FCRN / HSA binding molecules and methods of use

Abstract

Binding molecules are provided herein that comprise a human neonatal Fc receptor (FcRn) binding molecule and at least one antigen binding domain linked to the FcRn binding molecule. Also provided herein are polynucleotides, vectors, host cells, and production methods. Further provided is a method of treating antibody-mediated disorders with an FcRn / antigen binding molecule.

Description

[Technical Field]

[0001] The present disclosure relates to human neonatal Fc receptor (FcRn) / HSA binding molecules and methods of their use. [Background technology]

[0002] Immunoglobulin gamma (IgG) antibodies play a key role in the pathology of many diseases, including autoimmune diseases, inflammatory diseases, and disorders whose pathology is characterized by the overexpression of IgG antibodies.

[0003] The serum half-life of IgG is extended relative to that of other plasma proteins due in part to the binding of the Fc region of IgG to the Fc receptor, FcRn. FcRn binds IgG and recycles it to the extracellular compartment, protecting it from transport to degradative lysosomes. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, and the IgG / FcRn interaction is stronger at acidic endosomal pH than at extracellular physiological pH.

[0004] When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from lysosomal degradation and therefore has a reduced serum half-life. Thus, inhibiting IgG binding to FcRn reduces the serum half-life of IgG by preventing endosomal recycling of IgG. Agents that antagonize IgG binding to FcRn, such as FcRn-binding molecules, are useful for regulating, treating, or preventing antibody-mediated disorders, such as autoimmune or inflammatory diseases.

[0005] Efgartigimod is a modified human immunoglobulin (Ig) gamma (IgG)1-derived za allotype Fc that binds to human FcRn with nanomolar affinity. Efgartigimod encompasses the IgG1 Fc region and has been engineered using ABDEG technology to increase its affinity for FcRn at both physiological and acidic pH. Efgartigimod's increased affinity for FcRn at both acidic and physiological pH results in blockage of FcRn-mediated recycling of IgG. Efgartigimod is approved in the United States and Japan as a weekly intravenous infusion for use in the treatment of generalized myasthenia gravis and is under development for the treatment of several other antibody-mediated disorders.

[0006] FcRn also binds to serum albumin, a regulator of serum cholesterol levels, and recycles it. Advantageously, efgartigimod does not negatively affect serum albumin levels in human subjects. However, it has recently been shown that anti-FcRn antibodies can cause a decrease in serum albumin levels and a concomitant increase in serum cholesterol levels in human subjects, both of which are undesirable.

[0007] Thus, there is a need in the art for improved agents for use in the treatment of antibody-mediated disorders that antagonize FcRn binding to IgG and have a longer half-life, lower doses, less frequent administration, better maintenance of albumin levels, and / or reduced or eliminated FcRn degradation. Summary of the Invention

[0008] The present disclosure is broadly directed to neonatal Fc receptor (FcRn) binding molecules (FcRn / antigen binding molecules or FcRn / HSA binding molecules) linked to one or more antigen-binding domains that specifically bind to human serum albumin, and methods of using them. Unexpectedly, it is shown for the first time in this application that the inclusion of an HSA-binding moiety increases the stability (longevity) and FcRn occupancy of FcRn-binding molecules linked to one or more antigen-binding domains that specifically bind to HSA.

[0009] In one aspect, provided herein is an FcRn / antigen-binding molecule comprising an FcRn-binding molecule and a first antigen-binding domain, wherein the first antigen-binding domain is linked to the C-terminus of the FcRn-binding molecule, and the first antigen-binding domain specifically binds to human serum albumin (HSA).

[0010] In some embodiments, the first antigen-binding domain binds to HSA at pH 7.4 with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA. In some embodiments, the first antigen-binding domain binds to HSA at pH 5.5 with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA.

[0011] In some embodiments, the FcRn / antigen-binding molecule binds to HSA at pH 7.4 with a dissociation constant of greater than about 2.4 nM. In some embodiments, the FcRn / antigen-binding molecule binds to HSA at pH 5.5 with an equilibrium dissociation constant of greater than about 2.4 nM.

[0012] In some embodiments, the FcRn / antigen-binding molecule binds to FcRn at pH 5.5 and / or pH 6.0 with an affinity that is higher than the affinity of efgartigimod to FcRn at pH 5.5 and / or pH 6.0. In some embodiments, the FcRn / antigen-binding molecule binds to FcRn at pH 5.5 and / or pH 6.0 with an affinity that is lower than the affinity of efgartigimod to FcRn at pH 5.5 and / or pH 6.0.

[0013] In any of the above embodiments, binding affinity may optionally be measured by surface plasmon resonance.

[0014] In some embodiments, the FcRn binding molecule is a variant Fc region, wherein the variant Fc region comprises a first Fc domain and a second Fc domain that form a dimer.

[0015] In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first Fc domain and / or the second Fc domain comprises amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0016] In some embodiments, both the first Fc domain and the second Fc domain comprise amino acids Y, T, E, K, and F, respectively, at EU positions 252, 254, 256, 433, and 434. In some embodiments, both the first Fc domain and the second Fc domain comprise amino acids Y, T, E, K, F, and Y, respectively, at EU positions 252, 254, 256, 433, 434, and 436.

[0017] In some embodiments, the first Fc domain and / or the second Fc domain is an IgG Fc domain, e.g., an IgG1 Fc domain. In some embodiments, the first Fc domain and / or the second Fc domain is a human IgG Fc domain, e.g., a human IgG1 Fc domain.

[0018] In some embodiments, both the first Fc domain and the second Fc domain are IgG Fc domains, e.g., human IgG1 Fc domains. In some embodiments, both the first Fc domain and the second Fc domain are human IgG Fc domains, e.g., human IgG1 Fc domains.

[0019] In some embodiments, the first antigen-binding domain is covalently linked to the first Fc domain or the second Fc domain.

[0020] In some embodiments, the N-terminus of the first antigen-binding domain is fused to the C-terminus of the first Fc domain. In some embodiments, the N-terminus of the first antigen-binding domain is fused to the C-terminus of the second Fc domain. In some embodiments, the first antigen-binding domain is fused to the first Fc domain or the second Fc domain via a linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker is a GS linker, optionally 8 to 40 amino acids in length, optionally 20 or 30 amino acids in length.

[0021] In some embodiments, the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the amino acid sequences set forth in SEQ ID NO: 1, 2, or 3. In some embodiments, the first Fc domain and / or the second Fc domain comprises the amino acid sequence of SEQ ID NO: 2.

[0022] In some embodiments, both the first Fc domain and the second Fc domain comprise an amino acid sequence independently selected from the amino acid sequences set forth in SEQ ID NO: 1, 2, or 3. In some embodiments, both the first Fc domain and the second Fc domain comprise the amino acid sequence of SEQ ID NO: 2.

[0023] In some embodiments, the amino acid sequence of each of the first Fc domain and the second Fc domain consists of an amino acid sequence independently selected from the amino acid sequences set forth in SEQ ID NO: 1, 2, or 3. In some embodiments, the amino acid sequence of the first Fc domain or the amino acid sequence of the second Fc domain consists of SEQ ID NO: 2.

[0024] In some embodiments, the amino acid sequence of both the first Fc domain and the second Fc domain consists of SEQ ID NO:2.

[0025] In some embodiments, the variant Fc region comprises one or more mutations in amino acid residues that form the interface of the CH3 domain of the Fc domain.

[0026] In some embodiments, the amino acid sequence of the first Fc domain further comprises an amino acid W at EU position 366.

[0027] In some embodiments, the amino acid sequence of the first Fc domain comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO: 4, 5, or 6. In some embodiments, the amino acid sequence of the first Fc domain comprises the amino acid sequence of SEQ ID NO: 5.

[0028] In some embodiments, the amino acid sequence of the first Fc domain consists of an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO: 4, 5, or 6. In some embodiments, the amino acid sequence of the first Fc domain consists of the amino acid sequence of SEQ ID NO: 5.

[0029] In some embodiments, the amino acid sequence of the second Fc domain further comprises amino acids S, A, and V at EU positions 366, 368, and 407, respectively.

[0030] In some embodiments, the amino acid sequence of the second Fc domain comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO: 7, 8, or 9. In some embodiments, the amino acid sequence of the second Fc domain comprises the amino acid sequence of SEQ ID NO: 8.

[0031] In some embodiments, the amino acid sequence of the second Fc domain consists of an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NO: 7, 8, or 9. In some embodiments, the amino acid sequence of the second Fc domain consists of the amino acid sequence of SEQ ID NO: 8.

[0032] In some embodiments, the first antigen-binding domain is selected from a Fab fragment, sdAb, scFv, antibody mimetic, HSA, or an HSA-binding fragment thereof. In some embodiments, the antibody mimetic is anticalin or DARPin. In some embodiments, the sdAb is a VHH fragment.

[0033] In some embodiments, the first antigen-binding domain is any of the antigen-binding domains described herein. In some embodiments, the first antigen-binding domain is a VHH fragment, which comprises the CDR1, CDR2, and CDR3 amino acid sequences of any of the VHH fragments disclosed herein. In some embodiments, the first antigen-binding domain is a VHH fragment, which comprises the CDR1, CDR2, and CDR3 amino acid sequences of a VHH fragment comprising an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127.

[0034] In some embodiments, the first antigen-binding domain is a VHH fragment, and the VHH fragment comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the first antigen-binding domain is a VHH fragment, and the VHH fragment comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the first antigen-binding domain comprises an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the first antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 44.

[0035] In some embodiments, the FcRn / antigen-binding molecule further comprises one or more additional amino acids at the C-terminus of the first antigen-binding domain, e.g., when the first antigen-binding domain is a VHH fragment. In some embodiments, the one or more additional amino acids are selected from the group consisting of a) A, b) AG, c) GG, d) PP, and e) AA.

[0036] In some embodiments, the FcRn / antigen binding molecule further comprises a second antigen binding domain.

[0037] In some embodiments, the second antigen-binding domain is linked to the first Fc domain or the second Fc domain.

[0038] In some embodiments, the second antigen-binding domain is fused to the first Fc domain or the second Fc domain via a linker. In some embodiments, the linker is a non-cleavable linker. In some embodiments, the linker is a peptide linker. In some embodiments, the peptide linker is a GS linker, optionally 8 to 40 amino acids in length, optionally 20 or 30 amino acids in length.

[0039] In some embodiments, the second antigen-binding domain is fused to the first Fc domain or the second Fc domain via an IgG hinge region or portion thereof.

[0040] In some embodiments, the first antigen-binding domain is fused to a first Fc domain and the second antigen-binding domain is fused to a second Fc domain. In some embodiments, the second antigen-binding domain is fused to the C-terminus of the second Fc domain. In some embodiments, the second antigen-binding domain is fused to the N-terminus of the second Fc domain.

[0041] In some embodiments, the first antigen-binding domain is fused to a second Fc domain, and the second antigen-binding domain is fused to the first Fc domain. In some embodiments, the second antigen-binding domain is fused to the C-terminus of the first Fc domain. In some embodiments, the second antigen-binding domain is fused to the N-terminus of the first Fc domain.

[0042] In some embodiments, the second antigen-binding domain specifically binds to HSA.

[0043] In some embodiments, the second antigen-binding domain is selected from a Fab fragment, sdAb, scFv, antibody mimetic, HSA, or an HSA-binding fragment thereof. In some embodiments, the antibody mimetic is an anticalin or a DARPin. In some embodiments, the sdAb is a VHH fragment.

[0044] In some embodiments, the second antigen-binding domain is any of the antigen-binding domains described herein. In some embodiments, the second antigen-binding domain is a VHH fragment, which comprises the CDR1, CDR2, and CDR3 amino acid sequences of any of the VHH fragments disclosed herein. In some embodiments, the second antigen-binding domain is a VHH fragment, which comprises the CDR1, CDR2, and CDR3 amino acid sequences of a VHH fragment comprising an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127.

[0045] In some embodiments, the second antigen-binding domain is a VHH fragment, and the VHH fragment comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the second antigen-binding domain is a VHH fragment, and the VHH fragment comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the second antigen-binding domain comprises an amino acid sequence selected from SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the second antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 44.

[0046] In some embodiments, the FcRn / antigen-binding molecule further comprises one or more amino acids at the C-terminus of the second antigen-binding domain, e.g., when the second antigen-binding domain is a VHH fragment. In some embodiments, the one or more amino acids are selected from the group consisting of a) A, b) AG, c) GG, d) PP, and e) AA.

[0047] In some embodiments, the first antigen-binding domain and the second antigen-binding domain are identical.

[0048] In some embodiments, the FcRn / antigen binding molecule comprises an FcRn binding molecule and only one antigen binding domain linked to the FcRn binding molecule.

[0049] In one aspect, provided herein is an FcRn / antigen-binding molecule comprising a first heavy chain, wherein the first heavy chain comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180. In some embodiments, the first heavy chain comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 180. In some embodiments, the first heavy chain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180. In some embodiments, the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 180. In some embodiments, the first heavy chain further comprises one of additional amino acids added at the C-terminus, wherein the one of the additional amino acids is optionally selected from A, AG, GG, and PP.

[0050] In some embodiments, the FcRn / antigen-binding molecule further comprises a second heavy chain, wherein the second heavy chain consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the second heavy chain consists of the amino acid sequence of SEQ ID NO: 8.

[0051] In one aspect, the present specification provides an antigen-binding domain comprising the CDR1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence of a VHH fragment comprising an amino acid sequence selected from SEQ ID NOs: 43 to 74, 84 to 90, and 120 to 127.

[0052] In some embodiments, the first and / or second antigen binding domain comprises: a) an amino acid sequence comprising SEQ ID NO: 13 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); b) an amino acid sequence comprising SEQ ID NO: 14 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); c) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); d) an amino acid sequence comprising SEQ ID NO: 16 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); e) an amino acid sequence comprising SEQ ID NO: 17 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); f) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 18 (CDR2), and SEQ ID NO: 12 (CDR3); g) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 19 (CDR2), and SEQ ID NO: 12 (CDR3); h) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 20 (CDR2), and SEQ ID NO: 12 (CDR3); i) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 21 (CDR2), and SEQ ID NO: 12 (CDR3); j) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 22 (CDR2), and SEQ ID NO: 12 (CDR3); k) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 23 (CDR2), and SEQ ID NO: 12 (CDR3); l) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 24 (CDR2), and SEQ ID NO: 12 (CDR3); m) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 25 (CDR2), and SEQ ID NO: 12 (CDR3); n) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 26 (CDR2), and SEQ ID NO: 12 (CDR3); o) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 27 (CDR2), and SEQ ID NO: 12 (CDR3); p) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 28 (CDR2), and SEQ ID NO: 12 (CDR3); q) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 29 (CDR2), and SEQ ID NO: 12 (CDR3); r) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 30 (CDR2), and SEQ ID NO: 12 (CDR3); s) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 31 (CDR2), and SEQ ID NO: 12 (CDR3); t) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 32 (CDR2), and SEQ ID NO: 12 (CDR3); u) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 33 (CDR2), and SEQ ID NO: 12 (CDR3); v) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 34 (CDR3); w) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 35 (CDR3); x) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 36 (CDR3); y) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 37 (CDR3); z) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 38 (CDR3); aa) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 39 (CDR3); bb) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 40 (CDR3); cc) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 36 (CDR3); dd) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 21 (CDR2), and SEQ ID NO: 12 (CDR3); ee) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 41 (CDR2), and SEQ ID NO: 12 (CDR3); ff) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 20 (CDR2), and SEQ ID NO: 36 (CDR3); gg) the amino acid sequence comprising SEQ ID NO: 111 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); hh) an amino acid sequence comprising SEQ ID NO: 112 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3); ii) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 113 (CDR2), and SEQ ID NO: 12 (CDR3); jj) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 114 (CDR2), and SEQ ID NO: 12 (CDR3); kk) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 115 (CDR3); ll) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 116 (CDR3); mm) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 117 (CDR3); nn) an amino acid sequence comprising SEQ ID NO: 118 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 119 (CDR3); oo) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 77 (CDR3); pp) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 78 (CDR3); qq) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 79 (CDR3); rr) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 80 (CDR3); ss) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 81 (CDR3); tt) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 82 (CDR3), and uu) comprises an amino acid sequence selected from the group consisting of the amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2), and SEQ ID NO: 83 (CDR3).

[0053] In some embodiments, the antigen binding domain comprises an amino acid sequence comprising SEQ ID NO: 14 (CDR1), SEQ ID NO: 11 (CDR2), and SEQ ID NO: 12 (CDR3).

[0054] In some embodiments, the first and / or second antigen-binding domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the antigen-binding domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence set forth in SEQ ID NO: 44. In some embodiments, the first and / or second antigen-binding domain comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 43-74, 84-90, and 120-127. In some embodiments, the first and / or second antigen-binding domain comprises the amino acid sequence set forth in SEQ ID NO: 44.

[0055] In some embodiments, the antigen-binding domain is an sdAb. In some embodiments, the sdAb is a VHH fragment. In some embodiments, the antigen-binding domain further comprises one or more additional amino acids at the C-terminus of the VHH fragment. In some embodiments, the one or more additional amino acids are selected from the group consisting of a) A, b) AG, c) GG, d) PP, and e) AA.

[0056] In some embodiments, the antigen-binding domain specifically binds to HSA. In certain embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment binds to HSA with stronger affinity at neutral pH than at acidic pH. In some embodiments, the antigen-binding domain binds to HSA, optionally with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA, as measured by surface plasmon resonance.

[0057] Also provided is one or more isolated polynucleotides encoding any of the FcRn / antigen-binding molecules described herein or any of the antigen-binding domains described herein.

[0058] Also provided are expression vectors comprising any one or more of the isolated polynucleotides described herein.

[0059] Also provided is a host cell comprising any isolated one or more polynucleotides or any expression vector described herein.

[0060] Also provided is a method for producing an FcRn / antigen-binding molecule or an antigen-binding domain, the method comprising culturing a host cell described herein under conditions that allow expression of the FcRn / antigen-binding molecule or the antigen-binding domain.

[0061] Also provided is a pharmaceutical composition comprising an FcRn / antigen-binding molecule described herein or an antigen-binding domain described herein and at least one pharmaceutically acceptable carrier.

[0062] Also provided is an FcRn / antigen-binding molecule described herein, or an antigen-binding domain described herein, or a pharmaceutical composition thereof for use as a pharmaceutical.

[0063] Also provided is a method for reducing serum IgG in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of an FcRn / antigen-binding molecule described herein (e.g., an FcRn / HSA-binding molecule described herein), or an antigen-binding domain described herein, or a pharmaceutical composition thereof.

[0064] Also provided is a method of treating an antibody-mediated disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of an FcRn / antigen-binding molecule described herein (e.g., an FcRn / HSA-binding molecule described herein), or an antigen-binding domain described herein, or a pharmaceutical composition thereof.

[0065] In some embodiments, the antibody-mediated disorder is an IgG-mediated disorder. In some embodiments, the antibody-mediated disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of islet allograft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune disease of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura), and idiopathic thrombocytopenia.purpura), immune-mediated thrombocytopenia, or primary immune thrombocytopenia), autoimmune urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman's disease, celiac sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold aggregation disease, Crohn's disease, dilated cardiomyopathy, discoid lupus erythematosus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, and type VI encephalopathy. Factor II deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic inflammatory myopathy (IIM), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, immune-mediated necrotizing myopathy (IMNM), juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, lupus nephritis, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid Acne, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), myositis, paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigoid vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), antisynthetase syndrome (ASyS), primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, The disease is selected from the group consisting of: idiopathic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-body syndrome, systemic lupus erythematosus, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, dermatitis herpetiformis vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0066] In some embodiments, the FcRn / antigen-binding molecule or antigen-binding domain is administered to a subject simultaneously or sequentially with an additional therapeutic agent.

[0067] Also provided is an FcRn / antigen-binding molecule described herein or an antigen-binding domain described herein for use in treating an antibody-mediated disorder.

[0068] Also provided is the use of an FcRn / antigen-binding molecule described herein (e.g., an FcRn / HSA-binding molecule described herein) or an antigen-binding domain described herein for the manufacture of a medicament for treating an antibody-mediated disorder. [Brief explanation of the drawings]

[0069] [Figure 1] FIG. 1 is a schematic diagram of a representative two-arm (TA) Fc-ABDEG molecule with anti-HSAVHH fused at the N-terminus of both Fc domains.

[0070] [Figure 2] Pharmacokinetic profiles of individual cynomolgus monkeys treated with one intravenous (IV) dose of Fc-ABDEG molecule (TA-Alb23-Fc-ABDEG) with one anti-HSAVHH (Alb23) fused at the N-terminus of each Fc domain are shown; C1-3: 20 mg / kg, C4-6: 5 mg / kg. TA-Alb23-Fc-ABDEG concentration values ​​are plotted over time. Data points represent the mean ± SD of two duplicates (n = 2 duplicates, 2-fold study sample dilution in duplicate) and are shown per post-dose time point.

[0071] [Figure 3A] Pharmacodynamic profiles of individual cynomolgus monkeys treated with one IV dose of TA-Alb23-Fc-ABDEG; -C1-3: 20 mg / kg. Percent cynomolgus total serum IgG levels relative to pre-dose were plotted over time. Data points represent the mean ± SD of two duplicates (n = 2 duplicates, 2-fold study sample dilution in duplicate) and are shown per post-dose time point. [Figure 3B]Pharmacodynamic profile of an individual cynomolgus monkey treated with one IV dose of TA-Alb23-Fc-ABDEG; -C4-6: 5 mg / kg. Percent cynomolgus total serum IgG levels relative to pre-dose were plotted over time. Data points represent the mean ± SD of two duplicates (n = 2 duplicates, 2-fold study sample dilution in duplicate) and are shown per post-dose time point.

[0072] [Figure 4] TA-Alb23-Fc-ABDEG ADA development profile for individual cynomolgus monkeys treated with one IV dose of TA-Alb23-Fc-ABDEG; C1-3: 20 mg / kg, C4-6: 5 mg / kg. The developed immune response was plotted over time. Data points represent the mean ± SD of one duplicate (n = 1 duplicate, 1x study sample dilution in duplicate) and are shown per post-dose time point.

[0073] [Figure 5] FIG. 1 is a schematic diagram of a representative TA Fc-ABDEG molecule with anti-HSAVHH (Alb23) fused at the C-terminus of both Fc domains.

[0074] [Figure 6A] Figure 1 shows total circulating IgG levels in individual cynomolgus monkeys after a single IV bolus injection of an Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) with anti-HSAVHH (Alb23) fused via a 20GS linker at the C-terminus of both Fc domains. On day 0, monkeys in Group 1 (G1-1, G1-2, and G1-3) received a 30 mg / kg dose of TA-Fc-ABDEG-Alb23. The percentage of pre-dose at -5 minutes on day 0 was plotted over time (days post-injection) during the course of the study. The dashed line represents 100% of total serum IgG at baseline (day 0, -5 minutes) before TA-Fc-ABDEG-Alb23 injection. The dotted lines represent the maximum IgG level reduction observed in individual monkeys in each study group. Graphs show the mean ± SD of study samples analyzed in duplicate (technical replicates). [Figure 6B] Figure 1 shows total circulating IgG levels in individual cynomolgus monkeys after a single IV bolus injection of an Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) with anti-HSAVHH (Alb23) fused via a 20GS linker at the C-terminus of both Fc domains. On day 0, monkeys in Group 2 (G2-1, G2-2, and G2-3) received a 75 mg / kg dose of TA-Fc-ABDEG-Alb23. The percentage of pre-dose at -5 minutes on day 0 was plotted over time (days post-injection) during the course of the study. The dashed line represents 100% of total serum IgG at baseline (day 0, -5 minutes) before TA-Fc-ABDEG-Alb23 injection. The dotted line represents the maximum IgG level reduction observed in individual monkeys in each study group. Graphs show the mean ± SD of study samples analyzed in duplicate (technical replicates).

[0075] [Figure 7A] Figure 1 shows the pharmacokinetic profile of TA-Fc-ABDEG-Alb23 after a single IV bolus injection in cynomolgus monkeys. On day 0, monkeys in Group 1 (G1-1, G1-2, and G1-3) received a 30 mg / kg dose of TA-Fc-ABDEG-Alb23. TA-Fc-ABDEG-Alb23 levels in μg / mL for individual monkeys were plotted over time (days post-injection) during the course of the study for the 30 mg / kg dose group. The dashed line represents the sensitivity level of the TA-Fc-ABDEG-Alb23 PK ELISA, which has an LLOQ of 0.4 μg / mL. Data points represent the mean ± SD of study samples analyzed in duplicate (technical replicates). [Figure 7B]Figure 1 shows the pharmacokinetic profile of TA-Fc-ABDEG-Alb23 after a single IV bolus injection in cynomolgus monkeys. On day 0, monkeys in Group 2 (G2-1, G2-2, and G2-3) received a 75 mg / kg dose of TA-Fc-ABDEG-Alb23. TA-Fc-ABDEG-Alb23 levels in μg / mL for individual monkeys were plotted over time (days post-injection) during the course of the study for the 75 mg / kg dose group. The dashed line represents the sensitivity level of the TA-Fc-ABDEG-Alb23 PK ELISA, which has an LLOQ of 0.4 μg / mL. Data points represent the mean ± SD of study samples analyzed in duplicate (technical replicates).

[0076] [Figure 8A] Figure 1 shows the ADA response after a single IV bolus injection of TA-Fc-ABDEG-Alb23 in cynomolgus monkeys. On day 0, monkeys in Group 1 (G1-1, G1-2, and G1-3) received a 30 mg / kg dose of TA-Fc-ABDEG-Alb23. The ADA response to TA-Fc-ABDEG-Alb23 was analyzed by ELISA, and OD450 values ​​were plotted over time (days post-injection) during the course of the study. [Figure 8B] Figure 1 shows the ADA response after a single IV bolus injection of TA-Fc-ABDEG-Alb23 in cynomolgus monkeys. On day 0, monkeys in Group 2 (G2-1, G2-2, and G2-3) received a dose of 75 mg / kg of TA-Fc-ABDEG-Alb23. The ADA response to TA-Fc-ABDEG-Alb23 was analyzed by ELISA, and OD450 values ​​were plotted over time (days post-injection) during the course of the study.

[0077] [Figure 9A]Serum albumin levels (analyzed by BCG assay in 96-well plate format) after injection of TA-Fc-ABDEG-Alb23 are shown. On day 0, monkeys in Group 1 (G1-1, G1-2, and G1-3) received a 30 mg / kg dose of TA-Fc-ABDEG-Alb23. Percentages relative to pre-dose (-5 minutes on day 0) were plotted over time (days post-injection) during the course of the study. The dashed line represents 100% albumin 5 minutes before TA-Fc-ABDEG-Alb23 injection on day 0. Data points represent the mean ± SD of study samples analyzed in duplicate (technical replicates). [Figure 9B] Serum albumin levels (analyzed by BCG assay in 96-well plate format) after injection of TA-Fc-ABDEG-Alb23 are shown. On day 0, monkeys in Group 2 (G2-1, G2-2, and G2-3) received a 75 mg / kg dose of TA-Fc-ABDEG-Alb23. Percentages relative to pre-dose (-5 minutes on day 0) were plotted over time (days post-injection) during the course of the study. The dashed line represents 100% albumin 5 minutes before TA-Fc-ABDEG-Alb23 injection on day 0. Data points represent the mean ± SD of study samples analyzed in duplicate (technical replicates).

[0078] [Figure 10A] Figure 1 shows normalized tracer IgG1 after a single IV administration of TA-Fc-ABDEG molecules (TA-Fc-ABDEG-Alb23, TA-Fc-ABDEG-Alb23(modified), and TA-Fc-ABDEG-0GS-Alb23(modified); see Table S15 for construct description) at a dose of 30 mg / kg in AlbuMus mice, which have anti-HSAVHH fragments fused with or without 20GS linkers at the C-terminus of both Fc domains. Normalized hIgG1 (% pre-dose) after injection per group is shown. The change in hIgG1 concentration was plotted over time (days post-injection) as % of pre-dose at -1 h on day 0. Data points represent the mean ± SEM per time point for four mice per group. The dashed line represents the LLOQ of the ELISA readout. [Figure 10B] Figure 1 shows normalized tracer IgG1 after a single IV administration of TA-Fc-ABDEG molecules (TA-Fc-ABDEG-Alb23, TA-Fc-ABDEG-Alb23(modified), and TA-Fc-ABDEG-0GS-Alb23(modified); see Table S15 for construct description) at a dose of 30 mg / kg in AlbuMus mice, which have anti-HSAVHH fragments fused with or without 20GS linkers at the C-terminus of both Fc domains. Normalized total serum IgG (hIVIg, % pre-dose) after injection per group is shown. The change in hIVIg concentration was plotted over time (days post-injection) as a % of pre-dose at -1 h on day 0. Data points represent the mean ± SEM per time point for four mice per group.

[0079] [Figure 11]

[0039] Figure 1 shows serum PK of TA-Fc-ABDEG-Alb23(modified), TA-Fc-ABDEG-Alb23, and TA-Fc-ABDEG-0GS-Alb23(modified) after a single IV injection. Three groups of AlbuMus mice received a single 30 mg / kg dose of either TA-Fc-ABDEG-Alb23(modified), TA-Fc-ABDEG-Alb23, or TA-Fc-ABDEG-0GS-Alb23(modified). Serum concentrations of test article were plotted over time during the course of the study as an average per group. Data points represent the mean ± SEM of four animals per group.

[0080] [Figure 12]Figure 1 shows ADA responses after a single IV injection of TA-Fc-ABDEG-Alb23(modified), TA-Fc-ABDEG-Alb23, or TA-Fc-ABDEG-0GS-Alb23(modified) in individual AlbuMus mice. On day 0, mice received TA-Fc-ABDEG-Alb23(modified) (30 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), or TA-Fc-ABDEG-0GS-Alb23(modified) (30 mg / kg). ADA responses (OD450, right Y-axis) were overlaid with PK profiles (μg / mL, left Y-axis) over time (days post-injection, X-axis) per mouse per group. Each data point (PK and ADA) represents the average of study samples analyzed in duplicate (technical replicates).

[0081] [Figure 13]

[0049] Figure 1 shows normalized albumin levels (% pre-dose) in AlbuMus mice after a single IV injection of TA-Fc-ABDEG-Alb23(modified) (30 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), or TA-Fc-ABDEG-0GS-Alb23(modified) (30 mg / kg). Albumin levels are plotted over time (days post-injection) as a % of pre-dose (day 0, -1 hour) levels averaged per group. Data points represent the mean ± SEM per time point for four mice per group.

[0082] [Figure 14]Figure 1 shows the effect of linker length between the Fc-ABDEG and VHH fragments in a two-arm (TA)-Fc-ABDEG molecule with albumin-binding VHHs fused at the C-terminus of both Fc domains on FcRn degradation in HEK FcRn WT GFP+ cells in the presence or absence of human serum albumin (HSA). The presence of a 20GS linker in TA-Fc-ABDEG-Alb23 results in lower levels of FcRn degradation in vitro compared to TA-Fc-ABDEG-Alb23 with a 0GS linker (i.e., no linker). An anti-FcRn mAb (anti-FcRn mAb1), known to increase FcRn degradation, was included as a positive control. Bars represent the mean ± SEM of two individual experiments, each performed with two technical replicates.

[0083] [Figure 15] FIG. 1 shows a schematic diagram of representative two-arm and one-arm albumin-binding VHH Fc-ABDEG molecules according to the present invention.

[0084] [Figure 16A] Figure 1 shows the pH-dependent albumin binding profile of a two-arm (TA)-Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) with albumin-binding VHHs fused at the C-terminus of both Fc domains. [Figure 16B] Figure 1 shows the pH-dependent albumin binding profile of a one-arm (OA)-Fc-ABDEG molecule with an albumin-binding VHH fragment fused at the C-terminus of one Fc domain (OA-Fc-ABDEG-Alb23).

[0085] [Figure 17A] 1 shows the effect of one-arm Fc-ABDEG-Alb23 molecules on FcRn degradation in the presence or absence of HSA. HEK FcRn WT GFP+ cells were incubated with 2500 nM one-arm or two-arm Fc-ABDEG-Alb23 in the absence or presence of 10,000 nM HSA. [Figure 17B]Figure 1 shows the effect of the one-arm Fc-ABDEG-Alb23 molecule on FcRn degradation in the presence or absence of HSA. HEK FcRn WT GFP+ cells were incubated with 12,500 nM one-arm or two-arm Fc-ABDEG-Alb23 in the absence or presence of 50,000 nM HSA. Bars represent the mean ± SEM of duplicate wells and are the results of two independent runs.

[0086] [Figure 18] Figure 1 shows the effect of the one-arm Fc-ABDEG-2H11 molecule on FcRn degradation in the presence or absence of HSA. The pH-dependent HSA binding profile of each molecule is also shown to demonstrate that the use of VHHs with reduced albumin binding affinity reduces FcRn degradation. HEK FcRn WT GFP+ cells were incubated with 1 mg / mL Fc-ABDEG-VHHs in the absence or presence of 3.3 mg / mL HSA. Bars represent the mean ± SD of two independent experiments performed in duplicate.

[0087] [Figure 19A]Figure 1 shows normalized chimeric IgG1 (chIgG1) levels (% pre-dose) per group after injection in Tg32-hFc mice dosed with various two-armed and one-armed albumin-binding VHH Fc-ABDEG molecules. Four groups of Tg32-hFc mice received a single intraperitoneal (IP) injection of 30 mg / kg TA-Fc-ABDEG-Alb23, 30 mg / kg TA-Alb23-Fc-ABDEG, 25 mg / kg OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-armed construct), or PBS (control). The change in chIgG1 levels is plotted over time (days post-injection) as a % of pre-dose on day -3. Data points represent the mean ± SEM per time point for 4-5 mice per group. The Y-axis is presented in two segments: a lower segment to better understand chIgG1 depletion on days 1 to 7, and an upper segment to observe time points with chIgG1 levels above baseline. The dashed line represents the maximum depletion level of chIgG1 as a percentage of baseline.

[0088] [Figure 19B] Serum PK of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IP injection. Tg32-hFc mice received 30 mg / kg of TA-Fc-ABDEG-Alb23, 30 mg / kg of TA-Alb23-Fc-ABDEG, or 25 mg / kg of OA-Fc-ABDEG-Alb23 (equimolar doses). Serum concentrations of test articles were plotted over time during the course of the study as an average per group. Data points represent the mean ± SEM of five animals per group.

[0089] [Figure 20]Figure 1 shows ADA responses after a single IP injection of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, or OA-Fc-ABDEG-Alb23 in individual Tg32-hFc mice. On day 0, mice received a single IP injection of TA-Fc-ABDEG-Alb23 (30 mg / kg), TA-Alb23-Fc-ABDEG (30 mg / kg), or OA-Fc-ABDEG-Alb23 (25 mg / kg). ADA responses (OD450, right Y-axis) were overlaid with PK profiles (nM, left Y-axis) over time (days post-injection, X-axis) per mouse per group. Each data point (PK and ADA) represents the mean ± SEM of study samples analyzed in duplicate (technical replicates).

[0090] [Figure 21] Normalized post-injection albumin levels (% pre-dose) per group are shown. On day 0, Tg32-hFc mice received a single IP injection of TA-Fc-ABDEG-Alb23 (30 mg / kg), TA-Alb23-Fc-ABDEG (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), or PBS (control). Albumin levels were plotted over time (days post-injection) as a % of pre-dose (day -3) levels averaged per group. Data points represent the mean ± SEM per time point for 4-5 mice per group.

[0091] [Figure 22A]Figure 1 shows the PD / PK / serum albumin effects of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IV injection in AlbuMus mice. Four groups of mice received 30 mg / kg TA-Fc-ABDEG-Alb23, 30 mg / kg TA-Alb23-Fc-ABDEG, 25 mg / kg OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for five mice per group. Normalized post-injection tracer IgG levels (% pre-dose) per group are shown. The change in tracer IgG levels was plotted over time (days post-injection) as a % of pre-dose at -2 hours on day 0. [Figure 22B] Figure 1 shows the PD / PK / serum albumin effects of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IV injection in AlbuMus mice. Four groups of mice received 30 mg / kg TA-Fc-ABDEG-Alb23, 30 mg / kg TA-Alb23-Fc-ABDEG, 25 mg / kg OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for five mice per group. Figure 2 shows the serum PK of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IV injection. Serum concentrations of test article were plotted over time during the course of the study as an average per group. [Figure 22C]Figure 1 shows the PD / PK / serum albumin effects of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IV injection in AlbuMus mice. Four groups of mice received 30 mg / kg TA-Fc-ABDEG-Alb23, 30 mg / kg TA-Alb23-Fc-ABDEG, 25 mg / kg OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for five mice per group. Post-injection normalized albumin levels (% pre-dose) per group are shown. Albumin levels were plotted over time (days post-injection) as a % of pre-dose (day 0, -2 hours) averaged per group.

[0092] [Figure 23] Figure 1 shows the effect of one-arm Fc-ABDEG-Alb23 variant molecules on FcRn degradation in the presence or absence of HSA. HEK FcRn WT GFP+ cells were incubated with 12,500 nM Fc-ABDEG-VHH in the absence (solid bars) or presence of 50,000 nM HSA (striped bars). Bars represent the mean ± SEM of duplicate wells and are the results of two independent runs.

[0093] [Figure 24] The effect of OA-Fc-ABDEG-Alb23 with a 20GS linker and OA-Fc-ABDEG-Alb23-F32A with 20, 25, and 30GS linkers on FcRn degradation in the presence or absence of human serum albumin (HSA) is shown. HEK FcRn WT GFP+ cells were incubated with 12,500 nM of test molecules in the absence or presence of 50,000 nM HSA. Bars represent the mean ± SEM of individual experiments (indicated by n), each performed with two technical replicates.

[0094] [Figure 25A]Figure 1 shows the PD / PK effects of OA-Fc-ABDEG-Alb23-F32A with a 20GS linker, OA-Fc-ABDEG-Alb23-F32A with a 30GS linker, and OA-Fc-ABDEG-3Rab. Data points represent the mean ± SD of 3-4 animals per group. Figure 2 shows the pharmacokinetic profiles of OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg) after a single IP injection in AlbuMus Rag1KO mice. Serum concentrations of test article were plotted over time during the course of the study as an average per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph. [Figure 25B] Figure 1 shows the PD / PK effects of OA-Fc-ABDEG-Alb23-F32A with a 20GS linker, OA-Fc-ABDEG-Alb23-F32A with a 30GS linker, and OA-Fc-ABDEG-3Rab. Data points represent the mean ± SD of 3-4 animals per group. Normalized levels of total preloaded human IgG (% pre-dose) in Albuminus Rag1KO mice after a single IP administration of OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg) are shown. The change in total IgG concentration was plotted over time (days post-injection) as a % of pre-dose at -2 hours on day 0.

[0095] [Figure 26A]Figure 1 shows the PD effect of the OA-Fc-ABDEG-Alb23 Ala variant in AlbuMus Rag1KO mice. Normalized levels of total preloaded human IgG (% predose) after injection per dose group are shown. The change in total IgG concentration in AlbuMus Rag1KO mice after a single IP administration of ARGX-113 (efgartigimod; 20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg) is plotted over time (days post-injection) as a % of predose at -2 hours on day 0. Data points represent the mean ± SEM of 4–5 animals per group. [Figure 26B] Figure 1 shows the PD effect of the OA-Fc-ABDEG-Alb23 Ala variant in AlbuMus Rag1KO mice. Normalized levels of tracer human IgG (% pre-dose) are shown during the first 7 days of the study. The change in the concentration of tracer IgG in AlbuMus Rag1KO mice after a single IP injection of ARGX-113 (20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg) is plotted over time (days post-injection) as a % of pre-dose at -2 hours on day 0. Data points represent the mean ± SEM per time point for 4-5 mice per group. After day 4, tracer IgG concentrations reached the low level of quantification (LLOQ) in the groups treated with ARGX-113 and all OA-Fc-ABDEG-VHH molecules.

[0096] [Figure 26C]Pharmacokinetic profiles in Albumus Rag1KO mice after a single IP injection of ARGX-113 (efgartigimod; 20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg) are shown. Serum concentrations of test articles were plotted over time during the course of the study as an average per group. Data points represent the mean ± SD of 4-5 animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph.

[0097] [Figure 26D] Human serum albumin levels (% of pre-dose) in Albumus Rag1KO mice after a single IP administration of ARGX-113 (efgartigimod; 20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg) are shown. Albumin levels are plotted over time (days post-injection) as a percentage of pre-dose (day 0, -2 h) levels averaged per group. Data points represent the mean ± SEM per time point for 4-5 mice per group.

[0098] [Figure 27A] Figure 1 shows the differential pharmacokinetic profiles of Mota-Fab constructs when fused to Alb23-F32A following a single IP injection in AlbuMus Rag1KO mice. Serum concentrations of test article were plotted over time during the course of the study as an average per group. Data points represent the mean ± SD of 4-5 animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph. [Figure 27B]Figure 1 shows the differential pharmacokinetic profile of the Fc-ABDEG construct when fused to Alb23-F32A after a single IP injection in AlbuMus Rag1KO mice. Serum concentrations of test article were plotted over time during the course of the study as an average per group. Data points represent the mean ± SD of 4-5 animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph.

[0099] [Figure 28A] Figure 1 shows the pharmacodynamic (PD) profile in cynomolgus monkeys treated with one intravenous (IV) dose of Fc-ABDEG molecule (ABDEG-30GS-Alb23-SM), which comprises one anti-HSA VHH (Alb23-SM) with the F32A mutation fused at the C-terminus of the Fc domain. The percent cynomolgus monkey total serum IgG levels relative to pre-dose are plotted over time. Data points represent the mean ± SD of three individual monkeys (n=3) dosed with 10 mg / kg OA-Fc-ABDEG-Alb23. Data points with results from only one individual monkey are marked with an asterisk. Cynomolgus monkey PD profiles of an equimolar dose of efgaltigimod (model simulation) and a nearly equimolar dose of OA-HEL-ABDEG (experimental data) are plotted for comparison. Time points where the presence of ADA was detected and had a steep concentration decline in the PK curve are excluded from the graph. [Figure 28B]Figure 1 shows the pharmacodynamic (PD) profile in cynomolgus monkeys treated with one intravenous (IV) dose of Fc-ABDEG molecule (ABDEG-30GS-Alb23-SM), which comprises one anti-HSA VHH (Alb23-SM) with the F32A mutation fused at the C-terminus of the Fc domain. The percent cynomolgus monkey total serum IgG levels relative to pre-dose are plotted over time. Data points represent the mean ± SD of five individual monkeys (n=5) dosed with 60 mg / kg OA-Fc-ABDEG-Alb23. Data points with results from only one individual monkey are marked with an asterisk. Cynomolgus monkey PD profiles of an equimolar dose of efgaltigimod (model simulation) and a nearly equimolar dose of OA-HEL-ABDEG (experimental data) are plotted for comparison. Time points where the presence of ADA was detected and with a steep concentration decline in the PK curve are excluded from the graph.

[0100] [Figure 29A] Figure 1 shows the pharmacokinetic profile in cynomolgus monkeys treated with one intravenous (IV) dose of ABDEG-30GS-Alb23-SM. ABDEG-30GS-Alb23-SM concentration values ​​were plotted over time. Data points represent the mean ± SD of three individual monkeys (n=3) dosed with 10 mg / kg ABDEG-30GS-Alb23-SM. Data points with results from only one individual monkey are marked with an asterisk. PK profiles in cynomolgus monkeys of an equimolar dose of efgartigimod (model simulation) and approximately equimolar doses of OA-HEL-ABDEG (experimental data) and TA-ABDEG-Alb23 (experimental data) are plotted for comparison. Time points where the presence of ADA was detected and had a steep concentration decline in the PK curve are excluded from the graph. [Figure 29B]Figure 1 shows the pharmacokinetic profile in cynomolgus monkeys treated with one intravenous (IV) dose of ABDEG-30GS-Alb23-SM. ABDEG-30GS-Alb23-SM concentration values ​​were plotted over time. Data points represent the mean ± SD of five individual monkeys (n=5) dosed with 60 mg / kg of ABDEG-30GS-Alb23-SM. Data points with results from only one individual monkey are marked with an asterisk. PK profiles in cynomolgus monkeys of an equimolar dose of efgartigimod (model simulation) and approximately equimolar doses of OA-HEL-ABDEG (experimental data) and TA-ABDEG-Alb23 (experimental data) are plotted for comparison. Time points where the presence of ADA was detected and had a steep concentration decline in the PK curve are excluded from the graph.

[0101] [Figure 30] Serum albumin levels (analyzed by BCG assay) after injection of ABDEG-30GS-Alb23-SM are shown. On Day 1, Group 1 (n=3) received ABDEG-30GS-Alb23-SM at a dose of 10 mg / kg, and Groups 2 (n=2) and 3 (n=3) received ABDEG-30GS-Alb23-SM at a dose of 60 mg / kg. After a 4-week follow-up period, monkeys in Groups 1 and 2 received four booster doses of 60 mg / kg ABDEG-30GS-Alb23-SM once weekly on Days 29, 36, 43, and 50. Albumin concentrations were plotted over time during the course of the study. Dotted lines indicate administration of ABDEG-30GS-Alb23-SM. Data points represent the mean ± SD of individual monkeys per treatment group. The orange shaded area indicates the minimum and maximum albumin levels measured before dosing in the monkeys used in this study. The gray shaded area indicates the normal range of serum albumin in cynomolgus monkeys according to Park et al. (Lab Anim Res. 2016 Jun;32(2):79-86).

[0102] [Figure 31A]Normalized albumin levels (% predose) are shown in AlbuMus Rag1KO mice after four weekly IV injections of PBS (placebo), OA-Fc-ABDEG-30GS-Alb23-F32A (45 mg / kg), TA-Fc-ABDEG-Alb23 (50 mg / kg), anti-FcRn mAb1 (100 mg / kg), or anti-FcRn mAb2 (100 mg / kg). Albumin levels are plotted over time (days post-injection) as a percentage of predose (day -6) averaged per group. Data points represent the mean ± SEM per time point for 3-5 mice per group. Dotted lines indicate test article injections on days 0, 7, 14, and 21.

[0103] [Figure 31B] The effects of OA-Fc-ABDEG-30GS-Alb23-F32A (12.5 μM), TA-Fc-ABDEG-Alb23 (12.5 μM), anti-FcRn mAb1 (5 nM), or anti-FcRn mAb2 (500 nM) on FcRn degradation in the presence or absence of human serum albumin (HSA) are shown. HEK FcRn WT GFP+ cells were incubated with the indicated concentrations of test molecules in the absence or presence of 50,000 nM HSA. Bars represent the mean ± SEM of individual experiments (n indicated), each performed with two technical replicates.

[0104] [Figure 32] Figure 1 shows reduced binding of pre-existing ADA to ABDEG-30GS-Alb23-SM-A. Sera from 40 human individuals positive for pre-existing ADA to ABDEG were used. ABDEG-30GS-Alb23-SM, ABDEG-30GS-Alb23-SM-A, or PBS (blank, uncoated) was coated onto a 96-well plate, the plate was blocked with 1% PBS-casein, and serum was applied. Binding of pre-existing ADA to the test article was detected with HRP-conjugated anti-human Fab IgG. Absorbance values ​​at OD450 are plotted.

[0105] [Figure 33A] Figure 1 shows FcRn occupancy by efgartigimod (ARGX-113), ABDEG-30GS-Alb23-SM, and ABDEG-30GS-Alb23-SM-A. U937 cells were incubated with a titration series of test articles in the presence of 2,500 nM HSA. Free FcRn was detected with a fluorescently labeled anti-FcRn Fab fragment that recognizes the IgG-binding site on FcRn. Detected free FcRn levels were normalized to the FcRn levels in cells treated with assay buffer (placebo, 100%). The mean ± SD of two independent experiments, each performed in duplicate with technical replicates, is presented.

[0106] [Figure 33B] The effects of ABDEG-20GS-Alb23 (12.5 μM), ABDEG-30GS-Alb23-SM (12.5 μM), ABDEG-30GS-Alb23-SM-A (12.5 μM), and anti-FcRn mAb1 (5 nM) on FcRn degradation in the presence or absence of human serum albumin (HSA) are shown. HEK FcRn WT GFP cells were incubated with the indicated concentrations of test molecules in the absence or presence of 50,000 nM HSA. Bars represent the mean ± SD of at least three independent experiments, each performed with two technical replicates.

[0107] [Figure 34A] Figure 1 shows normalized levels (% pre-dose) of tracer human IgG in AlbuMus Rag1KO mice after a single IP injection of PBS (placebo), efgartigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). The change in tracer hIgG concentration is plotted over time (days post-injection) as a % of pre-dose at -2 hours on day 0. Data points represent the mean ± SEM per time point for five mice per group.

[0108] [Figure 34B] Figure 1 shows normalized levels of total preloaded human IgG (% predose) in Albumus Rag1KO mice after a single IP administration of PBS (placebo), efgartigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). The change in total IgG concentration is plotted over time (days post-injection) as a % of predose at -2 hours on day 0. Data points represent the mean ± SEM of five animals per group.

[0109] [Figure 34C] Figure 1 shows the pharmacokinetic profiles of efgartigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg) after a single IP injection in AlbuMus Rag1KO mice. Serum concentrations of test articles were plotted over time during the course of the study as an average per group. Data points represent the mean ± SD of five animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph. DETAILED DESCRIPTION OF THE INVENTION

[0110] The present disclosure provides engineered FcRn-binding molecules (FcRn / antigen-binding molecules) linked to one or more antigen-binding domains. In one aspect, an FcRn / antigen-binding molecule is provided, comprising an FcRn-binding molecule linked to an anti-HSA antigen-binding domain at the C-terminus, N-terminus, or at a position other than the C-terminus or N-terminus. In some embodiments, the FcRn / antigen-binding molecule comprises an FcRn-binding molecule and only one antigen-binding domain. Also provided herein are nucleic acids encoding such FcRn / antigen-binding molecules, vectors, host cells, methods of production, and methods for their use in treating antibody-mediated disorders.

[0111] definition As used herein, the term "FcRn" refers to neonatal Fc receptor. Exemplary FcRn molecules include human FcRn, encoded by the FCGRT gene as shown in RefSeq NM 004107. The amino acid sequence of the corresponding protein is shown in RefSeq NP_004098.

[0112] As used herein, the term "FcRn-binding molecule" refers to any agent that specifically binds to FcRn. As used herein, the term "FcRn antagonist" refers to any agent that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn (e.g., human FcRn). In one embodiment, the FcRn antagonist comprises an Fc region (e.g., a variant Fc region disclosed herein), specifically binds to FcRn via the Fc region, and inhibits the binding of immunoglobulins to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen-binding domain that binds to a target antigen and a variant Fc region. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen-binding fragment thereof that specifically binds to FcRn via its antigen-binding domain or its Fc region and inhibits the binding of the Fc region of an immunoglobulin (e.g., an IgG autoantibody) to FcRn. As used herein, the term "FcRn / antigen-binding molecule" refers to any agent that specifically binds to FcRn and specifically binds to another antigen. In some embodiments, the antigen is IgE, HEL, or HSA. In some embodiments, the antigen is HSA.

[0113] As used herein, the term "affinity" or "binding affinity" refers to the strength of the binding interaction between two molecules. As used herein, the term "equilibrium dissociation constant" or "K D The term "K" refers to the tendency of a bound complex of two molecules to dissociate into two free molecules. Thus, as binding affinity increases, the K D decreases.

[0114] As used herein, the term "specifically binds" refers to the ability of any molecule to bind preferentially to a given target. For example, a molecule that specifically binds to a given target can bind other molecules, generally with lower affinity, as determined, for example, by immunoassay, BIAcore™, KinExA 3000 instrument (Sapidyne Instruments, Boise, Id.), or other assays known in the art. In specific embodiments, a molecule that specifically binds to a given target has a K that is at least 2 logs, 2.5 logs, 3 logs, or 4 logs lower than the antigen when the molecule nonspecifically binds to another target. D or K D Combine under.

[0115] As used herein, the term "operably linked" refers to the linkage of polynucleotide sequence elements in a functional relationship. For example, a polynucleotide sequence is operably linked when it is placed into a functional relationship with another polynucleotide sequence. In some embodiments, a transcriptional regulatory polynucleotide sequence, e.g., a promoter, enhancer, or other expression control element, is operably linked to a protein-encoding polynucleotide sequence if it affects the transcription of the protein-encoding polynucleotide sequence. Operably linked elements can be contiguous or non-contiguous.

[0116] As used herein, the term "linked" refers to a physical connection (e.g., directly or indirectly connected) between amino acid sequences (e.g., different segments, regions, fragments, or domains). Linked regions, fragments, domains, and segments of the FcRn / antigen-binding molecules of the present disclosure can be contiguous or discontinuous (e.g., connected to each other via a linker). In some embodiments, the connection is a covalent bond. In some embodiments, the connection is a non-covalent bond.

[0117] As used herein, the term "covalently linked" refers to the linking of two molecules or chemical moieties by a covalent bond. In some embodiments, the covalent bond is a peptide bond or a disulfide bond. As used herein, the term "fused" refers to the linking of two peptides by a peptide bond or a peptide linker. In some embodiments, two proteins are fused together directly and contiguously by a peptide bond. In some embodiments, two proteins are fused indirectly and non-contiguously via a peptide linker. In some embodiments, one protein is fused at a first position to a peptide linker by a peptide bond, and a second protein is fused at a second position to a peptide linker by a peptide bond. As used herein, the term "non-covalently linked" refers to the linking of two molecules or chemical moieties by a non-covalent interaction or non-covalent bond. In some embodiments, non-covalent interactions or non-covalent bonds include hydrogen bonds, electrostatic bonds or interactions, halogen bonds, pi-stacking, and van der Waals interactions.

[0118] The determination of "percent identity" between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm used to compare two sequences is the algorithm of Karlin S & Altschul SF, (1990) PNAS 87:2264-2268, modified as in Karlin S & Altschul SF, (1993) PNAS 90:5873-5877, each of which is incorporated herein by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215:403, which is incorporated herein by reference in its entirety. BLAST nucleotide searches are performed with the NBLAST nucleotide program parameters set, for example, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., score=50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25:3389-3402. Alternatively, PSI BLAST can be used to perform an iterated search that detects distant relationships between molecules. Ibid. When utilizing BLAST, Gapped BLAST, and PSI BLAST programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) on the worldwide web at ncbi.nlm.nih.gov).Another specific, non-limiting example of a mathematical algorithm used for comparing sequences is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17, which is incorporated herein by reference in its entirety. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0119] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0120] As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising an antibody CDR, a VH domain (VH), or a VL domain (VL). Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (sdAbs), monovalent antibodies, single chain antibodies or single chain Fvs (scFvs), camelid antibodies, affibody molecules, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. Antibodies may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or species (e.g., murine IgG2a or IgG 2b ) immunoglobulin molecules.

[0121] As used herein, the term "antigen-binding domain" (or "antigen binding domain") refers to any polypeptide that specifically binds to an antigen. Examples of antigen-binding domains include polypeptides derived from antibodies, such as Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), single-chain Fvs (scFvs), CDRs, VH domains (VH), VL domains (VL), single-domain antibodies (sdAbs), VHH fragments, camelid antibodies, and antigen-binding fragments of any of the above. The term also encompasses synthetic antigen-binding proteins or antibody mimetic proteins, such as anticalins and DARPins.

[0122] In some embodiments, the antigen-binding domain is a VHH fragment. In some embodiments, the VHH fragment has one or more additional amino acids at its C-terminus. In some embodiments, the one or more additional amino acids are selected from the group consisting of A, AG, GG, and PP.

[0123] As used herein, the term "Fc region" refers to the portion of an immunoglobulin formed by the Fc domains of its two heavy chains. The Fc region may be a wild-type Fc region (native Fc region) or a variant Fc region. A native Fc region is a homodimer. The Fc region may be derived from any naturally occurring immunoglobulin. In some embodiments, the Fc region is formed from an IgA, IgD, IgE, or IgG heavy chain constant region. In some embodiments, the Fc region is formed from an IgG heavy chain constant region. In some embodiments, the IgG heavy chain is an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the Fc region is formed from an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises the G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype. See, e.g., Jefferis and Lefranc (2009) mAbs 1(4):332-338, and de Taeye et al., (2020) Front Immunol. 11:740, which are incorporated by reference in their entireties.

[0124] As used herein, the term "variant Fc region" refers to a variant of an Fc region having one or more changes relative to a native Fc region. Modifications can include amino acid substitutions, additions and / or deletions, attachment of additional moieties, and / or modifications of native glycans. The term encompasses heterodimeric Fc regions in which each of the constituent Fc domains is different. The term also encompasses single-chain Fc regions in which the constituent Fc domains are linked together by linker moieties.

[0125] As used herein, the term "Fc domain" refers to the portion of a single immunoglobulin heavy chain that comprises both the CH2 and CH3 domains of an antibody. In some embodiments, the Fc domain comprises at least a portion of the hinge (e.g., upper, middle, and / or lower hinge regions), the CH2 domain, and the CH3 domain. In some embodiments, the Fc domain does not comprise the hinge region.

[0126] As used herein, the term "hinge region" refers to the portion of a heavy chain molecule that connects the CH1 domain to the CH2 domain. In some embodiments, the hinge region is up to 70 amino acid residues in length. In some embodiments, this hinge region comprises approximately 11 to 17 amino acid residues and is flexible, thus allowing the two N-terminal antigen-binding regions to move independently. In some embodiments, the hinge region is 12 amino acid residues in length. In some embodiments, the hinge region is 15 amino acid residues in length. In some embodiments, the hinge region is 62 amino acid residues in length. The hinge region can be subdivided into three distinct domains: the upper, middle, and lower hinge domains. The FcRn / antigen-binding molecules of the present disclosure can comprise all or any portion of the hinge region. In some embodiments, the hinge region is derived from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence EPKSCDKTHTCPPCP (SEQ ID NO: 179).

[0127] As used herein, the term "FcRn-binding fragment" refers to a portion of an FcRn-binding molecule, e.g., a portion of the Fc region, that is sufficient to confer FcRn binding.

[0128] As used herein, the terms "one-armed," "one armed," "one-arm," "one arm," or "OA" refer to an FcRn / antigen-binding molecule comprising an FcRn-binding molecule linked to only one antigen-binding domain. In some embodiments, "one-armed," "one armed," "one-arm," "one arm," or "OA" refers to an FcRn / antigen-binding molecule comprising an Fc region comprising two heavy chain Fc domains, wherein one of the two heavy chain Fc domains is linked to the antigen-binding domain and the other heavy chain Fc domain is not linked to the antigen-binding domain. In some embodiments, the antigen-binding domain is linked to the C-terminus of one of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is linked to the N-terminus of one of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is linked to a position other than the N-terminus or C-terminus of one of the two heavy chain Fc domains. The linkage can be covalent or non-covalent. In some embodiments, the antigen-binding domain is fused to the C-terminus of one of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is fused to the N-terminus of one of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is fused to a position other than the N-terminus or C-terminus of one of the two heavy chain Fc domains.

[0129] As used herein, the terms "two-armed," "two-armed," "two-arm," "two-arm," or "TA" refer to an FcRn / antigen-binding molecule comprising an FcRn-binding molecule linked to two antigen-binding domains. In some embodiments, "two-armed," "two-armed," "two-arm," "two-arm," or "TA" refer to an FcRn / antigen-binding molecule comprising an Fc region comprising two heavy chain Fc domains, each of which is linked to an antigen-binding domain. In some embodiments, the antigen-binding domain is linked to the C-terminus of each of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is linked to the N-terminus of each of the two heavy chain Fc domains. In some embodiments, the antigen-binding domains are linked to a position other than the N- or C-terminus of each of the two heavy chain Fc domains. In some embodiments, one of the antigen-binding domains is linked to the N-terminus of one of the two heavy chain Fc domains, and the other antigen-binding domain is linked to the C-terminus of the other of the two heavy chain Fc domains. In some embodiments, one of the antigen-binding domains is linked to a position other than the N- or C-terminus of one of the two heavy chain Fc domains, and the other antigen-binding domain is linked to the N-terminus of the other of the two heavy chain Fc domains. In some embodiments, one of the antigen-binding domains is linked to a position other than the N- or C-terminus of one of the two heavy chain Fc domains, and the other antigen-binding domain is linked to the C-terminus of the other of the two heavy chain Fc domains. The linkage can be covalent or non-covalent. In some embodiments, the antigen-binding domain is fused to the C-terminus of each of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is fused to the N-terminus of each of the two heavy chain Fc domains, hi some embodiments, the antigen-binding domain is fused to a position other than the N-terminus or C-terminus of each of the two heavy chain Fc domains.In some embodiments, one of the antigen-binding domains is fused to the N-terminus of one of the Fc domains of the two heavy chains, and the other antigen-binding domain is fused to the C-terminus of the Fc domain of the other of the two heavy chains. In some embodiments, one of the antigen-binding domains is fused at a position other than the N-terminus or C-terminus of one of the Fc domains of the two heavy chains, and the other antigen-binding domain is fused to the N-terminus of the Fc domain of the other of the two heavy chains. In some embodiments, one of the antigen-binding domains is fused at a position other than the N-terminus or C-terminus of one of the Fc domains of the two heavy chains, and the other antigen-binding domain is fused to the C-terminus of the Fc domain of the other of the two heavy chains.

[0130] As used herein, the term "EU location" refers to the sequence of the nucleotide sequence of the nucleotide sequence described in Edelman, GM et al. Proc. Natl. Acad. USA, 63, 78-85 (1969), and Rabat et al., "Sequences of Proteins of Immunological Interest," USDept. Health and Human Services, 5 th The amino acid positions refer to the amino acid positions in the EU numbering convention for the Fc region as set out in the International Publication No. 1991.

[0131] As used herein, the term "antibody-mediated disorder" refers to any disorder in which the symptoms of the disorder are caused by abnormal levels of one or more antibodies in a subject. As used herein, the term "autoantibody-mediated disorder" refers to any disease or disorder in which the underlying pathology is caused, at least in part, by pathogenic IgG autoantibodies.

[0132] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or prophylactic measures as described herein. A method of "treatment" employs administering a polypeptide to a subject having or predisposed to a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of a disease or disorder, or a recurrent disease or disorder, or to extend the subject's survival beyond that which would be expected in the absence of such treatment. In some embodiments, a method of "treatment" employs administering a polypeptide to a subject having or predisposed to having a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate a disease or disorder, or a recurrent disease or disorder.

[0133] As used herein, in the context of administering therapy, the term "effective amount" refers to the amount of therapy that achieves the desired prophylactic or therapeutic effect.

[0134] As used herein, the term "dose" or "dosage" refers to the amount of a drug administered to a subject in a single administration.

[0135] As used herein, the terms "fixed dose" or "flat dose" both refer to a dose that does not vary based on subject characteristics (e.g., weight, e.g., within a set range; sex; age, e.g., within a set range, etc.).

[0136] As used herein, the term "equivalent dose" refers to a dose of a first and a second therapeutic agent where the number of molecules of the first and second therapeutic agents is approximately the same. In some embodiments, an equivalent dose is an equimolar dose. As used herein, the term "equimolar dose" refers to a dose of a first and a second therapeutic agent where the number of moles of the first and second agents is the same. In some embodiments, the first agent is an FcRn / antigen-binding molecule and the second agent is efgartigimod. In some embodiments, an equivalent dose is calculated using the observed molecular weights of the first and second agents. In some embodiments, an equivalent dose is calculated using the predicted molecular weights of the first and second agents. In some embodiments, an equivalent dose is calculated using the observed molecular weight of the first agent and the predicted molecular weight of the second agent. In some embodiments, an equivalent dose is calculated using the predicted molecular weight of the first agent and the observed molecular weight of the second agent.

[0137] As used herein, the terms "pharmacodynamics" and "PD" refer to the biological effect of a therapeutic agent on an organism. In some embodiments, the biological effect is modulation of the amount of circulating IgG in an organism administered the therapeutic agent. In some embodiments, the biological effect is modulation of the amount of circulating albumin in an organism administered the therapeutic agent. As used herein, the term "improved pharmacodynamics" or "improved PD" refers to an improvement in a desired biological effect in an organism administered the therapeutic agent. In some embodiments, improved pharmacodynamics comprises a reduction in the amount of circulating IgG in a subject. In some embodiments, improved pharmacodynamics comprises a maintenance of the amount of circulating albumin in a subject. In some embodiments, improved pharmacodynamics comprises a reduction in the amount of circulating IgG in a subject and a maintenance of the amount of circulating albumin in a subject. In some embodiments, the therapeutic agent is an FcRn / antigen binding molecule.

[0138] As used herein, the terms "pharmacokinetics" and "PK" refer to the effect of an organism on a therapeutic agent administered to the organism. In some embodiments, the effect is the metabolism and / or clearance of the therapeutic agent. In some embodiments, PK refers to the rate of metabolism and / or clearance of the therapeutic agent. As used herein, the term "improved pharmacokinetics" or "improved PK" refers to an improvement in the desired effect of an organism on a therapeutic agent administered to the organism. In some embodiments, improved pharmacokinetics refers to an improvement in the half-life (T 1 / 2 ), clearance, or an increase in area under the curve (AUC). In some embodiments, the therapeutic agent is an FcRn / antigen binding molecule.

[0139] As used herein, the term "subject," or "patient," or "participant" includes any human or non-human animal. In one embodiment, the subject, or patient, or participant is a human or non-human mammal. In one embodiment, the subject, or patient, or participant is a human.

[0140] As used herein, the terms "about" or "approximately," when referring to a measurable value, such as a dosage, encompass variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as appropriate for practicing the methods disclosed herein.

[0141] As used herein, the term "molecular weight" can refer to a "predicted molecular weight" or an "observed molecular weight." The "predicted molecular weight" of a protein is the sum of the molecular weights of all amino acids in the protein. In certain circumstances, the "predicted molecular weight" can differ from the "observed molecular weight" of a molecule. In some embodiments, these differences can occur in a protein due to alterations in glycosylation, glycanation, ubiquitination, phosphorylation, or proteolytic cleavage of the protein or complexes of additional proteins with a given protein.

[0142] FcRn / antigen binding molecule The present disclosure provides FcRn / antigen-binding molecules or fragments thereof. In some embodiments, the FcRn / antigen-binding molecules disclosed herein comprise an FcRn-binding molecule and at least one antigen-binding domain. The FcRn-binding molecule may be any of the FcRn-binding molecules described herein. Similarly, the antigen-binding domain may be any of the antigen-binding domains described herein. In some embodiments, the FcRn / antigen-binding molecule comprises only one antigen-binding domain (e.g., a one-arm FcRn / antigen-binding molecule). In some embodiments, the FcRn / antigen-binding molecule comprises two antigen-binding domains (e.g., a two-arm FcRn / antigen-binding molecule).

[0143] In some embodiments, the antigen-binding domain is linked to the C-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is linked to the N-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is linked to the FcRn-binding molecule at a position other than the C-terminus or N-terminus. The antigen-binding domain may be linked to the FcRn-binding molecule covalently or non-covalently.

[0144] In some embodiments, the antigen-binding domain is fused to the C-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is fused to the N-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is fused to the FcRn-binding molecule at a position other than the C-terminus or N-terminus.

[0145] In some embodiments, one antigen-binding domain is linked to or fused to the N-terminus of the FcRn-binding molecule, and another antigen-binding domain is linked to or fused to the C-terminus of the FcRn-binding molecule. In some embodiments, one antigen-binding domain is linked to or fused to a position other than the N-terminus or C-terminus of one of the FcRn-binding molecules, and another antigen-binding domain is linked to or fused to the N-terminus of the FcRn-binding molecule. In some embodiments, one antigen-binding domain is linked to or fused to a position other than the N-terminus or C-terminus of one of the FcRn-binding molecules, and another antigen-binding domain is linked to or fused to the C-terminus of the FcRn-binding molecule.

[0146] In some embodiments, the FcRn-binding molecule is an Fc region, e.g., a variant Fc region. In some embodiments, the antigen-binding domain is linked to or fused to the C-terminus of one of the Fc domains of the variant Fc region. In some embodiments, the antigen-binding domain is linked to or fused to the N-terminus of one of the Fc domains of the variant Fc region. In some embodiments, the antigen-binding domain is linked to or fused to the FcRn-binding molecule at a position other than the C-terminus or N-terminus.

[0147] In some embodiments, one antigen-binding domain is linked or fused to the C-terminus of one of the Fc domains of the variant Fc region, and another antigen-binding domain is linked or fused to the C-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is linked or fused to the N-terminus of one of the Fc domains of the variant Fc region, and another antigen-binding domain is linked or fused to the N-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is linked or fused to the N-terminus of one of the Fc domains of the variant Fc region, and another antigen-binding domain is linked or fused to the C-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is linked or fused to a position other than the N- or C-terminus of one of the Fc domains of the variant Fc region, and another antigen-binding domain is linked or fused to the N-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is linked or fused to a position other than the N-terminus or C-terminus of one of the Fc domains of the variant Fc region, and another antigen-binding domain is linked or fused to the C-terminus of the other Fc domain of the variant Fc region.

[0148] In some embodiments, the antigen-binding domain may be directly linked to or fused to the N-terminus or C-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is linked to the N-terminus or C-terminus of the FcRn-binding molecule via a linker. In some embodiments, the linker is a non-cleavable linker.

[0149] In some embodiments, the antigen-binding domain may be directly linked (e.g., fused) to the N-terminus or C-terminus of the Fc domain. In some embodiments, the antigen-binding domain is linked to the N-terminus or C-terminus of the Fc domain via a linker. The linker may be any suitable linker, including those described herein.

[0150] FcRn binding molecule The FcRn-binding molecules disclosed herein include any molecule that binds to FcRn, including, but not limited to, any anti-FcRn antibody, any anti-FcRn-binding region, or any Fc domain or Fc region.

[0151] In some embodiments, the FcRn binding molecule is an FcRn antagonist, which includes any molecule that binds to and inhibits FcRn, including, but not limited to, any anti-FcRn antibody, any anti-FcRn binding region, or any Fc domain or Fc region.

[0152] In some embodiments, the FcRn binding molecules disclosed herein comprise two, three, or four FcRn binding regions, eg, Fc regions.

[0153] In some embodiments, the FcRn-binding molecules disclosed herein comprise one or more Fc regions or FcRn-binding fragments thereof in combination with one or more antigen-binding domains (e.g., sdAb, Fab fragment, scFv, or antibody mimetic).

[0154] Any Fc region can be altered to produce a variant Fc region disclosed herein. Generally, the Fc region or FcRn-binding fragment thereof is from a human immunoglobulin. However, it is understood that the Fc region can be derived from the immunoglobulin of any other mammalian species, including, for example, Camelidae species, rodents (e.g., mouse, rat, rabbit, guinea pig), or non-human primate (e.g., chimpanzee, macaque) species. In addition, the Fc region or FcRn-binding portion thereof can be derived from any immunoglobulin class, including IgM, IgG, IgD, IgA, and IgE, and any immunoglobulin isotype, including IgG1, IgG2, IgG3, and IgG4. In one embodiment, the Fc region is an IgG Fc region (e.g., a human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., a human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising portions of several different Fc regions. Suitable examples of chimeric Fc regions are described in US2011 / 0243966A1, which is incorporated herein by reference in its entirety. Various Fc region gene sequences (e.g., human constant region gene sequences) are available in the form of public deposits.

[0155] The Fc region may be further truncated or internally deleted to produce its smallest FcRn-binding fragment. The ability of the Fc region fragment to bind to FcRn can be determined using any art-recognized binding assay, such as ELISA.

[0156] To enhance the manufacturability of the FcRn-binding molecules disclosed herein and FcRn / antigen-binding molecules containing them, the constituent Fc regions preferably do not contain any non-disulfide-bonded cysteine ​​residues. Thus, in one embodiment, the Fc regions do not contain any free cysteine ​​residues.

[0157] In some embodiments, any Fc variant or FcRn-binding fragment thereof that specifically binds to FcRn with increased affinity and reduced pH dependence relative to a native Fc region may be used herein. In one embodiment, the variant Fc region comprises amino acid changes, substitutions, insertions, and / or deletions that confer desired characteristics. In some embodiments, the FcRn-binding molecule comprises a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with higher affinity at pH 5.5 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn-binding molecule comprises a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with higher affinity at pH 6.0 and / or pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn-binding molecule comprises a variant Fc region or an FcRn-binding fragment thereof, which binds to FcRn with higher affinity at both acidic and neutral pH compared to the corresponding wild-type Fc region.

[0158] In some embodiments, the variant Fc region is derived from the Fc region of any native immunoglobulin. In some embodiments, the native immunoglobulin is a human immunoglobulin. In some embodiments, the immunoglobulin is IgA, IgD, IgE, or IgG. In some embodiments, the immunoglobulin is IgG. In some embodiments, the immunoglobulin is human IgA, human IgD, human IgE, or human IgG. In some embodiments, the immunoglobulin is human IgG. In some embodiments, the IgG is IgG1, IgG2, IgG3, or IgG4. In some embodiments, the human IgG is human IgG1, human IgG2, human IgG3, or human IgG4. In some embodiments, the variant Fc region is altered from a human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises a G1m1(a), G1m2(x), G1m3(f), or G1m17(z) allotype.

[0159] In some embodiments, the FcRn binding molecule is an FcRn antagonist.

[0160] In some embodiments, the variant Fc region or FcRn-binding fragment thereof comprises or consists of at least one Fc domain. In some embodiments, the variant Fc region comprises or consists of two Fc domains. In some embodiments, the Fc domains are the same. In some embodiments, the Fc domains are different. In certain embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein comprises one of the following: 237M, 238A, 239K, 248I, 250A, 250F, 250I, 250M, 250Q, 250S, 250V, 250W, 250Y, 252F, 252W, 252Y, 254T, 255E, 256D, 256E, 256Q, 257A, 257G, 257I, 25 7L, 257M, 257N, 257S, 257T, 257V, 258H, 265A, 270F, 286A, 286E, 289H, 297A, 298G, 303A, 305A, 307A, 307D, 307 F, 307G, 307H, 307I, 307K, 307L, 307M, 307N, 307P, 307Q, 307R, 307S, 307V, 307W, 307Y, 308A, 308F, 308I, 308L , 308M, 308P, 308Q, 308T, 309A, 309D, 309E, 309P, 309R, 311A, 311H, 311I, 312A, 312H, 314K, 314R, 315A, 315H, 317A, 325G, 332V, 334L, 360H, 376A, 378V, 380A, 382A, 384A, 385D, 385H, 386P, 387E, 389A, 389S, 424A, 428A, 4 and at least one amino acid or at least two amino acids selected from 28D, 428F, 428G, 428H, 428I, 428K, 428L, 428N, 428P, 428Q, 428S, 428T, 428V, 428W, 428Y, 433K, 434A, 434F, 434H, 434S, 434W, 434Y, 436H, 436I, and 436F, wherein positions are defined according to EU numbering.EU numbering refers to Edelman, GM et al., Proc. Natl. Acad. Sci. USA, 63:78-85 (1969), and Kabat et al., "Sequences of Proteins of Immunological Interest", USDept. Health and Human Services, 5. th edition, 1991. In some embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein is selected from the following: 237M, 238A, 239K, 248I, 250A, 250F, 250I, 250M, 250Q, 250S, 250V, 250W, 250Y, 252F, 252W, 252Y, 254T, 255E, 256D, 256E, 256Q, 257A, 257G, 257I, 257T ... L, 257M, 257N, 257S, 257T, 257V, 258H, 265A, 270F, 286A, 286E, 289H, 297A, 298G, 303A, 305A, 307A, 307D, 307F , 307G, 307H, 307I, 307K, 307L, 307M, 307N, 307P, 307Q, 307R, 307S, 307V, 307W, 307Y, 308A, 308F, 308I, 308L, 3 08M, 308P, 308Q, 308T, 309A, 309D, 309E, 309P, 309R, 311A, 311H, 311I, 312A, 312H, 314K, 314R, 315A, 315H, 31 7A, 325G, 332V, 334L, 360H, 376A, 378V, 380A, 382A, 384A, 385D, 385H, 386P, 387E, 389A, 389S, 424A, 428A, 428D , 428F, 428G, 428H, 428I, 428K, 428L, 428N, 428P, 428Q, 428S, 428T, 428V, 428W, 428Y, 433K, 434A, 434F, 434H, 434S, 434W, 434Y, 436H, 436I, and 436F, wherein positions are defined according to EU numbering, and any combination is contemplated.

[0161] In certain embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein comprises at least one non-naturally occurring amino acid or at least two non-naturally occurring amino acids selected from the following, as numbered according to the EU index as set forth in Kabat: 234, 235, 236, 239, 240, 241, 243, 244, 245, 247, 252, 254, 256, 262, 263, 264, 265, 266, 267, 269, 296, 297, 298, 299, 313, 325, 326, 327, 328, 329, 330, 332, 333, and 334. Optionally, at least one of the variant Fc domains may comprise non-naturally occurring amino acid residues at additional and / or alternative positions known to those of skill in the art (see, e.g., U.S. Patent Nos. 5,624,821, 6,277,375, 6,737,056, PCT Patent Publication Nos. 01 / 58957, 02 / 06919, 04 / 016750, 04 / 029207, 04 / 035752, and 05 / 040217, the contents of which are incorporated by reference herein in their entireties).

[0162] In certain embodiments, at least one of the variant Fc domains is selected from the group consisting of 234D, 234E, 234N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 235A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 235T, 235H, 235Y, 235I, 235V, 235F, 236E, 239D, 239E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240D, 240E, 240N, 239Q, 239F, 239T, 239H, 239Y, 240I, 240F ... 0A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L, 243Y, 243R, 2 43Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 262I, 262A, 262T, 262E, 2 63I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 2 64E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 2 66A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 269G, 297S, 297D, 297E, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 325V, 325H, 327G, 327W, 327N, 327L, at least one non-naturally occurring amino acid or at least two non-naturally occurring amino acids selected from the group consisting of 328S, 328M, 328D, 328E, 328N, 328Q, 328F, 328I, 328V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K, 330G, 330T, 330C, 330L, 330Y, 330V, 330I, 330F, 330R, 330H, 332D, 332S, 332W, 332F, 332E, 332N, 332Q, 332T, 332H, 332Y, and 332A.Optionally, at least one of the variant Fc domains may comprise additional and / or alternative non-naturally occurring amino acid residues known to those of skill in the art (see, e.g., U.S. Patent Nos. 5,624,821, 6,277,375, 6,737,056, PCT Patent Publication Nos. 01 / 58957, 02 / 06919, 04 / 016750, 04 / 029207, 04 / 035752, and 05 / 040217, the contents of which are incorporated by reference herein in their entireties).

[0163] Other known Fc domain variants that may be used in the compositions disclosed herein are described in Ghetie et al, 1997, Nat. Biotech. 15:637-40; Duncan et al, 1988, Nature 332:563-564; Lund et al, 1991, J. Immunol, 147:2657-2662; Lund et al, 1992, Mol. Immunol, 29:53-59; Alegre et al, 1994, Transplantation 57:1537-1543; Hutchins et al, 1995, Proc. Natl. Acad. Sci. USA, 92:11980-11984; Jefferis et al, 1995, Immunol Lett., 44:111-117; Lund et al, 1995, Faseb J.,9:115-119, Jefferis et al,1996,Immunol Lett.,54:101-104,Lund et al,1996,J.Immunol,157:4963-4969,Armour et al,1999,Eur J Immunol 29:2613-2624,Idusogie et al. al,2000,J.Immunol,164:4178-4184,Reddy et al,2000,J.Immunol,164:1925-1933,Xu et al,2000,Cell Immunol,200:16-26,Idusogie et al. al,2001,J.Immunol,166:2571-2575, Shields et al,2001,J Biol.Chem.,276:6591-6604, Jefferis et al,2002,Immunol Lett.,82:57-65, Presta et al,2002,Biochem Soc Trans.,30:487-490), U.S. Patent Nos. 5,624,821, 5,885,573, 5,677,425, 6,165,745, 6,277,375, 5,869,046, 6,121,022, 5,624,821, 5,648,260, 6,528,624, 6,194,551, 6,737,056, 6,821,505, No. 6,277,375, U.S. Patent Publication No. 2004 / 0002587, and PCT Patent Publication Nos. 94 / 29351, 99 / 58572, 00 / 42072, 02 / 060919, 04 / 029207, 04 / 099249, and 04 / 063351, the contents of which are incorporated herein by reference in their entireties.

[0164] In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, comprises or consists of two Fc domains. In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, comprises at least one Fc domain, wherein at least one Fc domain comprises amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In one embodiment, the variant Fc region, or FcRn-binding fragment thereof, comprises at least one Fc domain, wherein at least one Fc domain comprises amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively. In one embodiment, the variant Fc region or FcRn-binding fragment thereof comprises one Fc domain comprising amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively, and a second Fc domain comprising amino acids K and F at EU positions 433 and 434, respectively. In one embodiment, the variant Fc region or FcRn-binding fragment thereof comprises one Fc domain comprising amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively, and a second Fc domain comprising amino acids K and F at EU positions 433 and 434, respectively. In one embodiment, the variant Fc region or FcRn-binding fragment thereof consists of two Fc domains, both of which comprise amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively. In one embodiment, the variant Fc region or FcRn-binding fragment thereof consists of two Fc domains, both of which comprise amino acids Y, T, E, K, F, and Y at EU positions 252, 254, 256, 433, 434, and 436, respectively.

[0165] In certain embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein comprises:

[0166] (i) Q and L at EU positions 250 and 428, respectively;

[0167] (ii) P and A at EU positions 308 and 434, respectively;

[0168] (iii) P and Y at EU positions 308 and 434, respectively; or

[0169] (iv) comprising a combination of amino acids selected from Y, E, and Y at EU positions 252, 286, and 434, respectively.

[0170] In certain embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein is selected from the group consisting of G237M, P238A, S239K, K248I, T250A, T250F, T250I, T250M, T250Q, T250S, T250V, T250W, T250Y, M252F, M252W, M252Y, S254T, R255E, T256D, T256E, T256Q, P257A, P257G, P257I, P257L, P257R, P257S, P257R, P257R, P257S, P257R, P257S, P257T, P257R, P257S, P257R, P257S, P257T, P257R, P257S, P257T, P257R, P257S, P257T, P257R, P257S, P257T, P257T, P257T, P257T, P257G, P257I, P257L, P257T ... 57M, P257N, P257S, P257T, P257V, E258H, D265A, D270F, N286A, N286E, T289H, N297A, S298G, V303A, V305A, T307A, T307D, T307 F, T307G, T307H, T307I, T307K, T307L, T307M, T307N, T307P, T307Q, T307R, T307S, T307V, T307W, T307Y, V308A, V308F, V308I, V 308L, V308M, V308P, V308Q, V308T, V309A, V309D, V309E, V309P, V309R, Q311A, Q311H, Q311I, D312A, D312H, L314K, L314R, N31 5A, N315H, K317A, N325G, I332V, K334L, K360H, D376A, A378V, E380A, E382A, N384A, G385D, G385H, Q386P, P387E, N389A, N389S , S424A, M428A, M428D, M428F, M428G, M428H, M428I, M428K, M428L, M428N, M428P, M428Q, M428S, M428T, M428V, M428W, M428Y, H433K, N434A, N434F, N434H, N434S, N434W, N434Y, Y436H, Y436I, and Y436F, wherein positions are defined according to EU numbering.In some embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein is selected from the group consisting of: G237M, P238A, S239K, K248I, T250A, T250F, T250I, T250M, T250Q, T250S, T250V, T250W, T250Y, M252F, M252W, M252Y, S254T, R255E, T256D, T256E, T256Q, P257A, P257G, P257I, P257L, P257M , P257N, P257S, P257T, P257V, E258H, D265A, D270F, N286A, N286E, T289H, N297A, S298G, V303A, V305A, T307A, T307D, T307F, T307 G, T307H, T307I, T307K, T307L, T307M, T307N, T307P, T307Q, T307R, T307S, T307V, T307W, T307Y, V308A, V308F, V308I, V308L, V308 M, V308P, V308Q, V308T, V309A, V309D, V309E, V309P, V309R, Q311A, Q311H, Q311I, D312A, D312H, L314K, L314R, N315A, N315H, K31 7A, N325G, I332V, K334L, K360H, D376A, A378V, E380A, E382A, N384A, G385D, G385H, Q386P, P387E, N389A, N389S, S424A, M428A, M4 and Y436F, wherein the positions are defined according to EU numbering, and any combination of substitutions is contemplated.

[0171] In certain embodiments, at least one of the variant Fc domains or FcRn-binding fragments described herein comprises:

[0172] (i) M252Y, S254T, T256E, H433K, and N434F;

[0173] (ii) T250Q and M428L,

[0174] (iii) V308P and N434A,

[0175] (iv) V308P and N434Y, or

[0176] (v) comprising a combination of amino acid substitutions selected from M252Y, N286E, and N434Y.

[0177] In one embodiment, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of a polypeptide described herein, thereby altering (e.g., increasing or decreasing) the number of cysteine ​​residues in the hinge region, as described, for example, in U.S. Patent No. 5,677,425, which is incorporated herein by reference in its entirety. The number of cysteine ​​residues in the hinge region may be altered, for example, to facilitate assembly of the light and heavy chains or to alter (e.g., increase or decrease) the stability of the polypeptide.

[0178] In one embodiment, one, two, or more amino acid mutations (e.g., substitutions, insertions, or deletions) are introduced into the Fc region, Fc domain, or FcRn-binding fragment thereof that alter (e.g., decrease or increase) the half-life of the polypeptide in vivo. For examples of mutations that alter (e.g., decrease or increase) the half-life of an antibody in vivo, see, e.g., WO 02 / 060919, WO 98 / 23289, and WO 97 / 34631, and U.S. Patent Nos. 5,869,046, 6,121,022, 6,277,375, and 6,165,745, all of which are incorporated by reference in their entirety. In certain embodiments, one, two, or more amino acid mutations (e.g., substitutions, insertions, or deletions) have been introduced into the Fc region, Fc domain, or FcRn-binding fragment thereof to decrease the half-life of the polypeptide in vivo. In other embodiments, one, two, or more amino acid mutations (e.g., substitutions, insertions, or deletions) have been introduced into the Fc region, Fc domain, or FcRn-binding fragment thereof to increase the half-life of the antibody in vivo. In one embodiment, the Fc region or Fc domain can have one or more amino acid mutations (e.g., substitutions) in the second constant (CH2) domain (residues 231-340 of human IgG1) and / or the third constant (CH3) domain (residues 341-447 of human IgG1), which are numbered according to the EU numbering system. In one embodiment, the IgG1 constant region of a polypeptide described herein comprises a methionine (M) to tyrosine (Y) substitution at position 252, a serine (S) to threonine (T) substitution at position 254, and a threonine (T) to glutamic acid (E) substitution at position 256, numbered according to the EU numbering system. See U.S. Patent No. 7,658,921, which is incorporated herein by reference in its entirety.Variant Fc domains of this type, termed "YTE variants," have been shown to exhibit a four-fold increased half-life compared to the wild-type version of the same antibody (see Dall'Acqua WF et al., (2006) J Biol Chem 281:23514-24, which is incorporated herein by reference in its entirety). In one embodiment, the polypeptide comprises an IgG constant region, wherein the IgG constant region comprises one, two, three, or more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308-314, 385-389, and 428-436, which are numbered according to the EU numbering system.

[0179] In one embodiment, one, two, or more mutations (e.g., amino acid substitutions) are introduced into the Fc region, Fc domain, or FcRn-binding fragment thereof (e.g., the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (residues 341-447 of human IgG1, numbered according to the EU numbering system), and / or the hinge region (residues 216-230, numbered according to the EU numbering system)) of a polypeptide described herein, which increase or decrease the affinity of the antibody for an Fc receptor (e.g., an activating Fc receptor) on the surface of an effector cell. Mutations in the Fc region, Fc domain, or FcRn-binding fragment thereof that decrease or increase the affinity of the antibody for an Fc receptor, and techniques for introducing such mutations into an Fc receptor or fragment thereof, are known to those of skill in the art. Examples of mutations in an Fc region, Fc domain, or FcRn-binding fragment thereof that can be made to alter the affinity of the variant Fc region or FcRn-binding fragment thereof for an Fc receptor are described, for example, in Smith P et al., (2012) PNAS 109:6181-6186, U.S. Patent No. 6,737,056, and WO 02 / 060919, WO 98 / 23289, and WO 97 / 34631, all of which are incorporated by reference in their entirety.

[0180] In one embodiment, one, two, or more amino acid substitutions are introduced into the Fc region, Fc domain, or FcRn-binding fragment thereof to alter the effector function(s) of the polypeptide. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 239, 243, 267, 292, 297, 300, 318, 320, 322, 328, 330, 332, and 396, numbered according to the EU numbering system, can be replaced with a different amino acid residue, resulting in a polypeptide with altered affinity for an effector ligand but retaining the antigen-binding ability of the parent polypeptide. The effector ligand with altered affinity can be, for example, an Fc receptor. This approach is described in further detail in U.S. Patent Nos. 5,624,821 and 5,648,260, each of which is incorporated herein by reference in its entirety. In one embodiment, one or more amino acid substitutions are introduced into the Fc region or Fc domain of a polypeptide described herein to remove potential glycosylation sites on the Fc region or Fc domain, which may reduce Fc receptor binding (see, e.g., Shields RL et al., (2001) J Biol Chem 276:6591-604, which is incorporated herein by reference in its entirety). In one embodiment, one or more of the following mutations in the constant region of a polypeptide described herein may be made, which are numbered according to the EU numbering system: N297A substitution, N297Q substitution, L234A substitution, L234F substitution, L235A substitution, L235F substitution, L235V substitution, L237A substitution, S239D substitution, E233P substitution, L234V substitution, L235A substitution, C236 deletion, P238A substitution, S239D substitution, F243L substitution, D265A substitution, S267E substitution, L328F substitution, R292P substitution, Y300L substitution, A327Q substitution, P329A substitution, A330L substitution, I332E substitution, or P396L substitution.

[0181] In one embodiment, a mutation selected from the group consisting of D265A, P329A, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein. In one embodiment, a mutation selected from the group consisting of L235A, L237A, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein. In one embodiment, a mutation selected from the group consisting of S267E, L328F, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein. In one embodiment, a mutation selected from the group consisting of S239D, I332E, optionally A330L, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein. In one embodiment, a mutation selected from the group consisting of L235V, F243L, R292P, Y300L, P396L, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein. In one embodiment, a mutation selected from the group consisting of S267E, L328F, and combinations thereof, numbered according to the EU numbering system, may be made in the constant region of a polypeptide described herein.

[0182] In one embodiment, the Fc region, Fc domain, or FcRn-binding fragment thereof described herein comprises an IgG1 constant region with an N297Q or N297A amino acid substitution, as numbered according to the EU numbering system. In one embodiment, the Fc region, Fc domain, or FcRn-binding fragment thereof described herein comprises an IgG1 constant region with an N297Q or N297A amino acid substitution, as numbered according to the EU numbering system. In one embodiment, the Fc region, Fc domain, or FcRn-binding fragment thereof described herein comprises an IgG1 constant region with an N297Q or N297A amino acid substitution, as numbered according to the EU numbering system. In one embodiment, the Fc region, Fc domain, or FcRn-binding fragment thereof described herein comprises an IgG1 constant region with an N297Q or N297A amino acid substitution, as numbered according to the EU numbering system. In another embodiment, the Fc region, Fc domain, or FcRn-binding fragment thereof described herein comprises an IgG1 constant region with an N234A or N235A mutation, as numbered according to the EU numbering system. In one embodiment, the amino acid residues at positions in the constant region of an Fc region, Fc domain, or FcRn-binding fragment thereof described herein corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain, numbered according to the EU numbering system, are not L, L, and D, respectively. This approach is described in detail in WO 14 / 108483, which is incorporated herein by reference in its entirety. In one embodiment, the amino acids corresponding to positions L234, L235, and D265 in a human IgG1 heavy chain are F, E, and A, or A, A, and A, respectively, which are numbered according to the EU numbering system.

[0183] In one embodiment, the amino acids at positions 433, 434, and 436 of the heavy chain constant region according to the EU numbering system are K, F, and Y, respectively. In one embodiment, the amino acids at positions 252, 254, and 256 of the heavy chain constant region according to the EU numbering system are Y, T, and E, respectively. In one embodiment, the amino acids at positions 428 and 434 of the heavy chain constant region according to the EU numbering system are L and S, respectively. In one embodiment, the amino acids at positions 309, 311, and 434 of the heavy chain constant region according to the EU numbering system are D, H, and S, respectively.

[0184] In one embodiment, the polypeptide does not have amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively.

[0185] In one embodiment, one or more amino acids selected from amino acid residues 329, 331, and 322, numbered according to the EU numbering system, in the constant region of a polypeptide described herein can be replaced with a different amino acid residue, thereby causing the antibody to have altered C1q binding and / or reduced or abolished complement-dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 (Idusogie et al.), which is incorporated herein by reference in its entirety. In one embodiment, one or more amino acid residues within amino acid positions 231-238, numbered according to the EU numbering system, in the N-terminal region of the CH2 domain of a polypeptide described herein are altered, thereby altering the antibody's ability to fix complement. This approach is further described in WO 94 / 29351, which is incorporated herein by reference in its entirety. In one embodiment, the Fc region or Fc domain of a polypeptide described herein may be modified at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 30 The modified amino acids have been modified by mutating (e.g., introducing amino acid substitutions) one or more amino acids at positions 1, 303, 305, 307, 309, 312, 315, 320, 322, 324, 326, 327, 328, 329, 330, 331, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, ​​388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438, or 439, which are numbered according to the EU numbering system. This approach is further described in WO 00 / 42072, which is incorporated by reference in its entirety.

[0186] In one embodiment, any of the constant region mutations or modifications described herein may be introduced into one or both heavy chain constant regions of a polypeptide described herein having two heavy chain constant regions, hi one embodiment, any of the constant region mutations or modifications described herein may be introduced into the heavy chain constant region of a polypeptide described herein having one heavy chain constant region.

[0187] In one embodiment, the present disclosure provides a polypeptide comprising one, two, or three binding sites to human FcRn, which specifically binds to FcRn and functions as an antagonist.

[0188] In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 2. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region comprises the amino acid sequence of SEQ ID NO: 3. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region consists of the amino acid sequence of SEQ ID NO: 3.

[0189] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region comprises two Fc domains, the amino acid sequence of each of the Fc domains being independently selected from SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.

[0190] In certain embodiments, the variant Fc region is a heterodimer, and the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art (see, e.g., US Pat. No. 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn-binding molecule consists of a variant Fc region, wherein the variant Fc region consists of two Fc domains that form a heterodimer, and the amino acid sequence of each Fc domain is independently selected from SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. In one embodiment, the FcRn-binding molecule consists of or comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn-binding molecule consists of or comprises a variant Fc region, which consists of or comprises two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3. In one embodiment, the FcRn-binding molecule consists of or comprises a variant Fc region, which consists of or comprises two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain consists of or comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0191] In one embodiment, the FcRn-binding molecule comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:1.

[0192] In one embodiment, the FcRn-binding molecule comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:2.

[0193] In one embodiment, the FcRn-binding molecule comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains that form a homodimer, and the amino acid sequence of each of the Fc domains consists of or comprises the amino acid sequence of SEQ ID NO:3.

[0194] In one embodiment, the FcRn-binding molecule comprises a variant Fc region, wherein the variant Fc region comprises or consists of efgartigimod (CAS Registry No. 1821402-21-4). As used herein, the term "efgartigimod" is interchangeable with "efgartigimod alfa" and "ARGX-113." In some embodiments, efgartigimod is efgartigimod alfa-fcab.

[0195] In one embodiment, the variant Fc region is modified to promote heterodimerization. Such modifications are known in the art, and any suitable means for promoting heterodimerization can be used to generate the FcRn / antigen-binding molecules described herein. In some embodiments, the variant Fc region comprises one or more mutations in amino acid residues that form the interface of the CH3 domain of the Fc domain. In some embodiments, the variant Fc region comprises knob-into-hole mutations (see, e.g., WO 2006 / 028936, which is incorporated by reference in its entirety). In this technique, Ig heavy chain mispairing is reduced by mutating selected amino acids that form the interface of the CH3 domain in IgG. At positions within the CH3 domain where the two heavy chains directly interact, one or more amino acids with small side chains (holes) are introduced into the sequence of one heavy chain, and one or more amino acids with large side chains (knobs) are introduced into the corresponding interacting residue position(s) on the other heavy chain. The Fc domains of the Fc region may be composed of immunoglobulin chains of the same subclass (eg, IgG1 or IgG3) or different subclasses (eg, IgG1 and IgG3, or IgG3 and IgG4).

[0196] In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises the amino acid W at EU position 366. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises the amino acids S, A, and V at EU positions 366, 368, and 407, respectively. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises the amino acid W at EU position 366, and the other Fc domain comprises the amino acids S, A, and V at EU positions 366, 368, and 407, respectively.

[0197] In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acids E and D at EU positions 370 and 409, respectively, and the other Fc domain comprising amino acid K at EU positions 357 and 399. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising H and A at EU positions 364 and 405, respectively, and the other Fc domain comprising amino acids T and F at EU positions 349 and 394, respectively. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acids V, Y, A, and V at EU positions 350, 351, 405, and 407, respectively, and the other Fc domain comprising amino acids V, L, L, and W at EU positions 350, 366, 392, and 394, respectively. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acids D, M, and A at EU positions 360, 399, and 407, respectively, and the other Fc domain comprising amino acids R, R, V, and V at EU positions 345, 347, 366, and 409, respectively. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acid D at EU positions 409 and 392, and the other Fc domain comprising amino acid K at EU positions 399 and 356. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acids E, W, and C at EU positions 360, 409, and 349, respectively, and the other Fc domain comprising amino acids R, V, T, and C at EU positions 347, 399, 405, and 354, respectively.In some embodiments, the variant Fc region comprises or consists of two Fc domains, one Fc domain comprising amino acids E and W at EU positions 370 and 409, respectively, and the other Fc domain comprising amino acids N, V, and T at EU positions 357, 399, and 405, respectively.

[0198] In one embodiment, the FcRn-binding molecule consists of a variant Fc region, which comprises or consists of two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain is selected from an amino acid sequence comprising or consisting of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and / or the amino acid sequence of the second Fc domain is selected from an amino acid sequence comprising or consisting of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9. In one embodiment, the FcRn-binding molecule consists of a variant Fc region, which comprises or consists of two Fc domains that form a heterodimer, and the amino acid sequence of the first Fc domain is selected from an amino acid sequence comprising or consisting of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 9, and / or the amino acid sequence of the second Fc domain is selected from an amino acid sequence comprising or consisting of SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. In one embodiment, the FcRn-binding molecule consists of a variant Fc region, which comprises or consists of two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of SEQ ID NO: 4 and the amino acid sequence of the second Fc domain comprises or consists of SEQ ID NO: 7. In one embodiment, the FcRn-binding molecule consists of a variant Fc region, which comprises or consists of two Fc domains that form a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of SEQ ID NO: 5 and the amino acid sequence of the second Fc domain comprises or consists of SEQ ID NO: 8. In one embodiment, the FcRn-binding molecule consists of a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains that form a heterodimer, and wherein the amino acid sequence of the first Fc domain comprises or consists of SEQ ID NO: 6 and the amino acid sequence of the second Fc domain comprises or consists of SEQ ID NO: 9. In some embodiments, the FcRn-binding molecule is an FcRn antagonist. Table 1. Amino acid sequences of variant Fc regions [Table 1]

[0199] In some embodiments, the variant Fc region comprises a first Fc domain comprising amino acids Y, T, E, K, and F at EU positions 252, 254, 256, 433, and 434, respectively, and a second Fc domain comprising amino acids K and F at EU positions 433 and 434, respectively. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 3.

[0200] In some embodiments, the variant Fc region comprises a first Fc domain comprising amino acids Y, T, E, W, K, and F at EU positions 252, 254, 256, 366, 433, and 434, respectively, and a second Fc domain comprising amino acids S, A, V, K, and F at EU positions 366, 368, 407, 433, and 434, respectively. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 6.

[0201] In some embodiments, the variant Fc region comprises a first Fc domain comprising amino acids Y, T, E, S, A, V, K, and F at EU positions 252, 254, 256, 366, 368, 407, 433, and 434, respectively, and a second Fc domain comprising amino acids W, K, and F at EU positions 366, 433, and 434, respectively. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first Fc domain comprises the amino acid sequence of SEQ ID NO: 9.

[0202] In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), nipocalimab (M281), orilanolimab (ALXN1830 / SYNT001), or batoclimab (IMVT-1401 / RVT1401 / HBM9161).

[0203] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of immunoglobulins to FcRn is nipocalimab, also known as M281. Nipocalimab is a full-length "Fc-dead" IgG1 monoclonal antibody. Nipocalimab has been administered as an intravenous infusion in Phase 2 / 3 clinical trials for the treatment of myasthenia gravis (MG) and warm antibody autoimmune hemolytic anemia (WAIHA), and in Phase 2 clinical trials for the treatment of hemolytic disease of the fetus and newborn (HDFN), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS). Nipocalimab comprises the light chain (SEQ ID NO: 128) and heavy chain (SEQ ID NO: 129) sequences set forth in Table 2 below (the VL of SEQ ID NO: 128 and the VH of SEQ ID NO: 129 are underlined). Table 2. Nipocalimab heavy and light chain sequences [Table 2]

[0204] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolixizumab, also known as UCB 7665. Rozanolixizumab is a full-length humanized IgG4 monoclonal antibody. Rozanolixizumab has been administered as a subcutaneous infusion in clinical trials for MG, immune thrombocytopenia (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AIE), and myelin oligodendrocyte glycoprotein-associated disease (MOG-AD). Rozanolixizumab comprises the light chain (SEQ ID NO: 130) and heavy chain (SEQ ID NO: 131) sequences set forth in Table 3 below (the VL of SEQ ID NO: 130 and the VH of SEQ ID NO: 131 are underlined). Table 3. Heavy and light chain sequences of rozanolixizumab [Table 3]

[0205] In one embodiment, the antibody that specifically binds to FcRn and inhibits binding of the Fc region of an immunoglobulin to FcRn is orilanolimab, also known as SYNT001 / ALXN1830. Orilanolimab is another full-length humanized IgG4 monoclonal antibody. Orilanolimab is administered as an intravenous infusion in a Phase 2 clinical trial for the treatment of WAIHA and pemphigus. Orilanolimab comprises the light chain (SEQ ID NO: 132) and heavy chain (SEQ ID NO: 133) sequences set forth in Table 4 below (VL of SEQ ID NO: 132 and VH of SEQ ID NO: 133 are underlined). Table 4. Heavy and light chain sequences of orilanolimab [Table 4]

[0206] In one embodiment, the antibody that specifically binds to FcRn and inhibits binding of the Fc region of an immunoglobulin to FcRn is batoclimab, also known as IMVT1401 / RVT1401 / HBM9161. Batoclimab is another full-length "Fc-dead" IgG1 monoclonal antibody. Batoclimab has been administered as a subcutaneous injection in a Phase 2 clinical trial for the treatment of MG, ITP, Graves' ophthalmopathy, thyroid eye disease, and neuromyelitis optica spectrum disorder (NMOSD). Batoclimab comprises the light chain (SEQ ID NO: 134) and heavy chain (SEQ ID NO: 135) sequences set forth in Table 5 below (the VL of SEQ ID NO: 134 and the VH of SEQ ID NO: 135 are underlined). Table 5. Batoclimab heavy and light chain sequences [Table 5]

[0207] antigen-binding domain In one aspect, antigen-binding domains are provided by the present disclosure. In some embodiments, the FcRn / antigen-binding molecules disclosed herein comprise one or more FcRn-binding molecules in combination with one or more antigen-binding domains. In some embodiments, the FcRn / antigen-binding molecules disclosed herein comprise one or more Fc regions or FcRn-binding fragments thereof in combination with one or more antigen-binding domains. In some embodiments, the antigen-binding domain is a polypeptide derived from an antibody, including but not limited to, an sdAb (e.g., a VHH fragment), a Fab fragment, an scFv, a VH, or a VL. In some embodiments, the antigen-binding domain is a synthetic antigen-binding protein or an antibody mimetic protein, including but not limited to, anticalin or DARPin.

[0208] In some embodiments, the antigen-binding domain further comprises one or more amino acids added at its C-terminus. In some embodiments, the antigen-binding domain further comprises one or more amino acids added at the C-terminus, wherein the one or more amino acids are selected from A, AG, GG, and PP. In some embodiments, the C-terminus of the VHH is the amino acid sequence VTVSS (SEQ ID NO: 91). In some embodiments, the C-terminus of the VHH consists of the amino acid sequence VTVSS (SEQ ID NO: 91).

[0209] The antigen-binding domain can bind to any antigen. In some embodiments, the antigen is a non-human antigen, e.g., a protein or fragment thereof that is not normally expressed by humans and not normally found in humans. In some embodiments, the non-human antigen is a protein or fragment thereof that is not normally expressed by humans but can be found in humans. Examples of non-human antigens that can be found in humans include proteins or fragments thereof expressed by pathogens, such as bacterial or viral proteins or fragments thereof. These pathogenic proteins or fragments thereof can be found in humans due to infection and / or immunization. Thus, in some embodiments, the non-human antigen that can be found in humans is a viral antigen. In some embodiments, the non-human antigen is a non-human antigen not found in humans. Examples of non-human antigens not found in humans include proteins or fragments thereof that are not pathogenic and do not have a human counterpart, such as hen egg white lysozyme (HEL) or ovalbumin.

[0210] In some embodiments, the antigen is a human antigen, e.g., a protein or fragment thereof that is normally expressed by humans, hi some embodiments, the human antigen is selected from HSA or IgE.

[0211] In some embodiments, the antigen-binding domain specifically binds to HSA. In some embodiments, the antigen-binding domain specifically binds to HSA and is selected from a Fab fragment, an scFv, an sdAb, HSA, and an HSA-binding fragment thereof. In some embodiments, the antigen-binding domain specifically binds to HSA and is an sdAb, e.g., a VHH fragment. In some embodiments, the HSA comprises an amino acid sequence that is at least 95% identical to the amino acid sequence provided in GenBank Accession No. AAA98797.1. In some embodiments, the HSA comprises the amino acid sequence provided in GenBank Accession No. AAA98797.1.

[0212] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment comprises the CDR1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence of a VHH fragment comprising an amino acid sequence selected from SEQ ID NOs: 43 to 74, 84 to 90, and 120 to 127.

[0213] In some embodiments, the antigen-binding domain is a VHH fragment, wherein the VHH fragment comprises or consists of a combination of CDR1, CDR2, and CDR3, wherein 1, 2, 3, 4, or 5 amino acids are selected from the group consisting of SEQ ID NOs: 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 11, and 12; 16, 11, and 12; 17, 11, and 12; 10, 11, and 12; 8, and 12;10, 19, and 12;10, 20, and 12;10, 21, and 12;10, 22, and 12;10, 23, and 12;10, 24, and 12;10, 25, and 12;10, 26, and 12;10, 27, and 12;10, 28, and 12;10, 29, and 12;10, 30, and 12;10, 31, and 12;10, 32, and 12;10, 33, and 12;10, 11, and 34;10, 11, and 35;10, 11, and 36;10, 11, and 37;10, 11, and 38;10, 11, and 39;10, 11, and 40;15, 11, and 36;15, 21, and 12;10, 41, and 12;10, 20, and 36;111, 11, and 12;112, 11, and 12;10, 113, and 12;10, 11 4, and 12; 10, 11, and 115; 10, 11, and 116; 10, 11, and 117; 118, 11, and 119; 75, 76, and 77; 75, 76, and 78; 75, 76, and 79; 75, 76, and 80; 75, 76, and 81; 75, 76, and 82; and 75, 76, and 83.

[0214] In some embodiments, the antigen binding domain is a VHH fragment, and the VHH fragment is selected from the group consisting of SEQ ID NOs: 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 11, and 12; 16, 11, and 12; 17, 11, and 12; 10, 18, and 12; 10, 19, and 12; 10, 20, and 12; 10, 21, and 12; 10, 22, and 12; 10, 23, and 24; 3, and 12;10, 24, and 12;10, 25, and 12;10, 26, and 12;10, 27, and 12;10, 28, and 12;10, 29, and 12;10, 30, and 12;10, 31, and 12;10, 32, and 12;10, 33, and 12;10, 11, and 34;10, 11, and 35;10, 11, and 36;10, 11, and 37;10, 11, and 38;10, 11, and 39;10, 11, and 40;15, 11, and 36;15, 21, and 12;10, 41, and 12;10, 20, and 36;111, 11, and 12;112, 11, and 12;10, 113, and 12;10, 114, and 12;10, 11, and 115;10, 11, and 116;10, 11, and 117;118, 11, and 119 75, 76, and 77; 75, 76, and 78; 75, 76, and 79; 75, 76, and 80; 75, 76, and 81; 75, 76, and 82; and 75, 76, and 83, wherein one or more amino acids within one or more of the CDRs are substituted with alanine or histidine.

[0215] In some embodiments, the antigen binding domain is a VHH fragment, and the VHH fragment is selected from the group consisting of SEQ ID NOs: 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 11, and 12; 16, 11, and 12; 17, 11, and 12; 10, 18, and 12; 10, 19, and 12; 10, 20, and 12; 10, 21, and 12; 10, 22, and 23; 2, and 12;10, 23, and 12;10, 24, and 12;10, 25, and 12;10, 26, and 12;10, 27, and 12;10, 28, and 12;10, 29, and 12;10, 30, and 12;10, 31, and 12;10, 32, and 12;10, 33, and 12;10, 11, and 34;10, 11, and 35;10, 11, and 36;10, 11, and 37;10, 11, and 38;10, 11, and 39;10, 11, and 40;15, 11, and 36;15, 21, and 12;10, 41, and 12;10, 20, and 36;111, 11, and 12;112, 11, and 12;10, 113, and 12;10, 114, and 12;10, 11, and 115;10, 11, and 116; 10, 11, and 117; 118, 11, and 119; 75, 76, and 77; 75, 76, and 78; 75, 76, and 79; 75, 76, and 80; 75, 76, and 81; 75, 76, and 82; and 75, 76, and 83.

[0216]

[0217] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from SEQ ID NOs: 42 to 74, 84 to 90, and 120 to 127. In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment comprises or consists of an amino acid sequence selected from SEQ ID NOs: 42 to 74, 84 to 90, and 120 to 127.

[0218] Linker The antigen-binding domain can be linked to the N-terminus or C-terminus of the FcRn-binding molecule (e.g., Fc domain). Alternatively, the antigen-binding domain can be linked at a position other than the N-terminus or C-terminus of the FcRn-binding molecule (e.g., Fc domain). Preferably, the antigen-binding domain is linked to the C-terminus of the FcRn-binding molecule (e.g., Fc domain).

[0219] In some embodiments, the antigen-binding domain may be non-covalently linked to the FcRn-binding molecule. In some embodiments, the antigen-binding domain may be covalently linked to the FcRn-binding molecule.

[0220] In some embodiments, the antigen-binding domain can be directly linked (e.g., fused) to the N-terminus or C-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is linked to the N-terminus or C-terminus of the FcRn-binding molecule via a linker. In some embodiments, the linker is a non-cleavable linker.

[0221] In some embodiments, the antigen-binding domain may be directly linked (e.g., fused) to the N-terminus or C-terminus of the Fc domain. In some embodiments, the antigen-binding domain is linked to the N-terminus or C-terminus of the Fc domain via a linker. In some embodiments, the linker is a non-cleavable linker. As used herein, the term "non-cleavable linker" refers to a linker that is not readily cleaved by one or more of a given enzyme, chemical agent, or light irradiation. In some embodiments, the enzyme is a protease.

[0222] In some embodiments, the linker is a synthetic compound linker, such as a chemical crosslinker. Non-limiting examples of suitable commercially available crosslinkers include N-hydroxysuccinimide (NHS), disuccinimidyl suberate (DSS), bis(sulfosuccinimidyl)suberate (BS3), dithiobis(succinimidyl propionate) (DSP), dithiobis(sulfosuccinimidyl propionate) (DTSSP), ethylene glycol bis(succinimidyl succinate) (EGS), ethylene glycol bis(sulfosuccinimidyl succinate) (sulfo-EGS), disuccinimidyl tartrate (DST), disulfosuccinimidyl tartrate (sulfo-DST), bis[2-(succinimidooxycarbonyloxy)ethyl]sulfone (BSOCOES), and bis[2-(sulfosuccinimidooxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES).

[0223] As described above, the Fc domains disclosed herein may comprise a portion of a hinge region. Thus, the antigen-binding domain may be linked to the N-terminus of the Fc domain via this hinge region. In some embodiments, one or more amino acids are included between the C-terminus of the antigen-binding domain and the N-terminus of the Fc domain. In some embodiments, one or more amino acids included between the C-terminus of the antigen-binding domain and the N-terminus of the Fc domain are amino acids of a natural hinge region. In some embodiments, the C-terminus of the antigen-binding domain is fused to the N-terminus of the Fc domain via the hinge region or a portion thereof. In some embodiments, the hinge region is an IgG hinge region, e.g., a human IgG hinge region.

[0224] In some embodiments, the linker is a peptide linker. Examples of peptide linkers are well known, and one skilled in the art can select a suitable peptide linker for use in linking an antigen-binding domain to an FcRn-binding molecule, e.g., an Fc domain.

[0225] The peptide linker can be of any length. In some embodiments, the length and amino acid composition of the linker peptide sequence can be optimized to achieve the desired activity of the FcRn / antigen-binding molecule by varying the orientation and / or proximity of the polypeptide domains relative to each other. In some embodiments, the peptide linker is about 1 to about 100 amino acids in length, about 8 to about 40 amino acids in length, or about 15 to about 25 amino acids in length. In some embodiments, the peptide linker is 1 to 100 amino acids in length, 8 to 40 amino acids in length, or 15 to 25 amino acids in length. In some embodiments, the peptide linker is about 8 amino acids in length, about 9 amino acids in length, about 10 amino acids in length, about 11 amino acids in length, about 12 amino acids in length, about 13 amino acids in length, about 14 amino acids in length, about 15 amino acids in length, about 16 amino acids in length, about 17 amino acids in length, about 18 amino acids in length, about 19 amino acids in length, about 20 amino acids in length, about 21 amino acids in length, about 22 amino acids in length, about 23 amino acids in length, about 24 amino acids in length, about 25 amino acids in length, about 26 amino acids in length, about 27 amino acids in length, about 28 amino acids in length, about 29 amino acids in length, about 30 amino acids in length, about 31 amino acids in length, about 32 amino acids in length, about 33 amino acids in length, about 34 amino acids in length, about 35 amino acids in length, about 36 amino acids in length, about 37 amino acids in length, about 38 amino acids in length, about 39 amino acids in length, or about 40 amino acids in length. In some embodiments, the peptide linker is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids in length.

[0226] In some embodiments, the peptide linker contains only glycine and / or serine residues (e.g., a glycine-serine linker or GS linker). Examples of such peptide linkers include Gly(x)Ser (where x is 0-6), or Ser Gly(x) (where x is 0-6), (Gly Gly Gly Gly Ser)n (where n is an integer equal to or greater than 1), and (Ser Gly Gly Gly Gly)n (where n is an integer equal to or greater than 1). In some embodiments, the peptide linker comprises an amino acid sequence selected from the group consisting of (GGGGS)n and (SGGGG)n, where n is 1-8. In some embodiments, the linker peptide is modified so that the amino acid sequence GSG (which occurs at the junction of a traditional Gly / Ser linker peptide repeat) is absent. For example, in some embodiments, the peptide linker comprises an amino acid sequence selected from the group consisting of (GGGXX)nGGGGS and GGGGS(XGGGS)n (where X is any amino acid that can be inserted into the sequence and does not result in a polypeptide containing the sequence GSG, and n is 0-4). In some embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, where X1 is P, X2 is S, and n is 0-4. In some other embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, where X1 is G, X2 is Q, and n is 0-4. In some other embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, where X1 is G, X2 is A, and n is 0-4. In still other embodiments, the sequence of the linker peptide is GGGGS(XGGGS)n, where X is P, and n is 0-4. In some embodiments, a linker peptide of the present disclosure comprises or consists of the amino acid sequence (GGGGA)2GGGGS. In some embodiments, a linker peptide comprises or consists of the amino acid sequence (GGGGQ)2GGGGS. In other embodiments, a linker peptide comprises or consists of the amino acid sequence (GGGPS)2GGGGS. In other embodiments, a linker peptide comprises or consists of the amino acid sequence GGGGS(PGGGS)2.In yet other embodiments, the linker peptide comprises or consists of the amino acid sequence GSGGS or SGGSGS. In some embodiments, the linker peptide comprises or consists of the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 136), GGGGSGGGGS (SEQ ID NO: 181), or GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 182).

[0227] In some embodiments, the peptide linker is a GS linker about 20 or about 30 amino acids in length. In some embodiments, the peptide linker is a GS linker about 20 or 30 amino acids in length.

[0228] Heavy chain molecules In some embodiments, the FcRn / antigen-binding molecule can comprise a first heavy chain described herein. In some embodiments, the first heavy chain comprises an Fc domain and an antigen-binding domain connected by a linker. In some embodiments, the FcRn / antigen-binding molecule can further comprise a second heavy chain described herein. In some embodiments, the second heavy chain comprises an Fc domain and an antigen-binding domain connected by a linker. In some embodiments, the second heavy chain comprises an Fc domain. In some embodiments, the first and second heavy chains are the same. In some embodiments, the first and second heavy chains are different.

[0229] In some embodiments, the first and second heavy chains have the same Fc domain. In some embodiments, the first and second heavy chains have different Fc domains. In some embodiments, both the first and second heavy chains comprise an antigen-binding domain. In some embodiments, the antigen-binding domains in the first and second heavy chains are the same. In some embodiments, the antigen-binding domains in the first and second heavy chains are different. In some embodiments, the first heavy chain comprises an Fc domain and an antigen-binding domain, and the second heavy chain comprises an Fc but no antigen-binding domain. In some embodiments, the first heavy chain comprises an Fc domain and an antigen-binding domain, and the second heavy chain comprises an Fc domain but no antigen-binding domain or linker. In some embodiments, the first heavy chain comprises an Fc domain, an antigen-binding domain, and a linker, and the second heavy chain comprises an Fc domain but no antigen-binding domain or linker.

[0230] In some embodiments, the antigen-binding domain is linked to the N-terminus of the Fc domain. In some embodiments, the antigen-binding domain is linked to the C-terminus of the Fc domain. In some embodiments, the antigen-binding domain is linked to a position other than the N-terminus or C-terminus of the Fc domain.

[0231] In some embodiments, the antigen-binding domain is fused to the N-terminus of the Fc domain. In some embodiments, the antigen-binding domain is fused to the C-terminus of the Fc domain. In some embodiments, the antigen-binding domain is fused to a position other than the N-terminus or C-terminus of the Fc domain.

[0232] In some embodiments, the antigen-binding domain is linked to the N-terminus of the Fc domain by a linker. In some embodiments, the antigen-binding domain is linked to the C-terminus of the Fc domain by a linker. In some embodiments, the antigen-binding domain is linked to a position other than the N-terminus or C-terminus of the Fc domain by a linker.

[0233] In some embodiments, the antigen-binding domain is fused to the N-terminus of the Fc domain via a peptide linker. In some embodiments, the antigen-binding domain is fused to the C-terminus of the Fc domain via a peptide linker. In some embodiments, the antigen-binding domain is fused to a position other than the N-terminus or C-terminus of the Fc domain via a peptide linker.

[0234] In some embodiments, the Fc domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-9. In some embodiments, the Fc domain consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-9.

[0235] In some embodiments, the Fc domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 9. In some embodiments, the Fc domain consists of the amino acid sequence of any one of SEQ ID NOs: 1 to 9.

[0236] In some embodiments, the first and second heavy chains comprise the same Fc domain. In some embodiments, both the first and second heavy chains comprise an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second heavy chains comprise an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second heavy chains comprise an Fc domain comprising the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second heavy chains comprise an Fc domain consisting of the amino acid sequence of any one of SEQ ID NOs: 1-3.

[0237] In some embodiments, the first and second heavy chains comprise different Fc domains. In some embodiments, the first heavy chain comprises an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 4-6, and the second heavy chain comprises an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 7-9. In some embodiments, the first heavy chain comprises an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 4 to 6, and the second heavy chain comprises an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 7 to 9. In some embodiments, when the first heavy chain comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 4 or a variant thereof, the second heavy chain comprises an Fc domain comprising SEQ ID NO: 7 or a variant thereof. In some embodiments, when the first heavy chain comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 5 or a variant thereof, the second heavy chain comprises an Fc domain comprising SEQ ID NO: 8 or a variant thereof. In some embodiments, when the first heavy chain comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 6 or a variant thereof, the second heavy chain comprises an Fc domain comprising SEQ ID NO: 9 or a variant thereof.

[0238] In some embodiments, the first and second heavy chains further comprise a peptide linker. In some embodiments, the first and second heavy chains further comprise the same peptide linker. In some embodiments, the first and second heavy chains further comprise different peptide linkers. In some embodiments, the first heavy chain comprises an Fc domain, a peptide linker, and an antigen-binding domain, and the second heavy chain comprises an Fc domain but does not comprise a peptide linker or an antigen-binding domain. The peptide linker encoded by the first and second heavy chains can be any of those described herein. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 136, 180, or 181.

[0239] In some embodiments, the FcRn / antigen binding molecule comprises an amino acid sequence selected from Table 6 or a variant thereof. [Table 6] TIFF0007789236000007.tif249170TIFF0007789236000008.tif248170TIFF0007789236000009.tif245170 TIFF0007789236000010.tif248170TIFF0007789236000011.tif244170TIFF0007789236000012.tif244170

[0240] In some embodiments, the FcRn / antigen-binding molecule comprises or consists of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180. In some embodiments, the FcRn / antigen-binding molecule comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180.

[0241] In some embodiments, the FcRn / antigen-binding molecule comprises the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180 or a variant thereof, and one or more amino acids added at the C-terminus. In some embodiments, the FcRn / antigen-binding molecule comprises the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180 or a variant thereof, and one or more amino acids added at the C-terminus, wherein the one or more amino acids are selected from A, AG, GG, and PP.

[0242] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180, and the second heavy chain of the FcRn / antigen-binding molecule does not comprise an antigen-binding domain. In some embodiments, the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain. Optionally, the second heavy chain of the FcRn / antigen-binding molecule comprises or consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0243] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180, and the second heavy chain of the FcRn / antigen-binding molecule does not comprise an antigen-binding domain. In some embodiments, the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain. Optionally, the second heavy chain of the FcRn / antigen-binding molecule comprises or consists of the amino acid sequence of SEQ ID NO: 8.

[0244] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0245] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0246] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0247] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0248] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0249] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0250] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0251] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0252] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0253] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0254] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 142, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 142, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0255] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 142, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 142, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0256] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 143, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 143, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0257] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 143, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 143, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0258] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 144, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 144, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0259] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 144, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 144, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0260] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 145, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 145, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0261] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 145, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 145, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0262] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 146, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 146, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0263] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 146, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 146, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0264] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 147, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 147, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0265] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 147, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 147, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0266] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 148, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 148, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0267] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 148, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 148, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0268] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 149, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 149, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0269] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 149, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 149, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0270] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 150, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 150, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0271] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 150, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 150, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0272] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 151, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 151, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0273] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 151, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 151, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0274] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 152, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 152, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0275] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 152, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 152, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0276] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 153, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 153, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0277] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 153, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 153, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0278] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 154, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0279] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 154, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 154, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0280] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 155, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0281] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 155, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 155, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0282] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 156, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 156, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0283] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 156, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 156, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0284] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 157, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 157, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0285] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 157, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 157, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0286] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 158, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 158, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0287] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 158, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 158, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0288] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 159, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 159, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0289] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 159, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 159, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0290] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 160, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 160, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0291] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 160, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 160, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0292] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 161, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 161, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0293] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 161, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 161, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0294] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 162, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 162, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0295] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 162, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 162, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0296] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 163, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 163, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0297] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 163, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 163, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0298] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 164, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 164, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0299] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 164, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 164, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0300] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 165, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 165, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0301] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 165, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 165, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0302] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 166, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 166, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0303] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 166, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 166, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0304] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 167, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 167, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0305] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 167, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 167, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0306] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 168, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 168, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0307] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 168, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 168, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0308] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 169, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 169, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0309] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 169, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 169, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0310] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 170, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 170, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0311] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 170, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 170, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0312] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 171, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 171, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0313] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 171, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 171, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0314] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 172, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 172, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0315] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 172, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 172, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0316] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 173, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 173, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0317] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 173, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 173, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0318] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 174, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 174, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0319] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 174, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 174, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0320] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 175, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 175, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0321] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 175, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 175, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0322] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 176, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 176, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0323] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 176, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 176, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0324] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 180, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 180, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0325] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule comprises the amino acid sequence of SEQ ID NO: 180, and the second heavy chain of the FcRn / antigen-binding molecule comprises an Fc domain but does not comprise an antigen-binding domain, comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 180, and the second heavy chain of the FcRn / antigen-binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0326] In some embodiments, the FcRn / antigen-binding molecule comprises the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180 described herein or a variant thereof, and one or more amino acids added at the C-terminus. In some embodiments, the FcRn / antigen-binding molecule comprises the amino acid sequence of any one of SEQ ID NOs: 137 to 176 and 180 described herein or a variant thereof, and one or more amino acids added at the C-terminus, wherein the one or more amino acids are selected from A, AG, GG, and PP.

[0327] Polynucleotides, vectors, and production methods The present disclosure also provides polynucleotides encoding the FcRn / antigen-binding molecules or fragments thereof disclosed herein. In some embodiments, the polynucleotide encodes an antigen-binding domain of the present disclosure. In some embodiments, the polynucleotide encodes an FcRn-binding molecule of the present disclosure. In some embodiments, the polynucleotide encodes an Fc region of the present disclosure. In some embodiments, the polynucleotide encodes an Fc domain of the present disclosure. In some embodiments, the polynucleotide encodes one or more of an antigen-binding domain, an FcRn-binding molecule, and a linker. In some embodiments, the polynucleotide encodes an antigen-binding domain and an FcRn-binding molecule, and optionally, a linker. In some embodiments, the polynucleotide encodes one or more of an antigen-binding domain, an Fc region, and a linker. In some embodiments, the polynucleotide encodes an antigen-binding domain and an Fc region, and optionally, a linker. In some embodiments, the polynucleotide encodes an FcRn / antigen-binding molecule comprising one or more antigen-binding domains and an Fc region. In some embodiments, the polynucleotide encodes one or more of an antigen-binding domain, an Fc domain, and a linker. In some embodiments, the polynucleotide encodes an antigen-binding domain and an Fc domain, and optionally a linker. In some embodiments, the polynucleotide encodes an FcRn / antigen-binding molecule comprising one or more antigen-binding domains and one or more Fc domains. In some embodiments, the polynucleotide encodes one or more heavy chains of the present disclosure.

[0328] As used herein, an "isolated" polynucleotide or nucleic acid molecule is one that is separated from other nucleic acid molecules present in the nucleic acid molecule's natural source (e.g., in a mouse or human). Also, an "isolated" nucleic acid molecule, e.g., a cDNA molecule, may be substantially free of other cellular material or culture medium when produced by recombinant techniques, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the term "substantially free" includes preparations of polynucleotides or nucleic acid molecules having less than about 15%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (particularly less than about 10%) of other materials, e.g., cellular material, culture medium, other nucleic acid molecules, chemical precursors, and / or other chemicals. In one embodiment, the nucleic acid molecule(s) encoding a polypeptide described herein are isolated or purified.

[0329] In one aspect, provided herein is a polynucleotide comprising a nucleotide sequence encoding an FcRn-binding molecule or FcRn / antigen-binding molecule described herein. In another aspect, provided herein is a polynucleotide comprising a nucleotide sequence encoding an antigen-binding domain described herein. In another aspect, provided herein is a polynucleotide comprising a nucleotide sequence encoding an FcRn / antigen-binding molecule described herein. In another aspect, provided herein is a polynucleotide comprising a nucleotide sequence encoding an FcRn / HSA-binding molecule described herein.

[0330] The polynucleotide can comprise a nucleotide sequence encoding an sdAb (e.g., a VHH fragment), a Fab fragment, an scFv, a VH, or a VL comprising the FRs and CDRs of an antigen-binding domain described herein. The polynucleotide can also comprise a nucleotide sequence encoding an antibody mimetic described herein. In some embodiments, the polynucleotide can comprise a nucleotide sequence encoding a VHH fragment comprising the FRs and CDRs of an antigen-binding domain described herein. In some embodiments, the polynucleotide can comprise a nucleotide sequence encoding a light chain comprising the VL FRs and CDRs of an antigen-binding domain described herein, or a nucleotide sequence encoding a heavy chain comprising the VH FRs and CDRs of an antigen-binding domain described herein and / or an Fc domain described herein. In one embodiment, the polynucleotide encodes the VH, VL, heavy chain, and / or light chain of an antigen-binding domain described herein. In one embodiment, the polynucleotide encodes a first VH and a first VL of an antigen-binding domain described herein. In one embodiment, the polynucleotide encodes a second VH and a second VL of an antigen-binding domain described herein. In one embodiment, the polynucleotide encodes a first heavy chain and a first light chain of an antigen-binding domain described herein. In one embodiment, the polynucleotide encodes a second heavy chain and a second light chain of an antigen-binding domain described herein. In one embodiment, the polynucleotide encodes the VH and / or VL, or the heavy and / or light chain, of an antigen-binding domain described herein.

[0331] In some embodiments, the polynucleotide can comprise a nucleotide sequence encoding a first heavy chain described herein. In some embodiments, the first heavy chain comprises an Fc domain and an antigen-binding domain joined by a linker. In some embodiments, the polynucleotide can comprise a nucleotide sequence encoding a second heavy chain described herein. In some embodiments, the second heavy chain comprises an Fc domain and an antigen-binding domain joined by a linker. In some embodiments, the first and second heavy chains are the same. In some embodiments, the first and second heavy chains are different.

[0332] In some embodiments, the first and second heavy chains have the same Fc domain. In some embodiments, the first and second heavy chains have different Fc domains. In some embodiments, both the first and second heavy chains comprise an antigen-binding domain. In some embodiments, the antigen-binding domains in the first and second heavy chains are the same. In some embodiments, the antigen-binding domains in the first and second heavy chains are different. In some embodiments, the second heavy chain comprises an Fc domain but not an antigen-binding domain, and the first heavy chain comprises an Fc domain and an antigen-binding domain. In some embodiments, the second heavy chain comprises an Fc domain but not an antigen-binding domain or linker, and the first heavy chain comprises an Fc domain and an antigen-binding domain. In some embodiments, the second heavy chain comprises an Fc domain but not an antigen-binding domain or linker, and the first heavy chain comprises an Fc domain and an antigen-binding domain.

[0333] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding an Fc domain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-9. In some embodiments, the polynucleotide consists of a nucleotide sequence encoding an Fc domain comprising an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-9.

[0334] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding an Fc domain comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 9. In some embodiments, the polynucleotide comprises a nucleotide sequence encoding an Fc domain consisting of the amino acid sequence of any one of SEQ ID NOs: 1 to 9.

[0335] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding two or more Fc domains. In some embodiments, the polynucleotide comprises a nucleotide sequence encoding two Fc domains. In some embodiments, the polynucleotide comprises a first nucleotide sequence encoding a first Fc domain and a second nucleotide sequence encoding a second Fc domain. In some embodiments, the first nucleotide sequence and the second nucleotide sequence are comprised in different nucleic acid molecules. In some embodiments, the first nucleotide sequence and the second nucleotide sequence are comprised in the same nucleic acid molecule.

[0336] In some embodiments, the first and second nucleotide sequences encode the same Fc domain. In some embodiments, both the first and second nucleotide sequences encode an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second nucleotide sequences encode an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second nucleotide sequences encode an Fc domain comprising the amino acid sequence of any one of SEQ ID NOs: 1-3. In some embodiments, both the first and second nucleotide sequences encode an Fc domain consisting of the amino acid sequence of any one of SEQ ID NOs: 1-3.

[0337] In some embodiments, the first and second nucleotide sequences encode different Fc domains. In some embodiments, the first nucleotide sequence encodes an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 4-6, and the second nucleotide sequence encodes an Fc domain comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 7-9. In some embodiments, the first nucleotide sequence encodes an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 4 to 6, and the second nucleotide sequence encodes an Fc domain consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 7 to 9. In some embodiments, the first nucleotide sequence encodes an Fc domain consisting of the amino acid sequence of any one of SEQ ID NOs: 4 to 6, and the second nucleotide sequence encodes an Fc domain consisting of the amino acid sequence of any one of SEQ ID NOs: 7 to 9. In some embodiments, when the first nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 4 or a variant thereof, the second nucleotide sequence encodes SEQ ID NO: 7 or a variant thereof. In some embodiments, when the first nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 5 or a variant thereof, the second nucleotide sequence encodes SEQ ID NO: 8 or a variant thereof.In some embodiments, when the first nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 6 or a variant thereof, the second nucleotide sequence encodes SEQ ID NO: 9 or a variant thereof.

[0338] In some embodiments, the first and second nucleotide sequences also encode an antigen-binding domain. In some embodiments, the first and second nucleotide sequences encode the same antigen-binding domain. In some embodiments, the first and second nucleotide sequences encode different antigen-binding domains. In some embodiments, the first nucleotide sequence encodes an Fc domain and an antigen-binding domain, and the second nucleotide sequence encodes an Fc domain but not an antigen-binding domain. The antigen-binding domain encoded by the first and / or second nucleotide sequence can be any of those described herein.

[0339] In some embodiments, the first and second nucleotide sequences also encode a peptide linker. In some embodiments, the first and second nucleotide sequences encode the same peptide linker. In some embodiments, the first and second nucleotide sequences encode different peptide linkers. In some embodiments, the first nucleotide sequence encodes an Fc domain, a peptide linker, and an antigen-binding domain, and the second nucleotide sequence encodes an Fc domain but does not encode a peptide linker or an antigen-binding domain. In some embodiments, the first nucleotide sequence encodes an antigen-binding domain, a peptide linker, and an Fc domain, and the second nucleotide sequence encodes an Fc domain but does not encode a peptide linker or an antigen-binding domain. The peptide linker encoded by the first and / or second nucleotide sequence can be any of those described herein. In some embodiments, the linker comprises the amino acid sequence of SEQ ID NO: 136, 181, or 182.

[0340] In some embodiments, the polynucleotide comprises a nucleotide sequence that encodes a protein comprising or consisting of an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180.

[0341] In some embodiments, the polynucleotide comprises a nucleotide sequence that encodes a protein comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180.

[0342] In some embodiments, the first nucleotide sequence encodes a protein comprising or consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180, and the second nucleotide sequence encodes an Fc domain but does not encode an antigen-binding domain. Optionally, the second nucleotide sequence encodes a protein comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 8.

[0343] In some embodiments, the first nucleotide sequence encodes a protein comprising the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180, and the second nucleotide sequence encodes an Fc domain but does not encode an antigen-binding domain. Optionally, the second nucleotide sequence encodes a protein comprising the amino acid sequence of SEQ ID NO: 8. In some embodiments, the first nucleotide sequence comprises a nucleotide sequence encoding a protein consisting of the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180, and the second nucleotide sequence encodes an Fc domain but does not encode an antigen-binding domain. Optionally, the second nucleotide sequence encodes a protein consisting of the amino acid sequence of SEQ ID NO: 8.

[0344] Also provided herein are polynucleotides encoding the polypeptides provided above, which have been optimized, for example, by codon / RNA optimization, replacement with a heterologous signal sequence, and elimination of mRNA instability elements. Thus, methods for generating nucleic acids optimized for recombinant expression by introducing codon changes in mRNA and / or elimination of inhibitory regions can be performed by adapting the optimization methods described in, for example, U.S. Patent Nos. 5,965,726, 6,174,666, 6,291,664, 6,414,132, and 6,794,498, all of which are incorporated herein by reference in their entireties. For example, potential splice sites and instability elements (e.g., A / T or A / U-rich elements) within the RNA can be mutated without changing the amino acid encoded by the nucleic acid sequence to increase the stability of the RNA for recombinant expression. The alterations utilize the degeneracy of the genetic code, for example, by using alternative codons for the same amino acid. In one embodiment, it may be desirable to change one or more codons to encode a conservative variation, e.g., a similar amino acid having a similar chemical structure and properties and / or function as the native amino acid.

[0345] Polynucleotides can be obtained by any method known in the art, and the nucleotide sequence of a polynucleotide can be determined by any method known in the art. Nucleotide sequences encoding the proteins described herein, and modified versions of these antibodies, can be determined using methods well known in the art, i.e., nucleotide codons known to encode specific amino acids are assembled to generate a nucleic acid encoding the protein. Such polynucleotides encoding proteins can be assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier G et al., (1994) BioTechniques 17:242-6, which is incorporated herein by reference in its entirety); briefly, this involves synthesizing overlapping oligonucleotides containing portions of the antibody-encoding sequence, annealing and ligating these oligonucleotides, and then amplifying the ligated oligonucleotides by PCR.

[0346] Alternatively, polynucleotides encoding the proteins described herein can be generated from nucleic acid from a suitable source (e.g., a hybridoma) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of a known sequence can be performed using genomic DNA obtained from hybridoma cells producing the polypeptide of interest. Such PCR amplification methods can be used to obtain nucleic acid comprising a sequence encoding the polypeptide. The amplified nucleic acid can be cloned into a vector for expression in a host cell and further cloning.

[0347] If a clone containing nucleic acid encoding a particular polypeptide is not available, but the sequence of the polypeptide is known, nucleic acid encoding the polypeptide may be chemically synthesized or obtained from a suitable source (e.g., a cDNA library generated from, or nucleic acid isolated therefrom, preferably polyA+ RNA, any tissue or cell that expresses a polypeptide described herein) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence, or by cloning using oligonucleotide probes specific for the particular gene sequence to identify, e.g., a cDNA clone from a cDNA library that encodes the polypeptide. Amplified nucleic acids generated by PCR can then be cloned into replicable cloning vectors using any method well known in the art.

[0348] DNA encoding the proteins described herein can be readily isolated and sequenced using conventional procedures. Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed into an expression vector, which is then transfected into host cells, such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells (e.g., CHO cells from the CHO GS System™ (Lonza)), or myeloma cells that do not otherwise produce the proteins described herein.

[0349] Also provided are polynucleotides that hybridize under high stringency, intermediate or low stringency hybridization conditions to polynucleotides encoding the proteins described herein.

[0350] Hybridization conditions are described in the art and are known to those skilled in the art. For example, hybridization under stringent conditions can include hybridization to filter-bound DNA in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2x SSC / 0.1% SDS at about 50-65°C, and hybridization under highly stringent conditions can include hybridization to filter-bound nucleic acid in 6x SSC at about 45°C, followed by one or more washes in 0.1x SSC / 0.2% SDS at about 68°C. Hybridization under other stringent hybridization conditions is known to those skilled in the art and has been described, e.g., Ausubel FM et al., eds. (1989) Current Protocols in Molecular Biology, Vol. I, Green Publishing Associates, Inc. and John Wiley & Sons, Inc., New York, pages 6.3.1-6.3.6 and 2.10.3, which is incorporated herein by reference in its entirety.

[0351] In one aspect, provided herein are cells (e.g., host cells), and associated polynucleotides and expression vectors, that express (e.g., recombinantly express) the proteins described herein. Provided herein are vectors (e.g., expression vectors) for recombinant expression in host cells, preferably mammalian cells (e.g., CHO cells), comprising a polynucleotide that includes a nucleotide sequence encoding a protein described herein. Also provided herein are host cells for recombinant expression of the proteins described herein, comprising such vectors. In one aspect, provided herein are methods for producing the proteins described herein, comprising expressing a polypeptide from a host cell.

[0352] Recombinant expression of the proteins described herein generally involves the construction of an expression vector containing a polynucleotide encoding the polypeptide. Once a polynucleotide encoding a polypeptide described herein is obtained, a vector for producing the polypeptide can be produced by recombinant DNA technology using techniques well known in the art. Thus, methods for preparing a protein by expressing a polynucleotide containing a polypeptide-encoding nucleotide sequence are described herein. Methods well known to those skilled in the art can be used to construct an expression vector containing a polypeptide-encoding sequence and appropriate transcriptional and translational control signals. These methods include, for example, in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Also provided are replicable vectors containing a nucleotide sequence encoding a polypeptide described herein, wherein the nucleotide sequence is operably linked to a promoter. Such a vector can include, for example, a nucleotide sequence encoding a first heavy chain of the present disclosure (see, e.g., WO 86 / 05807 and WO 89 / 01036 and U.S. Pat. No. 5,122,464, which are incorporated by reference herein in their entireties), and a second heavy chain of the present disclosure can be cloned into such a vector for expression of the first heavy chain, the second heavy chain, or both the first and second heavy chains.

[0353] In one embodiment, the vector comprises a polynucleotide encoding an sdAb, Fab fragment, scFv, VHH fragment, VH, VL, heavy chain, and / or light chain of a polypeptide described herein. In another embodiment, the vector comprises a polynucleotide encoding the VH and VL of a polypeptide described herein. In another embodiment, the vector comprises polynucleotides encoding the heavy and light chains of a polypeptide described herein.

[0354] The expression vector can be transferred to a cell (e.g., a host cell) by conventional techniques, and the resulting cells can then be cultured by conventional techniques to produce a polypeptide or fragment thereof described herein. Thus, provided herein is a host cell containing a polynucleotide encoding a polypeptide or fragment thereof described herein, or a heavy or light chain thereof, or fragment thereof, or a single-chain antibody described herein, wherein the polynucleotide is operably linked to a promoter for expression of such sequence in the host cell.

[0355] In one embodiment, a host cell comprises a polynucleotide comprising one of the above first nucleotide sequences and one of the above second nucleotide sequences. In another embodiment, a host cell comprises a first polynucleotide comprising one of the above first nucleotide sequences and a second polynucleotide comprising one of the above first nucleotide sequences. In another embodiment, a host cell comprises a first vector comprising one of the above first nucleotide sequences and one of the above second nucleotide sequences. In another embodiment, a host cell comprises a first vector comprising one of the above first nucleotide sequences and one of the above second nucleotide sequences and a second vector comprising a second polynucleotide comprising one of the above first nucleotide sequences.

[0356] In some embodiments, an FcRn / antigen-binding molecule expressed by a first host cell associates with an FcRn / antigen-binding molecule expressed by a second host cell to form a two-armed FcRn / antigen-binding molecule. In some embodiments, an FcRn / antigen-binding molecule expressed by a first host cell associates with an FcRn-binding molecule expressed by a second host cell to form a one-armed FcRn / antigen-binding molecule. In some embodiments, a population of host cells comprising such a first host cell and such a second host cell is provided herein.

[0357] In some embodiments, provided herein is a population of vectors comprising a first vector comprising a polynucleotide encoding an FcRn / antigen-binding molecule and a second vector comprising a polynucleotide encoding an FcRn / antigen-binding molecule. In some embodiments, provided herein is a population of vectors comprising a first vector comprising a polynucleotide encoding an FcRn / antigen-binding molecule and a second vector comprising a polynucleotide encoding an FcRn-binding molecule. In some embodiments, provided herein is a population of vectors comprising a polynucleotide encoding an FcRn / antigen-binding molecule and a first vector comprising a polynucleotide encoding an FcRn / antigen-binding molecule. In some embodiments, provided herein is a population of vectors comprising a first vector comprising polynucleotides encoding two FcRn / antigen-binding molecules.

[0358] A variety of host-expression vector systems can be used to express the polypeptides described herein (see, e.g., U.S. Pat. No. 5,807,715, which is incorporated herein by reference in its entirety). Such host-expression systems represent the vehicle in which a coding sequence of interest may be produced and subsequently purified, and also represent cells that, when transformed or transfected with the appropriate nucleotide coding sequence, are capable of expressing the polypeptides described herein in situ. These include microorganisms such as bacteria (e.g., E. coli and B. subtilis), for example, bacteria transformed with recombinant bacteriophage DNA, plasmid DNA, or cosmid DNA expression vectors containing the FcRn / antigen-binding molecule coding sequence; yeast (e.g., Saccharomyces and Pichia), for example, yeast transformed with recombinant yeast expression vectors containing the FcRn / antigen-binding molecule coding sequence; insect cell systems, for example, insect cell systems infected with recombinant viral expression vectors (e.g., baculovirus) containing the FcRn / antigen-binding molecule coding sequence; plant cell systems (e.g., green algae, e.g., Chlamydomonas reinhardtii), for example, a plant cell line infected with a recombinant viral expression vector (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) containing the FcRn / antigen-binding molecule coding sequence, or a plant cell line transformed with a recombinant plasmid expression vector (e.g., Ti plasmid) containing the FcRn / antigen-binding molecule coding sequence; or a mammalian cell line (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7030, HsS78Bst, HeLa, NIH Examples of mammalian cell lines include, but are not limited to, mammalian cell lines harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or mammalian viruses (e.g., adenovirus late promoter; vaccinia virus 7.5K promoter).In one embodiment, cells for expressing the FcRn / antigen-binding molecules described herein are Chinese hamster ovary (CHO) cells, e.g., CHO cells from CHO GS System™ (Lonza). In one embodiment, the heavy and / or light chains produced by the CHO cells may have an N-terminal glutamine or glutamic acid residue replaced by pyroglutamic acid. In one embodiment, cells for expressing the polypeptides described herein are human cells, e.g., a human cell line. In one embodiment, the mammalian expression vector is pOptiVEC™ or pcDNA3.3. In one embodiment, bacterial cells, e.g., Escherichia coli, or eukaryotic cells (e.g., mammalian cells) are used for expression of recombinant polypeptides. For example, mammalian cells, e.g., CHO cells, are effective expression systems for antibodies in conjunction with vectors, e.g., the major immediate early gene promoter element from human cytomegalovirus (Foecking MK & Hofstetter H (1986) Gene 45:101-5, and Cockett MI et al., (1990) Biotechnology 8(7):662-7, each of which is incorporated herein by reference in its entirety). In one embodiment, the polypeptides described herein are produced by CHO cells or NS0 cells. In one embodiment, expression of a nucleotide sequence encoding a polypeptide described herein comprising two, three, or four binding sites to human FcRn is regulated by a constitutive promoter, an inducible promoter, or a tissue-specific promoter.

[0359] In bacterial systems, several expression vectors may be advantageously selected depending on the intended use for expressing the molecule. For example, when large quantities of such polypeptides are produced for the generation of pharmaceutical compositions of antibody molecules, vectors that direct the expression of high levels of fusion protein products that are easily purified may be desirable. Such vectors include, but are not limited to, the E. coli expression vector pUR278 (Ruether U & Mueller-Hill B (1983) EMBO J 2:1791-1794), in which coding sequences can be individually ligated into the vector in frame with the lac Z coding region to produce the fusion protein; and the pIN vector (Inouye S & Inouye M (1985) Nuc Acids Res 13:3101-3109; Van Heeke G & Schuster SM (1989) J Biol Chem 24:5503-5509), all of which are incorporated herein by reference in their entireties. Also, for example, pGEX vectors can be used to express foreign polypeptides as fusion proteins with glutathione 5-transferase (GST). Generally, such fusion proteins are soluble and can be easily purified from lysed cells by adsorption and binding to matrix glutathione agarose beads, followed by elution in the presence of free glutathione. pGEX vectors are designed to contain thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0360] In an insect system, for example, Autographa californica nuclear polyhedrosis virus (AcNPV) can be used as a vector to express foreign genes. The virus grows in Spodoptera frugiperda cells. Coding sequences can be cloned individually into non-essential regions of the virus (e.g., the polyhedrin gene) and placed under control of an AcNPV promoter (e.g., the polyhedrin promoter).

[0361] Several viral-based expression systems can be used in mammalian host cells. When adenovirus is used as an expression vector, the coding sequence of interest can be ligated to an adenovirus transcription / translation control complex, e.g., the late promoter and tripartite leader sequence. This chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion into a non-essential region of the viral genome (e.g., region E1 or E3) results in a recombinant virus that is viable and capable of expressing the molecule in infected hosts (see, e.g., Logan J & Shenk T (1984) PNAS 81(12):3655-9, incorporated herein by reference in its entirety). Specific initiation signals may also be required for efficient translation of the inserted coding sequence. These signals include the ATG initiation codon and adjacent sequences. Furthermore, the initiation codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translational control signals and initiation codons can be of a variety of origins, both natural and synthetic. The efficiency of expression can be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, etc. (see, e.g., Bitter G et al., (1987) Methods Enzymol. 153:516-544, which is incorporated herein by reference in its entirety).

[0362] In addition, a host cell strain may be chosen that modulates the expression of the inserted sequences, or modifies and processes the gene product in the specific fashion desired. Such modifications (e.g., glycosylation) and processing (e.g., cleavage) of protein products may be important for the function of the protein. Different host cells have characteristic and specific mechanisms for the post-translational processing and modification of proteins and gene products. An appropriate cell line or host system may be selected to ensure the correct modification and processing of the expressed foreign protein. To this end, eukaryotic host cells that possess the cellular machinery for proper processing of the primary transcript, glycosylation, and phosphorylation of the gene product may be used. Such mammalian host cells include, but are not limited to, CHO, VERO, BHK, HeLa, MDCK, HEK 293, NIH 3T3, W138, BT483, Hs578T, HTB2, BT2O, and T47D, NS0 (a mouse myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7O3O, COS (e.g., COS1 or COS), PER.C6, VERO, HsS78Bst, HEK-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20, BMT10, and HsS78Bst cells. In one embodiment, the proteins described herein are produced in mammalian cells, e.g., CHO cells.

[0363] In one embodiment, the polypeptides described herein comprise portions of antibodies with reduced or no fucose content. Such proteins can be produced using techniques known to those skilled in the art. For example, proteins can be expressed in cells that are deficient or lack the ability to fucosylate. In one example, a cell line with knockout of both alleles of α1,6-fucosyltransferase can be used to produce antibodies with reduced fucose content. The Potelligent® system (Lonza) is an example of such a system that can be used to produce antibodies with reduced fucose content.

[0364] For long-term, high-yield production of recombinant proteins, stable expression cells can be generated. For example, cell lines that stably express the proteins described herein can be engineered. In one embodiment, the cells provided herein stably express an antigen-binding domain, an FcRn / antigen-binding molecule, or an FcRn-binding molecule, which associates to form the one-armed or two-armed polypeptide described herein.

[0365] In certain embodiments, rather than using expression vectors containing viral origins of replication, host cells can be transformed with DNA controlled by appropriate expression control elements (e.g., promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc.) and a selectable marker. After introduction of the foreign DNA / polynucleotide, engineered cells can be allowed to grow in an enriched medium for 1-2 days and then switched to a selective medium. The selectable marker on the recombinant plasmid confers resistance to selection, allowing cells to stably integrate the plasmid into their chromosomes and grow to form foci, which can then be cloned and expanded into cell lines. This method can advantageously be used to engineer cell lines expressing polypeptides containing two, three, or four binding sites to human FcRn or fragments thereof described herein. Such engineered cell lines can be particularly useful in screening and evaluation of compositions that interact directly or indirectly with the polypeptides.

[0366] Several selection systems can be used, including, but not limited to, herpes simplex virus thymidine kinase (Wigler M et al., (1977) Cell 11(1):223-32), hypoxanthine guanine phosphoribosyltransferase (Szybalska EH & Szybalski W (1962) PNAS 48(12):2026-2034), and adenine phosphoribosyltransferase (Lowy I et al., (1980) Cell 22(3):817-23) genes in tk, hgprt, or aprt cells, respectively, all of which are incorporated herein by reference in their entirety. Furthermore, antimetabolite resistance is mediated by the following genes: dhfr, which confers resistance to methotrexate (Wigler M et al., (1980) PNAS 77(6):3567-70; O'Hare K et al., (1981) PNAS 78:1527-31); gpt, which confers resistance to mycophenolic acid (Mulligan RC & Berg P (1981) PNAS 78(4):2072-6); neo, which confers resistance to the aminoglycoside G-418 (Wu GY & Wu CH (1991) Biotherapy 3:87-95; Tolstoshev P (1993) Ann Rev Pharmacol Toxicol 32:573-596; Mulligan RC (1993) Science 260:926-932; and Morgan RA & Anderson WF (1993) Ann Rev Biochem 62:191-217, Nabel GJ & Felgner PL (1993) Trends Biotechnol 11(5):211-5); and hygro, which confers resistance to hygromycin (Santerre RF et al., (1984) Gene 30(1-3):147-56), all of which are incorporated herein by reference in their entireties.Methods generally known in the field of recombinant DNA technology can be routinely applied to select the desired recombinant clones, and such methods are described, for example, in Ausubel FM et al., (eds.), Current Protocols in Molecular Biology, John Wiley & Sons, NY (1993), Kriegler M, Gene Transfer and Expression, A Laboratory Manual, Stockton Press, NY (1990), and Chapters 12 and 13, Dracopoli NC et al., (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994), Colbere-Garapin F et al., (1981) J Mol Biol 150:1-14, all of which are incorporated herein by reference in their entirety.

[0367] Polypeptide expression levels can be increased by vector amplification (for a review, see Bebbington CR & Hentschel CCG, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, p. 163-188. DNA Cloning, Vol. III, A Practical Approach. D.M.Glover (ed.) (Academic Press, New York, 1987), which is incorporated herein by reference in its entirety). When the marker in the vector system is amplifiable, an increase in the level of inhibitor present in the host cell culture increases the number of copies of the marker gene, and because the amplified region is associated with the gene of interest, production of the polypeptide increases (Crouse GF et al., (1983) Mol Cell Biol 3:257-66, which is incorporated herein by reference in its entirety).

[0368] Host cells can be co-transfected with two or more expression vectors described herein. The two vectors can contain identical selectable markers, which allow for equal expression of polypeptides, such as a first heavy chain and a second heavy chain polypeptide. Host cells can be co-transfected with different amounts of two or more expression vectors. For example, host cells can be transfected with any one of the following ratios of the first expression vector to the second expression vector: approximately 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, or 1:50.

[0369] Alternatively, a single vector capable of encoding and expressing both polypeptides can be used. The coding sequence can comprise cDNA or genomic DNA. Expression vectors can be monocistronic or multicistronic. A multicistronic nucleic acid construct can encode 2, 3, 4, 5, 6, 7, 8, 9, 10, or more genes / nucleotide sequences, or 2-5, 5-10, or 10-20 genes / nucleotide sequences. For example, a bicistronic nucleic acid construct can comprise a promoter, a first gene, and a second gene in the following order: In such an expression vector, transcription of both genes can be driven by a promoter, translation of mRNA from the first gene can be via a cap-dependent scanning mechanism, and translation of mRNA from the second gene can be via a cap-independent mechanism, e.g., an IRES.

[0370] The polypeptides described herein, when produced by recombinant expression, can be purified by any method known in the art for the purification of proteins, for example, chromatography (e.g., ion exchange, affinity, particularly affinity to specific antigens following Protein A, and sizing column chromatography), centrifugation, differential solubility, or any other standard technique for the purification of proteins. Additionally, the polypeptides described herein can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.

[0371] In one embodiment, the polypeptides described herein are isolated or purified. In one embodiment, an isolated polypeptide is substantially free of other polypeptides having antigenic specificities different from the isolated polypeptide. For example, in certain embodiments, preparations of the proteins described herein are substantially free of cellular material and / or chemical precursors. The term "substantially free of cellular material" includes preparations of polypeptides in which the polypeptide is isolated from cellular components of the cells from which it is isolated or recombinantly produced. Thus, a polypeptide that is substantially free of cellular material includes preparations of polypeptides having less than about 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (by dry weight) of heterologous proteins (also referred to herein as "contaminating proteins") and / or variants of the polypeptide, e.g., different post-translationally modified forms of the polypeptide or other different versions of the polypeptide (e.g., polypeptide fragments). Additionally, when recombinantly produced, polypeptides are generally substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, 2%, 1%, 0.5%, or 0.1% of the volume of the protein preparation. When produced by chemical synthesis, polypeptides are generally substantially free of chemical precursors or other chemicals, i.e., separated from chemical precursors or other chemicals involved in the synthesis of the protein. Thus, such preparations of protein have less than about 30%, 20%, 10%, or 5% (by dry weight) of chemical precursors or compounds other than the molecule of interest. In one embodiment, the polypeptides described herein are isolated or purified.

[0372] The polypeptides described herein can be produced by any method known in the art for the synthesis of antibodies, for example, chemical synthesis or recombinant expression techniques. The methods described herein employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the art. These techniques are described, for example, in the references cited herein and are explained more fully in the literature.See, for example, Maniatis T et al., (1982) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press; Sambrook J et al., (1989) Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press; Sambrook J et al., (2001) Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel FM et al., Current Protocols in Molecular Biology, John Wiley & Sons (1987 and annually updated editions); Current Protocols in Immunology, John Wiley & Sons (1987 and annually updated editions); Gait (ed.) (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein (ed.) (1991) Oligonucleotides and Analogues: A Practical Approach, IRL Press; Birren B et al. al., (eds.) (1999) Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press, all of which are incorporated herein by reference in their entireties.

[0373] In one embodiment, a polypeptide described herein is prepared, expressed, produced, or isolated by any means, including production, e.g., via synthesis, genetic engineering of DNA sequences. In one embodiment, such a polypeptide comprises a sequence (e.g., a DNA sequence or an amino acid sequence) that does not naturally occur within the antibody germline repertoire of an animal or mammal (e.g., a human) in vivo.

[0374] Pharmaceutical Compositions In one aspect, the present disclosure provides pharmaceutical compositions comprising the FcRn / antigen-binding molecules disclosed herein for use in methods for treating antibody-mediated disorders (e.g., autoantibody-mediated disorders). In certain embodiments, these compositions comprise an FcRn / antigen-binding molecule comprising an FcRn-binding molecule and an antigen-binding domain. In some embodiments, the FcRn-binding molecule is an FcRn antagonist. In some embodiments, the FcRn antagonist comprises or consists of a variant Fc region or an FcRn-binding fragment thereof that inhibits binding of the Fc region of an immunoglobulin to FcRn. Generally, these FcRn antagonists inhibit binding of Fc-containing agents (e.g., antibodies and immunoadhesins) to FcRn in vivo, which results in an increased degradation rate of the Fc-containing agents and, concomitantly, reduced serum levels of these agents.

[0375] In some embodiments, an FcRn / antigen-binding molecule of the present disclosure has a molecular weight ranging from about 50 kDa to about 140 kDa, which is about one-third the molecular weight of full-length IgG (MW of about 150 kDa). In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of about 60 kDa to about 104 kDa. In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of 60 kDa to 104 kDa. In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of about 60 kDa. In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of about 104 kDa. In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of 60 kDa. In some embodiments, an FcRn / antigen-binding molecule has a molecular weight of 104 kDa.

[0376] The FcRn / antigen-binding molecules of the present disclosure have a predicted molecular weight ranging from about 50 kDa to about 140 kDa, which is about one-third the molecular weight of full-length IgG (MW of about 150 kDa). In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of about 60 kDa to about 104 kDa. In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of 60 kDa to 104 kDa. In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of about 60 kDa. In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of about 104 kDa. In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of 60 kDa. In some embodiments, the FcRn / antigen-binding molecules have a predicted molecular weight of 104 kDa.

[0377] The formulations disclosed herein include bulk drug compositions useful for manufacturing pharmaceutical compositions (e.g., compositions suitable for administration to a subject or patient) that can be used to prepare unit dosage forms. In one embodiment, the compositions of the invention are pharmaceutical compositions. Such compositions comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (e.g., FcRn / antigen-binding molecules) of the invention (or other prophylactic or therapeutic agents) and a pharmaceutically acceptable carrier.

[0378] In some embodiments, the pharmaceutical composition is formulated for administration to a subject via any suitable route of administration, including, but not limited to, intramuscular, intravenous, intradermal, intraperitoneal, subcutaneous, epidural, nasal, oral, rectal, topical, inhalation, buccal (e.g., sublingual), and transdermal administration. In one embodiment, the pharmaceutical composition is formulated to be suitable for intravenous administration to a subject. In one embodiment, the pharmaceutical composition is formulated to be suitable for subcutaneous administration to a subject.

[0379] Treatment method The present disclosure also provides a method for treating an antibody-mediated disorder (e.g., an autoantibody-mediated disorder) in a subject, the method comprising administering to the subject a therapeutically effective amount of an FcRn / antigen-binding molecule according to the present disclosure, or a pharmaceutical composition comprising the same.

[0380] In some embodiments, the antibody-mediated disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of islet allograft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), autoimmune disease of the adrenal gland, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura), and idiopathic thrombocytopenic purpura.purpura), immune-mediated thrombocytopenia, or primary immune thrombocytopenia), autoimmune urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman's disease, celiac sprue dermatitis, chronic fatigue and immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold aggregation disease, Crohn's disease, dilated cardiomyopathy, discoid lupus erythematosus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, and type VI encephalopathy. Factor II deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasture's syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic inflammatory myopathy (IIM), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA neuropathy, IgM polyneuropathy, immune-mediated necrotizing myopathy (IMNM), juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosus, lupus erythematosus, lupus nephritis, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid Acne, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), myositis, paraneoplastic bullous pemphigoid, gestational pemphigoid, pemphigoid vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), antisynthetase syndrome (ASyS), primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, The disease is selected from the group consisting of: idiopathic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjogren's syndrome, solid organ transplant rejection, stiff-body syndrome, systemic lupus erythematosus, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis, uveitis, dermatitis herpetiformis vasculitis, antineutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and Wegener's granulomatosis.

[0381] In one embodiment, the FcRn / antigen-binding molecule antagonizes FcRn binding to the antibody Fc region. In one embodiment, the FcRn / antigen-binding molecule does not antagonize FcRn binding to albumin.

[0382] The present disclosure provides a method for reducing serum IgG in a subject, the method comprising administering to the subject a therapeutically effective amount of an FcRn / antigen-binding molecule according to the present disclosure, or a pharmaceutical composition comprising the same. In one embodiment, at least one of the IgG subtypes is reduced in the subject after administration of the FcRn / antigen-binding molecule. In some embodiments, IgG1, IgG2, IgG3, IgG4, or any combination thereof is reduced. In some embodiments, the administration of the FcRn / antigen-binding molecule is a single administration (e.g., a single therapeutic administration) of the FcRn / antigen-binding molecule. In one embodiment, the level of serum IgG is reduced in the subject after administration of the FcRn / antigen-binding molecule compared to the baseline level of serum IgG.

[0383] In one embodiment, a reduction in total serum IgG of at least about 40% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 45% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 50% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 55% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 60% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 65%, about 70%, about 75%, or about 80% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 65% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 70% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 75% is achieved compared to baseline serum IgG levels. In one embodiment, a reduction in total serum IgG of at least about 80% is achieved compared to baseline serum IgG levels.

[0384] In one embodiment, the level of serum IgG is reduced in a subject after administration of the FcRn / antigen-binding molecule compared to the baseline level of serum IgG. In one embodiment, a reduction in total serum IgG of about 40% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 45% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 50% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 55% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 60% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 65%, about 70%, about 75%, or about 80% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 65% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 70% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 75% is achieved compared to the baseline serum IgG level. In one embodiment, a reduction in total serum IgG of about 80% is achieved compared to the baseline serum IgG level.

[0385] In one embodiment, the level of FcRn is not reduced in a subject after administration of the FcRn / antigen-binding molecule compared to the baseline level of FcRn. In one embodiment, an FcRn reduction of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to the baseline FcRn level. In one embodiment, an FcRn reduction of less than about 10% is observed compared to the baseline FcRn level.

[0386] In one embodiment, albumin levels are not reduced in a subject after administration of the FcRn / antigen-binding molecule compared to baseline albumin levels. In one embodiment, a reduction in albumin of less than about 1%, 2%, 3%, 4%, or 5% is observed compared to baseline albumin levels. In one embodiment, a reduction in albumin of less than about 10% is observed compared to baseline albumin levels.

[0387] In one embodiment, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin in a patient serum sample is analyzed using a bioanalytical method. In one embodiment, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin in a patient serum sample is analyzed using ELISA or an automated diagnostic analyzer (IVD). In one embodiment, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin in a patient serum sample is analyzed using ELISA. In one embodiment, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin in a patient serum sample is analyzed using an automated diagnostic analyzer (IVD). In one embodiment, total FcRn in a patient blood sample is analyzed using a bioanalytical method, preferably flow cytometry, microscopy, or immunoblotting.

[0388] In some embodiments, the reduction in total serum IgG is measured by the area under the percent reduction curve (AUEC). In some embodiments, the reduction in total serum IgG is measured by the clearance (CL) of total serum IgG.

[0389] In some embodiments, the clearance of total serum IgG is increased in a subject after administration of an FcRn / antigen-binding molecule. In some embodiments, the clearance of total serum IgG in a subject after a single therapeutic administration of the FcRn / antigen-binding molecule is equivalent to the clearance of total serum IgG in a subject after a single therapeutic administration of efgartigimod. In some embodiments, the clearance of total serum IgG in a subject after a single therapeutic administration of the FcRn / antigen-binding molecule is similar to or the same as the clearance of total serum IgG in a subject after a single therapeutic administration of efgartigimod. In some embodiments, the clearance of total serum IgG is increased in a subject after a single therapeutic administration of the FcRn / antigen-binding molecule compared to the clearance of total serum IgG after a single therapeutic administration of efgartigimod. In some embodiments, the clearance of total serum IgG in a subject is increased by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200% after a single therapeutic administration of the FcRn / antigen-binding molecule compared to the clearance of total serum IgG after a single therapeutic administration of efgartigimod.

[0390] In some embodiments, the clearance of total serum IgG in a subject after a single administration of the FcRn / antigen-binding molecule is similar to the clearance of total serum IgG in a subject after a single administration of an equivalent amount of efgartigimod. In some embodiments, the clearance of total serum IgG in a subject after a single administration of the FcRn / antigen-binding molecule is similar to or the same as the clearance of total serum IgG in a subject after a single administration of an equivalent amount of efgartigimod. In some embodiments, the clearance of total serum IgG is increased in a subject after a single administration of the FcRn / antigen-binding molecule compared to the clearance of total serum IgG after a single administration of an equivalent amount of efgartigimod. In some embodiments, the clearance of total serum IgG is increased in a subject after a single administration of the FcRn / antigen-binding molecule by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 125%, at least 150%, or at least 200% compared to the clearance of total serum IgG after a single administration of an equivalent amount of efgartigimod.

[0391] In some embodiments, clearance of FcRn / antigen-binding molecule is reduced in a subject after a single therapeutic administration of the FcRn / antigen-binding molecule compared to clearance of efgartigimod after a single therapeutic administration of efgartigimod. In some embodiments, clearance of FcRn / antigen-binding molecule is reduced in a subject after a single therapeutic administration of the FcRn / antigen-binding molecule by at least 1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, or at least 20-fold compared to clearance of efgartigimod after a single therapeutic administration of efgartigimod.

[0392] In some embodiments, clearance of FcRn / antigen-binding molecule is reduced in a subject after a single administration of FcRn / antigen-binding molecule compared to clearance of efgartigimod after a single administration of an equivalent amount of efgartigimod. In some embodiments, clearance of FcRn / antigen-binding molecule is reduced in a subject after a single administration of FcRn / antigen-binding molecule by at least 1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, or at least 20-fold compared to clearance of efgartigimod after a single administration of an equivalent amount of efgartigimod.

[0393] In some embodiments, the clearance of the FcRn / antigen-binding molecule in a subject is less than about 0.2, about 0.19, about 0.18, about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, or about 0.05 L / hour after a single administration of the FcRn / antigen-binding molecule. In some embodiments, the clearance of the FcRn / antigen-binding molecule in a subject is less than 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.1, 0.09, 0.08, 0.07, 0.06, or 0.05 L / hour after a single administration of the FcRn / antigen-binding molecule. In some embodiments, the clearance of the FcRn / antigen-binding molecule is in the range of about 0.05 to about 0.2 L / hour after a single administration of the FcRn antagonist. In some embodiments, the clearance of the FcRn / antigen-binding molecule in a subject after a single administration of the FcRn / antigen-binding molecule is about 0.2, about 0.19, about 0.18, about 0.17, about 0.16, about 0.15, about 0.14, about 0.13, about 0.12, about 0.11, about 0.1, about 0.09, about 0.08, about 0.07, about 0.06, or about 0.05 L / hour. In some embodiments, the clearance of the FcRn / antigen-binding molecule in a subject after a single administration of the FcRn antagonist is in the range of 0.05 to 0.2 L / hour. In some embodiments, the clearance of the FcRn / antigen-binding molecule in a subject is 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.1, 0.09, 0.08, 0.07, 0.06, or 0.05 1 / hour after a single administration of the FcRn / antigen-binding molecule.

[0394] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,z is a single-dose treatment with an FcRn / antigen-binding molecule followed by a single-dose treatment with efgartigimod in a subject. 1 / 2,z In some embodiments, the t of the FcRn / antigen-binding molecule is increased compared to 1 / 2,zis a single-dose treatment with an FcRn / antigen-binding molecule followed by a single-dose treatment with efgartigimod in a subject. 1 / 2,z at least 0.5-fold, at least 1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, or at least 20-fold increase compared to

[0395] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,z is the difference between the t value of efgartigimod after a single dose of FcRn / antigen binding molecule and the t value of efgartigimod after a single dose of an equivalent amount of efgartigimod in a subject. 1 / 2,z In some embodiments, the t of the FcRn / antigen-binding molecule is increased compared to 1 / 2,z is the difference between the t value of efgartigimod after a single dose of FcRn / antigen binding molecule and the t value of efgartigimod after a single dose of an equivalent amount of efgartigimod in a subject. 1 / 2,z at least 0.5-fold, at least 1-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 12-fold, at least 15-fold, or at least 20-fold increase compared to

[0396] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,zindicates that a subject's response to a single dose of FcRn / antigen-binding molecule is about 3 days, about 3.5 days, about 4 days, about 4.5 days, about 5 days, about 5.5 days, about 6 days, about 6.5 days, about 7 days, about 7.5 days, about 8 days, about 8.5 days, about 9 days, about 9.5 days, about 10 days, about 10.5 days, about 11 days, about 11.5 days, about 12 days, about 12.5 days, about 13 days, about 13.5 days, about 14 days, about 14.5 days, about 15 days, about 15.5 days, or about 16 days after administration of the FcRn / antigen-binding molecule. , about 16.5 days, about 17 days, about 17.5 days, about 18 days, about 18.5 days, about 19 days, about 19.5 days, about 20 days, about 20.5 days, about 21 days, about 21.5 days, about 22 days, about 22.5 days, about 23 days, about 23.5 days, about 24 days, about 24.5 days, about 25 days, about 25.5 days, about 26 days, about 26.5 days, about 27 days, about 27.5 days, about 28 days, about 28.5 days, about 29 days, about 29.5 days, or more than about 30 days.

[0397] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,z indicates that subjects showed improvement in blood glucose levels at 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, and 16 days after a single administration of FcRn / antigen-binding molecule. , 16.5 days, 17 days, 17.5 days, 18 days, 18.5 days, 19 days, 19.5 days, 20 days, 20.5 days, 21 days, 21.5 days, 22 days, 22.5 days, 23 days, 23.5 days, 24 days, 24.5 days, 25 days, 25.5 days, 26 days, 26.5 days, 27 days, 27.5 days, 28 days, 28.5 days, 29 days, 29.5 days, or more than 30 days.

[0398] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,z In some embodiments, the FcRn / antigen-binding molecule t 1 / 2,zindicates that a subject's response to a single dose of FcRn / antigen-binding molecule is about 3 days, about 3.5 days, about 4 days, about 4.5 days, about 5 days, about 5.5 days, about 6 days, about 6.5 days, about 7 days, about 7.5 days, about 8 days, about 8.5 days, about 9 days, about 9.5 days, about 10 days, about 10.5 days, about 11 days, about 11.5 days, about 12 days, about 12.5 days, about 13 days, about 13.5 days, about 14 days, about 14.5 days, about 15 days, about 15.5 days, or about 16 days after administration of the FcRn / antigen-binding molecule. , about 16.5 days, about 17 days, about 17.5 days, about 18 days, about 18.5 days, about 19 days, about 19.5 days, about 20 days, about 20.5 days, about 21 days, about 21.5 days, about 22 days, about 22.5 days, about 23 days, about 23.5 days, about 24 days, about 24.5 days, about 25 days, about 25.5 days, about 26 days, about 26.5 days, about 27 days, about 27.5 days, about 28 days, about 28.5 days, about 29 days, about 29.5 days, or about 30 days.

[0399] In some embodiments, the FcRn / antigen binding molecule t 1 / 2,z In some embodiments, the t of FcRn / antigen-binding molecule ranges from 3 days to 30 days. 1 / 2,z in subjects at 3 days, 3.5 days, 4 days, 4.5 days, 5 days, 5.5 days, 6 days, 6.5 days, 7 days, 7.5 days, 8 days, 8.5 days, 9 days, 9.5 days, 10 days, 10.5 days, 11 days, 11.5 days, 12 days, 12.5 days, 13 days, 13.5 days, 14 days, 14.5 days, 15 days, 15.5 days, 16 days after a single administration of FcRn / antigen-binding molecule. , 16.5 days, 17 days, 17.5 days, 18 days, 18.5 days, 19 days, 19.5 days, 20 days, 20.5 days, 21 days, 21.5 days, 22 days, 22.5 days, 23 days, 23.5 days, 24 days, 24.5 days, 25 days, 25.5 days, 26 days, 26.5 days, 27 days, 27.5 days, 28 days, 28.5 days, 29 days, 29.5 days, or 30 days.

[0400] In some embodiments, a one-arm FcRn / antigen-binding molecule of the present disclosure sweeps antigens more efficiently than a two-arm FcRn / antigen-binding molecule (e.g., a full-length antibody). In some embodiments, a one-arm FcRn / antigen-binding molecule sweeps antigens more efficiently than a corresponding two-arm FcRn / antigen-binding molecule. In other words, in some embodiments, removal of one arm of a two-arm FcRn / antigen-binding molecule results in a molecule that sweeps antigens more efficiently than a two-arm FcRn / antigen-binding molecule.

[0401] As used herein, "sweeping" refers to the ability of a molecule to remove an antigen from serum. "Sweeping" can be performed by a molecule (e.g., an antibody) that has both pH-sensitive antigen binding and at least a threshold level of binding to FcRn at neutral or physiological pH. For example, the sweeping molecule can bind to an antigen via its antigen-binding domain and to FcRn via its Fc region, resulting in cellular internalization of the antigen / sweeping antibody complex. The antigen can then be released from the complex in acidic endosomes and degraded. In some embodiments, the sweeping molecule, no longer bound to the antigen, can then be released by the cell (e.g., by exocytosis) and returned to serum.

[0402] In one embodiment, the FcRn / antigen-binding molecule is administered to a subject simultaneously or sequentially with an additional therapeutic agent. In one embodiment, the additional therapeutic agent is an anti-inflammatory agent. In one embodiment, the additional therapeutic agent is a corticosteroid. In one embodiment, the additional therapeutic agent is rituximab, daclizumab, basiliximab, muromonab-CD3, infliximab, adalimumab, omalizumab, efalizumab, natalizumab, tocilizumab, eculizumab, golimumab, canakinumab, ustekinumab, or belimumab. In one embodiment, the additional therapeutic agent is a leukocyte-depleting agent.

[0403] In one embodiment, the additional therapeutic agent is a B cell depleting agent. In one embodiment, the B cell depleting agent is an antibody. In one embodiment, the B cell depleting antibody is an antibody that specifically binds to CD10, CD19, CD20, CD21, CD22, CD23, CD24, CD37, CD53, CD70, CD72, CD74, CD75, CD77, CD79a, CD79b, CD80, CD81, CD82, CD83, CD84, CD85, or CD86.

[0404] In some embodiments, the FcRn / antigen-binding molecule is administered intravenously, ie, once every week, once every two weeks, once every three weeks, once every four weeks, once every month, or once every six weeks.

[0405] In some embodiments, the FcRn / antigen-binding molecule is administered subcutaneously. In some embodiments, the FcRn / antigen-binding molecule is administered subcutaneously once a week, once every two weeks, once every three weeks, once every four weeks, once every month, or once every six weeks. [Example]

[0406] The following examples are offered by way of illustration and not by way of limitation.

[0407] Example 1: Pharmacokinetics / Pharmacodynamics of Anti-HSA-ABDEG in Cynomolgus Monkeys The MHC class I-associated receptor FcRn plays a central role in regulating serum levels of IgG (Ghetie et al., (1996) Immunology Today 18(12):592-8) and albumin (Chaudhury et al., (2003) Journal of Experimental Medicine 197(3):315-22) and is ubiquitously expressed in, for example, endothelial cells, epithelial cells, and hematopoietic cells, such as monocytes, macrophages, dendritic cells, and B cells. The Fc portion of IgG binds to FcRn with high affinity at acidic pH (<6.5) but not at physiological pH (7.4) (Rodewald R., (1976) Journal of Cell Biology 71(2):666-9). A mutated human IgG1-derived antibody (MST-HN) binds to FcRn with higher affinity and reduced pH dependence in mice, effectively competing with wild-type IgG for FcRn-mediated transport, resulting in a rapid decrease in IgG levels (Vaccaro et al., (2005) Nature Biotechnology 23(10):1283-8). In humans, such FcRn blockers (or "ABDEGs" for antibodies that enhance IgG degradation) may be desirable in several therapeutic situations, such as the clearance of autoreactive antibodies in autoimmune diseases, such as systemic lupus erythematosus, myasthenia gravis, and immune thrombocytopenic purpura (ITP), or other antibody-mediated diseases.

[0408] Efgartigimod is a human IgG1 Fc fragment engineered using ABDEG Fc engineering technology. Its presumed in vivo mechanism of action is constitutive blockade of FcRn-mediated IgG recycling, resulting in IgG degradation. The efficacy of efgartigimod depends in large part on its pharmacokinetic properties. For this reason, it is desirable to explore ways to further improve the half-life of the efgartigimod molecule, which may allow for the use of lower doses and / or less frequent administration. An effective means of improving pharmacokinetic properties is through binding to long-lived plasma proteins. Albumin is the most abundant protein in plasma and has a half-life of 19 days in humans, making it an ideal carrier for therapeutic peptides / proteins.

[0409] The HSA-targeting VHH fragment Alb23 (SEQ ID NO: 42) was chosen to fuse to the N-terminus of both Fc domains of efgartigimod (TA-Alb23-Fc-ABDEG) to further extend the half-life of efgartigimod and slow its clearance (Figure 1). Alb23 is described in WO2012 / 175400, which is incorporated herein by reference in its entirety. The full-length sequence of TA-Alb23-Fc-ABDEG is: EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG (SEQ ID NO: 177).

[0410] The objective of the study was to evaluate the pharmacokinetic and pharmacodynamic properties of TA-Alb23-Fc-ABDEG after a single intravenous dose of 5 mg / kg or 20 mg / kg to cynomolgus monkeys.

[0411] In addition to measuring TA-Alb23-Fc-ABDEG in cynomolgus monkey serum, anti-drug antibody (ADA) determinations against TA-Alb23-Fc-ABDEG were performed to investigate any impact on drug exposure. Fusion of anti-HSA VHH fragments to the N-terminus of both Fc domains of the Fc-ABDEG molecule was predicted to prolong the half-life and potency of this Fc-ABDEG (TA-Alb23-Fc-ABDEG) compared with efgartigimod, as well as altered PD profile (endogenous IgG reduction).

[0412] Male cynomolgus monkeys (Macaca fascicularis) were divided into two test groups of three monkeys, Group 1 and Group 2, each with approximately equal mean body weight (pseudorandom weight stratification procedure) and naive history. Both Group 1 and Group 2 were treated with a single intravenous bolus injection (cephalic vein in the right arm) of 20 and 5 mg / kg bw of TA-Alb23-Fc-ABDEG, respectively. The dose level selection for this study was based on previous studies using efgartigimod.

[0413] Blood samples were collected for PK / PD / immunogenicity measurements on Study Day 1 (TD1) (pre-dose), TD1 (pre-dose), TD1 (5 min), TD2 (24 h post-dose), TD3, TD4, TD6, TD8, TD11, TD15, TD18, TD22, TD29, TD36, and TD43. Whole blood was collected into serum separator tubes, and the blood samples were allowed to clot at room temperature for approximately 30 minutes before centrifugation. Immediately after centrifugation, the serum samples were aliquoted into 3 x 150 μL aliquots and stored at -70°C or below until dispatch for analysis.

[0414] Pharmacokinetics was assessed by measuring TA-Alb23-Fc-ABDEG serum concentrations using a sandwich ELISA method. Briefly, mouse anti-ABDEG antibodies were coated onto a 96-well immunoplate to block nonspecific binding sites. Next, 100% serum samples were diluted to the concentration range of quantification (or at least the minimum required dilution factor (MRD)) and added to the immunoplate along with a set of fresh calibration standards and quality control (QC) samples. Finally, TA-Alb23-Fc-ABDEG levels were visualized by the subsequent addition of HRP-conjugated goat anti-human Fc F(ab')2 and the chromogenic substrate tetramethylbenzidine (TMB). The enzymatic reaction was stopped with sulfuric acid, and optical density values ​​at 450 nm were recorded using a Tecan plate reader.

[0415] Pharmacodynamics was assessed by measuring total cynomolgus monkey IgG serum levels using a sandwich ELISA method. Briefly, polyclonal anti-monkey IgG antibodies (gamma chain specific) were coated onto a 96-well immunoplate to block nonspecific binding sites. Next, 100% serum samples were diluted to a concentration range for quantification and added to the immunoplate along with a set of fresh calibration standards and quality control (QC) samples. Total serum rabbit IgG levels were detected and visualized by the subsequent addition of HRP-conjugated goat anti-rabbit Fc F(ab')2 and the chromogenic substrate tetramethylbenzidine (TMB). The enzymatic reaction was stopped with sulfuric acid, and optical density values ​​at 450 nm were recorded using a Tecan plate reader.

[0416] Immunogenicity of the human IgG1 portion, ABDEG substitution, or anti-HSA portion of the molecule was measured using a sandwich ELISA method. Briefly, TA-Alb23-Fc-ABDEG was coated onto a 96-well immunoplate, and nonspecific binding sites were blocked. Dilutions of serum samples from several post-dose time points of the cynomolgus monkey study were applied. Anti-drug antibodies (ADA) were detected and visualized by the subsequent addition of an HRP-conjugated anti-monkey IgG monoclonal antibody (gamma chain specific) and the chromogenic substrate tetramethylbenzidine (TMB). Optical density values ​​were recorded using a Tecan plate reader.

[0417] Pharmacokinetic data revealed a clear improvement in the half-life of Fc-ABDEG upon conjugation to an anti-HSA VHH fragment (Alb23), with half-lives ranging from 13.4 to 54 days in the different groups, with an average of 26.5 and 28.2 days for the 20 mg / kg and 5 mg / kg doses, respectively (Figure 2). Pharmacokinetic parameters evaluated per dose group or per single animal (half-life (T 1 / 2 ), C max A summary of the dose-proportionality coefficients (DPF), area under the curve (AUC), and dose-proportionality coefficient (DPF) are presented in Tables S1 and S2, respectively. DPF calculations were based on the obtained AUC values. AUC was calculated by GraphPad Prism 7, setting the baseline as y=0 and ignoring peaks below the baseline or less than 10% of the distance from minimum to maximum Y. Half-lives were calculated by GraphPad Prism 7 using a two-phase decay model up to day 10 (ADA at day 14). The mean half-life, C per dose group, shown in Table S1 max , and AUC were calculated based on the mean TA-Alb23-Fc-ABDEG serum concentrations per post-dose time point for individual monkeys per dose group (n = 2 duplicates, 1x duplicate per study sample dilution) (values ​​are shown in Table S2). Table S1: Mean pharmacokinetic parameters of TA-Alb23-Fc-ABDEG per dose group [Table 7] Results represent the mean ± SD of one triplicate per PK parameter (n = 1 triplicate, 3 monkeys per dose group). *For monkeys c1 and c3, only one value was included because an accurate two-phase collapse fit could not be established (see Table S2). Table S2: Pharmacokinetic parameters of TA-Alb23-Fc-ABDEG per individual animal [Table 8] Results represent the mean ± SD of two duplicates per PK parameter (n = 2 duplicates, 2-fold study sample dilution in duplicate). *T 1 / 2 was determined up to day 10 (ADA at day 14) using a biphasic decay. **The two-phase decay fit is unclear and requires accurate T 1 / 2 Could not get value.

[0418] The PK profile of TA-Alb23-Fc-ABDEG after intravenous administration demonstrated a dramatically increased half-life of the Fc-ABDEG molecule compared to efgartigimod. The calculated C values ​​are within the range expected when considering the estimated mean blood volume of cynomolgus monkeys is 65 mL / kg. The predicted C values ​​for the 20 and 5 mg / kg dose groups were 559 and 140 μg / mL, respectively. The half-lives for the TA-Alb23-Fc-ABDEG molecule were 26.5 and 28.2 days for the 20 mg / kg and 5 mg / kg dose groups, respectively; for efgartigimod, this is approximately 1.5 days. A clear decrease in TA-Alb23-Fc-ABDEG serum levels was observed by day 10 in most animals, which correlates with detectable levels of anti-drug antibodies at this time point. The AUC values ​​showed a linear increase with the administered dose, as demonstrated by a DPF of 0.9 between the 5 mg / kg and 20 mg / kg groups.

[0419] The IgG reduction was small but dose-dependent, and no pharmacodynamic effect was observed at a dose of 5 mg / kg. An IgG clearance effect was observed at a dose of 20 mg / kg of TA-Alb23-Fc-ABDEG, with a maximum 25% reduction in IgG levels (when C3 was omitted) compared to baseline values. The time to maximum PD effect (T min ) is significantly longer, taking 21 and 28 days for the 5 mg / kg and 20 mg / kg dose groups, respectively.

[0420] Total IgG levels in cynomolgus monkey serum after a single dose of 5 or 20 mg / kg bw of TA-Alb23-Fc-ABDEG are shown relative to pre-dose levels in Figures 3A-3B. Pharmacodynamic parameters for different animals are shown in Tables S3 and S4. Table S3 Pharmacodynamic parameters of TA-Alb23-Fc-ABDEG per individual animal [Table 9] Results represent the mean ± SD of two duplicates per PD parameter (n = 2 duplicates, 2-fold study sample dilution in duplicate). *C3 was excluded from the analysis. Table S4: Mean pharmacodynamic parameters of TA-Alb23-Fc-ABDEG per dose group [Table 10] Results represent the mean ± SD of one triplicate per PD parameter (n = 1 triplicate, 3 monkeys per dose group). *C3 was excluded from the analysis.

[0421] All animals treated with TA-Alb23-Fc-ABDEG developed anti-drug antibodies by day 10. The animal immune responses are shown in Figure 4. When antibodies against the human IgG1 portion, the ABDEG substitution, or the anti-HSA portion of the molecule were present in cynomolgus monkey serum study samples, an increase in OD450 could be detected. ADA development was observed in all animals 10 days after injection of the TA-Alb23-Fc-ABDEG molecule in both dosing groups. C2, C3, and C6 exhibited significantly higher OD signals than the other monkeys, indicating a more pronounced immune response than the other monkeys. Because C2, C3, and C6 were not from the same dose group, this is not assumed to be related to the administered TA-Alb23-Fc-ABDEG dose (5 mg / kg vs. 20 mg / kg).

[0422] The objective of this study was to determine the pharmacokinetic, pharmacodynamic, and immunogenic properties of a two-arm N-terminal anti-HSA-Fc-ABDEG (TA-Alb23-Fc-ABDEG) antibody after single intravenous bolus injections of 5 mg / kg and 20 mg / kg in cynomolgus monkeys. The addition of two anti-HSA VHH fragments at the N-terminus of Fc-ABDEG was predicted to extend the half-life and potency of the molecule compared with efgartigimod. In this study, the pharmacokinetic profile of TA-Alb23-Fc-ABDEG demonstrated an increased half-life of the Fc-ABDEG molecule compared with efgartigimod. The half-lives for the TA-Alb23-Fc-ABDEG molecule were 26.5 and 28.2 days for the 20 mg / kg and 5 mg / kg dose groups, respectively, compared with approximately 1.5 days for efgartigimod. However, the TA-Alb23-Fc-ABDEG molecule had minimal effects on endogenous cynomolgus monkey serum IgG in both dose groups (the maximum observed reduction was 25% compared to pre-dose levels; 20 mg / kg dose group). This contrasts markedly with data from other studies in cynomolgus monkeys, in which administration of 20 mg / kg efgartigimod resulted in at least a 50% reduction in total serum IgG within the first 10 days after injection. In vitro studies suggest that the functionality of TA-Alb23-Fc-ABDEG is lower than that of efgartigimod. Furthermore, accelerated TA-Alb23-Fc-ABDEG clearance was observed in most animals by day 10, corresponding to detectable levels of anti-drug antibodies at this time point.

[0423] Example 2: Pharmacokinetics / Pharmacodynamics of Fc-ABDEG anti-HSA in Cynomolgus Monkeys As described in Example 1, efgartigimod (Fc-ABDEG fragment) fused at the N-terminus to the HSA-targeting VHH fragment Alb23 (Alb23-Fc-ABDEG, which has two Alb23 albumin-binding arms at the N-terminus) demonstrated an increased half-life in cynomolgus monkeys but no apparent pharmacodynamic effect on the clearance of endogenous cynomolgus monkey IgG. It was hypothesized that the placement of the anti-HSA VHH fragment at the N-terminus of Fc-ABDEG might prevent the Fc-ABDEG portion of the molecule from occupying FcRn, thus resulting in less efficient competition with endogenous IgG for binding to FcRn. Therefore, for this study, efgartigimod was fused at the C-terminus of efgartigimod with two Alb23 VHHs (TA-Fc-ABDEG-Alb23) (Figure 5). The full-length sequence of TA-Fc-ABDEG-Alb23 is DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS (SEQ ID NO: 178).

[0424] Previously, prolonged PK with TA-Fc-ABDEG-Alb23 (a C-terminal anti-HSA VHH fragment) was observed in human FcRn and human albumin transgenic AlbuMus mice. Importantly, in the same model, Fc-ABDEG-Alb23 also demonstrated a significant PD effect on the clearance of circulating preloaded human IgG, in contrast to TA-Alb23-Fc-ABDEG (an N-terminal anti-HSA VHH fragment). These findings allowed further investigation of TA-Fc-ABDEG-Alb23 (a C-terminal anti-HSA VHH fragment) in cynomolgus monkeys.

[0425] The animal procedures used in this study were reviewed and approved by the PharmaLegacy Laboratories IACUC. Briefly, a total of six naive female cynomolgus monkeys (2.5-5 kg) were randomly assigned to two groups. Monkeys received a single IV dose of 30 or 75 mg / kg of TA-Fc-ABDEG-Alb23 via ...

Claims

1. A heterodimeric protein comprising a first polypeptide and a second polypeptide, a) the first polypeptide comprises a first Fc domain comprising the amino acid sequence of SEQ ID NO: 5, and a VHH comprising the CDR1, CDR2, and CDR3 amino acid sequences of the VHH amino acid sequence set forth in SEQ ID NO: 44, wherein the VHH specifically binds to human serum albumin (HSA); and b) the heterodimeric protein, wherein the second polypeptide comprises a second Fc domain comprising the amino acid sequence of SEQ ID NO:

8.

2. The heterodimeric protein of claim 1, wherein the CDR1, CDR2, and CDR3 amino acid sequences are set forth in SEQ ID NO: 14, SEQ ID NO: 11, and SEQ ID NO: 12, respectively.

3. The heterodimeric protein of claim 1, wherein the VHH comprises the amino acid sequence of SEQ ID NO:

44.

4. The heterodimeric protein according to claim 1, wherein the amino acid sequence of the VHH consists of the amino acid sequence of SEQ ID NO:

44.

5. 5. The heterodimeric protein according to claim 4, further comprising one or more additional amino acids at the C-terminus of said VHH, wherein said one or more additional amino acids are: a) A, b) A.G., c) G G, d) PP, and e) AA.

6. The heterodimeric protein according to claim 1, wherein the VHH is fused to the C-terminus of the first Fc domain via a peptide linker.

7. The heterodimeric protein according to claim 6 , wherein the peptide linker is a GS linker that is 20 or 30 amino acids in length.

8. The heterodimeric protein of claim 1, wherein the amino acid sequence of the first Fc domain consists of the amino acid sequence of SEQ ID NO:

5.

9. The heterodimeric protein of claim 1, wherein the amino acid sequence of the second Fc domain consists of the amino acid sequence of SEQ ID NO:

8.

10. A heterodimeric protein comprising a first polypeptide having the amino acid sequence of SEQ ID NO: 180 and a second polypeptide having the amino acid sequence of SEQ ID NO:

8.

11. The heterodimeric protein of claim 10, wherein the amino acid sequence of the first polypeptide consists of the amino acid sequence of SEQ ID NO: 180, and the amino acid sequence of the second polypeptide consists of the amino acid sequence of SEQ ID NO:

8.

12. The heterodimeric protein according to claim 11, wherein the heterodimeric protein consists of the first polypeptide and the second polypeptide.

13. A pharmaceutical composition comprising the heterodimeric protein according to any one of claims 1 to 12.

14. A pharmaceutical composition for use in the treatment of an IgG-mediated disorder, comprising the heterodimeric protein of any one of claims 1 to 12.

15. A pharmaceutical composition for use in reducing serum IgG in a subject, comprising the heterodimeric protein according to any one of claims 1 to 12.

16. One or more polynucleotides encoding the heterodimeric protein according to any one of claims 1 to 12.

17. 17. One or more expression vectors comprising one or more polynucleotides of claim 16.

18. 17. A host cell comprising one or more polynucleotides of claim 16.

19. 20. A method for producing a heterodimeric protein, comprising culturing the host cell of claim 18 under conditions that allow expression of the heterodimeric protein.

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