, Myositis, Narcolepsy, Neonatal lupus, nephritides, Nephropathy, IgA nephropathy, Neuromyelitis optica / devic disease, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections), Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Pars planitis (peripheral uveitis), Parkinson’s disease,, Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cholangitis, Primary sclerosing cholangitis, Progesterone dermatitis, Progressive hemifacial atrophy (PHA) Parry romberg syndrome, Psoriasis, Psoriatic arthritis, Pulmonary Alveolar Proteinosis (PAP), Pure red cell aplasia (PRCA), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive arthritis, Relapsing polychondritis, renal scarring, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome or Autoimmune poly endocrine syndrome type II, Scleritis, Scleroderma, Sjogren’s, Stiff person syndrome (SPS), ischemic stroke, somatic trauma, Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis / giant cell arteritis, Thrombocytopenic purpura (TTP), Thrombotic thrombocytopenic purpura (Ttp), Thyroid Eye Disease (TED), Tolosa-Hunt syndrome (THS), transplant rejection, antibody-mediated graft rejection, Transverse myelitis, traumatic brain injury, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt- Koyanagi-Harada disease, Warm autoimmune hemolytic anemia and combinations thereof. The present disclosure includes the following non-limiting Examples.

[0772] EXAMPLES

[0773] Example 1: Generation of multifunctional FcRn antagonists Multiple multifunctional FcRn antagonists were generated with different target specificities (Table 1) on wildtype (WT) or modified IgG Fc backbones (i.e., IgGl Fc and IgG4 Fc). Modified Fc backbones incorporated different Fc modifications including ‘YPY’ (M252Y, V308P, N434Y), ‘YPY’ plus ‘LALA’ (L234A, L235A, M252Y, V308P, N434Y), ‘YEY’ (M252Y, N286E, N434Y), or ‘YEY’ plus ‘LALA’ (L234A, L235A, M252Y, N286E, N434Y).

[0774] Table 1: Exemplary multifunctional FnRn antagonists with wildtype (WT) Fc and ‘YPY’ and ‘YEY’ Fc domain modifications

[0775]

[0776]

[0777]

[0778] Example 2: Binding affinity of soluble human FcRn / p2m to multifunctional FcRn antagonists

[0779] The affinity of soluble human FcRn / p2m (analyte) to anti-FXII / FXIIa or anti-C2 antibodies in Table 1 with and without YPY and YEY Fc modifications (ligand) was determined at 37°C using surface plasmon resonance instruments (Biacore™ 8K instrument). Briefly, human FcRn / p2m was injected at increasing concentrations onto antibodies (ligands) captured onto the respective antigen surface pre-immobilised on a carboxymethyl dextran surface of CM5 sensorchips using standard NHS / EDC chemistry at pH 5. Each antibody was captured at the beginning of each cycle to approximately -4,000 RU. Analyte-ligand interactions were measured at either pH 7.3 or pH 6.0. Analyte concentrations range from 0.2 to 50 pM at pH 7.3, and from 0.02 to 5 pM when tested at pH 6.0. Analyte samples were prepared in 2-fold serial dilutions from a 50 pM stock prepared in the appropriate running buffer adjusted to either pH 7.3 or 6.0. Each analyte concentration was tested in duplicate. Human FcRn / p2m (2 pg / mL) was used for surface conditioning. Analyte association and dissociation were monitored for 120 and 300 seconds, respectively. The ligand surface was regenerated with two short (30s) pulses of IM Tris-HCl pH 8. Sensorgrams were double referenced using reference surface and blank buffer injection data. Rate constants and binding affinities were calculated using Biacore™ Insight Evaluation software (Cytiva™ Live Sciences) by fitting the raw sensorgram data obtained at pH 6.0 to a 1 : 1 kinetic model with local Rmax and null refraction index (RI=0) or raw sensorgram data obtained at pH 7.3 to a steadystate 1 : 1 model with global Rmax and null refraction index (RI=0).

[0780] Antibodies with specificity for FXII / FXIIa or C2 with modified Fc domains (incorporating YPY or YEY Fc mutations) had a markedly enhanced affinity for FcRn at acidic pH (up to -1000 fold for YPY) compared to antibodies with a WT backbone. Binding of antibodies with a YPY Fc backbone was approximately 10-fold higher compared to binding of antibodies with a YEY Fc. In addition, antibodies with YEY or YPY Fc modifications were able to interact with FcRn at neutral pH, with affinities in the range of 1464 to 3043 nM, on both IgGl and IgG4 backbones with or without LALA modifications. As expected, minimal interaction of antibodies with WT backbone with FcRn was observed at neutral pH.

[0781] The binding affinities of soluble human FcRn / p2m against the surface-captured antibodies are shown in Tables 2-5. Table 2. Binding affinity of soluble human FcRn / p2m measured against surface- captured anti-FXII / FXIIa antibodies at pH 6,0,

[0782] Table 3. Binding affinity of soluble human FcRn / p2m measured against surface- captured anti-FXII / FXIIa antibodies at pH 7,3,

[0783] Table 4. Binding affinity of soluble human FcRn / p2m measured against surface- captured anti-complement C2 antibodies at pH 6,0, Table 5. Binding affinity of soluble human FcRn / p2m measured against surface- captured anti-complement C2 antibodies at pH 7,3, Example 3: Binding affinity of multifunctional FcRn antagonists to recombinant soluble antigens under neutral (pH 7.3) and acidic (pH 6.0) conditions

[0784] The affinity of soluble antigens including human complement C2 proteins (e.g. C2 zymogen and activated C2b domain) and soluble activated FXIIabeta to their respective anti-C2 and anti-FXII / FXIIa antibodies was determined at 37°C using surface plasmon resonance instruments (Biacore™ 8K and 4000 instruments).

[0785] Briefly, soluble antigens (analyte) were injected at increasing concentrations (1.95 nM to 500 nM) onto antibodies (ligands) captured onto an anti-human IgG surface. The capture surface was prepared by immobilising anti-human IgG onto the carboxymethyl dextran surface of CM5 sensorchips to -14,000 RU using standard NHS / EDC chemistry at pH 5. Analyte association and dissociation were monitored for 120 and 600 seconds, respectively. The flow rate remained constant at 30 pl / min during analyte analysis. Sensorgram data was double subtracted using reference surface and blank buffer injection data obtained within each experiment. Rate constants (ka and kd) and affinity values (KD) were calculated using Biacore™ Insight Evaluation software (Cytiva™ Live Sciences) by fitting the raw sensorgram data to a 1 : 1 kinetic model adjusted for local Rmax and null refraction index (RI=0) software.

[0786] The immobilised anti -human IgG surface was pre-conditioned with ten injections (30s each) of polyclonal IgG, prepared at 2 pg / mL before affinity analysis. Ligand levels in the active spot of each flow cell ranged from 100 to 200 RU in each cycle. No antibody was captured onto the reference channel used forbackground subtraction. Unreacted sites and reference surfaces were treated with 30s injection of 1 pg / mL of polyclonal IgG before analyte injections. Active and reference surfaces were regenerated at the end of each experimental cycle with 100 mM H3PO4 (60s). The impact of local pH conditions on the interaction was evaluated in buffers prepared at pH 6.0 (e.g. citrate buffer) or pH 7.3 (e.g. Hepes). Each analyte concentration was tested in duplicate injections. Buffers and solutions were filtered (0.22 pm) immediately before use.

[0787] Antibodies with specificity for FXII / FXIIa and Complement C2 / C2b were investigated for binding affinity to their antigens at both neutral and acidic pH (as shown in Tables 6-9) by SPR. All antibodies retained binding to target at acidic pH albeit with relatively low affinity as compared to binding at neutral pH for some antibodies. Binding to antigen target was largely unaffected by Fc modification or IgGl or IgG4 backbone. Table 6. Binding affinity of FXIIaBeta measured against surface-captured anti-

[0788] FXII / FXIIa antibodies at pH 7,3,

[0789] NB = no binding Table 7. Binding affinity of FXIIaBeta measured against surface-captured anti

[0790] Table 8. Binding affinity of human complement C2 zymogen (huC2) and activated C2 (huC2b) proteins measured against surface captured anti-huC2 / C2b antibodies at pH 7,3, mAb (Ligand) Analyte ka (1 / Ms) kd (1 / s) Kp (nM) N

[0791] 4D8LC05_G4[YPY] huC2 pH 7.3 5.19E+04 5.62E-04 10.9 22

[0792] 4D8LC05_G4[YPY] huC2b pH 7,3 3.38E+04 7.89E-04 23,4 20

[0793] Table 9. Binding affinity of human complement C2 zymogen (huC2) and activated C2 (huC2b) proteins measured against surface captured anti-huC2 / C2b antibodies at pH 6,0, mAb (Ligand) Analyte ka (l / Ms) kd (1 / s) Kp (nM) N

[0794] 4D8LC05_G4[YPY] huC2 pH 6.0 1.04E+05 8.63E-04 8.4 4

[0795] 4D8LC05 G4[YPY] huC2b pH 6,0 2.47E+04 9.84E-04 39,9 4 Example 4: Reactivity of multifunctional FcRn antagonists with target antigen by ELISA

[0796] To determine the reactivity of multifunctional FcRn antagonists with their target protein antigen, ELISA assays were performed.

[0797] Briefly, wells of a 96 well plate were coated with 100 pl of the target proteins at 2 ug / ml concentration and incubated at 4°C overnight. Proteins used as target were human FXIIa (Enzyme Research Laboratories™ cat# HFXIIa 1212a), murine IL-6 (R&D systems™, cat #406-ML), and murine uPA (R&D Systems™ cat# 1114-SE). The next day the wells were blocked with 200 pl per well of 4% skim milk in TBS (pH7.4) / T0.05 for 1 hour at room temperature. Then antibody dilutions in 4% skim milk in TBS / T0.05 were added and incubated for one hour. The plate was washed 5x with TBS / T0.05 and then 100 pl per well of anti (human-Fc)-HRP (Jackson ImmunoResearch Laboratories Inc.™ cat# 109-035-098) at a 1 / 5000 dilution was added and incubated for one hour. The plate was washed 5x with TBS / T0.05 followed by developing with 100 pl per well of TMB substrate for 10 minutes. The reaction was quenched with 50 pl per well of 2M phosphoric acid and the absorbance was read at 450 nM in the Ensight™ plate reader.

[0798] As shown in Figure 1A, anti-FXII / FXIIa antibodies 3F7 and 3F7-VR112 interacted with FXIIa as expected, with or without modification of the Fc domain with YPY or LALA-YPY and whether on human IgGl or IgG4 backbone. Similarly, in Figure IB, anti-IL-6 (ALD518-P18) and Figure 1C, anti-uPA (mUl) antibodies reacted with murine IL-6 and murine uPA respectively, independent of Fc modifications or whether on human IgGl or IgG4 backbones.

[0799] Example 5: Potent inhibition of FXIIa by anti-FXII / FXIIa multifunctional FcRn antagonists in a chromogenic assay

[0800] To determine whether the anti-FXII antibodies inhibited FXIIa activity, a chromogenic assay was performed.

[0801] Briefly, in each well of a 96 well plate, 20 pl of FXIIa (Enzyme Research Laboratories™ cat# HFXIIa 1212a) at 0.05 pg / pl in assay buffer (200 mM Tris / HCl pH 7.8; final FXIIa concentration 0.005 pg / pl) was mixed with 40 pl assay buffer and 100 pl of antibodies and incubated at 37°C for 30 min to 1 h. Then 40 pl chromogenic FXII substrate S2302 (Chromogenix™ cat# 439454; final concentration in the assay 0.8 mM) was added and incubated at 37°C for 15 min. The reaction was subsequently stopped with 40 pl 20% acetic acid and absorbance was read at 405 nm in an Ensight™ plate reader. A decrease in absorbance indicates inhibition of FXIIa activity. As shown in Figure 2, all anti-FXII / FXIIa antibodies potently inhibited FXIIa activity in the chromogenic assay, and potency did not appear to be impacted by Fc modifications including YPY or LALA mutations or whether on a IgGl or IgG4 backbone.

[0802] Example 6: Inhibition of coagulation by anti-FXII / FXIIa multifunctional FcRn antagonists in the aPTT assay

[0803] To determine whether the IgG backbone (IgGl or IgG4) or Fc modifications (YPY or YPY plus LALA) affected coagulation time of the anti-FXII / FXIIa antibodies, aPTT assays were performed. The aPTT assay measures the time it takes for a fibrin clot to form after the addition of activators of the intrinsic and common pathway of coagulation.

[0804] Briefly, citrated platelet-poor human plasma (PPP) from 10 males and 10 females was pooled and 405 pl of PPP was then incubated with 45 pl of antibody (at a final concentration of 1 uM).

[0805] The aPTT assay was carried out as per the Compact X™ clotting analyzer (Behnk Elektronik™) protocol. Briefly, this involved the fully automated addition of DAPTTIN TC (consisting of silica and sulfatide as surface activators, and a mixture of purified phospholipids) and CaCh to the PPP / antibody mixtures, incubation at 37°C and then measurement for fibrin clot formation.

[0806] As shown in Figure 3, all anti-FXII / FXIIa specific antibodies extended coagulation time with the affinity matured 3F7-VR112 variant of the anti-FXII / FXIIa antibody 3F7 more potent than the parental 3F7. Potency was not affected by backbone, IgGl or IgG4, or by inclusion of Fc modifications YPY or YPY plus LALA. The control antibody, BM4, had no effect on coagulation time. Data shown are mean of duplicate measurements for each antibody. The dashed line is for comparison with the coagulation time of FVIII-deficient plasma (n = 3 replicates), the solid line is for comparison with the coagulation time of control plasma (n = 5 replicates).

[0807] Example 7: Inhibition of uPA activity by anti-uPA multifunctional FcRn antagonists.

[0808] A uPA activity assay was used to determine if the anti-uPA antibodies would inhibit the functional activity of mouse two-chain uPA (tc-uPA).

[0809] Briefly, in a 96-well white opaque plate, anti-uPA antibodies and WT Fc control antibodies were pre-incubated with 50 ng / well of mouse two chain uPA (tc-uPA) (R&D systems™, #11143-SE) for 30 minutes at room temperature in 50 mM Tris, 0.01% (v / v) Tween 20, pH 8.5. The substrate Z-Gly-Gly-Arg-AMC HC1 (Bachem™, #4002155) was then added at a final concentration of 0.5 mM and the luminescence signal was immediately acquired every 5 minutes over a 2-hour period using a Tecan™ plate reader. The resulting increase in luminescence signal over time correlates with uPA activity. For each antibody concentration, the area under the curve (AUC) was determined and data points were fitted to a 4-parameter logistic curve fit using GraphPad Prism™.

[0810] As shown in Figure 4, all anti-uPA antibodies (mUl) were able to inhibit uPA activity, with no apparent impact of Fc modifications YPY or LALA-YPY or of Fc backbone, IgGl or IgG4.

[0811] Example 8: Inhibition of mouse IL-6 mediated proliferation by anti-IL-6 multifunctional FcRn antagonists

[0812] To investigate whether anti-IL6 antibodies inhibited mouse IL-6 mediated proliferation, a B9 proliferation assay was performed.

[0813] Briefly, mouse B9 cells (B cell hybridoma line, ECACC) were cultured in cell media (RPMI (Gibco™, cat #1875093) containing 10% FBS (Sigma™, cat #12003C), 100 U / ml penicillin / streptomycin (Gibco™, cat #15140-122), 2 mM Glutamax™ (Gibco™, cat # 35050-061), and 50 pg / mL human IL-6 (R&D systems™, cat #206-IL- 010 / CF) at 37°C with 5% CO2. Prior to use the cells were washed in assay media three times to remove any residual cytokine prior to the assay screen and then resuspended in Assay Media (RPMI (Gibco™) containing 10 % FBS (Sigma™), 100 U / ml penicillin / streptomycin (Gibco™, cat # 15140-122), 2 mM Glutamax (Gibco™, cat #35050-061)) and left to starve for 3 hours. Following starvation, the B9 cells were washed in assay media once and counted using the Vi-CELL™ cell counter. The cells were then resuspended to a density of 2 x 104cells / mL and 100 pl transferred to a 96 well tissue culture plate (TPP™, cat #92096) to achieve a final cell count of 2 x 103cells per well. Antibodies were prepared at 200 pg / ml (1.33 pM) and serially diluted 1 / 5 for 8 points, 50 pl was added to the corresponding cells to achieve a final starting concentration of 50 pg / ml (333.3 nM). The cells were then treated with 1 ng / ml mIL-6 (R&D systems, cat #406-ML-025) by preparing the stock solution to 4x the final concentration (4 ng / ml) and adding 50 pl to each well. The cells were incubated for 72 hours, at 37°C, 5% CO2. After the incubation the endpoint reading was measured using the Vialight™ Plus kit (Lonza™, cat #LT07-121) following the manufacturer’s instructions, (Vialight™, Lonza™, cell proliferation and cytotoxicity assays). Data was analysed in GraphPad Prism™ for IC50 values using a log(inhibitor) vs. response - Variable slope (four parameters) fit.

[0814] As shown in Figure 5, anti-IL-6 antibodies inhibited mouse IL-6 mediated proliferation of B9 cells and there was no significant difference between the parental antibody ALD518-P18 and the anti-IL6 antibody with the [YPY] Fc modification (ALD518-P 18_hG4[YPY]).

[0815] Example 9: Inhibition of human IL-6 mediated proliferation by anti-IL-6 multifunctional FcRn antagonists

[0816] To investigate whether anti-IL6 antibodies inhibited human IL-6 mediated proliferation, a human IL-6 cell proliferation assay was performed.

[0817] Briefly, HEK-Blue™ IL-6 cells (InvivoGen™, cat #hkb-hil6) were gently rinsed twice with pre-warmed phosphate buffered saline (PBS), and cells detached in the presence of PBS for 2-3 min at 37°C. Following centrifugation, cells were resuspended in fresh, pre-warmed Assay Media (DMEM high glucose (Sigma™, cat #D6546), 10 % FBS (Sigma™, cat #120030), 100 U / ml penicillin / streptomycin (Gibco™, cat # 15140- 122), 2 mM Glutamax™ (Gibco™, cat # 35050-061) at 5xl05cells / ml. Cells were plated at 5xl04cells per well by adding 100 pL of the cell suspension to each well. Antibodies were diluted to a starting concentration of 400 ng / ml and titrated 10-fold for 8 points. 50 pl of each antibody titration was added to the corresponding well to achieve a final top concentration of 100 ng / ml. Human IL-6 (R&D systems™, cat #206-IL-010 / CF) was diluted to 0.4 ng / ml and 50 pL was added to the wells to achieve a final concentration of 0.1 ng / ml. The plates were left to incubate for 24 hours at 37°C, 5% CO2. The following day Quanti-Blue™ (QB) solution (InvivoGen™, #rep-qbs) was prepared by adding the QB reagent and QB buffer at 1 / 100 in H2O. 180 pL of the Quanti-Blue solution was added to an empty 96 flat bottom plate. 20 pL of the cell supernatant was transferred to Quanti-Blue plate. The plate was placed into the incubator and left to incubate for 1.5-2 hours. Once the reaction had saturated, the plate was read on a Tecan plate reader using 620 nm wavelength. Data was analysed in Graph Pad Prism™ for IC50 values using a log(inhibitor) vs. response - Variable slope (four parameters) fit.

[0818] As shown in Figure 6, anti-IL-6 antibodies inhibited human IL-6 mediated proliferation of the HEK-Blue™ IL-6 cells and there was no significant difference between the parental antibody ALD518-P18 and the anti-IL6 antibody with the [YPY] Fc modification (ALD518-P18_hG4[YPY]). Example 10: In vitro complement activity of anti-C2 / C2b multifunctional FcRn antagonists

[0819] Wieslab complement in vitro assays were used to determine if the anti-huC2 / C2b antibody with the IgG4[YPY] modification (4D8LC05_G4[YPY]) was able to inhibit the huC2b activity comparable to the non-YPY version (4D8LC05 G4).

[0820] Wieslab assays for the classical, lectin and alternative pathways were performed using methods previously described (Wymann, S., et al, 2021; J Biol Chem 296, 100200) and according to the manufacturer’s recommendations (Svar, Sweden).

[0821] As shown in Figure 7, 4D8LC05 with and without YPY-Fc modification had comparable in vitro activity in the classical and lectin pathways and, as expected, did not inhibit the alternative pathway.

[0822] Example 11: Pharmacokinetic analysis of anti-FXII / XIIa multifunctional FcRn antagonists in wild-type mice

[0823] Pharmacokinetic (PK) analysis of anti-FXII / FXIIa antibodies or isotype control followed the specific quantification and bioanalytic evaluation of 3F7_G4[YPY], 3F7_G4, 3F7-VR112_G4[YPY], 3F7-VR112 G4 and BM4_G4[YPY] from C57BL / 6J mouse plasma samples after single IV dose administration was conducted. All antibodies were dosed at 30 mg / kg.

[0824] Blood sampling was performed after grouping animals in 2 cohorts (n=3 per timepoint). For cohort 1, samples were taken at pre-dose, 0.0833 h, 1 h, 8 h, 48 h, 96 h and 192 h whereas for cohort 2, samples were taken at pre-dose, 0.25 h, 3 h, 24 h, 72 h, 144 h, and 240 h. For both cohorts, samples were taken from vena saphena. The lower limit of quantitation (LLOQ) for tested antibodies was reported with 0.625 pg / mL for anti-FXII / FXIIa antibodies, and 1.250 pg / mL for BM4_G4[YPY],

[0825] The assessment of human IgG levels in samples taken from WT mice administered with anti-FXII / FXIIa, anti-IL6 and BM4 antibodies both on [YPY] or WT control backbones was performed by ELISA. Briefly, immuno-Plate Maxisorp plates were coated with goat anti-human IgG Fc antibody (Sigma™) in Carbonate-Bicarbonate Buffer (Sigma™) overnight at room temperature (RT). The plate was then washed three times with wash buffer (Tris-Buffered Saline with Tween 20; Thermo Scientific) and then incubated with a blocking solution (Tris Buffered Saline with 1% BSA; Sigma™) for 1.5 hr at RT. Following three washes, the plates were incubated (1.5 hr at RT) with dilution series of the test YPY antibodies and their respective unmodified Fc control antibodies diluted in wash buffer (TBS-T) to generate internal standard curves, as well as the mouse plasma samples taken at the time points described above post i.v. injection of 30 mg / kg of each test antibody to quantify huIgG levels over time. Every mouse plasma sample was measured in at least 5 different dilutions to guarantee sufficient data points. Plates were again washed as above and incubated with a goat-anti -huIgG Fc-HRP detection antibody (Sigma™) diluted in TBS-T for 1 hr at RT. Following final three washes, plates were incubated with l-step Ultra TMB-ELISA chromogen (Thermo Fisher™) for 30 minutes in the dark at RT. A stop solution (0.25 mM H2SO4) was applied and the plates then read at 450 nm.

[0826] A non-compartmental analysis (NCA) employing a sparse PK calculation method was performed to analyze the PK profiles of all antibodies. For treatment groups having values below LLOQ (BLQ) before the end of sampling time, LLOQ / 2 was taken for the first BLQ value observed after the last measured concentration. All other BLQ values were set as data missing. Accordingly, for groups 3F7_G4[YPY] and 3F7-G4, LLOQ / 2 (0.3125 pg / mL) was considered at 24 h post administration (p.a.) and for group BM4_G4[YPY] LLOQ / 2 (0.625 pg / mL) was considered at 48 h p.a. for PK analysis. Outlier evaluation was performed for 90% confidence by Dixon's Q test, a test intended to find outliers in very small datasets (Dean and Dixon, Analytical chemistry. 1951; 23(4):636-638), and additionally by plausibility check. Thereof calculated PK parameters not fulfilling quality parameters (adjusted R2> 0.85, percent extrapolated AUC < 20%, or span > 1.5 half-lives) were flagged as not reliable.

[0827] A NCA performed with Phoenix WinNonlin™ (version 8.3.1.5014) to compare the PK profiles demonstrated comparable time-concentration profiles for the FcfYPY] variants with FXII / FXIIa-binding (3F7_G4[YPY] and 3F7-VR112_G4[YPY]), as well as for the Fc[WT] variants with FXIEFXIIa-binding (3F7 G4 and 3F7-VR112 G4).

[0828] In comparison to the FcfYPY] variants with FXII / FXIIa binding, the isotype control (BM4_G4[YPY]) group had a slightly longer PK profile but was still markedly shorter than antibodies with WT Fc backbone (as shown in Table 10, Figure 8). All mAbs showed comparable Cmax and comparable Vc, suggesting initial plasmatic drug distribution.

[0829] For groups treated with FcfYPY] (3F7_G4[YPY] and 3F7-VR112_G4[YPY]), drug product was no longer detected after 8 h p.a., whereas it was not detected for BM4_G4[YPY] treatment group after 24 h p.a.

[0830] Since there was no impact on PK from affinity maturation of the FXII / FXIIa binding site, the difference between anti-FXII / FXIIa antibodies and isotype control may be due to, e.g.: FcRn binding differences related to the human kappa vs human lambda sequences in the constant part of the light chain; differences in the variable domains (different species, different isotype and different germline); or to differences in FXII / FXIIa binding of the anti-FXII / FXIIa antibodies.

[0831] The PK of Fc[WT] variants with FXII / FXIIa-binding was characterized by a steep initial slope up to ~8 h p.a. and a shallow slope during the terminal phase. Differences in PK were mostly attributed to the YPY modification in the Fc fragment, with lower AUCiast (~20-fold), short ti / 2 (>50-fold), MRT (>50-fold) and high clearance (>30-fold) as well as smaller steady state and terminal volumes of distribution (plasmatic vs. additional extraplasmatic distribution) of FcfYPY] variants as compared to Fc[WT] variants. The PK profiles of FcfYPY] variants is a likely reflection of the higher FcRn affinity of the FcfYPY] variants at neutral pH. Neutral pH binding facilitates FcRn mediated internalization, and antibodies with FcfYPY] are more likely to remain bound, blocking the FcRn site for recycling of not only endogenous IgG but that of the free FcfYPY] variant. In contrast, antibodies with WT Fc backbones have poor FcRn mediated cellular uptake and engage with FcRn only within the acidic environment of the endosomes following internalization by fluid phase endocytosis, a less efficient process than receptor mediated internalization, and are then recycled and released back into plasma.

[0832] Table 10: Key non-compartmental analysis parameters of pharmacokinetics (PK) of anti-FXII / FXIIa antibodies and isotype control detected in mouse plasma following a single intravenous injection at 30 mg / kg.

[0833] # At least one of the quality parameters is not fulfilled. Consider values with caution. Note: Cmax, AUCiast and Vcresults provide reliable comparison of all treatment groups

[0834] Example 12: Pharmacokinetic analysis of anti-IL6 multifunctional FcRn antagonists in wild-type mice

[0835] The PK of the anti-IL6 antibody (ALD518-P18_G4[YPY]) and its non-YPY control (ALD518-P18 G4) was examined in wild type mice. Experimental conditions including dose, number and type of animals, time points and methodology were as described for PK studies of anti-FXII / FXIIa antibodies abve, with the lower limit of quantitation (LLOQ) for detection of human IgG by ELISA determined as 1.25 pg / mL for both anti-IL6 antibodies. Inter-cohort variability of exposure of the WT Fc ALD518- P18 G4 group resulted in a zig-zagging PK profile, and an unreliable description of the terminal phase with adjusted R2 < 0.60, so only parameters not related to terminal phase were reported.

[0836] A NCA performed with Phoenix WinNonlin™ (version 8.3.1.5014) to compare the PK profiles demonstrated that time-concentration profiles for the ALD518- P18_G4[YPY] group had a significantly shorter PK profile than the WT Fc control group (ALD518-P18 G4) as also described above for the anti-FXII / FXIIa DuFO mAbs. Both mAbs showed comparable Cmax and CO, resulting in comparable Vc, suggesting initial plasmatic drug distribution (Table 11, Figure 9).

[0837] As shown in Figure 9, the PK profile of the ALD518-P18_G4[YPY] group was significantly shorter than that of the WT Fc control group ALD518-P18_G4, in line with the higher FcRn affinity of ALD518-P18_G4[YPY].

[0838] For the group treated with ALD518-P18_G4[YPY], drug product was no longer detected after 24 h p.a. In line with this observation, ALD518-P 18_G4[YPY] had a lower AUCiast (~10-fold) compared to the WT Fc group ALD518-P18 G4. The ALD518- P18_G4[YPY] group showed short ti / 2, MRT and high clearance as well as small steady state and terminal volumes of distribution suggesting plasmatic drug distribution.

[0839] Table 11: Key non-compartmental analysis parameters of pharmacokinetics (PK) of anti-IL6 antibodies and isotype control detected in mouse plasma following a single intravenous injection at 30 mg / kg. ND: Not determined based on uncertainty in terminal phase related to inter-animal and inter-cohort variability

[0840] Example 13: Antagonism of FcRn recycling by anti-FXII / XIIa and anti-IL6 multifunctional FcRn antagonists in wild-type mice The multifunctional FcRn antagonists of the disclosure were designed with two primary mechanisms, 1) antagonism of FcRn mediated recycling of IgG (including that of autoantibodies within the context of autoimmune disease or alloantibodies within a transplant setting) and 2) inhibition and / or depletion of a soluble mediator of inflammation, target X. Blood sampled from wild type mice for PK studies above was also examined for impact of antibodies on FcRn recycling through determining the levels of endogenous mouse IgG.

[0841] Briefly, endogenous mouse IgG levels were determined by ELISA from the mouse plasma samples. Immuno-Plate Maxisorp plates were coated with goat anti-mouse Ig antibody (Southern Biotech, USA) diluted in DPBS Buffer (GIBCO™) overnight at room temperature (RT). The plates were washed three times with wash buffer (Phosphate buffered saline with 0,05% Tween 20™; Thermo Scientific) and then incubated with a blocking solution (PBS with 1% BSA; Sigma™) for 1 hr at RT. After another three washes, a mouse IgG standard (Sigma™) diluted in wash-buffer (PBS-T) and mouse plasma samples were added to wells and incubated for 2 hr at RT. Every mouse plasma sample was measured in at least 5 different dilutions to guarantee sufficient data points. Plates were then washed as above, incubated with a goat anti-mouse IgGHRP conjugated detection antibody (Southern Biotech™, USA) diluted in wash buffer (PBS-T) for 1 hr at RT, washed again, then incubated with l-step Ultra TMB-ELISA chromogen (Thermo Fisher™) for 30 minutes in the dark at RT. A stop solution (0.25 mM H2SO4) was applied and the plates then read at 450 nm.

[0842] As shown in Figures 10 and 11, antibodies modified with YPY, were able to antagonise FcRn mediated recycling of IgG, as indicated by the reduction in endogenous murine IgG levels. Maximal endogenous IgG reduction varied from ~60 to 80 % for the different molecules and was observed between 48 to 96 hours post intravenous drug administration at 30 mg / kg.

[0843] Example 14: Pharmacokinetic analysis of anti-C2 / C2b multifunctional FcRn antagonists in wild-type mice

[0844] The antibodies 4D8LC05_G4[YPY] and 4D8LC05 G4 were administered as a single bolus intravenous injection in wild-type mice (n= 9 for [YPY] version and n= 12 for WT Fc version) in doses of 10 mg / kg. The [YPY] version was also administered in a dose of 100 mg / kg.

[0845] Blood sampling was performed after grouping animals in different cohorts (n=3 per timepoint). For animals administered the [YPY] version, samples were collected in 3 cohorts until 48 h post administration. For animals administered the WT Fc version, samples were collected in 4 cohorts until 168 hr. Pre-dose samples were also taken at 5 to 7 days prior to administration of test items. All samples were taken from retrobulbar plexus.

[0846] Evaluation of huIgG levels to assess the PK of the anti-huC2 / C2b mAbs was performed according to the ELISA described above with a few minor changes. A rabbit anti-human IgG4 antibody (GeneTex™) was used for coating, PBS with 0.05% Tween 20 (Sigma™) was used as wash buffer and Casein in PBS as blocking solution. A mouse anti-human IgG4_POD (Invitrogen™) was used to detect huIgG levels. As seen in for anti-FXII antibodies, the PK profile of the anti-C2 / C2b [YPY] group, was significantly shorter than that of the WT Fc control group. As shown in Figure 12, there was a dose dependent difference of the [YPY] group injected at 10 mg / kg versus 100 mg / kg.

[0847] Example 15: Antagonism of FcRn recycling by anti-C2 / C2b multifunctional FcRn antagonists in wild-type mice

[0848] Evaluation of mouse endogenous IgG levels was performed as described above using an enzyme-linked immunosorbent assay (ELISA) method specific for murine IgG. Pre-dose normalized endogenous IgG level was used to compare the efficacy of anti- huC2 / C2b antibodies in enhancing endogenous IgG clearance.

[0849] As demonstrated for other multifunctional FcRn antagonists, the anti-huC2 / C2b [YPY] antibody administered in wild type mice reduced the levels of endogenous IgG, reflecting its ability to antagonise FcRn IgG recycling (Figure 13).

[0850] Example 16: Pharmacokinetics and pharmacodynamics of anti-C2 / C2b multifunctional FcRn antagonists in cynomolgus monkeys

[0851] The antibodies 4D8LC05_G4[YPY] and 4D8LC05 G4 were administered intravenously at 10 mg / kg separately into cynomolgus monkeys, and both serum and plasma samples were collected at several time points post-administration, as well as samples taken pre-dose. The non-YPY control molecule 4D8LC05 G4 was also administered at 25 mg / kg.

[0852] Total circulating antibody levels were measured (pg / mL) from plasma at time points up to 696 hr post-administration using an ELISA-based method. Serum samples were assessed for classical and lectin pathway activity ex vivo using Wieslab™ complement inhibition assays specific for those pathways (Svar™, Sweden), according to the manufacturer’s recommendations and also as previously described (Wymann et al 2022 Biochem J). Total monkey IgG concentration was measured by a Cynomolgus Monkey ELISA kit (Hoelzel Biotech™, Germany), according to the manufacturer’s recommendations. Free C2 levels were measured using an ELISA-based method using anti-C2 mAbs generated in-house.

[0853] As observed in mice, PK exposure for the anti-C2 / C2b antibody [YPY] (4D8LC05_G4[YPY]) was less than parental antibody with WT backbone, consistent with engagement with FcRn and uptake at neutral pH (Figure 14).

[0854] In addition, as shown in Figure 15, the anti-C2 / C2b [YPY] antibody (4D8LC05_G4[YPY]) administered at 10 mg / kg in monkeys was effective at driving down the levels of endogenous monkey IgG, by approximately 30 %, consistent with its ability to antagonise FcRn recycling of IgG. In contrast, the levels of endogenous IgG in monkeys administered with the control anti-C2 mAb (hu4D8LC05-G4) were largely unaffected.

[0855] Administration of the anti-C2 / C2b [YPY] antibody (4D8LC05_G4[YPY]) resulted in a reduction in free C2 levels in plasma (Figure 16), similar to that observed with the parental antibody with WT backbone (i.e., without YPY], A rebound in free C2 levels was, however, observed earlier in monkeys dosed with the anti-C2 / C2b [YPY] molecule. Data obtained ex vivo by Wieslab assay of plasma samples diluted 1 : 100 suggested the anti-C2 / C2b [YPY] was more effective at reducing C2-mediated classical and lectin pathway activity than the parental antibody with WT backbone (Figure 17).

[0856] Example 17: Pharmacokinetic analysis of anti-uPA multifunctional FcRn antagonists in wild-type mice

[0857] Pharmacokinetic (PK) analysis of anti-uPA antibodies or isotype control followed the specific quantification and bioanalytic evaluation of mUl_G4[YPY], mUl_G4, BM4_G1[YPY] and BM4 G4 from male C57BL / 6J mouse plasma samples after single IV dose administration was conducted. All antibodies were dosed at 30 mg / kg.

[0858] Blood sampling was performed after grouping animals in 2 cohorts (n=3 per timepoint). For cohort 1, samples were taken at pre-dose, 0.0833 h, 1 h, 8 h, 48 h, 96 h and 192 h whereas for cohort 2, samples were taken at pre-dose, 0.25 h, 3 h, 24 h, 72 h, 144 h, and 240 h. For both cohorts, samples were taken from vena saphena. The lower limit of quantitation (LLOQ) for the tested antibodies was reported with 1.25 pg / mL for mUl_G4[YPY], 0.625 pg / mL for mUl_G4 and BM4_G4, and 0.156 pg / mL for BM4_G1[YPY],

[0859] The assessment of human IgG levels in samples taken from WT mice administered with anti-uPA and BM4 antibodies on [YPY] or wt backbone was performed by ELISA. Briefly, immuno-Plate Maxisorp plates were coated with goat antihuman IgG Fc antibody (Sigma™) in Carbonate-Bicarbonate Buffer (Sigma™) overnight at room temperature (RT). The plate was then washed three times with wash buffer (Tris-Buffered Saline with Tween 20; Sigma™) and then incubated with a blocking solution (Tris Buffered Saline with 1% BSA; Sigma™) for 1.5 h at RT. Following three washes, the plates were incubated (1.5 h at RT) with dilution series of the test [YPY] or wt Fc antibodies diluted in wash buffer (TBS-T) to generate internal standard curves, as well as the mouse plasma samples taken at the time points described above post i.v. injection of 30 mg / ...

Claims

CLAIMS1. A protein comprising:(i) a target binding domain, wherein the target binding domain specifically binds to a soluble molecule associated with inflammation; and(ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

2. The protein of claim 1, wherein the target binding domain is:(A)(i) a Fv;(ii) a single chain Fv fragment (scFv);(iii) a dimeric scFv (di-scFv);(iv) a nanobody;(v) a minibody;(vi) a diabody;(vii) a triabody;(viii) a tetrabody;(ix) a Fab;(x) a F(ab’)2;(xi) a lipocalin;(xii) an anticalin;(xiii) a soluble receptor;(xiv) a T-cell receptor;(xv) an adnectin;(xvi) an affibody;(xvii) an avimer; or(xviii) a designed ankyrin repeat protein (DARPin); and / or(B) an antigen binding domain of an antibody.

3. An antibody comprising:(i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and(ii)a modified immunoglobulin G (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the target binding domain specifically binds to the soluble molecule at neutral pH and optionally at acidic pH.

4. The protein of claim 1 or claim 2, or the antibody of claim 3, wherein on administering the protein or antibody to a subject, binding of the target binding domain to the soluble molecule causes a reduction in a level of the soluble molecule in circulation of the subject and / or binding of the modified IgG Fc to FcRn causes reduced circulating Fc-containing proteins and / or antibodies in the subject.

5. The protein of any one of claims 1 , 2 or 4, or the antibody of claims 3 or 4, wherein the modified Fc region comprises:(A) one or more amino acid substitutions selected from the group consisting of(i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system;(ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system;(iii) alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system;(iv) tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system,(v) glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system;(vi) proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system;(vii) glycine substituted for proline at a position corresponding to amino acid 329 according to the EU numbering system;(viii) tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; and(ix) combinations thereof; and / or(B)(i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering systemand tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or(ii) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

6. The protein or antibody of claim 5, wherein the modified Fc region further comprises:(i) alanine substituted for leucine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system; or(ii) alanine substituted for phenylalanine at a position corresponding to amino acid 234 according to the EU numbering system and alanine substituted for leucine at a position corresponding to amino acid 235 according to the EU numbering system.

7. An antibody comprising:(i) a target binding domain that specifically binds to a soluble molecule associated with inflammation; and(ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:(i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or(ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

8. The protein of any one of claims 1, 2 or 4 to 6, or the antibody of any one of claims 3 to 7, wherein:(i) the target binding domain specifically binds to the soluble molecule at neutral and acidic pH; and / or(ii)the target binding domain specifically binds and inhibits the soluble molecule; and / or(iii)the soluble molecule is selected from the group consisting of a B-lymphocyte stimulator (BLyS), a complement component, a cytokine, a chemokine, an enzyme, a coagulation factor and combinations thereof.

9. The protein or antibody of claim 8, wherein:(A)(i) the complement component is C2 and / or C2b,(ii)the coagulation factor is Factor XII or an activated form thereof;(iii)the enzyme is urokinase-type plasminogen activator (uPA);(iv)the cytokine is interleukin 6; and / or(B) the soluble molecule is a human soluble molecule.

10. The protein of any one of claims 2, 4 to 6, 8 or 9, or the antibody of any one of claims 3 to 9, wherein the antibody is a monospecific or a multispecific antibody, optionally wherein the multispecific antibody is a bispecific antibody.

11. The protein of any one of claims 1, 2, 4 to 6 or 8 to 10, or the antibody of any one of claims 3 to 10, wherein the target binding domain corresponds to, or is derived from an antigen binding domain of an antibody selected from the group consisting of adalimumab, belimumab, bimekizumab, golimumab, guselkumab, infliximab, ixekizumab, lebrikizumab, mirikizumab, netakimab, olokizumab, ozoralizumab, risankizumab, secukinumab, siltuximab, sutimlimab, tezepelumab, tildrakizumab, tralokinumab, ustekinumab, vunakizumab, ebdarokimab, xeligekimab, garadacimab, abelacimab, cendakimab, clazakizumab, dazukibart, depemokimab, garetosmab, gefurulimab, itepekimab, pamrevlumab, picankibart, sibeprenlimab, tozorakimab, gumokimab, ziltivekimab, suvemcitug, and combinations thereof.

12. The protein of any one of claims 1, 2, 4 to 6 or 8 to 10, wherein the target binding domain corresponds to, or is derived from, a soluble receptor domain of a moleculeselected from the group consisting of atacicept, aflibercept, briobacept, conbercept, etanercept, dalantercept, inbakicept, lenercept, luspatercept, olamkicept, opinercept, povetacicept, ramatercept, sotatercept, sozinibercept, telitacicept, tulinercept.

13. An antibody comprising:(i) a target binding domain that specifically binds to a blood soluble molecule selected from the group consisting of complement component C2 / C2b, Factor Xll / XIIa, urokinase-type plasminogen activator (uPA), interleukin 6 and combinations thereof; and(ii)a modified immunoglobulin (IgG) fragment crystallizable (Fc) domain with increased binding affinity for a neonatal fragment crystallizable receptor (FcRn) compared to an unmodified IgG Fc domain, wherein the modified IgG Fc domain comprises:(i) a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, a proline substituted for valine at a position corresponding to amino acid 308 according to the EU numbering system and a tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system; or(ii)a tyrosine substituted for methionine at a position corresponding to amino acid 252 according to the EU numbering system, glutamic acid substituted for asparagine at a position corresponding to amino acid 286 according to the EU numbering system and tyrosine substituted for asparagine at a position corresponding to amino acid 434 according to the EU numbering system.

14. The protein of any one of claims 1, 2, 4 to 6 or 8 to 12, or the antibody of any one of claims 3 to 13, wherein:(i) the modified Fc region is from an IgGl or an IgG4 constant region;(ii)the modified Fc region is from a stabilized IgG4 constant region;(iii)the modified Fc has a reduced ability to induce effector function;(iv)the binding affinity of the Fc to FcRn is measured at neutral and / or acidic pH;(v) the protein or antibody has a reduced circulating blood plasma half-life compared to a protein or antibody with an unmodified Fc domain; and / or(vi)the protein or antibody has prolonged and / or increased in vivo target inhibition and / or FcRn inhibition compared to a protein or antibody with an unmodified Fc domain.

15. The protein of any one of claims 1, 2, 4 to 6, 8 to 12 or 14, or the antibody of any one of claims 4 to 14, wherein the modified Fc is an IgGl Fc further comprises the following amino acid substitutions:(i) an alanine substituted for leucine at a position corresponding to amino acid 234 and an alanine substituted for leucine at a position corresponding to amino acid 235; and / or(ii) a glycine substituted for a proline at a position corresponding to amino acid 329, wherein the amino acid substitutions are according to the EU numbering system.

16. The protein of any one of claims 1, 2, 4 to 6, 8 to 12, 14 or 15, or the antibody of any one of claims 4 to 15, wherein:(i) the modified Fc is indirectly linked to the target-binding domain of the antibody via a linker, wherein the linker is a peptide linker comprising between 2 and 31 amino acids in length; or(ii)the modified Fc is directly linked to the target binding domain of the antibody.

17. The protein of any one of claims 1, 2, 4 to 6, 8 to 12 or 14 to 16, or the antibody of any one of claims 4 to 16, for use as a medicament.

18. A method of reducing circulating antibodies in a subject in need thereof and / or of treating or preventing progression of an antibody-mediated disorder in a subject in need thereof and / or of treating or preventing an inflammatory mediated condition in a subject and / or of reducing anti-donor alloantibodies in a subject in need thereof, the method comprising administering the protein of any one of claims 1, 2, 4 to 6, 8 to 12 or 14 to 17, or the antibody of any one of claims 4 to 17, to the subject.

19. The method of claim 18, wherein:(i) the subject is suffering from an autoimmune disease, is a transplant recipient and has developed or is at risk of developing anti-donor antibodies, or has developed anti-drug antibodies or is at risk of developing anti-drug antibodies; and / or(ii)the inflammatory-mediated condition is selected from the group consisting of Achalasia, Addison’s disease, Adult Still’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, ANCA-associated vasculitis, Ankylosing spondylitis, Anti-GBM / Anti-TBM nephritis, anti-phospholipid syndrome, antibody mediated rejection, Antiphospholipid syndrome, atypical haemolytic- uremic syndrome, autoimmune haemolytic anemia, Autoimmune angioedema,Autoimmune dysautonomia, Autoimmune encephalitis, Autoimmune hepatitis, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, Benign mucosal pemphigoid (Mucous membrane pemphigoid), Bullous pemphigoid, C3-glomerulonephritis, Castleman disease (CD), Celiac disease, cerebral infarction, Chagas disease, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or Eosinophilic granulomatosis (EGPA), Cicatricial pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Complex regional pain syndrome (formerly known as reflex sympathetic dystrophy), Congenital heart block, Coxsackie myocarditis, CREST syndrome, Crohn’s disease, delayed graft function, Dense Deposit Disease, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’s syndrome, Endometriosis, Eosinophilic esophagitis (EoE), Eosinophilic fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, glomerulosclerosis, Goodpasture’s syndrome, Granulomatosis with polyangiitis, graft salvage, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpes gestationis or pemphigoid gestationis (PG), Hidradenitis suppurativa (HS) (Acne inversa), Huntington’s disease, IgA nephropathy, IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP), Inclusion body myositis (IBM), Interstitial cystitis (IC), ischemia-reperfusion injury, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus, Lyme disease chronic, Meniere’s disease, Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD), motor neuron disease, Mucha-Habermann disease, Multifocal motor neuropathy (MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myelin oligodendrocyte glycoprotein antibody disorder, Myositis, Narcolepsy, Neonatal lupus, nephritides, Nephropathy, IgA nephropathy, Neuromyelitis optica / devic disease, Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR), PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections),Paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Pars planitis (peripheral uveitis), Parkinson’s disease,, Parsonage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMS syndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Primary biliary cholangitis, Primary sclerosing cholangitis, Progesterone dermatitis, Progressive hemifacial atrophy (PHA) Parry romberg syndrome, Psoriasis, Psoriatic arthritis, Pulmonary Alveolar Proteinosis (PAP), Pure red cell aplasia (PRC A), Pyoderma gangrenosum, Raynaud’s phenomenon, Reactive arthritis, Relapsing polychondritis, renal scarring, Restless legs syndrome (RLS), Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome or Autoimmune polyendocrine syndrome type II, Scleritis, Scleroderma, Sjogren’s, Stiff person syndrome (SPS), ischemic stroke, somatic trauma, Susac’s syndrome, Sympathetic ophthalmia (SO), Takayasu’s arteritis, Temporal arteritis / giant cell arteritis, Thrombocytopenic purpura (TTP), Thrombotic thrombocytopenic purpura (Ttp), Thyroid Eye Disease (TED), Tolosa-Hunt syndrome (THS), transplant rejection, antibody-mediated graft rejection, Transverse myelitis, traumatic brain injury, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, Vogt-Koyanagi-Harada disease, Warm autoimmune hemolytic anemia and combinations thereof.

20. The method of claim 19, wherein the protein or the antibody or the composition:(i) is administered in an amount effective to reduce endogenous IgG levels by at least 30% (compared to in the absence of protein or antibody administration); and / or(ii) antagonizes IgG recycling.

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