Fcrn / hsa binding molecules and methods of use

Abstract

Provided herein are binding molecules comprising 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 methods of production. Further provided herein are methods of treating antibody mediated disorders with FcRn / antigen binding molecules.

Description

Technical Field

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

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

[0003] The half-life of IgG in serum is extended relative to that of other plasma proteins, in part due to the binding of the Fc region of IgG to the Fc receptor FcRn. FcRn binds to IgG and protects IgG from transport to degradative lysosomes by recycling it back to the extracellular compartment. This recycling is facilitated by the pH-dependent binding of IgG to FcRn, with the IgG / FcRn interaction being 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, the unbound IgG is not protected from lysosomal degradation and will therefore have a shortened serum half-life. Therefore, inhibiting the binding of IgG to FcRn will shorten the serum half-life of IgG by preventing endosomal recycling of IgG. Agents that antagonize the binding of IgG to FcRn, such as FcRn binding molecules, can be used to regulate, treat or prevent antibody-mediated disorders, such as autoimmune diseases or inflammatory diseases.

[0005] Efgartigimod is a modified human immunoglobulin (Ig) γ (IgG) 1 derived za allotype Fc that binds to human FcRn with nanomolar affinity. Efgartigimod contains an 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 blocking of FcRn-mediated IgG recycling. In the United States and Japan, Efgartigimod has been approved as a weekly intravenous injection for the treatment of systemic myasthenia gravis, and is being developed for the treatment of several other antibody-mediated diseases.

[0006] FcRn also binds and recycles serum albumin, which is a regulator of serum cholesterol levels. Advantageously, igamod 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] Therefore, there is a need in the art for improved agents that antagonize FcRn binding to IgG with longer half-life, lower dosage, less frequent administration, better maintenance of albumin levels and / or reduced or eliminated FcRn degradation for the treatment of antibody-mediated disorders. Summary of the invention

[0008] The present disclosure relates broadly 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 use thereof. It is shown for the first time in the present application that unexpectedly, inclusion of an HSA binding moiety increases the stability (lifespan) 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 wherein 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 a lower affinity 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 a lower affinity than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA.

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

[0012] In some embodiments, the FcRn / antigen binding molecule binds to FcRn at pH 5.5 and / or at pH 6.0 with a higher affinity than the affinity of igatimod for 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 at pH 6.0 with a lower affinity than the affinity of igatimod for FcRn at pH 5.5 and / or pH 6.0.

[0013] In any of the above embodiments, binding affinity can 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 and / or second Fc domain comprises amino acids Y, T, E, K, and F located at EU positions 252, 254, 256, 433, and 434, respectively. In some embodiments, the first and / or second Fc domain comprises amino acids Y, T, E, K, F, and Y located at EU positions 252, 254, 256, 433, 434, and 436, respectively.

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

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

[0018] In some embodiments, both the first Fc domain and the second Fc domain are IgG Fc domains, such as IgG1 Fc domains. In some embodiments, both the first Fc domain and the second Fc domain are human IgG Fc domains, such as 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 group consisting of 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 group consisting of 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 group consisting of 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 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 group consisting of the amino acid sequence 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 group consisting of the amino acid sequence 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 group consisting of the amino acid sequence 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 group consisting of the amino acid sequence 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, an sdAb, a scFv, an 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.

[0033] In some embodiments, the first antigen binding domain is any antigen binding domain described herein. In some embodiments, the first antigen binding domain is a VHH fragment comprising the following: CDR1, CDR2 and CDR3 amino acid sequences of any VHH fragment disclosed herein. In some embodiments, the first antigen binding domain is a VHH fragment comprising the following: CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment comprising an amino acid sequence selected from SEQ ID NO: 43-74, 84-90 and 120-127.

[0034] In some embodiments, the first antigen binding domain is a VHH fragment comprising an amino acid sequence 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 comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown 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 shown in SEQ ID NO: 44.

[0035] In some embodiments, for example, when the first antigen binding domain is a VHH fragment, the FcRn / antigen binding molecule further comprises one or more additional amino acids located at the C-terminus of the first antigen binding domain. 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 a portion thereof.

[0040] In some embodiments, the first antigen binding domain is fused to the first Fc domain and the second antigen binding domain is fused to the 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 the 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, an sdAb, a scFv, an 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 antigen binding domain described herein. In some embodiments, the second antigen binding domain is a VHH fragment comprising the following: CDR1, CDR2 and CDR3 amino acid sequences of any VHH fragment disclosed herein. In some embodiments, the second antigen binding domain is a VHH fragment comprising the following: CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment comprising an amino acid sequence selected from SEQ ID NO: 43-74, 84-90 and 120-127.

[0045] In some embodiments, the second antigen binding domain is a VHH fragment comprising an amino acid sequence 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 comprising an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown 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 shown in SEQ ID NO: 44.

[0046] In some embodiments, for example, when the second antigen binding domain is a VHH fragment, the FcRn / antigen binding molecule further comprises one or more amino acids located at the C-terminus of the second antigen binding domain. 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] On the one hand, there is provided herein 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 NO: 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 an amino acid sequence of any one of SEQ ID NO: 137-176 and 180. In some embodiments, the first heavy chain comprises or consists of an amino acid sequence of SEQ ID NO: 180. In some embodiments, the first heavy chain further comprises one or more amino acids added at the C-terminus, which are 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, provided herein is an antigen binding domain comprising the CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 43-74, 84-90 and 120-127.

[0052] In some embodiments, the first antigen binding domain and / or the second antigen binding domain comprises an amino acid sequence selected from the group consisting of:

[0053] a) an amino acid sequence comprising SEQ ID NO: 13 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0054] b) an amino acid sequence comprising SEQ ID NO: 14 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0055] c) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0056] d) an amino acid sequence comprising SEQ ID NO: 16 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0057] e) an amino acid sequence comprising SEQ ID NO: 17 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0058] f) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 18 (CDR2) and SEQ ID NO: 12 (CDR3);

[0059] g) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 19 (CDR2) and SEQ ID NO: 12 (CDR3);

[0060] h) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 20 (CDR2) and SEQ ID NO: 12 (CDR3);

[0061] i) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 21 (CDR2) and SEQ ID NO: 12 (CDR3);

[0062] j) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 22 (CDR2) and SEQ ID NO: 12 (CDR3);

[0063] k) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 23 (CDR2) and SEQ ID NO: 12 (CDR3);

[0064] 1) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 24 (CDR2) and SEQ ID NO: 12 (CDR3);

[0065] m) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 25 (CDR2) and SEQ ID NO: 12 (CDR3);

[0066] n) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 26 (CDR2) and SEQ ID NO: 12 (CDR3);

[0067] o) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 27 (CDR2) and SEQ ID NO: 12 (CDR3);

[0068] p) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 28 (CDR2) and SEQ ID NO: 12 (CDR3);

[0069] q) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 29 (CDR2) and SEQ ID NO: 12 (CDR3);

[0070] r) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 30 (CDR2) and SEQ ID NO: 12 (CDR3);

[0071] s) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 31 (CDR2) and SEQ ID NO: 12 (CDR3);

[0072] t) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 32 (CDR2) and SEQ ID NO: 12 (CDR3);

[0073] u) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 33 (CDR2) and SEQ ID NO: 12 (CDR3);

[0074] v) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 34 (CDR3);

[0075] w) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 35 (CDR3);

[0076] x) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 36 (CDR3);

[0077] y) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 37 (CDR3);

[0078] z) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 38 (CDR3);

[0079] aa) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 39 (CDR3);

[0080] bb) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 40 (CDR3);

[0081] cc) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 36 (CDR3);

[0082] dd) an amino acid sequence comprising SEQ ID NO: 15 (CDR1), SEQ ID NO: 21 (CDR2) and SEQ ID NO: 12 (CDR3);

[0083] ee) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 41 (CDR2) and SEQ ID NO: 12 (CDR3);

[0084] ff) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 20 (CDR2) and SEQ ID NO: 36 (CDR3);

[0085] gg) an amino acid sequence comprising SEQ ID NO: 111 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0086] hh) an amino acid sequence comprising SEQ ID NO: 112 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3);

[0087] ii) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 113 (CDR2) and SEQ ID NO: 12 (CDR3);

[0088] jj) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 114 (CDR2) and SEQ ID NO: 12 (CDR3);

[0089] kk) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 115 (CDR3);

[0090] 11) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 116 (CDR3);

[0091] mm) comprises an amino acid sequence of SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 117 (CDR3);

[0092] nn) an amino acid sequence comprising SEQ ID NO: 118 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 119 (CDR3);

[0093] oo) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 77 (CDR3);

[0094] pp) comprises an amino acid sequence of SEQ ID NO:75 (CDR1), SEQ ID NO:76 (CDR2) and SEQ ID NO:78 (CDR3);

[0095] qq) an amino acid sequence comprising SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 79 (CDR3);

[0096] rr) an amino acid sequence comprising SEQ ID NO:75 (CDR1), SEQ ID NO:76 (CDR2) and SEQ ID NO:80 (CDR3);

[0097] ss) comprises an amino acid sequence of SEQ ID NO:75 (CDR1), SEQ ID NO:76 (CDR2) and SEQ ID NO:81 (CDR3);

[0098] tt) an amino acid sequence comprising SEQ ID NO:75 (CDR1), SEQ ID NO:76 (CDR2) and SEQ ID NO:82 (CDR3); and

[0099] uu) comprises the amino acid sequence of SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 83 (CDR3).

[0100] 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).

[0101] In some embodiments, the first antigen binding domain and / or the second antigen binding domain comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 43-74, 84-90 and 120-127. In some embodiments, the antigen binding domain comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO: 44. In some embodiments, the first antigen binding domain and / or the second antigen binding domain comprises an amino acid sequence selected from the group consisting of the amino acid sequence shown in SEQ ID NO: 43-74, 84-90 and 120-127. In some embodiments, the first antigen binding domain and / or the second antigen binding domain comprises an amino acid sequence shown in SEQ ID NO: 44.

[0102] 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 located 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.

[0103] In some embodiments, the antigen binding domain specifically binds to HSA. In specific embodiments, the antigen binding domain is a VHH fragment that binds to HSA with a stronger affinity at neutral pH than at acidic pH. In some embodiments, the antigen binding domain binds to HSA with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA, optionally as measured by surface plasmon resonance.

[0104] Also provided are one or more isolated polynucleotides encoding any of the FcRn / antigen binding molecules described herein or any of the antigen binding domains described herein.

[0105] Also provided is an expression vector comprising any one or more of the isolated polynucleotides described herein.

[0106] Also provided is a host cell comprising any one or more of the isolated polynucleotides or any of the expression vectors described herein.

[0107] Also provided is a method for producing an FcRn / antigen binding molecule or antigen binding domain, the method comprising culturing a host cell as described herein under conditions allowing expression of the FcRn / antigen binding molecule or antigen binding domain.

[0108] Also provided is a pharmaceutical composition comprising an FcRn / antigen binding molecule as described herein or an antigen binding domain as described herein and at least one pharmaceutically acceptable carrier.

[0109] Also provided is an FcRn / antigen binding molecule as described herein, or an antigen binding domain as described herein, or a pharmaceutical composition thereof for use as a medicament.

[0110] Also provided is a method of 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 as described herein (e.g., an FcRn / HSA binding molecule as described herein), or an antigen binding domain as described herein, or a pharmaceutical composition thereof.

[0111] Also provided is a method of treating an antibody-mediated disorder in a subject, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of an FcRn / antigen binding molecule as described herein (e.g., an FcRn / HSA binding molecule as described herein), or an antigen binding domain as described herein, or a pharmaceutical composition thereof.

[0112] 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: allogeneic islet transplant rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, anti-neutrophil cytoplasmic autoantibodies (ANCA), adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia or primary immune thrombocytopenia), autoimmune urticaria, Behcet's disease, bullous Pemphigus (BP), cardiomyopathy, Castleman's disease, celiac sprue, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Chargar-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII 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, atrophic lichen sclerosus, lupus erythematosus, lupus nephritis, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), myositis, paraneoplastic bullous pemphigoid, pemphigoid gestationis, pemphigus 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, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, solid organ transplant rejection, stiff-person 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.

[0113] In some embodiments, the FcRn / antigen binding molecule or antigen binding domain and the additional therapeutic agent are administered to the subject simultaneously or sequentially.

[0114] Also provided is an FcRn / antigen binding molecule as described herein or an antigen binding domain as described herein for use in treating an antibody-mediated disorder.

[0115] Also provided is the use of an FcRn / antigen binding molecule as described herein (eg, an FcRn / HSA binding molecule as described herein) or an antigen binding domain as described herein for the manufacture of a medicament for treating an antibody-mediated disorder. BRIEF DESCRIPTION OF THE DRAWINGS

[0116] Figure 1 is equipped with two Fc domains fused at the N-terminus to anti-HSA VHH Schematic diagram of a representative two-arm (TA) Fc-ABDEG molecule.

[0117] Figure 2 showed that the efficacy of an intravenous (IV) dose of a 5-mercaptoethanol-containing ... VHH Pharmacokinetic profiles of individual cynomolgus monkeys treated with the Fc-ABDEG molecule (TA-Alb23-Fc-ABDEG) of (Alb23); C1-3: 20 mg / kg, C4-6: 5 mg / kg. TA-Alb23-Fc-ABDEG concentration values ​​were plotted over time. Data points show the mean ± SD of 2 replicates (n = 2 replicates, 2-fold study sample dilutions in duplicate) as the result for each post-administration time point.

[0118] Figures 3A to 3B Shown are the pharmacodynamic profiles of individual cynomolgus monkeys treated with one IV dose of TA-Alb23-Fc-ABDEG; – C1-3: 20 mg / kg ( Figure 3A ), –C4-6: 5 mg / kg ( Figure 3B ). The % of total serum IgG levels in cynomolgus monkeys before dosing are plotted over time. Data points show the mean ± SD of 2 replicates (n = 2 replicates, 2-fold study sample dilutions in duplicate) as the result for each post-administration time point.

[0119] Figure 4TA-Alb23-Fc-ABDEG ADA development curves are shown 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 developing immune response is plotted over time. Data points show the mean ± SD of 1 replicate (n = 1 replicate, 1-fold study sample dilution in duplicate) as the result for each post-administration time point.

[0120] Figure 5 is equipped with anti-HSA fused at the C-terminus of two Fc domains VHH Schematic representation of a representative TA Fc-ABDEG molecule of (Alb23).

[0121] Figures 6A to 6B Shown in the presence of anti-HSA equipped with two Fc domains fused at the C-terminus via a 20GS linker VHH Total circulating IgG levels in individual cynomolgus monkeys after a single IV bolus injection of the Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) of (Alb23). 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 ( Fig. 6A ), while monkeys in Group 2 (G2-1, G2-2, and G2-3) received 75 mg / kg dose of TA-Fc-ABDEG-Alb23 ( Figure 6B ). The percentage relative to the pre-dose at -5 min on day 0 is plotted over time (days after injection) during the course of the study. The dashed line represents 100% of total serum IgG at baseline (day 0, -5 min) before TA-Fc-ABDEG-Alb23 injection. The dotted line represents the maximum IgG level reduction observed in individual monkeys in each study group. The graph shows the mean ± SD of the study samples analyzed in duplicate (technical repeats).

[0122] Figures 7A to 7B The pharmacokinetic profile of TA-Fc-ABDEG-Alb23 after a single IV bolus injection in cynomolgus monkeys is 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, while monkeys in group 2 (G2-1, G2-2, and G2-3) received a 75 mg / kg dose of TA-Fc-ABDEG-Alb23. For 30 mg / kg ( Fig. 7A ) and for 75 mg / kg ( Figure 7B) dose group, the TA-Fc-ABDEG-Alb23 levels (in μg / mL) of individual monkeys are plotted over time (days after injection) during the course of the study. The dashed line represents the sensitivity level of the TA-Fc-ABDEG-Alb23 PK ELISA with an LLOQ of 0.4 μg / mL. The data points show the mean ± SD of the study samples analyzed in duplicate (technical replicates).

[0123] Figures 8A to 8B Figure 2 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 ( Fig. 8A ), while monkeys in Group 2 (G2-1, G2-2, and G2-3) received 75 mg / kg dose of TA-Fc-ABDEG-Alb23 ( Figure 8B ). ADA responses to TA-Fc-ABDEG-Alb23 were analyzed by ELISA, and OD450 values ​​were plotted over time (days post-injection) during the course of the study.

[0124] Figures 9A to 9B Serum albumin levels after injection of TA-Fc-ABDEG-Alb23 are shown (analyzed using the BCG assay in a 96-well plate format). 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 ( Fig.9A ), while monkeys in Group 2 (G2-1, G2-2, and G2-3) received 75 mg / kg dose of TA-Fc-ABDEG-Alb23 ( Fig. 9B ). The percentage relative to pre-dose (day 0, min -5) is plotted over time (days post-injection) during the course of the study. The dashed line represents 100% albumin at day 0, 5 min before TA-Fc-ABDEG-Alb23 injection. Data points show the mean ± SD of study samples analyzed in duplicate (technical replicates).

[0125] Figures 10A to 10BShown is tracer IgG1 normalized after a single IV administration of TA-Fc-ABDEG molecules with anti-HSAVHH fragments fused to the C-termini of both Fc domains, with or without a 20GS linker (TA-Fc-ABDEG-Alb23, TA-Fc-ABDEG-Alb23(mod), and TA-Fc-ABDEG-OGS-Alb23(mod); see Table S15 for a description of the constructs) at a dose of 30 mg / kg in AlbuMus mice. Fig. 10A Normalized hIgG1 after injection per group (% before administration) is shown. Changes in hIgG1 concentration over time (days after injection) are plotted relative to % before administration at day 0-1h. Data points show mean ± SEM of 4 mice per group per time point. Dashed line represents LLOQ of ELISA readings. Fig. 10B Normalized total serum IgG (hIVIg, pre-dose %) after injection is shown for each group. The change in hIVIg concentration over time (days after injection) is plotted relative to the % pre-dose at day 0-1 h. Data points show the mean ± SEM of 4 mice per group at each time point.

[0126] Fig.11 Serum PK of TA-Fc-ABDEG-Alb23 (mod), TA-Fc-ABDEG-Alb23 and TA-Fc-ABDEG-OGS-Alb23 (mod) after single IV injection is shown. Three groups of AlbuMus mice received a single 30 mg / kg dose of TA-Fc-ABDEG-Alb23 (mod), TA-Fc-ABDEG-Alb23 or TA-Fc-ABDEG-OGS-Alb23 (mod). During the course of the study, the serum concentration of the test item was plotted with the mean value over time in each group. Data points show the mean value ± SEM of 4 animals in each group.

[0127] Fig.12ADA reaction after single IV injection of TA-Fc-ABDEG-Alb23 (mod), TA-Fc-ABDEG-Alb23 or TA-Fc-ABDEG-OGS-Alb23 (mod) in individual AlbuMus mice. Day 0, mice received TA-Fc-ABDEG-Alb23 (mod) (30 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg) or TA-Fc-ABDEG-OGS-Alb23 (mod) (30 mg / kg). The ADA reaction (OD450, right Y axis) of each mouse in each group overlaps with the PK curve (μ g / mL, left Y axis) over time (number of days after injection, X axis). Each data point (PK and ADA) represents the mean value of the research sample analyzed in duplicate (technical repetition).

[0128] Fig.13 Normalized albumin levels (pre-dose %) after a single IV injection of TA-Fc-ABDEG-Alb23 (mod) (30 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg) or TA-Fc-ABDEG-OGS-Alb23 (mod) (30 mg / kg) in AlbuMus mice are shown. Albumin levels are plotted over time (days post-injection) as % relative to pre-dose (day 0, -1 h), and the average is taken for each group. Data points show the mean ± SEM of 4 mice per group at each time point.

[0129] Fig.14 Shown in the presence or absence of human serum albumin (HSA), the impact of the joint length between Fc-ABDEG and VHH fragments in the double-arm (TA)-Fc-ABDEG molecule with albumin binding VHH fused at the C-terminal of two Fc domains on FcRn degradation in HEK FcRn WT GFP+ cells. Compared with TA-Fc-ABDEG-Alb23 with OGS joint (i.e., no joint), the presence of 20GS joints in TA-Fc-ABDEG-Alb23 leads to lower FcRn degradation levels in vitro. Anti-FcRn mAb (anti-FcRn mAb1) known to increase FcRn degradation is included as a positive control. Histograms represent the mean ± SEM of two separate experiments each performed in two technical replicates.

[0130] Fig.15 Schematic diagram showing representative two-armed and one-armed albumin binding VHH Fc-ABDEG molecules according to the invention.

[0131] Figures 16A to 16BA two-armed (TA)-Fc-ABDEG molecule with albumin-binding VHH fused at the C-termini of two Fc domains (TA-Fc-ABDEG-Alb23; Fig.16A ) and a one-armed (OA)-Fc-ABDEG molecule with an albumin-binding VHH fragment fused to the C-terminus of one Fc domain (OA-Fc-ABDEG-Alb23; Fig. 16B )'s pH-dependent albumin binding curve.

[0132] Figures 17A to 17B Shown is the effect of the single-armed Fc-ABDEG-Alb23 molecule on FcRn degradation in the presence or absence of HSA. Fig.17A Shown are HEK FcRn WT GFP+ cells incubated with 2500 nM one- or two-armed Fc-ABDEG-Alb23 in the absence or presence of 10,000 nM HSA. Fig. 17B Shown are HEK FcRn WT GFP+ cells incubated with 12,500 nM single- or dual-armed Fc-ABDEG-Alb23 in the absence or presence of 50,000 nM HSA. Bar graphs represent mean ± SEM of duplicate wells; results of two independent runs.

[0133] Fig.18 The effect of the single-armed Fc-ABDEG-2H11 molecule on FcRn degradation in the presence or absence of HSA is shown. The pH-dependent HSA binding curve for each molecule is also shown to illustrate that the use of VHHs with reduced albumin binding affinity can reduce FcRn degradation. HEK FcRn WT GFP+ cells were incubated with 1 mg / mL Fc-ABDEG-VHH in the absence of HSA or in the presence of 3.3 mg / mL HSA. The bar graph represents the mean ± SD of two independent experiments performed in duplicate.

[0134] Fig.19ANormalized chimeric IgG1 (chIgG1) levels (pre-dose %) after injection in each group of Tg32-hFc mice administered with various double-arm and single-arm albumin-bound VHH Fc-ABDEG molecules are shown. 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 double-arm constructs) or PBS (control). The change of chIgG1 levels over time (days after injection) is plotted relative to the % before administration on day -3. The data points show the mean ± SEM of 4-5 mice per group at each time point. The Y axis is presented by 2 segments: the lower segment is used to better understand the chIgG1 depletion from day 1 to day 7, and the upper segment is used to observe the time point when the chIgG1 level is higher than the baseline. The dashed line indicates the maximum depletion level of chIgG1, expressed as a percentage of baseline.

[0135] Fig.19B Serum PK of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG and OA-Fc-ABDEG-Alb23 after single IP injection is shown. Tg32-hFc mice received 30mg / kg TA-Fc-ABDEG-Alb23, 30mg / kg TA-Alb23-Fc-ABDEG or 25mg / kg OA-Fc-ABDEG-Alb23 (equimolar dose). During the course of the study, the serum concentration of the test item was plotted with the mean value of each group over time. Data points show the mean ± SEM of 5 animals in each group.

[0136] Fig. 20 ADA reaction after single IP injection of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG or OA-Fc-ABDEG-Alb23 is shown in individual Tg32-hFc mice. On the 0th day, 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). The ADA reaction (OD450, right Y axis) of each mouse in each group overlaps with the PK curve (nM, left Y axis) over time (number of days after injection, X axis). Each data point (PK and ADA) represents the mean ± SEM of the research sample analyzed in duplicate (technical repetition).

[0137] Fig.21Normalized albumin levels after injection are shown for each group (% before administration). 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 after injection) relative to % before administration (day -3), and the average was taken for each group. Data points show the mean ± SEM of 4-5 mice per group at each time point.

[0138] Figures 22A to 22C Shown are 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 the double-arm construct at 30 mg / kg) or PBS on day 0. Data points show the mean ± SEM of 5 mice per group at each time point. Fig.22A Normalized tracer IgG levels after injection for each group are shown (% pre-dose). Changes in tracer IgG levels over time (days post-injection) are plotted as % relative to pre-dose at day 0-2 hours. Fig. 22B Serum PK of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 following a single IV injection is shown. Serum concentrations of the test items were plotted as the mean values ​​for each group over time during the course of the study. Fig. 22C Normalized albumin levels after injection (% before dosing) are shown for each group. Albumin levels were plotted over time (days after injection) as % relative to pre-dose (day 0 - 2 hours) and averaged for each group.

[0139] Fig.23 Shown is the effect of one-armed 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 of HSA (solid bars) or the presence of 50,000 nM HSA (striped bars). The bar graphs represent the mean ± SEM of duplicate wells; the results of two independent runs.

[0140] Fig.24Shown is the effect of OA-Fc-ABDEG-Alb23 with 20 GS linkers and OA-Fc-ABDEG-Alb23-F32A with 20, 25 and 30 GS linkers on FcRn degradation in the presence or absence of human serum albumin (HSA). HEK FcRn WT GFP+ cells were incubated with 12500 nM of the test molecule in the absence or presence of 50,000 nM HSA. The bar graphs represent the mean ± SEM of each experiment (indicated by n), each performed in two technical replicates.

[0141] Figures 25A to 25B 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 are shown. Data points show mean ± SD of 3-4 animals per group. Fig.25A Pharmacokinetic curves 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 are shown. During the course of the study, serum concentrations of the test items were plotted as the mean values ​​over time for each group. Values ​​below the lower limit of quantitation (LLOQ) were excluded from the graph. Fig.25B Shown are normalized levels of total preloaded human IgG in Albumus Rag1KO (% pre-dose) following 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). Total IgG concentrations are plotted over time (days post-injection) as % pre-dose relative to day 0-2h.

[0142] Figures 26A to 26B Showing the PD effects of OA-Fc-ABDEG-Alb23 Ala variant in AlbuMus Rag1KO mice. Fig.26ANormalized levels of total preloaded human IgG after injection for each dose group are shown (% pre-dose). Total IgG concentrations in AlbuMus Rag1KO mice over time (days post-injection) following a single IP administration of ARGX-113 (Agamod; 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 plotted relative to % pre-dose on day 0-2h. Data points show mean ± SEM of 4-5 animals per group. Fig.26B Normalized levels of tracer human IgG during the first 7 days of the study are shown (% pre-dose). Concentrations of tracer IgG in Albumus Rag1KO mice following 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) are plotted over time (days post-injection) as % relative to pre-dose at day 0-2h. Data points show mean ± SEM of 4-5 mice per group per time point. After day 4, the concentration of tracer IgG reached the low level of quantification (LLOQ) in the groups treated with ARGX-113 and all OA-Fc-ABDEG-VHH molecules.

[0143] Fig.26C Pharmacokinetic profiles are shown for ARGX-113 (Agamod; 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) in AlbuMus Rag1KO mice following a single IP injection. Serum concentrations of the test items were plotted as the mean over time per group during the course of the study. Data points show the mean ± SD of 4-5 animals per group. Values ​​below the lower limit of quantitation (LLOQ) were excluded from the graph.

[0144] Fig.26DShown are the levels of human serum albumin in AlbuMus Rag1KO mice (% relative to pre-dose) following a single IP administration of ARGX-113 (Agamod; 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). Albumin levels are plotted over time (days post-injection) as % relative to the mean pre-dose (Day 0 - 2 h) for each group. Data points show the mean ± SEM of 4-5 mice per group per time point.

[0145] Figures 27A to 27B Mota-Fab constructs ( Fig.27A ) and Fc-ABDEG constructs ( Fig.27B ) and Alb23-F32A fusion different pharmacokinetic curves. During the study process, the serum concentration of the test item was plotted as the average value over time in each group. The data points show the average value ± SD of 4-5 animals in each group. Values ​​below the lower limit of quantification (LLOQ) were excluded from the figure.

[0146] Figures 28A to 28B Pharmacodynamic (PD) curves in cynomolgus monkeys treated with an intravenous (IV) dose of an anti-HSAVHH Fc-ABDEG molecule (ABDEG-30GS-Alb23-SM) equipped with an F32A mutation (Alb23-SM) fused to the C-terminus of the Fc domain are shown. Total serum IgG% relative to pre-dose cynomolgus monkeys is plotted over time. Data points show that OA-Fc-ABDEG-Alb23 was administered at 10 mg / kg ( Fig.28A ) and 3 individual monkeys (n=3) were dosed with 60 mg / kg ( Fig.28B ) are average values ​​± SD for 5 individual monkeys (n = 5) dosed with ADA. Data points with results for only one individual monkey are marked with asterisks. PD curves of equimolar doses of agamod (model simulation) and nearly equimolar doses of OA-HEL-ABDEG (experimental data) in cynomolgus monkeys are plotted for comparison. Time points at which the presence of ADA was detected and the concentration dropped sharply in the PK curve were excluded from the figure.

[0147] Figures 29A to 29BPharmacokinetic curves in cynomolgus monkeys treated with one intravenous (IV) dose of ABDEG-30GS-Alb23-SM are shown. ABDEG-30GS-Alb23-SM concentration values ​​are plotted over time. Data points show that ABDEG-30GS-Alb23-SM was administered at 10 mg / kg ( Fig.29A ) and 3 individual monkeys (n=3) were dosed with 60 mg / kg ( Fig.29B ) are average values ​​± SD of 5 individual monkeys (n = 5) dosed with ADA. Data points with results for only one individual monkey are marked with asterisks. The PK curves of equimolar doses of Agamod (model simulation) and nearly equimolar doses of OA-HEL-ABDEG (experimental data) and TA-ABDEG-Alb23 (experimental data) in cynomolgus monkeys are plotted for comparison. The time points at which the presence of ADA is detected and the concentration in the PK curve drops sharply are excluded from the figure.

[0148] Fig.30 Serum albumin levels after injection of ABDEG-30GS-Alb23-SM (analyzed with BCG assay) are shown. On day 1, Group 1 (n=3) received a 10 mg / kg dose of ABDEG-30GS-Alb23-SM; and Groups 2 (n=2) and 3 (n=3) received a 60 mg / kg dose of ABDEG-30GS-Alb23-SM. After a 4-week follow-up period, monkeys in Groups 1 and 2 were additionally administered four times, once a week, with 60 mg / kg of ABDEG-30GS-Alb23-SM on days 29, 36, 43, and 50. The concentration of albumin was plotted over time during the course of the study. The dotted line represents the administration of ABDEG-30GS-Alb23-SM. The data points show the mean ± SD of individual monkeys in each treatment group. The orange shaded area shows the minimum and maximum levels of albumin measured before dosing in the monkeys used in this study. The grey shaded area shows the normal range of serum albumin in cynomolgus monkeys according to Park et al. (Lab Anim Res. 2016 Jun;32(2):79–86).

[0149] Fig.31ANormalized albumin levels (pre-dose %) following 4 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) in AlbuMus Rag1KO mice are shown. Albumin levels are plotted over time (days post-injection) as % relative to pre-dose (day -6), and the mean is taken for each group. Data points show mean ± SEM of 3-5 mice per group at each time point. Dashed lines show injections of test items at Day 0, Day 7, Day 14, and Day 21.

[0150] Fig.31B Shown are 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). HEK FcRn WT GFP+ cells were incubated with the indicated concentrations of test molecules in the absence of HSA or in the presence of 50,000 nM HSA. The bar graphs represent the mean ± SEM of each experiment (indicated by n), each performed in two technical replicates.

[0151] Fig.32 Showing reduced binding of pre-existing ADA to ABDEG-30GS-Alb23-SM-A. Sera from 40 human individuals with pre-existing ADA positive for ABDEG were used. ABDEG-30GS-Alb23-SM, ABDEG-30GS-Alb23-SM-A or PBS (blank, no coating) were coated in 96-well plates, the plates were blocked with 1% PBS-casein, and the sera were applied. Binding of pre-existing ADA to the test article was detected with HRP-conjugated anti-human Fab IgG. OD values ​​are plotted. 450 The absorbance value at .

[0152] Fig.33AShowing the occupancy of FcRn by ARGX-113, ABDEG-30GS-Alb23-SM and ABDEG-30GS-Alb23-SM-A. In the presence of 2,500 nM HSA, U937 cells were incubated with a series of titration test items. Free FcRn was detected with a fluorescently labeled anti-FcRn Fab fragment that recognizes the IgG binding site on FcRn. The detected free FcRn levels were normalized to the FcRn levels in cells treated with assay buffer (placebo, 100%). Presented are the mean ± SD of 2 independent experiments, each performed in technical replicates.

[0153] Fig.33B Shown are 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). HEK FcRn WT GFP+ cells were incubated with the indicated concentrations of test molecules in the absence of HSA or in the presence of 50,000 nM HSA. The bar graphs represent the mean ± SD of at least three independent experiments each performed in two technical replicates.

[0154] Fig.34A Normalized levels of tracer human IgG (pre-dose %) are shown in AlbuMus Rag1KO mice after a single IP injection of PBS (placebo), Agamod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). The tracer hIgG concentration is plotted over time (days post-injection) as % relative to pre-dose at day 0-2h. Data points show mean ± SEM of 5 mice per group at each time point.

[0155] Fig.34B Shown are normalized levels of total preloaded human IgG in AlbuMus Rag1KO (pre-dose %) after a single IP administration of PBS (placebo), Agamod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). The total IgG concentration was plotted over time (days post-injection) relative to the % pre-dose at day 0-2h. Data points show the mean ± SEM of 5 animals per group.

[0156] Fig.34C Pharmacokinetic curves of Agamod (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 are shown. During the course of the study, the serum concentrations of the test items were plotted as the mean values ​​over time for each group. The data points show the mean ± SD of 5 animals in each group. Values ​​below the lower limit of quantitation (LLOQ) were excluded from the figure. DETAILED DESCRIPTION

[0157] The present disclosure provides engineered FcRn binding molecules (FcRn / antigen binding molecules) connected to one or more antigen binding domains. In one aspect, an FcRn / antigen binding molecule is provided, comprising an FcRn binding molecule connected to an anti-HSA antigen binding domain at the C-terminus, or at the N-terminus, or at a position other than the C-terminus or the 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 manufacture, and methods of their use in treating antibody-mediated diseases.

[0158] definition

[0159] As used herein, the term "FcRn" refers to the 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.

[0160] 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) that specifically binds to FcRn and inhibits the binding of immunoglobulins to FcRn through the Fc region. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In one embodiment, the FcRn antagonist comprises an antigen binding domain and a variant Fc region that binds to a target antigen. In one embodiment, the term "FcRn antagonist" refers to an antibody or antigen binding fragment thereof that specifically binds to FcRn 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.

[0161] 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 " refers to the tendency of a two-molecule binding complex to dissociate into two free molecules. Therefore, as the binding affinity increases, K D reduce.

[0162] As used herein, the term "specific binding" refers to the ability of any molecule to preferentially bind to a given target. For example, a molecule that specifically binds to a given target may bind to other molecules, usually with lower affinity, as determined by, for example, immunoassays, BIAcore TM , KinEx A3000 instrument (Sapidyne Instruments, Boise, supra) or other assays known in the art. In a specific embodiment, a molecule that specifically binds to a given target has a K that is higher than when the molecule non-specifically binds to another target. D K of at least 2 logs, 2.5 logs, 3 logs, 4 logs or less D Binds to antigen.

[0163] As used herein, the term "operably linked" refers to polynucleotide sequence elements being linked in a functional relationship. For example, when a polynucleotide sequence is in a functional relationship with another polynucleotide sequence, the polynucleotide sequence is operably linked. In some embodiments, if a transcriptional regulatory polynucleotide sequence (e.g., a promoter, enhancer, or other expression control element) affects the transcription of a polynucleotide sequence encoding a protein, the transcriptional regulatory polynucleotide sequence is operably linked to a polynucleotide sequence encoding the protein. Operably linked elements may be continuous or non-continuous.

[0164] As used herein, the term "connected" refers to a physical connection (e.g., direct or indirect connection) between amino acid sequences (e.g., different segments, regions, fragments or domains). The connected regions, fragments, domains and segments of the FcRn / antigen binding molecules of the present disclosure can be continuous or non-continuous (e.g., connected to each other through a linker). In some embodiments, the connection is covalent. In some embodiments, the connection is non-covalent.

[0165] As used herein, the term "covalently linked" refers to the connection 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 "fusion" refers to the connection of two peptides by a peptide bond or a peptide linker. In some embodiments, two proteins are directly and continuously fused together by a peptide bond. In some embodiments, two proteins are indirectly and non-continuously fused by a peptide linker. In some embodiments, a protein is fused to a peptide linker by a peptide bond at a first position, and a second protein is fused to a peptide linker by a peptide bond at a second position. As used herein, the term "non-covalently linked" refers to the connection of two molecules or chemical moieties by a non-covalent interaction or bond. In some embodiments, non-covalent interactions or bonds include hydrogen bonds, electrostatic bonds or interactions, halogen bonds, π stacking, and van der Waals interactions.

[0166] 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 for comparing two sequences is the algorithm of Karlin S and Altschul SF, (1990) PNAS 87:2264-2268, as modified in Karlin S and Altschul SF, (1993) PNAS 90:5873-5877, each of which is incorporated herein by reference in its entirety. Such algorithms are 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 can be performed with the NBLAST nucleotide program parameter set (e.g., with 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 parameter set (e.g., with score = 50, word length = 3) to obtain amino acid sequences homologous to protein molecules described herein. In order to obtain gap alignments for comparison purposes, gap BLAST as described in Altschul SF et al., (1997) Nuc Acids Res 25:3389-3402 can be utilized, which is incorporated herein by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterative search for distance relationships between detection molecules. Same as above. When utilizing BLAST, gap BLAST, and PSI BLAST programs, the default parameters of the corresponding programs (e.g., XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) on the World Wide Web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm for sequence comparison is the algorithm of Myers and Miller, (1988) CABIOS 4:11-17, which is incorporated herein by reference in its entirety. This 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 to compare amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 may be used.

[0167] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating the percent identity, typically only exact matches are counted.

[0168] As used herein, the term "antibody" or "antibodies" includes full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH domains (VH) or VL domains (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 Fv (scFv), camelid antibodies, affibody molecules, VHH fragments, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), anti-idiotypic (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), and antigen-binding fragments of any of the foregoing. The antibody can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or species (e.g., mouse IgG 2a or IgG 2b ).

[0169] 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 (sdFv), single-chain Fvs (scFv), CDRs, VH domains (VH), VL domains (VL), single-domain antibodies (sdAb), VHH fragments, camelid antibodies, and antigen-binding fragments of any of the above. The term also encompasses synthetic antigen-binding proteins or antibody-mimicking proteins, such as, for example, anticalins and DARPins.

[0170] 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.

[0171] 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. The native Fc region is a homodimer. The Fc region may be derived from any natural immunoglobulin. In some embodiments, the Fc region is formed by IgA, IgD, IgE or IgG heavy chain constant regions. In some embodiments, the Fc region is formed by IgG heavy chain constant regions. 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 by an IgG1 heavy chain constant region. In some embodiments, the IgG1 heavy chain constant region comprises G1m1 (a), G1m2 (x), G1m3 (f) or G1m17 (z) allotypes. 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 herein by reference in their entireties.

[0172] 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. The changes may include amino acid substitutions, additions and / or deletions, attachment of additional moieties, and / or changes in 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 a linker moiety.

[0173] As used herein, the term "Fc domain" refers to a portion of a single immunoglobulin heavy chain that includes both the CH2 domain and the CH3 domain of an antibody. In some embodiments, the Fc domain includes at least a portion of the hinge region (e.g., upper, middle and / or lower hinge region), the CH2 domain, and the CH3 domain. In some embodiments, the Fc domain does not include a hinge region.

[0174] As used herein, the term "hinge region" refers to the portion of the heavy chain molecule that joins 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, the hinge region comprises about 11 to 17 amino acid residues and is flexible, thereby allowing 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 different domains: upper, middle and lower hinge domains. The FcRn / antigen binding molecules of the present disclosure may include all or any portion of the hinge region. In some embodiments, the hinge region is from an IgG1 antibody. In some embodiments, the hinge region comprises the amino acid sequence of EPKSCDKTHTCPPCP (SEQ ID NO: 179).

[0175] As used herein, the term "FcRn-binding fragment" refers to a portion of an FcRn-binding molecule sufficient to confer FcRn binding, e.g., a portion of the Fc region.

[0176] As used herein, the term "one-armed / one armed", "one-arm / one arm" or "OA" refers to an FcRn / antigen binding molecule comprising an FcRn binding molecule connected 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 an Fc domain of two heavy chains, wherein one of the Fc domains of the two heavy chains is connected to the antigen binding domain, and the other Fc domain of the two heavy chains is not connected to the antigen binding domain. In some embodiments, the antigen binding domain is connected to the C-terminus of one of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is connected to the N-terminus of one of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is connected to a position other than the N-terminus or C-terminus of one of the Fc domains of the two heavy chains. The connection can be covalent or non-covalent. In some embodiments, the antigen binding domain is fused to the C-terminus of one of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is fused to the N-terminus of one of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is fused to a position other than the N-terminus or C-terminus of one of the Fc domains of the two heavy chains.

[0177] As used herein, the term "two-armed / two armed", "two-arm / two arm" or "TA" refers to an FcRn / antigen binding molecule comprising an FcRn binding molecule connected to two antigen binding domains. In some embodiments, "two-armed / two armed", "two-arm / two arm" or "TA" refers to an FcRn / antigen binding molecule comprising an Fc region comprising an Fc domain of two heavy chains, wherein each of the Fc domains of the two heavy chains is connected to an antigen binding domain. In some embodiments, the antigen binding domain is connected to the C-terminus of each of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is connected to the N-terminus of each of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is connected to a position other than the N-terminus or C-terminus of each of the Fc domains of the two heavy chains. In some embodiments, one of the antigen binding domains is connected to the N-terminus of one of the Fc domains of the two heavy chains, and the other antigen binding domain is connected to the C-terminus of the other Fc domain of the two heavy chains. In some embodiments, one of the antigen binding domains is connected to 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 connected to the N-terminus of the other Fc domain of the two heavy chains. In some embodiments, one of the antigen binding domains is connected to 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 connected to the C-terminus of the other Fc domain of the two heavy chains. The connection can be covalent or non-covalent. In some embodiments, the antigen binding domain is fused to the C-terminus of each of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is fused to the N-terminus of each of the Fc domains of the two heavy chains. In some embodiments, the antigen binding domain is fused to a position other than the N-terminus or C-terminus of each of the Fc domains of the two heavy chains. 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 other Fc domain of the two heavy chains. In some embodiments, one of the antigen binding domains is fused to 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 other Fc domain of the two heavy chains. In some embodiments, one of the antigen binding domains is fused to 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 other Fc domain of the two heavy chains.

[0178] As used herein, the term "EU position" refers to the amino acid position of the Fc region according to the EU numbering convention as described in Edelman, GM et al. Proc. Natl. Acad. USA, 63, 78-85 (1969) and Rabat et al., "Sequences of Proteins of Immunological Interest," U. Sept. Health and Human Services, 5th Edition, 1991.

[0179] 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 the 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.

[0180] As used herein, the terms "treat", "treating", and "treatment" refer to therapeutic or preventive measures as described herein. The method of "treating" employs administering a polypeptide to a subject suffering from a disease or disorder or susceptible to such a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder or to prolong the survival of the subject beyond the expected survival in the absence of such treatment. In some embodiments, the method of "treating" employs administering a polypeptide to a subject suffering from a disease or disorder or susceptible to such a disease or disorder to prevent, cure, delay, reduce the severity of, or ameliorate the disease or disorder or recurring disease or disorder.

[0181] As used herein, the term "effective amount" in the context of administering a therapy to a subject refers to that amount of the therapy that achieves the desired prophylactic or therapeutic effect.

[0182] As used herein, the term "dose" or "administration" refers to the amount of a pharmaceutical agent administered to a subject in a single administration.

[0183] As used herein, the terms "fixed dose" or "uniform dose" both refer to a dose that does not vary based on the characteristics of the subject (e.g., weight, e.g., within a set range; sex; age, e.g., within a set range; etc.).

[0184] As used herein, the term "equivalent dose" refers to the dose of the first therapeutic agent and the second therapeutic agent, wherein the number of molecules of the first agent and the second agent is approximately the same. In some embodiments, the equivalent dose is an equimolar dose. As used herein, the term "equimolar dose" refers to the dose of the first therapeutic agent and the second therapeutic agent, wherein the number of moles of the first agent and the second agent is the same. In some embodiments, the first agent is an FcRn / antigen binding molecule and the second agent is Agamod. In some embodiments, the observed molecular weight of the first agent and the second agent is used to calculate the equivalent dose. In some embodiments, the predicted molecular weight of the first agent and the second agent is used to calculate the equivalent dose. In some embodiments, the observed molecular weight of the first agent and the predicted molecular weight of the second agent are used to calculate the equivalent dose. In some embodiments, the predicted molecular weight of the first agent and the observed molecular weight of the second agent are used to calculate the equivalent dose. In some embodiments, the predicted molecular weight of the first agent and the observed molecular weight of the second agent are used to calculate the equivalent dose.

[0185] 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 the regulation of the amount of circulating IgG in an organism to which the therapeutic agent is administered. In some embodiments, the biological effect is the regulation of the amount of circulating albumin in an organism to which the therapeutic agent is administered. As used herein, the terms "improved pharmacodynamics" or "improved PD" refer to the improvement of a desired biological effect in an organism to which a therapeutic agent is administered. In some embodiments, the improved pharmacodynamics includes a reduction in the amount of circulating IgG in a subject. In some embodiments, the improved pharmacodynamics includes the maintenance of the amount of circulating albumin in a subject. In some embodiments, the improved pharmacodynamics includes a reduction in the amount of circulating IgG in a subject and the maintenance of the amount of circulating albumin in a subject. In some embodiments, the therapeutic agent is an FcRn / antigen binding molecule.

[0186] 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 metabolic rate and / or clearance rate of the therapeutic agent. As used herein, the terms "improved pharmacokinetics" or "improved PK" refer to an improvement in an organism's desired effect on a therapeutic agent administered to the organism. In some embodiments, improved pharmacokinetics include an improvement in the half-life (T / V) of the therapeutic agent in a subject. 1 / 2 ), clearance rate or area under the curve (AUC). In some embodiments, the therapeutic agent is an FcRn / antigen binding molecule.

[0187] 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.

[0188] As used herein, when referring to a measurable value, such as a dosage, the term "about" or "approximately" encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as long as it is suitable for performing the methods disclosed herein.

[0189] As used herein, the term "molecular weight" may 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 the amino acids in the protein. In some cases, the "predicted molecular weight" of a molecule may differ from the "observed molecular weight". In some embodiments, these differences may occur in a protein due to changes in glycosylation, glycanation, ubiquitination, phosphorylation, or proteolytic cleavage of the protein or other proteins in complex with a given protein.

[0190] FcRn / antigen binding molecules

[0191] The present disclosure provides FcRn / antigen binding molecules or fragments thereof. In some embodiments, the FcRn / antigen binding molecules disclosed herein comprise FcRn binding molecules and at least one antigen binding domain. The FcRn binding molecules can be any FcRn binding molecules described herein. Similarly, the antigen binding domain can be any antigen binding domain described herein. In some embodiments, the FcRn / antigen binding molecules comprise only one antigen binding domain (e.g., single-armed FcRn / antigen binding molecules). In some embodiments, the FcRn / antigen binding molecules comprise two antigen binding domains (e.g., double-armed FcRn / antigen binding molecules).

[0192] In some embodiments, the antigen binding domain is connected to the C-terminus of the FcRn binding molecule. In some embodiments, the antigen binding domain is connected to the N-terminus of the FcRn binding molecule. In some embodiments, the antigen binding domain is connected to the FcRn binding molecule at a position other than the C-terminus or the N-terminus. The antigen binding domain can be covalently or non-covalently linked to the FcRn binding molecule.

[0193] 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 the N-terminus.

[0194] In some embodiments, one antigen binding domain is connected or fused to the N-terminus of the FcRn binding molecule, and the other antigen binding domain is connected or fused to the C-terminus of the FcRn binding molecule. In some embodiments, one antigen binding domain is connected or fused to a position other than the N-terminus or C-terminus of one of the FcRn binding molecules, and the other antigen binding domain is connected or fused to the N-terminus of the FcRn binding molecule. In some embodiments, one antigen binding domain is connected or fused to a position other than the N-terminus or C-terminus of one of the FcRn binding molecules, and the other antigen binding domain is connected or fused to the C-terminus of the FcRn binding molecule.

[0195] In some embodiments, the FcRn binding molecule is an Fc region, such as a variant Fc region. In some embodiments, the antigen binding domain is connected 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 connected 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 connected or fused to the FcRn binding molecule at a position other than the C-terminus or the N-terminus.

[0196] In some embodiments, one antigen binding domain is connected or fused to the C-terminus of one of the Fc domains of the variant Fc region, and the other antigen binding domain is connected or fused to the C-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen binding domain is connected or fused to the N-terminus of one of the Fc domains of the variant Fc region, and the other antigen binding domain is connected or fused to the N-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen binding domain is connected or fused to the N-terminus of one of the Fc domains of the variant Fc region, and the other antigen binding domain is connected or fused to the C-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen binding domain is connected 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 the other antigen binding domain is connected 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 the other antigen binding domain is linked or fused to the C-terminus of the other Fc domain of the variant Fc region.

[0197] In some embodiments, the antigen binding domain can be directly connected or fused to the N-terminus or C-terminus of the FcRn binding molecule. In some embodiments, the antigen binding domain is connected 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.

[0198] In some embodiments, the antigen binding domain can be directly connected (e.g., fused) to the N-terminus or C-terminus of the Fc domain. In some embodiments, the antigen binding domain is connected to the N-terminus or C-terminus of the Fc domain via a linker. The linker can be any suitable linker, including those described herein.

[0199] FcRn binding molecules

[0200] 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.

[0201] 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.

[0202] In some embodiments, the FcRn binding molecules disclosed herein comprise two, three, or four FcRn binding regions, such as Fc regions.

[0203] 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).

[0204] Any Fc region can be changed to produce a variant Fc region as disclosed herein. In general, the Fc region or its FcRn binding fragment is from a human immunoglobulin. However, it should be understood that the Fc region can be derived from the immunoglobulin of any other mammalian species, including, for example, camel species, rodents (e.g., mice, rats, rabbits, guinea pigs) or non-human primates (e.g., orangutans, macaques) species. In addition, the Fc region or its FcRn binding portion 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., human IgG region). In one embodiment, the Fc region is an IgG1 Fc region (e.g., human IgG1 region). In one embodiment, the Fc region is a chimeric Fc region comprising a portion 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.A variety of Fc region gene sequences (eg, human constant region gene sequences) are available in the form of publicly available deposits.

[0205] The Fc region may be further truncated or internally deleted to generate a minimal FcRn binding fragment thereof. The ability of the Fc region fragment to bind to FcRn may be determined using any art-recognized binding assay, such as ELISA.

[0206] In order to enhance the manufacturability of the FcRn binding molecules and FcRn / antigen binding molecules containing the same as disclosed herein, it is preferred that the constituent Fc regions do not contain any non-disulfide bonded cysteine ​​residues. Thus, in one embodiment, the Fc region does not contain free cysteine ​​residues.

[0207] In some embodiments, any Fc variant or its FcRn binding fragment that specifically binds to FcRn with increased affinity and reduced pH dependence relative to the native Fc region can 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 its FcRn binding fragment, 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 its FcRn binding fragment, which binds to FcRn with higher affinity at pH 6.0 and / or at pH 7.4 compared to the corresponding wild-type Fc region. In some embodiments, the FcRn binding molecule comprises a variant Fc region or its FcRn binding fragment, which binds to FcRn with higher affinity at both acidic and neutral pH compared to the corresponding wild-type Fc region.

[0208] In some embodiments, the variant Fc region is derived from the Fc region of any natural immunoglobulin. In some embodiments, the natural 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, IgG is IgG1, IgG2, IgG3 or IgG4. In some embodiments, human IgG is human IgG1, human IgG2, human IgG3 or human IgG4. In some embodiments, the variant Fc region is different from the human IgG1 Fc region. In some embodiments, the human IgG1 Fc region comprises G1m1 (a), G1m2 (x), G1m3 (f) or G1m17 (z) allotypes.

[0209] In some embodiments, the FcRn binding molecule is an FcRn antagonist.

[0210] 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 identical. 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 at least one amino acid or at least two amino acids selected from the group consisting of: 237M; 238A; 239K; 248I; 250A; 250F; 250I; 250M; 250Q; 250S; 250V; 250W; 250Y; 252F; 252W; 252Y; 254T; 255E; 256D; 256E; 256Q; 257A; 257M; 238A; 239K; 248I; 250A; 250F; 250I; 250M; 250Q; 250S; 250V; 250W; 250Y; 252F; 252W; 252Y; 254T; 255E; 256D; 256E; 256Q; 257A; 257M; 238A; 239K; 248I; 250 7G; 257I; 257L; 257M; 257N; 257S; 257T; 257V; 258H; 265A; 270F; 286A; 286E; 289H; 297A; 298G; 303A; 30 5A; 307A; 307D; 307F; 307G; 307H; 307I; 307K; 307L; 307M; 307N; 307P; 307Q; 307R; 307S; 307V; 307W; 307 Y; 308A; 308F; 308I; 308L; 308M; 308P; 308Q; 308T; 309A; 309D; 309E; 309P; 309R; 311A; 311H; 311I; 312 A; 312H; 314K; 314R; 315A; 315H; 317A; 325G; 332V; 334L; 360H; 376A; 378V; 380A; 382A; 384A; 385D; 385 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, where positions are defined according to EU numbering. EU numbering refers to the convention for Fc regions described in Edelman, GM et al., Proc. Natl. Acad. Sci. USA, 63:78-85 (1969); and Kabat et al., in "Sequences of Proteins of Immunological Interest", U. Sept. Health and Human Services, 5th ed., 1991.In some embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein comprises 2, 3, 4, or 5 amino acids selected from: 237M; 238A; 239K; 248I; 250A; 250F; 250I; 250M; 250Q; 250S; 250V; 250W; 250Y; 252F; 252W; 252Y; 254T; 255E; 256D; 256E; 256Q; 257A; 257G; 257 I;257L;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; 308M; 308P; 308Q; 308T; 309A; 309D; 309E; 309P; 309R; 311A; 311H; 311I; 312A; 312H; 3 14K; 314R; 315A; 315H; 317A; 325G; 332V; 334L; 360H; 376A; 378V; 380A; 382A; 384A; 385D; 385H; 386P; 38 and 436F, wherein positions are defined according to EU numbering and any combination thereof is contemplated.

[0211] 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 group consisting of 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 as numbered by the EU index as set forth in Kabat. 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 skilled in the art (see, e.g., U.S. Pat. Nos. 5,624,821; 6,277,375; 6,737,056; PCT Patent Publications WO 01 / 58957; WO 02 / 06919; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752 and WO 05 / 040217, the contents of which are incorporated herein by reference in their entireties).

[0212] In certain embodiments, at least one of the variant Fc domains comprises at least one non-naturally occurring amino acid or comprises at least two non-naturally occurring amino acids 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, 240A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 243W, 243L, 243Y, 243R, 243Q, 244H, 245A, 247V, 247G, 252Y, 254T, 256E, 262I, 262 A, 262T, 262E, 263I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 264R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 265Y, 265F, 265V, 265I, 265 L, 265H, 265T, 266I, 266A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 269R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 296I, 296H, 269G, 29 7S, 297D, 297E, 298H, 298I, 298T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 299F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 325A, 325T, 32 28A, 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 as numbered by the EU index as set forth in Kabat.Optionally, at least one of the variant Fc domains may comprise additional and / or substituted non-naturally occurring amino acid residues known to those skilled in the art (see, e.g., U.S. Pat. Nos. 5,624,821; 6,277,375; 6,737,056; PCT Patent Publications WO 01 / 58957; WO 02 / 06919; WO 04 / 016750; WO 04 / 029207; WO 04 / 035752 and WO 05 / 040217, the contents of which are incorporated herein by reference in their entireties).

[0213] Other known Fc domain variants that can be used in the compositions disclosed herein include, but are not limited to, 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., 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., 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; 6,277,375; U.S. Patent Publication No. 2004 / 0002587 and PCT Publication Nos. WO 94 / 29351; WO 99 / 58572; WO 00 / 42072; WO 02 / 060919; WO 04 / 029207; WO 04 / 099249; WO 04 / 063351, the contents of which are incorporated by reference in their entirety.

[0214] 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 comprising amino acids Y, T, E, K and F located 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 comprising amino acids Y, T, E, K, F and Y located at EU positions 252, 254, 256, 433, 434 and 436, respectively. In one embodiment, the variant Fc region or FcRn binding fragment thereof comprises an 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 an 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.

[0215] In certain embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein comprises a combination of amino acids selected from:

[0216] (i) Q and L at EU positions 250 and 428, respectively;

[0217] (ii) P and A at EU positions 308 and 434, respectively;

[0218] (iii) P and Y at EU positions 308 and 434, respectively; or

[0219] (iv) Y, E and Y at EU positions 252, 286 and 434, respectively.

[0220] In certain embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein comprises at least one amino acid substitution 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; P25 7L; P257M; P257N; P257S; P257T; P257V; E258H; D265A; D270F; N286A; N286E; T289H; N297A; S298G; V303A; V305A; T307A; T 307D; T307F; T307G; T307H; T307I; T307K; T307L; T307M; T307N; T307P; T307Q; T307R; T307S; T307V; T307W; T307Y; V308A ;V308F; V308I; V308L; V308M; V308P; V308Q; V308T; V309A; V309D; V309E; V309P; V309R; Q311A; Q311H; Q311I; D312A; D3 12H; L314K; L314R; N315A; N315H; K317A; N325G; I332V; K334L; K360H; D376A; A378V; E380A; E382A; N384A; G385D; G385H; wherein positions are defined by EU numbering.In some embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein comprises 2, 3, 4, or 5 amino acid substitutions 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; P257 L;P257M;P257N;P257S;P257T;P257V;E258H;D265A;D270F;N286A;N286E;T289H;N297A;S298G;V303A;V305A;T307A;T307 D; T307F; T307G; T307H; T307I; T307K; T307L; T307M; T307N; T307P; T307Q; T307R; T307S; T307V; T307W; T307Y; V308A; V308 F; V308I; V308L; V308M; V308P; V308Q; V308T; V309A; V309D; V309E; V309P; V309R; Q311A; Q311H; Q311I; D312A; D312H; L314 K; L314R; N315A; N315H; K317A; N325G; I332V; K334L; K360H; D376A; A378V; E380A; E382A; N384A; G385D; G385H; Q386P; P387 and Y436F, wherein positions are defined according to EU numbering and wherein any combination of substitutions is contemplated.

[0221] In certain embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein comprises a combination of amino acid substitutions selected from:

[0222] (i) M252Y, S254T, T256E, H433K and N434F;

[0223] (ii) T250Q and M428L;

[0224] (iii) V308P and N434A;

[0225] (iv) V308P and N434Y; or

[0226] (v) M252Y, N286E and N434Y.

[0227] In one embodiment, one, two or more mutations (e.g., amino acid substitutions) are introduced into the hinge region of a polypeptide described herein such that the number of cysteine ​​residues in the hinge region is altered (e.g., increased or decreased), as described in, e.g., 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 can be altered, e.g., to facilitate assembly of light and heavy chains, or to alter (e.g., increase or decrease) the stability of a polypeptide.

[0228] 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 its FcRn binding fragment to change (e.g., reduce or increase) the in vivo half-life of the polypeptide. See, e.g., International Publication No. 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 herein by reference in their entirety as examples of mutations that will change (e.g., reduce or increase) the in vivo half-life of an antibody. In certain embodiments, one, two or more amino acid mutations (e.g., substitutions, insertions or deletions) are introduced into the Fc region, Fc domain or its FcRn binding fragment to reduce the in vivo half-life of a polypeptide. In other embodiments, one, two or more amino acid mutations (e.g., substitutions, insertions or deletions) are introduced into the Fc region, Fc domain or its FcRn binding fragment to increase the in vivo half-life of the antibody. In one embodiment, the Fc region or Fc domain may 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) numbered according to the EU numbering system. In one embodiment, the constant region of the IgG1 of the 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 according to the EU numbering system. See U.S. Patent No. 7,658,921, which is incorporated herein by reference in its entirety. This type of mutant Fc domain (referred to as a "YTE mutant") has been shown to have 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 certain embodiments, the polypeptide comprises an IgG constant region comprising 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 numbered according to the EU numbering system.

[0229] 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., CH2 domain (residues 231-340 of human IgG1) and / or CH3 domain (residues 341-447 of human IgG1 numbered according to the EU numbering system)) and / or hinge region (residues 216-230 numbered according to the EU numbering system) of a polypeptide described herein to increase or decrease the affinity of the antibody for an Fc receptor on the surface of an effector cell (e.g., an activated Fc receptor). 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 the Fc region, Fc domain, or FcRn binding fragment thereof that can be used to alter the affinity of the variant Fc region, or FcRn binding fragment thereof, for an Fc receptor are described in, e.g., Smith P et al., (2012) PNAS 109:6181-6186, U.S. Pat. No. 6,737,056, and International Publication Nos. WO 02 / 060919; WO 98 / 23289; and WO 97 / 34631, all of which are incorporated herein by reference in their entirety.

[0230] In one embodiment, one, two or more amino acid substitutions are introduced into the Fc region, Fc domain or its FcRn binding fragment to change the effector function 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 by different amino acid residues so that the polypeptide has a changed affinity for the effector ligand, but retains the antigen binding ability of the parent antibody. The effector ligand with changed affinity can be, for example, an Fc receptor. This method is described in more 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 can be 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 can 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 may be made in the constant region of a polypeptide described herein: 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, numbered according to the EU numbering system.

[0231] In one embodiment, mutations selected from the group consisting of D265A, P329A and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein. In one embodiment, mutations selected from the group consisting of L235A, L237A and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein. In one embodiment, mutations selected from the group consisting of S267E, L328F and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein. In one embodiment, mutations selected from the group consisting of S239D, I332E, optionally A330L and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein. In one embodiment, mutations selected from the group consisting of L235V, F243L, R292P, Y300L, P396L and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein. In one embodiment, mutations selected from the group consisting of S267E, L328F and combinations thereof numbered according to the EU numbering system can be carried out in the constant region of a polypeptide as described herein.

[0232] In one embodiment, the Fc region, Fc domain or its FcRn binding fragment described herein comprises a constant region of an IgG1 having an N297Q or N297A amino acid substitution numbered according to the EU numbering system. In one embodiment, the Fc region, Fc domain or its FcRn binding fragment described herein comprises a constant region of an IgG1 having a mutation selected from the group consisting of D265A, P329A and combinations thereof numbered according to the EU numbering system. In one embodiment, the Fc region, Fc domain or its FcRn binding fragment described herein comprises a constant region of an IgG1 having a mutation selected from the group consisting of L234A, L235A and combinations thereof numbered according to the EU numbering system. In another embodiment, the Fc region, Fc domain or its FcRn binding fragment described herein comprises a constant region of an IgG1 having a mutation selected from the group consisting of L234F, L235F, N297A and combinations thereof numbered according to the EU numbering system. In one embodiment, the amino acid residues in the constant region of the 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 International Publication No. 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 (numbered according to the EU numbering system) are F, E, and A, respectively; or A, A, and A.

[0233] In one embodiment, according to the EU numbering system, the amino acids at positions 433, 434, and 436 of the heavy chain constant region are K, F, and Y, respectively. In one embodiment, according to the EU numbering system, the amino acids at positions 252, 254, and 256 of the heavy chain constant region are Y, T, and E, respectively. In one embodiment, according to the EU numbering system, the amino acids at positions 428 and 434 of the heavy chain constant region are L and S, respectively. In one embodiment, according to the EU numbering system, the amino acids at positions 309, 311, and 434 of the heavy chain constant region are D, H, and S, respectively.

[0234] 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.

[0235] 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 such that the antibody has altered C1q binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in more 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 to 238 (numbered according to the EU numbering system) in the N-terminal region of the CH2 domain of a polypeptide described herein are altered to alter the ability of the antibody to fix complement. This approach is further described in International Publication No. 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 is modified to increase the ability of the antibody to mediate antibody-dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the polypeptide for an Fc receptor by mutating one or more amino acids (e.g., introducing an amino acid substitution) at the following positions numbered according to the EU numbering system: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 434, 435, 437, 438 or 439. This method is further described in International Publication No. WO 00 / 42072, which is incorporated herein by reference in its entirety.

[0236] In one embodiment, any constant region mutation or modification described herein can be introduced into one or both heavy chain constant regions of a polypeptide with two heavy chain constant regions described herein. In one embodiment, any constant region mutation or modification described herein can be introduced into the heavy chain constant region of a polypeptide with one heavy chain constant region described herein.

[0237] In one embodiment, the present disclosure provides a polypeptide comprising one, two or three binding sites for human FcRn, which polypeptide specifically binds to FcRn and functions as an antagonist.

[0238] 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.

[0239] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region comprises two Fc domains, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3.

[0240] In certain embodiments, the variant Fc region is a heterodimer in which the constituent Fc domains are different from each other. Methods for producing Fc heterodimers are known in the art (see, e.g., US 8,216,805, which is incorporated herein by reference in its entirety). In one embodiment, the FcRn binding molecule is composed of a variant Fc region, wherein the variant Fc region is composed of two Fc domains forming a heterodimer, wherein the amino acid sequence of each of the Fc domains is independently selected from SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3. In one embodiment, the FcRn binding molecule is composed of or comprises a variant Fc region, wherein the variant Fc region is composed of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1, and the amino acid sequence of the second Fc domain comprises or consists of 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, wherein the variant Fc region consists of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of the second Fc domain comprises or consists of 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, wherein the variant Fc region consists of or comprises two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 3, and the amino acid sequence of the second Fc domain comprises or consists of the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0241] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region comprises or consists of two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0242] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0243] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region consists of or comprises two Fc domains forming a homodimer, wherein the amino acid sequence of each of the Fc domains comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0244] In one embodiment, the FcRn binding molecule comprises a variant Fc region, wherein the variant Fc region comprises or consists of agamod (CAS Reg. No. 1821402-21-4). As used herein, the term "agamod" is interchangeable with "agamod α" and "ARGX-113". In some embodiments, agamod is agamod α-fcab.

[0245] In one embodiment, the variant Fc region is modified to promote heterodimerization. Such modifications are known in the art, and any suitable method that promotes heterodimerization can be used to generate FcRn / antigen binding molecules described herein. In some embodiments, the variant Fc region comprises one or more mutations of amino acid residues at the interface of the CH3 domain forming the Fc domain. In some embodiments, the variant Fc region comprises a knob-hole structure mutation (see, e.g., Intl. Publ. WO 2006 / 028936, which is incorporated by reference in its entirety). In this technology, the mispairing of Ig heavy chains is reduced by mutations to form the selected amino acids at the interface of the CH3 domain in IgG. At the position where the two heavy chains directly interact in the CH3 domain, one or more amino acids with a small side chain (hole) are introduced into the sequence of one heavy chain, and one or more amino acids with a large side chain (knob) are introduced into the corresponding interaction residue position on the other heavy chain. The Fc domain of the Fc region can be composed of immunoglobulin chains of the same subclass (eg, IgG1 or IgG3) or of different subclasses (eg, IgG1 and IgG3, or IgG3 and IgG4).

[0246] In some embodiments, the variant Fc region comprises or consists of two Fc domains, wherein one of the Fc domains comprises the amino acid W at EU position 366. In some embodiments, the variant Fc region comprises or consists of two Fc domains, wherein one of the Fc domains 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, wherein one of the Fc domains 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.

[0247] In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises amino acids E and D at EU positions 370 and 409, respectively, and the other comprises amino acid K at EU positions 357 and 399. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises amino acids H and A at EU positions 364 and 405, respectively, and the other comprises 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 of which comprises amino acids V, Y, A, and V at EU positions 350, 351, 405, and 407, respectively, and the other comprises 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 of which comprises amino acids D, M, and A at EU positions 360, 399, and 407, respectively, and the other comprises 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 of which comprises amino acids D at EU positions 409 and 392, and the other comprises amino acids K at EU positions 399 and 356. In some embodiments, the variant Fc region comprises or consists of two Fc domains, one of which comprises amino acids E, W, and C at EU positions 360, 409, and 349, respectively, and the other comprises 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, wherein one Fc domain comprises amino acids E and W at EU positions 370 and 409, respectively, and the other Fc domain comprises amino acids N, V, and T at EU positions 357, 399, and 405, respectively.

[0248] 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 forming a heterodimer, wherein the amino acid sequence of the first Fc domain is selected from the group consisting of amino acid sequences 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 the group consisting of amino acid sequences 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, wherein the variant Fc region comprises or consists of two Fc domains forming a heterodimer, wherein the amino acid sequence of the first Fc domain is selected from the group consisting of amino acid sequences 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 the group consisting of amino acid sequences 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, wherein the variant Fc region comprises or consists of two Fc domains forming 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, wherein the variant Fc region comprises or consists of two Fc domains forming 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 forming a heterodimer, 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.

[0249] Table 1. Amino acid sequences of variant Fc regions

[0250]

[0251]

[0252] 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.

[0253] 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.

[0254] 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.

[0255] In one embodiment, the anti-FcRn antibody is rozanolimab (UCB7665), nicalizumab (M281), onorimumab (ALXN1830 / SYNT001), or bartolimumab (IMVT-1401 / RVT1401 / HBM9161).

[0256] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is nikalimab, also known as M281. Nikalimab is a full-length "Fc dead" IgG1 monoclonal antibody. In Phase 2 / 3 clinical trials for the treatment of myasthenia gravis (MG) and warm autoimmune hemolytic anemia (WAIHA), and in Phase 2 clinical trials for the treatment of fetal and neonatal hemolytic disease (HDFN), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and Sjögren's syndrome (SS), nikalimab has been administered as an intravenous infusion. Nikalimab comprises the light chain (SEQ ID NO: 128) and heavy chain (SEQ ID NO: 129) sequences shown in Table 2 below (VL of SEQ ID NO: 128 and VH of SEQ ID NO: 129 are underlined):

[0257] Table 2. Heavy and light chain sequences of nikalimab

[0258]

[0259] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is rozanolizumab, also known as UCB 7665. Rozanolizumab is a full-length humanized IgG4 monoclonal antibody. In clinical trials for MG, immune thrombocytopenia (ITP), chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune encephalitis (AIE), and myelin oligodendrocyte glycoprotein antibody-related disease (MOG-AD), rozanolizumab has been administered as a subcutaneous infusion. Rozanolizumab comprises the light chain (SEQ ID NO: 130) and heavy chain (SEQ ID NO: 131) sequences shown in Table 3 below (VL of SEQ ID NO: 130 and VH of SEQ ID NO: 131 are underlined):

[0260] Table 3. Heavy and light chain sequences of rozanolimumab

[0261]

[0262] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Onorimab, also known as SYNT001 / ALXN1830. Onorimab is another full-length humanized IgG4 monoclonal antibody. In Phase 2 clinical trials for the treatment of WAIHA and pemphigus, Onorimab has been administered as an intravenous infusion. Onorimab comprises the light chain (SEQ ID NO: 132) and heavy chain (SEQ ID NO: 133) sequences shown in Table 4 below (VL of SEQ ID NO: 132 and VH of SEQ ID NO: 133 are underlined):

[0263] Table 4. Heavy and light chain sequences of Onorimab

[0264]

[0265]

[0266] In one embodiment, the antibody that specifically binds to FcRn and inhibits the binding of the Fc region of an immunoglobulin to FcRn is Bartolimab, also known as IMVT1401 / RVT1401 / HBM9161. Bartolimab is a full-length "Fc-invalid" IgG1 monoclonal antibody. In Phase 2 clinical trials for the treatment of MG, ITP, Graves' ophthalmopathy, thyroid eye disease, and neuromyelitis optica spectrum disorders (NMOSD), Bartolimab has been administered as a subcutaneous injection. Bartolimab comprises the light chain (SEQ ID NO: 134) and heavy chain (SEQ ID NO: 135) sequences shown in Table 5 below (VL of SEQ ID NO: 134 and VH of SEQ ID NO: 135 are underlined):

[0267] Table 5. Heavy and light chain sequences of Batolimumab

[0268]

[0269] Antigen binding domain

[0270] In one aspect, the present disclosure provides antigen binding domains. In some embodiments, the FcRn / antigen binding molecules disclosed herein include one or more FcRn binding molecules combined with one or more antigen binding domains. In some embodiments, the FcRn / antigen binding molecules disclosed herein include one or more Fc regions or FcRn binding fragments thereof combined 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 sdAb (e.g., VHH fragment), Fab fragment, scFv, VH or VL. In some embodiments, the antigen binding domain is a synthetic antigen binding protein or antibody mimetic protein, including but not limited to anticalin or DARPin.

[0271] 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 selected from A, AG, GG and PP added at the C-terminus. In some embodiments, the C-terminus of VHH is the amino acid sequence VTVSS (SEQ ID NO: 91). In some embodiments, the C-terminus of VHH consists of the amino acid sequence VTVSS (SEQ ID NO: 91).

[0272] Antigen binding domains can bind to any antigen. In some embodiments, the antigen is a non-human antigen, for example, a protein or fragment thereof that is not usually expressed by humans and is not usually found in the human body. In some embodiments, a non-human antigen is a protein or fragment thereof that is not usually expressed by humans but can be found in the human body. Examples of non-human antigens that can be found in the human body include proteins or fragments thereof expressed by pathogens, such as bacterial or viral proteins or fragments thereof. Due to infection and / or immunity, these pathogenic proteins or fragments thereof can be found in the human body. Therefore, in some embodiments, the non-human antigens that can be found in the human body are viral antigens. In some embodiments, non-human antigens are non-human antigens that are not found in the human body. Examples of non-human antigens that are not found in the human body include proteins or fragments thereof that are non-pathogenic and have no human counterparts, such as, for example, hen egg lysozyme (HEL) or ovalbumin.

[0273] In some embodiments, the antigen is a human antigen, such as a protein normally expressed by humans or a fragment thereof. In some embodiments, the human antigen is selected from HSA or IgE.

[0274] 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, a 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, such as a VHH fragment. In some embodiments, 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, HSA comprises an amino acid sequence provided in GenBank Accession No.: AAA98797.1.

[0275] In some embodiments, the antigen binding domain is a VHH fragment comprising the following: 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.

[0276] In some embodiments, the antigen binding domain is a VHH fragment comprising or consisting of a combination of CDR1, CDR2, and CDR3, wherein 1, 2, 3, 4, or 5 amino acids differ in at least one of the amino acid sequences selected from: SEQ IDNO: 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 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, 1 14 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;

[0277] In some embodiments, the antigen binding domain is a VHH fragment comprising or consisting of a combination of CDR1, CDR2, and CDR3 selected from the group consisting of: SEQ ID NO: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 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.

[0278] In some embodiments, the antigen binding domain is a VHH fragment comprising or consisting of a combination of CDR1, CDR2, and CDR3 selected from the group consisting of: SEQ ID NO: 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 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, 1 1, 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; 14 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;

[0279] In some embodiments, the antigen binding domain is a VHH fragment comprising or consisting of an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from SEQ ID NOs: 42-74, 84-90 and 120-127. In some embodiments, the antigen binding domain is a VHH fragment comprising or consisting of an amino acid sequence selected from SEQ ID NOs: 42-74, 84-90 and 120-127.

[0280] Connectors

[0281] The antigen binding domain can be connected to the N-terminus or C-terminus of the FcRn binding molecule (e.g., Fc domain). Alternatively, the antigen binding domain can be connected to 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 connected to the C-terminus of the FcRn binding molecule (e.g., Fc domain).

[0282] 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.

[0283] In some embodiments, the antigen binding domain can be directly connected (e.g., fused) to the N-terminus or C-terminus of the FcRn binding molecule. In some embodiments, the antigen binding domain is connected 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.

[0284] In some embodiments, the antigen binding domain can be directly connected (e.g., fused) to the N-terminus or C-terminus of the Fc domain. In some embodiments, the antigen binding domain is connected to the N-terminus or C-terminus of the Fc domain via a joint. In some embodiments, the joint is a non-cleavable joint. As used herein, the term "non-cleavable joint" refers to a joint that is not easily cut by one or more of a given enzyme, chemical agent, or light irradiation. In some embodiments, the enzyme is a protease.

[0285] In some embodiments, the linker is a synthetic compound linker, such as, for example, a chemical cross-linking agent. Non-limiting examples of commercially available suitable cross-linking agents 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-(succinimidyloxycarbonyloxy)ethyl]sulfone (BSOCOES) and bis[2-(sulfosuccinimidyloxycarbonyloxy)ethyl]sulfone (sulfo-BSOCOES).

[0286] As described above, the Fc domain disclosed herein may include a portion of a hinge region. Therefore, the antigen binding domain can be connected to the N-terminus of the Fc domain via the 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, the 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 native 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, such as a human IgG hinge region.

[0287] 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 linking the antigen binding domain to an FcRn binding molecule, such as an Fc domain.

[0288] The peptide linker can be any length. In some embodiments, the length and amino acid composition of the linker peptide sequence can be optimized to change the orientation and / or proximity of the polypeptide domains to each other to achieve the desired activity of the FcRn / antigen binding molecule. In some embodiments, the length of the peptide linker is between about 1 and about 100 amino acids, between about 8 and about 40 amino acids, or between about 15 amino acids and about 25 amino acids. In some embodiments, the length of the peptide linker is between 1 and 100 amino acids, between 8 and 40 amino acids, or between 15 and 25 amino acids. 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 amino acids in length, 9 amino acids in length, 10 amino acids in length, 11 amino acids in length, 12 amino acids in length, 13 amino acids in length, 14 amino acids in length, 15 amino acids in length, 16 amino acids in length, 17 amino acids in length, 18 amino acids in length, 19 amino acids in length, 20 amino acids in length, 21 amino acids in length, 22 amino acids in length, 23 amino acids in length, 24 amino acids in length, 25 amino acids in length, 26 amino acids in length, 27 amino acids in length, 28 amino acids in length, 29 amino acids in length, 30 amino acids in length, 31 amino acids in length, 32 amino acids in length, 33 amino acids in length, 34 amino acids in length, 35 amino acids in length, 36 amino acids in length, 37 amino acids in length, 38 amino acids in length, 39 amino acids in length, or 40 amino acids in length.

[0289] In some embodiments, the peptide linker contains only glycine and / or serine residues (e.g., glycine-serine linker or GS linker). Examples of such peptide linkers include: Gly(x)Ser, wherein x is 0 to 6; or Ser Gly(x), wherein x is 0 to 6; (Gly Gly Gly Gly Ser)n, wherein n is an integer of 1 or greater; and (Ser Gly Gly Gly Gly)n, wherein n is an integer of 1 or greater. In some embodiments, the peptide linker includes an amino acid sequence selected from the group consisting of: (GGGGS)n and (SGGGG)n, wherein n is 1 to 8. In some embodiments, the linker peptide is modified so that the amino acid sequence GSG (which appears at the junction of the traditional Gly / Ser linker peptide repeats) is not present. For example, in some embodiments, the peptide linker includes an amino acid sequence selected from the group consisting of: (GGGXX)nGGGGS and GGGGS(XGGGS)n, wherein X is any amino acid that can be inserted into the sequence and does not produce a polypeptide comprising the sequence GSG, and n is 0 to 4. In some embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, and X1 is P and X2 is S and n is 0 to 4. In some other embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, and X1 is G and X2 is Q and n is 0 to 4. In some other embodiments, the sequence of the linker peptide is (GGGX1X2)nGGGGS, and X1 is G and X2 is A and n is 0 to 4. In yet other embodiments, the sequence of the linker peptide is GGGGS(XGGGS)n, and X is P and n is 0 to 4. In some embodiments, the linker peptide of the present disclosure comprises or consists of the amino acid sequence (GGGGA)2GGGGS. In some embodiments, the linker peptide comprises or consists of the amino acid sequence (GGGGQ)2GGGGS. In another embodiment, the linker peptide comprises or consists of the amino acid sequence (GGGPS)2GGGGS. In another embodiment, the linker peptide comprises the amino acid sequence GGGGS (PGGGS) 2 or consists of it. In yet another embodiment, the linker peptide comprises the amino acid sequence GSGGS or SGGSGS or consists of it. In some embodiments, the linker peptide comprises the amino acid sequence GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 136), GGGGSGGGGS (SEQ ID NO: 181) or GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 182) or consists of it.

[0290] In some embodiments, the peptide linker is a GS linker of about 20 or about 30 amino acids in length. In some embodiments, the peptide linker is a GS linker of 20 or 30 amino acids in length.

[0291] Heavy chain molecule

[0292] In some embodiments, the FcRn / antigen binding molecule may comprise a first heavy chain as described herein. In some embodiments, the first heavy chain comprises an Fc domain and an antigen binding domain connected by a joint. In some embodiments, the FcRn / antigen binding molecule may further comprise a second heavy chain as described herein. In some embodiments, the second heavy chain comprises an Fc domain and an antigen binding domain connected by a joint. In some embodiments, the second heavy chain comprises an Fc domain. In some embodiments, the first heavy chain and the second heavy chain are the same. In some embodiments, the first heavy chain and the second heavy chain are different.

[0293] In some embodiments, the first heavy chain and the second heavy chain have the same Fc domain. In some embodiments, the first heavy chain and the second heavy chain have different Fc domains. In some embodiments, both the first heavy chain and the second heavy chain include an antigen binding domain. In some embodiments, the antigen binding domains on the first heavy chain and the second heavy chain are the same. In some embodiments, the antigen binding domains on the first heavy chain and the second heavy chain are different. In some embodiments, the first heavy chain includes an Fc domain and an antigen binding domain, while the second heavy chain includes Fc but does not include an antigen binding domain. In some embodiments, the first heavy chain includes an Fc domain and an antigen binding domain, while the second heavy chain includes an Fc domain but does not include an antigen binding domain or a joint. In some embodiments, the first heavy chain includes an Fc domain, an antigen binding domain and a joint, while the second heavy chain includes an Fc domain but does not include an antigen binding domain or a joint.

[0294] In some embodiments, the antigen binding domain is attached to the N-terminus of the Fc domain. In some embodiments, the antigen binding domain is attached to the C-terminus of the Fc domain. In some embodiments, the antigen binding domain is attached to a position other than the N-terminus or C-terminus of the Fc domain.

[0295] 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.

[0296] In some embodiments, the antigen binding domain is connected to the N-terminus of the Fc domain via a linker. In some embodiments, the antigen binding domain is connected to the C-terminus of the Fc domain via a linker. In some embodiments, the antigen binding domain is connected to a position other than the N-terminus or C-terminus of the Fc domain via a linker.

[0297] 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.

[0298] 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.

[0299] In some embodiments, the Fc domain comprises the amino acid sequence of any one of SEQ ID NOs: 1-9. In some embodiments, the Fc domain consists of the amino acid sequence of any one of SEQ ID NOs: 1-9.

[0300] In some embodiments, the first heavy chain and the second heavy chain comprise the same Fc domain. In some embodiments, both the first heavy chain and the second heavy chain comprise an Fc domain, which 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 NO: 1-3. In some embodiments, both the first heavy chain and the second heavy chain comprise an Fc domain, which 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 NO: 1-3. In some embodiments, both the first heavy chain and the second heavy chain comprise an Fc domain, which comprises an amino acid sequence of any one of SEQ ID NO: 1-3. In some embodiments, both the first heavy chain and the second heavy chain comprise an Fc domain, which consists of an amino acid sequence of any one of SEQ ID NO: 1-3.

[0301] In some embodiments, the first heavy chain and the second heavy chain 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: 4-6, 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: 7-9. In some embodiments, the first heavy chain comprises an Fc domain comprising an 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 of any one of SEQ ID NOs: 7-9. In some embodiments, when the first heavy chain comprises an Fc domain comprising an 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 an 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 an 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.

[0302] In some embodiments, the first heavy chain and the second heavy chain further comprise a peptide linker. In some embodiments, the first heavy chain and the second heavy chain further comprise the same peptide linker. In some embodiments, the first heavy chain and the second heavy chain 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 chain and the heavy chain can be any peptide linker described herein. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 136, 180 or 181.

[0303] In some embodiments, the FcRn / antigen binding molecule comprises an amino acid sequence selected from Table 6 or a variant thereof.

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311] 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: 137-176 and 180. In some embodiments, the FcRn / antigen binding molecule comprises or consists of an amino acid sequence of any one of SEQ ID NOs: 137-176 and 180.

[0312] In some embodiments, the FcRn / antigen binding molecule comprises the amino acid sequence of any one of SEQ ID NOs: 137-176 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: 137-176 and 180, or a variant thereof, and one or more amino acids selected from A, AG, GG, and PP added at the C-terminus.

[0313] In some embodiments, the first heavy chain of 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: 137-176 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 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.

[0314] 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.

[0315] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 137, 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 the amino acid sequence of SEQ ID NO: 137, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0317] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 138, 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 the amino acid sequence of SEQ ID NO: 138, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0319] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 139, 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 the amino acid sequence of SEQ ID NO: 139, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0321] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 140, 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 the amino acid sequence of SEQ ID NO: 140, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0323] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 141, 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 the amino acid sequence of SEQ ID NO: 141, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0325] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 142, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 142, 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 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0327] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 143, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 143, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0328] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0329] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 144, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 144, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0330] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0331] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 145, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 145, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0332] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0333] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 146, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 146, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0334] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0335] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 147, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 147, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0336] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0337] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 148, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 148, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0338] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0339] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 149, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 149, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0340] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0341] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 150, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 150, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0342] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0343] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 151, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 151, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0344] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0345] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 152, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 152, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0346] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0347] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 153, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 153, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0348] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0349] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 154, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 154, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0350] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0351] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 155, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 155, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0352] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0353] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 156, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 156, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0354] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0355] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 157, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 157, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0356] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0357] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 158, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 158, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0358] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0359] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 159, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 159, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0360] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0361] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 160, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 160, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0362] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0363] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 161, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 161, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0364] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0365] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 162, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 162, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0366] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0367] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 163, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 163, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0368] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0369] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 164, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 164, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0370] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0371] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 165, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 165, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0372] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0373] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 166, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 166, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0374] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0375] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 167, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 167, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0376] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0377] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 168, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 168, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0378] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0379] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 169, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 169, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0380] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0381] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 170, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 170, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0382] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0383] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 171, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 171, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0384] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0385] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 172, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 172, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0386] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0387] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 173, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 173, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0388] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0389] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 174, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 174, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0390] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0391] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 175, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 175, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0392] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0393] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 176, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 176, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0394] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0395] In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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 SEQ ID NO: 180, and the second heavy chain of the FcRn / antigen binding molecule comprises an Fc domain comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. In some embodiments, the first heavy chain of the FcRn / antigen binding molecule 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: 180, and the second heavy chain of the FcRn / antigen binding molecule consists of the amino acid sequence of SEQ ID NO: 8.

[0396] 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 comprising the amino acid sequence of SEQ ID NO: 8, but does not comprise an antigen binding domain. 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.

[0397] In some embodiments, the FcRn / antigen binding molecule comprises an amino acid sequence of any one of SEQ ID NOs: 137-176 and 180 as 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 an amino acid sequence of any one of SEQ ID NOs: 137-176 and 180 as described herein, or a variant thereof, and one or more amino acids selected from A, AG, GG, and PP added at the C-terminus.

[0398] Polynucleotides, vectors and methods of producing

[0399] The present disclosure also provides polynucleotides encoding FcRn / antigen binding molecules disclosed herein or fragments thereof. In some embodiments, polynucleotides encode antigen binding domains of the present disclosure. In some embodiments, polynucleotides encode FcRn binding molecules of the present disclosure. In some embodiments, polynucleotides encode Fc regions of the present disclosure. In some embodiments, polynucleotides encode Fc domains of the present disclosure. In some embodiments, polynucleotides encode one or more of antigen binding domains, FcRn binding molecules and joints. In some embodiments, polynucleotides encode antigen binding domains and FcRn binding molecules, and optionally joints. In some embodiments, polynucleotides encode one or more of antigen binding domains, Fc regions and joints. In some embodiments, polynucleotides encode antigen binding domains and Fc regions, and optionally joints. In some embodiments, polynucleotides encode FcRn / antigen binding molecules comprising one or more antigen binding domains and Fc regions. In some embodiments, polynucleotides encode one or more of antigen binding domains, Fc domains and joints. In some embodiments, polynucleotides encode antigen binding domains and Fc domains, and optionally joints. In some embodiments, the polynucleotides encode an FcRn / antigen binding molecule comprising one or more antigen binding domains and one or more Fc domains. In some embodiments, the polynucleotides encode one or more heavy chains of the disclosure.

[0400] As used herein, "isolated" polynucleotides or nucleic acid molecules are polynucleotides or nucleic acid molecules that are separated from other nucleic acid molecules present in the natural source of nucleic acid molecules (e.g., in mice or humans). In addition, "isolated" nucleic acid molecules, such as cDNA molecules, can be substantially free of other cellular materials or culture media when produced by recombinant technology, or substantially free of chemical precursors or other chemicals when chemically synthesized. For example, the wording "substantially free" includes preparations of polynucleotides or nucleic acid molecules with less than about 15%, 10%, 5%, 2%, 1%, 0.5% or 0.1% (particularly less than about 10%) of other substances (e.g., cellular materials, culture media, other nucleic acid molecules, chemical precursors and / or other chemicals). In one embodiment, the nucleic acid molecules encoding the polypeptides described herein are separated or purified.

[0401] In one aspect, provided herein are polynucleotides comprising a nucleotide sequence encoding an FcRn binding molecule or an FcRn / antigen binding molecule described herein. In another aspect, provided herein are polynucleotides comprising a nucleotide sequence encoding an antigen binding domain described herein. In another aspect, provided herein are polynucleotides comprising a nucleotide sequence encoding an FcRn / antigen binding molecule described herein. In another aspect, provided herein are polynucleotides comprising a nucleotide sequence encoding an FcRn / HSA binding molecule described herein.

[0402] The polynucleotide may include a nucleotide sequence encoding an sdAb (e.g., VHH fragment), a Fab fragment, a scFv, a VH or a VL comprising the FR and CDR of the antigen-binding domain described herein. The polynucleotide may also include a nucleotide sequence encoding an antibody mimetic as described herein. In some embodiments, the polynucleotide may include a nucleotide sequence encoding a VHH fragment, which VHH fragment includes the FR and CDR of the antigen-binding domain described herein. In some embodiments, the polynucleotide may include a nucleotide sequence encoding a light chain comprising a VL FR and CDR of an antigen-binding domain described herein or a nucleotide sequence encoding a heavy chain comprising a VH FR and CDR of an antigen-binding domain described herein and / or an Fc domain as described herein. In one embodiment, the polynucleotide encodes the VH, VL, heavy chain and / or light chain of the antigen-binding domain described herein. In one embodiment, the polynucleotide encodes the first VH and the first VL of the antigen-binding domain described herein. In one embodiment, the polynucleotide encodes the second VH and the second VL of the antigen-binding domain described herein. In one embodiment, the polynucleotide encodes the first heavy chain and the first light chain of the 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 a VH and / or VL, or a heavy chain and / or a light chain of an antigen binding domain described herein.

[0403] In some embodiments, the polynucleotide may include a nucleotide sequence encoding a first heavy chain as described herein. In some embodiments, the first heavy chain includes an Fc domain and an antigen binding domain connected by a joint. In some embodiments, the polynucleotide may include a nucleotide sequence encoding a second heavy chain as described herein. In some embodiments, the second heavy chain includes an Fc domain and an antigen binding domain connected by a joint. In some embodiments, the first heavy chain and the second heavy chain are the same. In some embodiments, the first heavy chain and the second heavy chain are different.

[0404] In some embodiments, the first heavy chain and the second heavy chain have the same Fc domain. In some embodiments, the first heavy chain and the second heavy chain have different Fc domains. In some embodiments, both the first heavy chain and the second heavy chain include an antigen binding domain. In some embodiments, the antigen binding domains on the first heavy chain and the second heavy chain are the same. In some embodiments, the antigen binding domains on the first heavy chain and the second heavy chain are different. In some embodiments, the second heavy chain includes an Fc domain but does not include an antigen binding domain, and the first heavy chain includes an Fc domain and an antigen binding domain. In some embodiments, the second heavy chain includes an Fc domain but does not include an antigen binding domain or a joint, and the first heavy chain includes an Fc domain and an antigen binding domain. In some embodiments, the second heavy chain includes an Fc domain but does not include an antigen binding domain or a joint, and the first heavy chain includes an Fc domain and an antigen binding domain and a joint.

[0405] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding 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: 1-9. In some embodiments, the polynucleotide consists of a nucleotide sequence encoding 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: 1-9.

[0406] 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: 1-9. 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: 1-9.

[0407] 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 contained in different nucleic acid molecules. In some embodiments, the first nucleotide sequence and the second nucleotide sequence are contained in the same nucleic acid molecule.

[0408] In some embodiments, the first nucleotide sequence and the second nucleotide sequence encode the same Fc domain. In some embodiments, both the first nucleotide sequence and the second nucleotide sequence encode an Fc domain, which 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 NO: 1-3. In some embodiments, both the first nucleotide sequence and the second nucleotide sequence encode an Fc domain, which 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 NO: 1-3. In some embodiments, both the first nucleotide sequence and the second nucleotide sequence encode an Fc domain comprising an amino acid sequence of any one of SEQ ID NO: 1-3. In some embodiments, both the first nucleotide sequence and the second nucleotide sequence encode an Fc domain consisting of an amino acid sequence of any one of SEQ ID NO: 1-3.

[0409] In some embodiments, the first nucleotide sequence and the second nucleotide sequence 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: 4-6, 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: 7-9. In some embodiments, the first nucleotide sequence encodes an Fc domain comprising an 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 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 of any one of SEQ ID NOs: 4-6, and the second nucleotide sequence encodes an Fc domain consisting of an amino acid sequence of any one of SEQ ID NOs: 7-9. 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.

[0410] In some embodiments, the first nucleotide sequence and the second nucleotide sequence also encode antigen binding domains. In some embodiments, the first nucleotide sequence and the second nucleotide sequence encode the same antigen binding domains. In some embodiments, the first nucleotide sequence and the second nucleotide sequence encode different antigen binding domains. In some embodiments, the first nucleotide sequence encodes the Fc domain and the antigen binding domain, and the second nucleotide sequence encodes the Fc domain but does not encode the antigen binding domain. The antigen binding domain encoded by the first nucleotide sequence and / or the second nucleotide sequence can be any antigen binding domain described herein.

[0411] In some embodiments, the first nucleotide sequence and the second nucleotide sequence also encode a peptide joint. In some embodiments, the first nucleotide sequence and the second nucleotide sequence encode the same peptide joint. In some embodiments, the first nucleotide sequence and the second nucleotide sequence encode different peptide joints. In some embodiments, the first nucleotide sequence encodes an Fc domain, a peptide joint and an antigen-binding domain, and the second nucleotide sequence encodes an Fc domain but does not encode a peptide joint or an antigen-binding domain. In some embodiments, the first nucleotide sequence encodes an antigen-binding domain, a peptide joint and an Fc domain, and the second nucleotide sequence encodes an Fc domain but does not encode a peptide joint or an antigen-binding domain. The peptide joint encoded by the first nucleotide sequence and / or the second nucleotide sequence can be any peptide joint as described herein. In some embodiments, the joint comprises an amino acid sequence of SEQ ID NO:136, 181 or 182.

[0412] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding 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.

[0413] In some embodiments, the polynucleotide comprises a nucleotide sequence encoding a protein comprising or consisting of the amino acid sequence of any one of SEQ ID NOs: 137-176 and 180.

[0414] In some embodiments, the first nucleotide sequence 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, 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 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.

[0415] 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.

[0416] Also provided herein is a polynucleotide encoding a polypeptide as provided above, which is optimized, for example, by codon / RNA optimization, replacement with a heterologous signal sequence and elimination of mRNA instability elements. The method for generating an optimized nucleic acid for recombinant expression by introducing codon changes and / or eliminating the inhibitory zone in mRNA can be performed by adjusting accordingly, for example, U.S. Patent Nos. 5,965,726; 6,174,666; 6,291,664; 6,414,132; and the optimization method described in 6,794,498, all of which are incorporated herein by reference in their entirety. For example, potential splicing sites and unstable elements (e.g., elements rich in A / T or A / U) in 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. These changes utilize the degeneracy of the genetic code, for example, using alternative codons of the same amino acid. In one embodiment, one or more codons may need to be changed to encode conservative mutations, for example, similar amino acids with chemical structures and properties and / or functions similar to the original amino acids.

[0417] Polynucleotides can be obtained by any method known in the art, and the nucleotide sequence of the polynucleotides is determined. The nucleotide sequence encoding the protein described herein and the modified form of these antibodies can be determined using methods well known in the art, i.e., the nucleotide codons known to encode specific amino acids are assembled in a manner to generate nucleic acids encoding proteins. 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), in short, it involves synthesizing overlapping oligonucleotides containing sequence portions encoding antibodies, annealing and connection of these oligonucleotides, and then amplifying the connected oligonucleotides by PCR.

[0418] Alternatively, polynucleotides encoding proteins described herein can be generated from nucleic acids from suitable sources (e.g., hybridomas) using methods well known in the art (e.g., PCR and other molecular cloning methods). For example, PCR amplification using synthetic primers that hybridize to the 3' and 5' ends of known sequences can be performed using genomic DNA obtained from hybridoma cells that produce a polypeptide of interest. Such PCR amplification methods can be used to obtain nucleic acids comprising sequences encoding polypeptides. Amplified nucleic acids can be cloned into vectors for expression in host cells and for further cloning.

[0419] If a clone containing a nucleic acid encoding a particular polypeptide is not available, but the sequence of the polypeptide is known, the nucleic acid encoding the polypeptide can be chemically synthesized or obtained from a suitable source (e.g., a cDNA library generated from nucleic acid (preferably poly A+RNA) isolated from any tissue or cell expressing the polypeptides described herein) by PCR amplification using synthetic primers that hybridize to the 3' and 5' ends of the sequence, or by cloning using oligonucleotide probes specific for a particular gene sequence to identify, for example, cDNA clones from a cDNA library encoding the polypeptide. The amplified nucleic acid generated by PCR can then be cloned into a replicable cloning vector using any method well known in the art.

[0420] DNA encoding the proteins described herein can be readily isolated and sequenced using conventional methods. Hybridoma cells can serve as a source of such DNA. Once isolated, the DNA can be placed in an expression vector, which is then transfected into a host cell, such as an E. coli cell, a simian COS cell, a Chinese hamster ovary (CHO) cell (e.g., from a CHO GS System TM (Lonza) CHO cells) or myeloma cells that do not otherwise produce the proteins described herein.

[0421] Also provided are polynucleotides that hybridize under high stringency, medium or lower stringency hybridization conditions to a polynucleotide encoding a protein described herein.

[0422] Hybridization conditions have been described in the art and are known to those skilled in the art. For example, hybridization under stringent conditions may include DNA hybridization bound to a filter in 6x sodium chloride / sodium citrate (SSC) at about 45°C, followed by one or more washes in 0.2xSSC / 0.1% SDS at about 50°C-65°C; hybridization under highly stringent conditions may involve nucleic acid hybridization bound to a filter in 6xSSC at about 45°C, followed by one or more washes in 0.1xSSC / 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, see, 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, pp. 6.3.1-6.3.6 and 2.10.3, which are incorporated herein by reference in their entirety.

[0423] In one aspect, cells (e.g., host cells) expressing (e.g., recombinantly) proteins described herein are provided herein, as well as related polynucleotides and expression vectors. Vectors (e.g., expression vectors) comprising polynucleotides are provided herein, which comprise nucleotide sequences encoding proteins described herein for recombinant expression in host cells, preferably mammalian cells (e.g., CHO cells). Host cells comprising such vectors for recombinantly expressing proteins described herein are also provided herein. In one aspect, methods for producing proteins described herein are provided herein, comprising expressing polypeptides from host cells.

[0424] The recombinant expression of proteins described herein generally involves constructing an expression vector containing a polynucleotide encoding a polypeptide. Once a polynucleotide encoding a polypeptide described herein is obtained, a vector for producing a polypeptide can be produced by recombinant DNA technology using techniques well known in the art. Therefore, a method for preparing a protein by expressing a polynucleotide containing a polypeptide encoding nucleotide sequence is 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 transcription and translation control signals. These methods include, for example, in vitro recombinant DNA technology, synthetic technology, and in vivo gene recombination. A replicable vector is also provided, which comprises a nucleotide sequence encoding a polypeptide described herein that is operably linked to a promoter. Such vectors may, for example, include a nucleotide sequence encoding a first heavy chain of the present disclosure (see, for example, International Publication Nos. WO 86 / 05807 and WO 89 / 01036; and U.S. Patent No. 5,122,464, which are incorporated herein by reference in their entirety), and the second heavy chain of the present disclosure may be cloned into this vector for expressing the first heavy chain, the second heavy chain, or both the first heavy chain and the second heavy chain.

[0425] In one embodiment, the vector comprises a polynucleotide encoding a sdAb, a Fab fragment, a scFv, a VHH fragment, a VH, a VL, a heavy chain and / or a light chain of a polypeptide described herein. In another embodiment, the vector comprises a polynucleotide encoding a VH and a VL of a polypeptide described herein. In another embodiment, the vector comprises a polynucleotide encoding a heavy chain and a light chain of a polypeptide described herein.

[0426] The expression vector can be transferred to a cell (e.g., a host cell) by conventional techniques, and the resulting cell can then be cultured by conventional techniques to produce a polypeptide or fragment thereof as described herein. Therefore, provided herein is a host cell containing a polynucleotide encoding a polypeptide or fragment thereof as described herein, or a heavy chain or light chain thereof, or a fragment thereof, or a single-chain antibody as described herein, the polynucleotide being operably linked to a promoter for expressing such sequences in a host cell.

[0427] In one embodiment, the host cell comprises a polynucleotide containing one of the first nucleotide sequences and one of the second nucleotide sequences described above. In another embodiment, the host cell comprises a first polynucleotide containing one of the first nucleotide sequences described above and a second polynucleotide containing one of the first nucleotide sequences described above. In another embodiment, the host cell comprises a first vector containing one of the first nucleotide sequences described above and one of the second nucleotide sequences. In another embodiment, the host cell comprises a first vector containing one of the first nucleotide sequences described above and one of the second nucleotide sequences, and a second vector containing a second polynucleotide, the second polynucleotide comprising one of the first nucleotide sequences described above.

[0428] In some embodiments, the FcRn / antigen binding molecule expressed by the first host cell associates with the FcRn / antigen binding molecule expressed by the second host cell to form a two-armed FcRn / antigen binding molecule. In some embodiments, the FcRn / antigen binding molecule expressed by the first host cell associates with the FcRn binding molecule expressed by the second host cell to form a single-armed FcRn / antigen binding molecule. In some embodiments, provided herein is a host cell population comprising such a first host cell and such a second host cell.

[0429] In some embodiments, provided herein are vector populations comprising a first vector and a second vector, the first vector comprising a polynucleotide encoding an FcRn / antigen binding molecule, and the second vector comprising a polynucleotide encoding an FcRn / antigen binding molecule. In some embodiments, provided herein are vector populations comprising a first vector and a second vector, the first vector comprising a polynucleotide encoding an FcRn / antigen binding molecule, and the second vector comprising a polynucleotide encoding an FcRn binding molecule. In some embodiments, provided herein are vector populations comprising a first vector, the first vector comprising a polynucleotide encoding an FcRn / antigen binding molecule and a polynucleotide encoding an FcRn / antigen binding molecule. In some embodiments, provided herein are vector populations comprising a first vector, the first vector comprising a polynucleotide encoding two FcRn / antigen binding molecules.

[0430] 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 vehicles by which the coding sequences of interest can be produced and subsequently purified, but also represent cells that can express the polypeptides described herein in situ when transformed or transfected with the appropriate nucleotide coding sequences. These include, but are not limited to, microorganisms such as bacteria (e.g., Escherichia coli and Bacillus subtilis) transformed with, for example, recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing FcRn / antigen binding molecule coding sequences; yeast (e.g., Saccharomyces and Pichia) transformed with, for example, recombinant yeast expression vectors containing FcRn / antigen binding molecule coding sequences; insect cell systems infected with, for example, recombinant virus expression vectors (e.g., baculovirus) containing FcRn / antigen binding molecule coding sequences; plant cell systems (e.g., green algae, such as Chlamydomonas reinhardtii) infected with, for example, recombinant virus expression vectors (e.g., cauliflower mosaic virus CaMV; tobacco mosaic virus TMV) or transformed with, for example, recombinant plasmid expression vectors (e.g., Ti plasmid) containing FcRn / antigen binding molecule coding sequences; or mammalian cell systems (e.g., COS (e.g., COS1 or COS), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7030, HsS78Bst, HeLa, NIH 3T3, HEK-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20 and BMT10 cells), which contain, for example, a recombinant expression construct containing a promoter derived from the genome of a mammalian cell (e.g., a metallothionein promoter) or a promoter derived from a mammalian virus (e.g., adenovirus late promoter; vaccinia virus 7.5K promoter). In one embodiment, the cells used to express the FcRn / antigen binding molecules described herein are Chinese hamster ovary (CHO) cells, such as those from the CHO GS System TM In one embodiment, the heavy chain and / or light chain produced by the CHO cells may have an N-terminal glutamine or glutamic acid residue replaced by pyroglutamic acid. In one embodiment, the cells used to express the polypeptides described herein are human cells, such as human cell lines. In one embodiment, the mammalian expression vector is pOptiVEC TMOr pcDNA3.3. In one embodiment, bacterial cells such as Escherichia coli or eukaryotic cells (e.g., mammalian cells) are used to express recombinant polypeptides. For example, mammalian cells such as CHO cells, combined with vectors such as major intermediate early gene promoter elements from human cytomegalovirus, are effective expression systems for antibodies (Foecking MK and 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, the expression of the nucleotide sequence encoding the polypeptides comprising two, three or four binding sites for human FcRn described herein is regulated by a constitutive promoter, an inducible promoter or a tissue-specific promoter.

[0431] In bacterial systems, many expression vectors can be advantageously selected according to the intended use of the molecule to be expressed. For example, when a large number of such polypeptides are to be produced, in order to produce a pharmaceutical composition of an antibody molecule, it may be necessary to instruct a carrier for the high-level expression of a fusion protein product that is easily purified. Such carriers include, but are not limited to, the E. coli expression vector pUR278 (Ruether U and Mueller-Hill B (1983) EMBO J 2: 1791-1794), in which the coding sequence can be individually connected to a carrier in a framework with a lac Z coding region, thereby producing a fusion protein; pIN vectors (Inouye S and Inouye M (1985) Nuc Acids Res 13: 3101-3109; Van Heeke G and Schuster SM (1989) J Biol Chem 24: 5503-5509); etc., all of which are incorporated herein by reference in their entirety. For example, pGEX vectors can also be used to express exogenous polypeptides as fusion proteins with glutathione 5-transferase (GST). In general, 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 include thrombin or factor Xa protease cleavage sites so that the cloned target gene product can be released from the GST moiety.

[0432] For example, in insect systems, Autographa californica nuclear polyhedrosis virus (AcNPV) can be used as a vector for expressing foreign genes. The virus grows in Spodoptera frugiperda cells. The coding sequence can be cloned individually into a non-essential region of the virus (e.g., a polyhedrin gene) and placed under the control of an AcNPV promoter (e.g., a polyhedrin promoter).

[0433] In mammalian host cells, many virus-based expression systems can be used. In the case of using adenovirus as an expression vector, the coding sequence of interest can be connected to an adenovirus transcription / translation control complex, for example, a late promoter and a tripartite leader sequence. The chimeric gene can then be inserted into the adenovirus genome by in vitro or in vivo recombination. Insertion in a non-essential region of the viral genome (e.g., E1 region or E3 region) will produce a recombinant virus that is viable and capable of expressing the molecule in an infected host (see, e.g., Logan J and Shenk T (1984) PNAS 81 (12): 3655-9, which is incorporated herein by reference in its entirety). The effective translation of the inserted coding sequence may also require a specific start signal. These signals include an ATG start codon and adjacent sequences. In addition, the start codon must be in phase with the reading frame of the desired coding sequence to ensure translation of the entire insert. These exogenous translation control signals and start codons can have a variety of sources, including natural and synthetic. Expression efficiency may be enhanced by the inclusion of appropriate transcription enhancer elements, transcription terminators, and the like (see, e.g., Bitter G et al., (1987) Methods Enzymol. 153:516-544, which is incorporated herein by reference in its entirety).

[0434] In addition, host cell strains can be selected that regulate the expression of inserted sequences or modify and process gene products in a desired specific manner. 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 characteristics and specific mechanisms for post-translational processing and modification of proteins and gene products. Suitable cell lines or host systems can be selected to ensure the correct modification and processing of the expressed foreign proteins. For this reason, eukaryotic host cells with cellular machinery for appropriate processing of primary transcripts, glycosylation and phosphorylation of gene products can 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, BT20 and T47D, NS0 (a murine myeloma cell line that does not endogenously produce any immunoglobulin chains), CRL7030, 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 such as CHO cells.

[0435] In one embodiment, the polypeptides described herein comprise a portion of an antibody having reduced fucose content or no fucose content. Such proteins can be produced using techniques known to those skilled in the art. For example, the protein can be expressed in cells lacking or lacking fucosylation ability. In one example, a cell line with two alleles of α1,6-fucosyltransferase knocked out can be used to produce antibodies with reduced fucose content. The ANTIBODYNAMIC® system (Lonza) is an example of such a system that can be used to generate antibodies with reduced fucose content.

[0436] 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, cells provided herein stably express antigen binding domains, FcRn / antigen binding molecules or FcRn binding molecules that associate to form single-arm or double-arm polypeptides described herein.

[0437] In some aspects, instead of using an expression vector containing a viral origin of replication, a host cell can be transformed with a DNA and a selectable marker controlled by appropriate expression control elements (e.g., promoters, enhancers, sequences, transcription terminators, polyadenylation sites, etc.). After introducing foreign DNA / polynucleotides, the engineered cell can be allowed to grow in an enriched medium for one to two days, and then switched to a selective medium. The selectable marker in the recombinant plasmid confers resistance to selection, and allows cells to stably integrate the plasmid into their chromosome and grow to form a focus, which can then be cloned and expanded into a cell line. The method can be advantageously used in a cell line of engineered expression polypeptides comprising two, three or four binding sites or fragments thereof for human FcRn as described herein. This type of engineered cell line can be particularly useful for screening and evaluating compositions that interact directly or indirectly with polypeptides.

[0438] A number of selection systems can be used, including but not limited to the herpes simplex virus thymidine kinase (Wigler M et al., (1977) Cell 11(1):223-32), hypoxanthine guanine phosphoribosyltransferase (Szybalska EH and Szybalski W (1962) PNAS 48(12):2026-2034), and adenine phosphoribosyltransferase (Lowy I et al., (1980) Cell 22(3):817-23) genes in tk cells, hgprt cells, or aprt cells, respectively, all of which are incorporated herein by reference in their entirety. In addition, antimetabolite resistance can be used as the basis for selection for 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 and Berg P (1981) PNAS 78(4):2072-6); neo, which confers resistance to the aminoglycoside G-418 (Wu GY and 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 and Anderson WF (1993) Ann Rev Biochem 62: 191-217; Nabel GJ and 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 entirety.Methods well known in the art 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 in Chapters 12 and 13, Dracopoli NC et al. (eds.), Current Protocols in Human Genetics, John Wiley & Sons, NY (1994); Colbère-Garapin F et al., (1981) J Mol Biol 150:1-14, all of which are incorporated herein by reference in their entirety.

[0439] The expression level of the polypeptide can be increased by vector amplification (for review, see, Bebbington CR and Hentschel CCG, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, pp. 163-188 in DNA Cloning, Vol. III, A Practical Approach. DM 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 will increase the copy number of the marker gene. Since the amplified region is associated with the gene of interest, the yield of the polypeptide will also increase (Crouse GF et al., (1983) Mol Cell Biol 3: 257-66, which is incorporated herein by reference in its entirety).

[0440] Host cells can be co-transfected with two or more expression vectors described herein. The two vectors can contain the same selectable marker, which enables polypeptides (such as the first heavy chain and the second heavy chain polypeptide) to be expressed equally. Host cells can be co-transfected with two or more expression vectors of different amounts. For example, host cells can be transfected with the first expression vector and the second expression vector of any one of the following ratios: about 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.

[0441] Alternatively, a single vector encoding and capable of expressing two polypeptides can be used. The coding sequence can include cDNA or genomic DNA. The expression vector can be a monocistronic or polycistronic. The polycistronic nucleic acid construct can encode 2, 3, 4, 5, 6, 7, 8, 9, 10 or more genes / nucleotide sequences, or in the range of 2-5, 5-10 or 10-20 genes / nucleotide sequences. For example, a bicistronic nucleic acid construct can include a promoter, a first gene and a second gene in the following order. In this expression vector, the transcription of the two genes can be driven by the promoter, and the translation of the mRNA from the first gene can be carried out by a cap-dependent scanning mechanism, and the translation of the mRNA from the second gene can be carried out by a cap-independent mechanism, for example, by IRES.

[0442] Once a polypeptide described herein is produced by recombinant expression, it can be purified by any method known in the art for purifying proteins, such as by chromatography (e.g., ion exchange, affinity, particularly by affinity for a specific antigen after protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for purifying proteins. In addition, the polypeptides described herein can be fused to heterologous polypeptide sequences described herein or known in the art to facilitate purification.

[0443] In one embodiment, polypeptides described herein are separated or purified. In one embodiment, separated polypeptides are polypeptides that are substantially free of other polypeptides having different antigenic specificities from the separated polypeptides. For example, in certain embodiments, protein preparations described herein are substantially free of cellular material and / or chemical precursors. The wording "substantially free of cellular material" includes polypeptide preparations in which the polypeptide is separated from the cellular components of the cell that separates or recombinantly produces the polypeptide. Therefore, polypeptides substantially free of cellular material include polypeptide preparations with 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 polypeptide variants (e.g., different post-translational modified forms of polypeptides or other different versions of polypeptides (e.g., polypeptide fragments)). When the polypeptide is recombinantly produced, it is also generally substantially free of culture medium, i.e., culture medium accounts for less than about 20%, 10%, 2%, 1%, 0.5% or 0.1% of the volume of the protein preparation. When a polypeptide is produced by chemical synthesis, it is generally substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals involved in protein synthesis. Thus, such protein preparations 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 polypeptide described herein is isolated or purified.

[0444] The polypeptides described herein can be produced by any method known in the art for synthesizing proteins, such as by chemical synthesis or by recombinant expression techniques. Unless otherwise indicated, the methods described herein employ conventional techniques in molecular biology, microbiology, genetic analysis, recombinant DNA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization, and related fields within the skill of the art. For example, these techniques are described in the references cited herein and are fully explained in the literature. See, e.g., 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, 2nd ed., 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 annual updates); Current Protocols in Immunology, John Wiley & Sons (1987 and annual updates); Gait (ed.) (1984) Oligonucleotide Synthesis: A Practical Approach, IRL Press; Eckstein (ed.) (1991) Oligonucleotides and Analogues: A Practical Approach, IRL Press; Birren et al., Current Protocols in Molecular Biology, John Wiley & Sons (1987 and annual updates); B et al. (eds.) (1999) Genome Analysis: A Laboratory Manual, Cold Spring Harbor Laboratory Press, all of which are incorporated herein by reference in their entirety.

[0445] In one embodiment, the polypeptides described herein are prepared, expressed, produced or isolated by any means involving production, e.g., via synthesis of a DNA sequence, genetic engineering. In one embodiment, such polypeptides comprise sequences (e.g., DNA sequences or amino acid sequences) that are not naturally present in the antibody germline repertoire in an animal or mammal (e.g., human).

[0446] Pharmaceutical composition

[0447] On the one hand, the present disclosure provides a pharmaceutical composition comprising the FcRn / antigen binding molecules disclosed herein, which are used in the method for treating antibody-mediated diseases (e.g., autoantibody-mediated diseases). In certain embodiments, these compositions comprise FcRn / antigen binding molecules, which comprise FcRn binding molecules and antigen binding domains. In some embodiments, the FcRn binding molecules are FcRn antagonists. In some embodiments, the FcRn antagonists comprise variant Fc regions or their FcRn binding fragments that inhibit the binding of the Fc region of an immunoglobulin to FcRn or are composed thereof. In general, these FcRn antagonists inhibit the binding of agents (e.g., antibodies and immunoadhesins) containing Fc to FcRn in vivo, which results in an increase in the degradation rate of agents containing Fc and a decrease in the serum levels of these agents.

[0448] In some embodiments, the FcRn / antigen binding molecules of the present disclosure have a molecular weight ranging from about 50kDa (which is about one-third of the molecular weight of a full-length IgG (MW about 150kDa)) to about 140kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of about 60kDa to about 104kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of 60kDa to 104kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of about 60kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of about 104kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of 60kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of 104kDa. In some embodiments, the FcRn / antigen binding molecules have a molecular weight of 104kDa.

[0449] In some embodiments, the FcRn / antigen binding molecules of the present disclosure have a predicted molecular weight ranging from about 50kDa (which is about one-third of the molecular weight of a full-length IgG (MW about 150kDa)) to about 140kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of about 60kDa to about 104kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of 60kDa to 104kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of about 60kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of about 104kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of 60kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of 104kDa. In some embodiments, the FcRn / antigen binding molecules have a predicted molecular weight of 104kDa.

[0450] The formulations disclosed herein include bulk pharmaceutical compositions that can be used to make pharmaceutical compositions (e.g., compositions suitable for administration to subjects or patients), which can be used to prepare unit dosage forms. In one embodiment, the composition of the invention is a pharmaceutical composition. Such compositions comprise a preventive or therapeutically effective amount of one or more of the present invention's preventive or therapeutic agents (e.g., FcRn / antigen binding molecules) (or other preventive or therapeutic agents) and a pharmaceutically acceptable carrier.

[0451] In some embodiments, the pharmaceutical compositions are formulated for administration to a subject by any suitable route of administration, including but not limited to intramuscular, intravenous, intradermal, intraperitoneal, subcutaneous, epidural, nasal, oral, rectal, topical, inhaled, buccal (e.g., sublingual), and transdermal administration. In one embodiment, the pharmaceutical compositions are formulated to be suitable for intravenous administration to a subject. In one embodiment, the pharmaceutical compositions are formulated to be suitable for subcutaneous administration to a subject.

[0452] Treatment

[0453] The present disclosure also provides a method for treating an antibody-mediated disorder (eg, 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.

[0454] In some embodiments, the antibody-mediated disorder is an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of: allogeneic pancreatic islet transplant rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, anti-neutrophil cytoplasmic autoantibodies (ANCA), adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia or primary immune thrombocytopenia), autoimmune urticaria, Behcet's disease, bullous Pemphigus (BP), cardiomyopathy, Castleman's disease, celiac sprue, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Chargar-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII 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, atrophic lichen sclerosus, lupus erythematosus, lupus nephritis, Meniere's disease, mixed connective tissue disease, mucous membrane pemphigoid, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), myositis, paraneoplastic bullous pemphigoid, pemphigoid gestationis, pemphigus 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, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, solid organ transplant rejection, stiff-person 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.

[0455] In one embodiment, the FcRn / antigen binding molecule antagonizes the binding of FcRn to the Fc region of an antibody. In one embodiment, the FcRn / antigen binding molecule does not antagonize the binding of FcRn to albumin.

[0456] The present disclosure provides a method for reducing serum IgG in a subject, the method comprising administering to a subject a therapeutically effective amount of FcRn / antigen binding molecules according to the present disclosure or a pharmaceutical composition comprising the same. In one embodiment, after administering FcRn / antigen binding molecules, at least one of the IgG subtypes in the subject is reduced. In certain embodiments, IgG1, IgG2, IgG3, IgG4, or any combination thereof is reduced. In certain embodiments, the administration of FcRn / antigen binding molecules is a single administration (e.g., a single therapeutic administration) of FcRn / antigen binding molecules. In one embodiment, after administering FcRn / antigen binding molecules, the level of serum IgG in the subject is reduced compared to the baseline level of serum IgG.

[0457] In one embodiment, at least about 40% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 45% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 50% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 55% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 60% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 65%, about 70%, about 75% or about 80% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 65% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 70% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 75% reduction in total serum IgG is obtained compared to baseline serum IgG levels. In one embodiment, at least about 80% reduction in total serum IgG is obtained compared to baseline serum IgG levels.

[0458] In one embodiment, after administration of the FcRn / antigen binding molecule, the level of serum IgG in the subject is reduced compared to the baseline level of serum IgG. In one embodiment, a total serum IgG reduction of about 40% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 45% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 50% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 55% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 60% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 65%, about 70%, about 75% or about 80% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 65% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 70% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 75% is obtained compared to the baseline serum IgG level. In one embodiment, a total serum IgG reduction of about 80% is obtained compared to the baseline serum IgG level.

[0459] In one embodiment, after administration of the FcRn / antigen binding molecule, the level of FcRn in the subject is not reduced compared to the baseline level of FcRn. In one embodiment, a reduction of less than about 1%, 2%, 3%, 4% or 5% in FcRn is observed compared to the baseline FcRn level. In one embodiment, a reduction of less than about 10% in FcRn is observed compared to the baseline FcRn level.

[0460] In one embodiment, after administration of the FcRn / antigen binding molecule, the level of albumin in the subject is not reduced compared to the baseline level of albumin. In one embodiment, a reduction in albumin of less than about 1%, 2%, 3%, 4% or 5% compared to the baseline albumin level is observed. In one embodiment, a reduction in albumin of less than about 10% compared to the baseline albumin level is observed.

[0461] In one embodiment, the total IgG, FcRn / antigen binding molecules, FcRn or albumin in the serum sample of the patient are analyzed using a bioanalysis method. In one embodiment, the total IgG, FcRn / antigen binding molecules, FcRn or albumin in the serum sample of the patient are analyzed using ELISA or an automatic diagnostic analyzer (IVD). In one embodiment, the total IgG, FcRn / antigen binding molecules, FcRn or albumin in the serum sample of the patient are analyzed using ELISA. In one embodiment, the total IgG, FcRn / antigen binding molecules, FcRn or albumin in the serum sample of the patient are analyzed using an automatic diagnostic analyzer (IVD). In one embodiment, the total FcRn in the blood sample of the patient is analyzed using a bioanalysis method, preferably flow cytometry, microscopy or immunoblotting.

[0462] 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 rate (CL) of total serum IgG.

[0463] In some embodiments, after administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is increased. In some embodiments, after a single therapeutic administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is comparable to the clearance rate of total serum IgG in the subject after a single therapeutic administration of agamod. In some embodiments, after a single therapeutic administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is similar or identical to the clearance rate of total serum IgG in the subject after a single therapeutic administration of agamod. In some embodiments, after a single therapeutic administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is increased compared to the clearance rate of total serum IgG after a single therapeutic administration of agamod. In some embodiments, after a single therapeutic administration of the FcRn / antigen binding molecule, the clearance of total serum IgG in the 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% compared to the clearance of total serum IgG after a single therapeutic administration of igamod.

[0464] In some embodiments, after a single administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is comparable to the clearance rate of total serum IgG in the subject after a single administration of an equal amount of agamod. In some embodiments, after a single administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is similar or identical to the clearance rate of total serum IgG in the subject after a single administration of an equal amount of agamod. In some embodiments, after a single administration of FcRn / antigen binding molecules, the clearance rate of total serum IgG in the subject is increased compared to the clearance rate of total serum IgG after a single administration of an equal amount of agamod. In some embodiments, after a single administration of the FcRn / antigen binding molecule, 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% compared to the clearance of total serum IgG after a single administration of an equivalent amount of igamod.

[0465] In some embodiments, after a single therapeutic administration of the FcRn / antigen binding molecule, the clearance rate of the FcRn / antigen binding molecule in the subject is reduced compared to the clearance rate of igatimod after a single therapeutic administration of igatimod. In some embodiments, after a single therapeutic administration of the FcRn / antigen binding molecule, the clearance rate of the FcRn / antigen binding molecule in the subject is reduced by at least 1 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times, or at least 20 times compared to the clearance rate of igatimod after a single therapeutic administration of igatimod.

[0466] In some embodiments, after a single administration of FcRn / antigen binding molecules, the clearance rate of FcRn / antigen binding molecules in the subject is reduced compared to the clearance rate of agamod after a single administration of an equivalent amount of agamod. In some embodiments, after a single administration of FcRn / antigen binding molecules, the clearance rate of FcRn / antigen binding molecules in the subject is reduced by at least 1 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times or at least 20 times compared to the clearance rate of agamod after a single administration of an equivalent amount of agamod.

[0467] In some embodiments, after a single administration of the FcRn / antigen binding molecule, the clearance rate of the FcRn / antigen binding molecule in the 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 / h. In some embodiments, after a single administration of the FcRn / antigen binding molecule, the clearance rate of the FcRn / antigen binding molecule in the 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 / h. In some embodiments, after a single administration of an FcRn antagonist, the clearance rate of the FcRn / antigen binding molecule is in the range of about 0.05 to about 0.2 l / h. In some embodiments, after a single administration of an FcRn / antigen binding molecule, the clearance rate of the FcRn / antigen binding molecule in the subject 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 / h. In some embodiments, after a single administration of an FcRn antagonist, the clearance rate of the FcRn / antigen binding molecule is in the range of 0.05 to 0.2 l / h. In some embodiments, the clearance rate of the FcRn / antigen binding molecule in the subject after a single administration of the FcRn / antigen binding molecule 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 / h.

[0468] In some embodiments, after a single therapeutic administration of an FcRn / antigen binding molecule, the t of the FcRn / antigen binding molecule in a subject is 1 / 2,z Compared with the t of agamod after a single therapeutic administration of agamod 1 / 2,z In some embodiments, after a single therapeutic administration of FcRn / antigen binding molecules, the t of FcRn / antigen binding molecules in the subject is 1 / 2,z Compared with the t of agamod after a single therapeutic administration of agamod 1 / 2,z Compared to an increase of at least 0.5 times, at least 1 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times or at least 20 times.

[0469] In some embodiments, after a single administration of an FcRn / antigen binding molecule, the t 1 / 2,z The t of agamod after a single administration of the same amount of agamod 1 / 2,z In some embodiments, after a single administration of FcRn / antigen binding molecules, the t of FcRn / antigen binding molecules in the subject is 1 / 2,z The t of agamod after a single administration of the same amount of agamod 1 / 2,z Compared to an increase of at least 0.5 times, at least 1 times, at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 12 times, at least 15 times or at least 20 times.

[0470] In some embodiments, after a single administration of an FcRn / antigen binding molecule, the t 1 / 2,z More than 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, about 16 days, about 16.5 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 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.

[0471] In some embodiments, after a single administration of an FcRn / antigen binding molecule, the t 1 / 2,zMore than 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, 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.

[0472] In some embodiments, the FcRn / antigen binding molecule 1 / 2,z In the range of about 3 days to about 30 days. In some embodiments, after a single administration of FcRn / antigen binding molecules, the t of FcRn / antigen binding molecules in the subject is 1 / 2,z 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, about 16 days, about 16.5 days, about 17 days 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.

[0473] In some embodiments, the FcRn / antigen binding molecule 1 / 2,z In the range of 3 days to 30 days. In some embodiments, after a single administration of FcRn / antigen binding molecules, the t of FcRn / antigen binding molecules in the subject is 1 / 2,z3 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, 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.

[0474] In some embodiments, the single-armed FcRn / antigen binding molecules of the present disclosure are more effective in clearing antigens than double-armed FcRn / antigen binding molecules (such as, for example, full-length antibodies). In some embodiments, the single-armed FcRn / antigen binding molecules are more effective in clearing antigens than the corresponding double-armed FcRn / antigen binding molecules. In other words, in some embodiments, removing one arm of the double-armed FcRn / antigen binding molecule produces a molecule that clears antigens more effectively than the double-armed FcRn / antigen binding molecule.

[0475] As used herein, "clearing" refers to the ability of a molecule to remove an antigen from serum. "Clearing" can be performed by molecules (such as, for example, antibodies) that have at least a threshold level of pH-sensitive antigen binding and binding to FcRn at neutral or physiological pH. For example, a clearing molecule can be bound to an antigen via an antigen binding domain and bound to FcRn via an Fc region, resulting in cellular internalization of an antigen / clearing antibody complex. The antigen can then be released from the complex in the acidic endosome and degraded. In certain embodiments, the clearing molecule that is no longer bound to the antigen can then be released by the cell (for example, by exocytosis) back into the serum.

[0476] In one embodiment, the FcRn / antigen binding molecules and other therapeutic agents are administered to the subject simultaneously or sequentially. In one embodiment, the other therapeutic agent is an anti-inflammatory agent. In one embodiment, the other therapeutic agent is a corticosteroid. In one embodiment, the other therapeutic agent is rituximab, daclizumab, basiliximab, muromonab-CD3, infliximab, adalimumab, omalizumab, efalizumab, natalizumab, tocilizumab, eculizumab, golimumab, canakinumab, ustekinumab or belimumab. In one embodiment, the other therapeutic agent is a leukocyte depleting agent.

[0477] 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.

[0478] In some embodiments, the FcRn / antigen binding molecule is administered intravenously. In some embodiments, the FcRn / antigen binding molecule is administered intravenously once a week, once every two weeks, once every three weeks, once every four weeks, once a month, or once every six weeks.

[0479] 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 a month, or once every six weeks.

[0480] Examples

[0481] The following examples are offered by way of illustration and not limitation.

[0482] Example 1: Pharmacokinetics / pharmacodynamics of anti-HSA-ABDEG in cynomolgus monkeys

[0483] The MHC class I-related receptor FcRn plays an important 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 does not bind at physiological pH (7.4) (Rodewald R., (1976) Journal of Cell Biology 71(2):666-9). Mutated human IgG1-derived antibodies (MST-HN) bind to FcRn with higher affinity and reduced pH dependence, and effectively compete with wild-type IgG for FcRn-mediated transport, resulting in a rapid decrease in IgG levels in mice (Vaccaro et al., (2005) Nature Biotechnology 23(10):1283-8). In humans, such FcRn blockers (or "ABDEGs", antibodies for enhancing IgG degradation) may be desirable in a variety of therapeutic situations, for example, clearance of autoreactive antibodies in autoimmune diseases such as systemic lupus erythematosus, myasthenia gravis, and immune thrombocytopenic purpura (ITP) or other antibody-mediated diseases.

[0484] Agamod is a human IgG1 Fc fragment using ABDEG Fc engineering technology. Its presumed mechanism of action in vivo is a constitutive blockade of FcRn-mediated IgG recycling, leading to IgG degradation. The effectiveness of Agamod depends largely on its pharmacokinetic properties. To this end, it is necessary to explore methods to further improve the half-life of the Agamod molecule, which can allow the use of lower doses and / or less frequent administration. An effective way to improve pharmacokinetic properties is by binding to long-lived plasma proteins. Albumin is the most abundant protein in plasma, has a half-life of 19 days in humans, and can represent the best carrier for therapeutic peptides / proteins.

[0485] The HSA-targeted VHH fragment Alb23 (SEQ ID NO: 42) was selected to be fused to the N-termini of the two Fc domains of agamod (TA-Alb23-Fc-ABDEG) to further prolong the half-life of agamod and delay its clearance ( Figure 1 ). Alb23 is described in WO 2012 / 175400 (incorporated herein by reference in its entirety). The full-length sequence of TA-Alb23-Fc-ABDEG is:

[0486] EVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNW YVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSPG(SEQ ID NO:177).

[0487] The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of TA-Alb23-Fc-ABDEG after a single intravenous administration of 5 mg / kg or 20 mg / kg to cynomolgus monkeys.

[0488] In addition to measuring TA-Alb23-Fc-ABDEG in cynomolgus monkey serum, an assay for anti-drug antibodies (ADA) against TA-Alb23-Fc-ABDEG was performed to investigate any effect on drug exposure. N-terminal fusion of the anti-HSAVHH fragment to both Fc domains of the Fc-ABDEG molecule is expected to prolong the half-life and efficacy of this Fc-ABDEG (TA-Alb23-Fc-ABDEG) compared to agamod (altered PD profile (reduced endogenous IgG)).

[0489] Male cynomolgus monkeys (Macaca fascicularis) were divided into 2 test groups, i.e., Group 1 and Group 2, each consisting of 3 monkeys with roughly equal average body weights (pseudo-random weight stratification procedure) and no medical history. Group 1 and Group 2 were treated with a single intravenous bolus (cephalic vein of the right arm) of 20 and 5 mg / kg body weight of TA-Alb23-Fc-ABDEG, respectively. The dose level of this study was selected based on early studies using Agamod.

[0490] Blood samples were collected for PK / PD / immunogenicity measurements at the following times: Test Day 1 (TD1) (pre-dose), TD1 (before dosing), TD1 (5 min), TD2 (24 hours after dosing), TD3, TD4, TD6, TD8, TD11, TD15, TD18, TD22, TD29, TD36, and TD43. Whole blood was collected in serum separator tubes, and blood samples were allowed to clot at room temperature for approximately 30 minutes before centrifugation. Serum samples were immediately aliquoted into 3 x 150 μL aliquots after centrifugation and stored at -70°C or colder until shipped for analysis.

[0491] Pharmacokinetics was assessed by measuring TA-Alb23-Fc-ABDEG serum concentrations using a sandwich ELISA method. In short, mouse anti-ABDEG antibodies were coated on 96-well immunoplates and nonspecific binding sites were blocked. Next, 100% serum samples were diluted to a quantitative concentration range (or at least the minimum required dilution (MRD)) and added to the immunoplate together with fresh calibration standards and a set of quality control (QC) samples. Finally, TA-Alb23-Fc-ABDEG levels were visualized by subsequently adding HRP-conjugated goat anti-human Fc F (ab') 2 and chromogenic substrate tetramethylbenzidine (TMB). The enzymatic reaction was terminated with sulfuric acid, and the optical density value at 450nm was recorded using a Tecan plate reader.

[0492] Pharmacodynamics was assessed by measuring total cynomolgus monkey IgG serum levels using a sandwich ELISA method. In brief, polyclonal anti-monkey IgG antibodies (γ chain specific) were coated on 96-well immunoplates and nonspecific binding sites were blocked. Next, 100% serum samples were diluted to a quantitative concentration range and added to the immunoplate along with fresh calibration standards and a set of quality control (QC) samples. The total level of serum rabbit IgG was 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 terminated with sulfuric acid and the optical density values ​​at 450nm were recorded using a Tecan plate reader.

[0493] The immunogenicity of the human IgG1 portion, ABDEG substitution or anti-HSA portion of the molecule was measured by using a sandwich ELISA method. In short, TA-Alb23-Fc-ABDEG was coated on a 96-well immunoplate and nonspecific binding sites were blocked. Dilutions of serum samples from several time points after administration from the cynomolgus monkey study were applied. Anti-drug antibodies (ADA) were detected and visualized by subsequently adding HRP-conjugated anti-monkey IgG monoclonal antibodies (γ chain specific) and the chromogenic substrate tetramethylbenzidine (TMB). Optical density values ​​were recorded using a Tecan plate reader.

[0494] Pharmacokinetic data showed that the half-life of Fc-ABDEG was significantly improved by conjugation with the anti-HSA VHH fragment (Alb23), ranging from 13.4 days to 54 days in different groups, with the average half-life of 20 mg / kg and 5 mg / kg doses being 26.5 days and 28.2 days, respectively ( Figure 2 The estimated pharmacokinetic parameters (half-life (T 1 / 2 ), C 最大 An overview of the AUC, area under the curve (AUC), and dose proportional factor (DPF) are presented in Table S1 and Table S2, respectively. The DPF calculation was based on the AUC values ​​obtained. AUC was calculated by GraphPad Prism 7, where the baseline was set to y = 0, and peaks below the baseline or less than 10% of the distance from the minimum to the maximum Y were ignored. The half-life was also calculated by GraphPad Prism 7 using a two-phase decay model until day 10 (ADA as of day 14). The mean half-life, C for each dose group were calculated based on the mean TA-Alb23-Fc-ABDEG serum concentration at each post-administration time point for individual monkeys in each dose group (n = 2 replicates, each study sample was diluted 1-fold in duplicate) (values ​​shown in Table S2). 最大 and AUC, as shown in Table S1.

[0495] Table S1: Mean pharmacokinetic parameters of TA-Alb23-Fc-ABDEG in each dose group

[0496]

[0497] Results show the mean ± SD of 1 triplicate for each PK parameter (n = 1 triplicate, 3 monkeys per dose group).

[0498] *Only one value is included because for monkeys C1 and C3, an accurate two-phase decay fit could not be established (see Table S2).

[0499] Table S2: Pharmacokinetic parameters of TA-Alb23-Fc-ABDEG for each individual animal

[0500]

[0501] Results show the mean ± SD of 2 replicates (n = 2 replicates, 2-fold study sample dilutions in duplicate) for each PK parameter.

[0502] *T 1 / 2 A two-phase decay was used to determine until day 10 (ADA as of day 14).

[0503] **The two-phase decay fitting is unclear and it is impossible to obtain accurate T 1 / 2 value.

[0504] Compared with agamod, the PK curve of TA-Alb23-Fc-ABDEG after intravenous administration shows that the half-life of Fc-ABDEG molecules is significantly increased. When considering the estimated mean blood volume of macaques (which is 65mL / kg), the calculated C maximum is within the expected range. The predicted C maximums of 20mg / kg and 5mg / kg dosage groups are 559μg / mL and 140μg / mL, respectively. For 20mg / kg and 5mg / kg dosage groups, the half-life of TA-Alb23-Fc-ABDEG molecules is 26.5 days and 28.2 days, respectively, while for agamod, this is about 1.5 days. As of the 10th day, a significant decrease in TA-Alb23-Fc-ABDEG serum levels was observed in most animals, which was related to the detectable level of anti-drug antibodies at that time. The AUC value shows a linear increase with the administered dose, and the DPF between the 5mg / kg and 20mg / kg groups is 0.9, which proves this point.

[0505] The decrease in IgG was small but dose-dependent; no pharmacodynamic effect was observed at a dose of 5 mg / kg. IgG clearance was observed at a dose of 20 mg / kg of TA-Alb23-Fc-ABDEG; the maximum IgG level was reduced by 25% compared with the baseline value (when C3 was excluded). Moreover, the time to achieve the maximum PD effect (T 最小 ) is quite long. The 5mg / kg and 20mg / kg dose groups required 21 days and 28 days, respectively.

[0506] Total IgG levels in cynomolgus monkey serum after a single dose of 5 or 20 mg / kg bw TA-Alb23-Fc-ABDEG relative to pre-dose levels are shown in Figures 3A to 3B The pharmacodynamic parameters of different animals are shown in Tables S3 and S4.

[0507] Table S3: Pharmacodynamic parameters of TA-Alb23-Fc-ABDEG for each individual animal

[0508]

[0509] Results show the mean ± SD of 2 replicates (n = 2 replicates, 2-fold sample dilutions studied in duplicate) for each PD parameter.

[0510] *C3 was excluded from the analysis.

[0511] Table S4: Average pharmacodynamic parameters of TA-Alb23-Fc-ABDEG in each dose group

[0512]

[0513] Results show mean ± SD of 1 triplicate for each PD parameter (n = 1 triplicate, 3 monkeys per dose group).

[0514] *C3 was excluded from the analysis.

[0515] All animals treated with TA-Alb23-Fc-ABDEG produced anti-drug antibodies on day 10. The immune responses of the animals were as Figure 4 As shown in. When antibodies to the human IgG1 portion of the molecule, the ABDEG substitution or the anti-HSA portion are present in the cynomolgus monkey serum study samples, an increase in OD450 can be detected. In both dosing groups, ADA development was observed in all animals 10 days after injection of the TA-Alb23-Fc-ABDEG molecule. C2, C3 and C6 showed significantly higher OD signals and more obvious immune responses than other monkeys, and since they were not derived from the same dose group, it is speculated that it is not related to the TA-Alb23-Fc-ABDEG dose administered (5 mg / kg versus 20 mg / kg).

[0516] The objective of the study was to determine the pharmacokinetic, pharmacodynamic, and immunogenic properties of double-armed N-terminal anti-HSA-Fc-ABDEG (TA-Alb23-Fc-ABDEG) following a single intravenous bolus injection of 5 mg / kg and 20 mg / kg in cynomolgus monkeys. It was predicted that the addition of two anti-HSA VHH fragments to the N-terminus of Fc-ABDEG would extend the half-life and efficacy of the molecule compared to agamod. In this study, the PK profile of TA-Alb23-Fc-ABDEG demonstrated an increased half-life of the Fc-ABDEG molecule compared to agamod. The half-life of the TA-Alb23-Fc-ABDEG molecule was 26.5 days and 28.2 days for the 20 mg / kg and 5 mg / kg dose groups, respectively, while for agamod, this was approximately 1.5 days. However, in both dosing groups, the TA-Alb23-Fc-ABDEG molecule had minimal effect on endogenous cynomolgus monkey serum IgG (the maximum observed decrease was 25% compared to pre-dose levels; 20 mg / kg dose group). This is in sharp contrast to data from other studies in cynomolgus monkeys, in which administration of 20 mg / kg of igamod resulted in at least a 50% decrease in total serum IgG within the first 10 days after injection. In vitro testing indicated that TA-Alb23-Fc-ABDEG was less functional than igamod. In addition, accelerated clearance of TA-Alb23-Fc-ABDEG was observed in most animals by day 10, which corresponded to detectable levels of anti-drug antibodies by this time point. Example 2: Pharmacokinetics / pharmacodynamics of Fc-ABDEG-anti-HSA in cynomolgus monkeys

[0517] As described in Example 1, agamod (Fc-ABDEG fragment) fused at its N-terminus to the HSA-targeted VHH fragment Alb23 (Alb23-Fc-ABDEG with two Alb23 albumin-binding arms at the N-terminus) exhibited increased half-life in cynomolgus monkeys, but had no apparent pharmacodynamic effect on the clearance of endogenous cynomolgus IgG. It was hypothesized that positioning the anti-HSA VHH fragment at the N-terminus of Fc-ABDEG might prevent the Fc-ABDEG portion of the molecule from occupying FcRn and, therefore, might result in a reduced efficiency in competing with endogenous IgG for binding to FcRn. Therefore, for this study, agamod was fused at the C-terminus of agamod to two Alb23 VHHs (TA-Fc-ABDEG-Alb23) ( Figure 5 ). The full-length sequence of TA-Fc-ABDEG-Alb23 is:

[0518] DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDG SFFLYSKLTVDKSRWQQGNVFSCSVMHEALKFHYTQKSLSLSLSPGGGGSGGGSGGGGSGGGGSEVQLLESGGGLVQPGGSLRLSCAASGFTFRSFGMSWVRQAPGKGPEWVSSISGSGSDTLYADSVKGRFTISRDNSKNTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS(SEQ ID NO:178).

[0519] Earlier, prolonged PK of TA-Fc-ABDEG-Alb23 (anti-HSA VHH fragment at the C-terminus) was observed in human FcRn and human albumin transgenic AlbuMus mice. Importantly, in the same model, Fc-ABDEG-Alb23 also exhibited a significant PD effect on the clearance of circulating preloaded human IgG compared to TA-Alb23-Fc-ABDEG (anti-HSA VHH fragment at the N-terminus). These findings enabled further studies of TA-Fc-ABDEG-Alb23 (anti-HSA VHH fragment at the C-terminus) in cynomolgus monkeys.

[0520] The procedures applied to animals in this study were reviewed and approved by PharmaLegacy Laboratories IACUC. In short, a total of 6 untreated female cynomolgus monkeys (2.5-5kg) were randomly divided into 2 groups. Monkeys were given a single IV dose of 30 or 75 mg / kg TA-Fc-ABDEG-Alb23 via the cephalic vein or saphenous vein. According to the schedule described in Table S5, blood samples were collected before treatment (before dosing) and after treatment for 4 weeks for PD, PK, ADA, albumin determination, and for hematology, clinical biochemistry and coagulation analysis.

[0521] Table S5: Sample collection summary

[0522]

[0523] Pharmacodynamics was assessed by measuring total cynomolgus monkey IgG serum levels using a qualified sandwich ELISA. Briefly, recombinant mouse anti-monkey IgG (Southern Biotech, Cat. No. 4700-01, l°H3418-SH51) was coated on a 96-well immunoplate at 0.5 μg / mL. The study serum samples were diluted 1:500,000 and incubated on the coated immunoplate with a fresh 10-point cynomolgus monkey IgG calibration curve (MyBioSource, Cat. No. MBS135162, LOT CY-GF-816) and the following 3 frozen quality control (QC) samples in a temperature-controlled shaking incubator at 22°C for 2 hours: HQC, diluted QC (100% cynomolgus monkey serum diluted 1:500,000) and LQC. IgG was detected for 1 hour by HRP-conjugated mouse anti-monkey IgG (Southern Biotech, Cat. No. 4700-05, l°H3418-YG59D). The plates were developed by adding tetramethylbenzidine (TMB) substrate for approximately 15 minutes. The enzymatic reaction was terminated with sulfuric acid and the optical density values ​​at 450 nm were recorded using a Tecan plate reader. Pooled cynomolgus monkey serum was used. The ELISA method was fully qualified in terms of calibration range, precision, accuracy, specificity, dilution linearity and drug interference.

[0524] The concentration of TA-Fc-ABDEG-Alb23 in monkey serum was determined using a sandwich electrochemiluminescent immunoassay (ECLIA) method. Briefly, after blocking nonspecific binding sites, streptavidin-coated 96-well MSD SECTOR plates were coated with biotinylated mouse anti-ABDEG for 1 h. Next, 100% of the study serum samples were diluted to the quantitative concentration range or at least the minimum required dilution (MRD) and incubated on the immunoplate with a fresh 12-point calibration curve containing 200000 ng / mL to 390 ng / mL of TA-Fc-ABDEG-Alb23 (Evitria, #903724.1, E17404, 12214-SEC) in 100% pooled monkey serum and two sets of frozen QC samples (HQC, MQC and LQC) in a temperature-controlled shaking incubator at 22°C for 1 hour. TA-Fc-ABDEG-Alb23 was detected by subsequent addition of sulfo-tagged VHH fragments for 30 minutes. The levels of TA-Fc-ABDEG-Alb23 were obtained after 5 minutes of incubation in 1x MSD READ buffer using an MSD reader. The applied ECLIA method was internally certified in terms of calibration range, precision, accuracy, matrix effect, selectivity, dilution linearity and stability. The MRD of the method was set to 1:50 and the sensitivity (LLOQ) was 390.6ng / mL in 100% serum.

[0525] use Version 8.3 ( 1998-2020, Certara LP, USA) for non-compartmental PK analysis (NCA). NCA analysis was performed on individual plasma concentrations of each animal. In the study, the NCA calculation method “Linear Up Log Down” and the dose option “IV bolus” were applied.

[0526] The presence of immune response to TA-Fc-ABDEG-Alb23 was measured using sandwich ELISA. In short, TA-Fc-ABDEG-Alb23 was coated on a 96-well immunoplate at 1 μg / mL, and nonspecific binding sites were blocked with 1% casein-PBS (G-Bioscience, part number 097B, batch number 212206). Pre- and post-administration cynomolgus monkey serum was diluted 1:10...

Claims

1. An FcRn / antigen binding molecule comprising a variant IgG Fc region and a first antigen binding domain, wherein the first antigen binding domain is linked to the C-terminus of the variant IgG Fc region, and wherein the first antigen binding domain specifically binds to human serum albumin (HSA), wherein the variant IgG Fc region comprises a first Fc domain and a second Fc domain that form a dimer, and wherein the first Fc domain and / or the second Fc domain comprise amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively.

2. The FcRn / antigen binding molecule of claim 1, wherein the first antigen binding domain specifically binds to HSA at pH 7.4 with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA, optionally as measured by surface plasmon resonance.

3. The FcRn / antigen binding molecule of claim 1 or 2, wherein the first antigen binding domain specifically binds to HSA at pH 5.5 with an affinity lower than the binding affinity of Alb23 (SEQ ID NO: 42) to HSA, optionally as measured by surface plasmon resonance.

4. The FcRn / antigen binding molecule according to any one of claims 1 to 3, which specifically binds to HSA at pH 7.4 with an equilibrium dissociation constant greater than about 2.4 nM, optionally as measured by surface plasmon resonance.

5. The FcRn / antigen binding molecule according to any one of claims 1 to 4, which specifically binds to HSA at pH 5.5 with an equilibrium dissociation constant greater than about 2.4 nM, optionally as measured by surface plasmon resonance.

6. The FcRn / antigen binding molecule according to any one of claims 1 to 5, which binds to FcRn at pH 5.5 and / or pH 6.0 with an affinity higher than the affinity of igamod for FcRn at pH 5.5 and / or pH 6.0, optionally as measured by surface plasmon resonance.

7. The FcRn / antigen binding molecule according to any one of claims 1 to 6, which binds to FcRn at pH 5.5 and / or pH 6.0 with an affinity lower than the affinity of igamod for FcRn at pH 5.5 and / or pH 6.0, optionally as measured by surface plasmon resonance.

8. The FcRn / antigen binding molecule of any one of claims 1 to 7, wherein 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.

9. The FcRn / antigen binding molecule of any one of claims 1 to 8, wherein both the first Fc domain and the second Fc domain comprise amino acids Y, T, E, K and F located at EU positions 252, 254, 256, 433 and 434, respectively.

10. The FcRn / antigen binding molecule of any one of claims 1 to 9, wherein both the first Fc domain and the second Fc domain comprise amino acids Y, T, E, K, F and Y at EU positions 252, 254, 256, 433, 434 and 436, respectively. 11 . The FcRn / antigen binding molecule according to any one of claims 1 to 10, wherein the first Fc domain and / or the second Fc domain is an IgG1 Fc domain.

12. The FcRn / antigen binding molecule according to any one of claims 1 to 10, wherein the first Fc domain and / or the second Fc domain is a human IgG Fc domain.

13. The FcRn / antigen binding molecule according to any one of claims 1 to 12, wherein the first Fc domain and / or the second Fc domain is a human IgG1 Fc domain.

14. The FcRn / antigen binding molecule of any one of claims 1 to 11, wherein the first Fc domain and the second Fc domain are both IgG1 Fc domains.

15. The FcRn / antigen binding molecule of any one of claims 1 to 12, wherein the first Fc domain and the second Fc domain are both human IgG Fc domains.

16. The FcRn / antigen binding molecule according to any one of claims 1 to 15, wherein the first Fc domain and the second Fc domain are both human IgG1 Fc domains.

17. The FcRn / antigen binding molecule of any one of claims 1 to 16, wherein the first antigen binding domain is covalently linked to the first Fc domain or the second Fc domain.

18. The FcRn / antigen binding molecule according to any one of claims 1 to 17, wherein the N-terminus of the first antigen binding domain is fused to the C-terminus of the first Fc domain.

19. The FcRn / antigen binding molecule according to any one of claims 1 to 17, wherein the N-terminus of the first antigen binding domain is fused to the C-terminus of the second Fc domain.

20. The FcRn / antigen binding molecule of any one of claims 1 to 19, wherein the first antigen binding domain is fused to the first Fc domain or the second Fc domain via a linker.

21. The FcRn / antigen binding molecule of claim 20, wherein the linker is a non-cleavable linker.

22. The FcRn / antigen binding molecule according to claim 20 or 21, wherein the linker is a peptide linker.

23. The FcRn / antigen binding molecule of claim 22, wherein the peptide linker is a GS linker, optionally 8 to 40 amino acids in length, optionally 20 or 30 amino acids in length.

24. The FcRn / antigen binding molecule according to any one of claims 1 to 23, wherein the first Fc domain and / or the second Fc domain comprises an amino acid sequence independently selected from the group consisting of the amino acid sequence shown in SEQ ID NO: 1, 2 or 3.

25. The FcRn / antigen binding molecule of claim 24, wherein the first Fc domain and / or the second Fc domain comprises the amino acid sequence of SEQ ID NO:

2.

26. The FcRn / antigen binding molecule of claim 25, wherein the first Fc domain and the second Fc domain both comprise an amino acid sequence independently selected from the group consisting of the amino acid sequence shown in SEQ ID NO: 1, 2 or 3.

27. The FcRn / antigen binding molecule of claim 26, wherein both the first Fc domain and the second Fc domain comprise the amino acid sequence of SEQ ID NO:

2.

28. The FcRn / antigen binding molecule according to any one of claims 1 to 23, wherein 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 following: The amino acid sequence shown in SEQ ID NO: 1, 2 or 3.

29. The FcRn / antigen binding molecule of claim 28, wherein 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.

30. The FcRn / antigen binding molecule of claim 29, wherein the amino acid sequences of both the first Fc domain and the second Fc domain consist of SEQ ID NO:

2.

31. The FcRn / antigen binding molecule according to any one of claims 1 to 23, wherein the variant Fc region comprises one or more mutations in amino acid residues forming the interface of the CH3 domain of the Fc domain.

32. The FcRn / antigen binding molecule according to any one of claims 1 to 23 and 31, wherein the amino acid sequence of the first Fc domain further comprises amino acid W at EU position 366.

33. The FcRn / antigen binding molecule of claim 32, wherein the amino acid sequence of the first Fc domain comprises an amino acid sequence selected from the group consisting of the amino acid sequence shown in SEQ ID NO: 4, 5 or 6.

34. The FcRn / antigen binding molecule of claim 33, wherein the amino acid sequence of the first Fc domain comprises the amino acid sequence of SEQ ID NO:

5.

35. The FcRn / antigen binding molecule of claim 33, wherein the amino acid sequence of the first Fc domain consists of an amino acid sequence selected from the group consisting of: The amino acid sequence shown in SEQ ID NO:4, 5 or 6.

36. The FcRn / antigen binding molecule of claim 35, wherein the amino acid sequence of the first Fc domain consists of the amino acid sequence of SEQ ID NO:

5.

37. The FcRn / antigen binding molecule of any one of claims 1 to 23 and 31 to 36, wherein 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.

38. The FcRn / antigen binding molecule of claim 37, wherein the amino acid sequence of the second Fc domain comprises an amino acid sequence selected from the group consisting of the amino acid sequence shown in SEQ ID NO: 7, 8 or 9.

39. The FcRn / antigen binding molecule of claim 38, wherein the amino acid sequence of the second Fc domain comprises the amino acid sequence of SEQ ID NO:

8.

40. The FcRn / antigen binding molecule of claim 38, wherein the amino acid sequence of the second Fc domain consists of an amino acid sequence selected from the group consisting of: The amino acid sequence shown in SEQ ID NO:7, 8 or 9.

41. The FcRn / antigen binding molecule of claim 40, wherein the amino acid sequence of the second Fc domain consists of the amino acid sequence of SEQ ID NO:

8.

42. The FcRn / antigen binding molecule according to any one of claims 1 to 41, wherein the first antigen binding domain is selected from a Fab fragment, a sdAb, a scFv, an antibody mimetic, HSA or an HSA binding fragment thereof.

43. The FcRn / antigen binding molecule of claim 42, wherein the antibody mimetic is an anticalin or a DARPin.

44. The FcRn / antigen binding molecule of claim 42, wherein the sdAb is a VHH fragment.

45. The FcRn / antigen binding molecule of claim 44, wherein the first antigen binding domain is a VHH fragment comprising the CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment, wherein the VHH fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 43-74, 84-90 and 120-127.

46. ​​The FcRn / antigen binding molecule of claim 44 or 45, wherein the first antigen binding domain is a VHH fragment comprising an amino acid sequence selected from the group consisting of: 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); 1) 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) an 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); 11) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 116 (CDR3); mm) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 83 (CDR3).

47. The FcRn / antigen binding molecule according to any one of claims 44 to 46, wherein the first antigen binding domain is a VHH fragment comprising an amino acid sequence comprising SEQ ID NO: 14 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3).

48. The FcRn / antigen binding molecule of any one of claims 44 to 46, wherein the first antigen binding domain is a VHH fragment comprising 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 the group consisting of the amino acid sequences shown in SEQ ID NOs: 43-74, 84-90 or 120-127.

49. The FcRn / antigen binding molecule of any one of claims 44 to 48, wherein the first antigen binding domain is a VHH fragment 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 shown in SEQ ID NO:

44.

50. The FcRn / antigen binding molecule according to any one of claims 44 to 46, wherein the first antigen binding domain comprises an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOs: 43-74, 84-90 or 120-127.

51. The FcRn / antigen binding molecule according to any one of claims 44 to 50, wherein the first antigen binding domain comprises the amino acid sequence shown in SEQ ID NO:

44.

52. The FcRn / antigen binding molecule according to any one of claims 44 to 51, further comprising one or more additional amino acids located at the C-terminus of the VHH fragment.

53. The FcRn / antigen binding molecule of claim 52, wherein 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.

54. The FcRn / antigen binding molecule of any one of claims 1 to 53, further comprising a second antigen binding domain.

55. The FcRn / antigen binding molecule of claim 54, wherein the second antigen binding domain is linked to the first Fc domain or the second Fc domain.

56. The FcRn / antigen binding molecule of claim 54 or 55, wherein the second antigen binding domain is fused to the first Fc domain or the second Fc domain via a linker.

57. The FcRn / antigen binding molecule of claim 56, wherein the linker is a non-cleavable linker.

58. The FcRn / antigen binding molecule of claim 56 or 57, wherein the linker is a peptide linker.

59. The FcRn / antigen binding molecule of claim 58, wherein the peptide linker is a GS linker, optionally 8 to 40 amino acids in length, optionally 20 or 30 amino acids in length.

60. The FcRn / antigen binding molecule of any one of claims 54 to 58, wherein the second antigen binding domain is fused to the first Fc domain or the second Fc domain via an IgG hinge region or a portion thereof.

61. The FcRn / antigen binding molecule of any one of claims 54 to 60, wherein the first antigen binding domain is fused to the first Fc domain, and the second antigen binding domain is fused to the second Fc domain.

62. The FcRn / antigen binding molecule of claim 61, wherein the second antigen binding domain is fused to the C-terminus of the second Fc domain.

63. The FcRn / antigen binding molecule of claim 61, wherein the second antigen binding domain is fused to the N-terminus of the second Fc domain.

64. The FcRn / antigen binding molecule of any one of claims 54 to 60, wherein the first antigen binding domain is fused to the second Fc domain, and the second antigen binding domain is fused to the first Fc domain.

65. The FcRn / antigen binding molecule of claim 64, wherein the second antigen binding domain is fused to the C-terminus of the first Fc domain.

66. The FcRn / antigen binding molecule of claim 64, wherein the second antigen binding domain is fused to the N-terminus of the first Fc domain.

67. The FcRn / antigen binding molecule of any one of claims 54 to 66, wherein the second antigen binding domain specifically binds to HSA.

68. The FcRn / antigen binding molecule of claim 67, wherein the second antigen binding domain is selected from a Fab fragment, an sdAb, a scFv, an antibody mimetic, HSA or an HSA binding fragment thereof.

69. The FcRn / antigen binding molecule of claim 68, wherein the antibody mimetic is an anticalin or a DARPin.

70. The FcRn / antigen binding molecule of claim 68, wherein the sdAb is a VHH fragment.

71. The FcRn / antigen binding molecule of claim 70, wherein the second antigen binding domain is a VHH fragment comprising the CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment, wherein the VHH fragment comprises an amino acid sequence selected from the group consisting of SEQ ID Nos: 43-74, 84-90 and 120-127.

72. The FcRn / antigen binding molecule of claim 70 or 71, wherein the second antigen binding domain is a VHH fragment comprising an amino acid sequence selected from the group consisting of: 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); 1) 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) an 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); 11) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 116 (CDR3); mm) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 83 (CDR3).

73. The FcRn / antigen binding molecule according to any one of claims 70 to 72, wherein the second antigen binding domain is a VHH fragment comprising an amino acid sequence comprising SEQ ID NO: 14 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 12 (CDR3).

74. The FcRn / antigen binding molecule of any one of claims 70 to 72, wherein the second antigen binding domain is a VHH fragment 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 shown in SEQ ID NO:43-74, 84-90 or 120-127.

75. The FcRn / antigen binding molecule of any one of claims 70 to 74, wherein the second antigen binding domain is a VHH fragment 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 shown in SEQ ID NO:

44.

76. The FcRn / antigen binding molecule according to any one of claims 70 to 72, wherein the second antigen binding domain comprises an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOs: 43-74, 84-90 or 120-127.

77. The FcRn / antigen binding molecule of any one of claims 70 to 76, wherein the second antigen binding domain comprises the amino acid sequence shown in SEQ ID NO:

44.

78. The FcRn / antigen binding molecule according to any one of claims 70 to 77, further comprising one or more amino acids located at the C-terminus of the VHH fragment.

79. The FcRn / antigen binding molecule of claim 78, wherein the one or more amino acids are selected from the group consisting of: a) A; b) AG; c) GG; d) PP; and e)AA.

80. The FcRn / antigen binding molecule of any one of claims 54 to 79, wherein the first antigen binding domain and the second antigen binding domain are identical.

81. An FcRn / antigen binding molecule comprising a first heavy chain, wherein the first heavy chain 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 NO: 137-176 or 180.

82. The FcRn / antigen binding molecule of claim 81, wherein the first heavy chain 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 SEQ ID NO:

180.

83. The FcRn / antigen binding molecule of claim 81, wherein the first heavy chain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 137-176 or 180.

84. The FcRn / antigen binding molecule according to any one of claims 81 to 83, wherein the first heavy chain comprises or consists of the amino acid sequence of SEQ ID NO:

180.

85. The FcRn / antigen binding molecule according to any one of claims 81 to 84, wherein the first heavy chain further comprises one or more amino acids added at the C-terminus of the first heavy chain, which are optionally selected from A, AG, GG and PP.

86. The FcRn / antigen binding molecule of any one of claims 81 to 85, further comprising 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.

87. The FcRn / antigen binding molecule of claim 86, wherein the second heavy chain consists of the amino acid sequence of SEQ ID NO:

8.

88. An antigen binding domain comprising the CDR1, CDR2 and CDR3 amino acid sequences of a VHH fragment, wherein the VHH fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 43-74, 84-90 and 120-127.

89. The antigen binding domain of claim 88, comprising an amino acid sequence selected from the group consisting of: 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); 1) 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) an 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); 11) an amino acid sequence comprising SEQ ID NO: 10 (CDR1), SEQ ID NO: 11 (CDR2) and SEQ ID NO: 116 (CDR3); mm) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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) comprises an amino acid sequence of 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 the amino acid sequence of SEQ ID NO: 75 (CDR1), SEQ ID NO: 76 (CDR2) and SEQ ID NO: 83 (CDR3).

90. The antigen binding domain of claim 88 or 89, wherein 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).

91. An antigen binding domain according to claim 88 or 89, wherein 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 shown in SEQ ID NO:43-74, 84-90 or 120-127.

92. An antigen binding domain according to any one of claims 88 to 91, wherein 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 shown in SEQ ID NO:

44.

93. The antigen binding domain of claim 88 or 89, wherein the antigen binding domain comprises the amino acid sequence shown in SEQ ID NO: 43-74, 84-90 or 120-127.

94. The antigen binding domain of any one of claims 88 to 93, wherein the antigen binding domain comprises the amino acid sequence shown in SEQ ID NO:

44.

95. The antigen binding domain of any one of claims 88 to 94, wherein the antigen binding domain is a sdAb.

96. The antigen binding domain of claim 95, wherein the sdAb is a VHH fragment.

97. The antigen binding domain of claim 96, further comprising one or more additional amino acids located at the C-terminus of the VHH fragment.

98. The antigen binding domain of claim 97, wherein 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.

99. The antigen binding domain of any one of claims 88 to 98, wherein the antigen binding molecule specifically binds to HSA.

100. The antigen binding domain of claim 99, wherein the antigen binding domain specifically binds to HSA with an affinity that is lower than the binding affinity of Alb23 (SEQ ID NO: 42) for HSA, optionally as measured by surface plasmon resonance.

101. One or more isolated polynucleotides encoding an FcRn / antigen binding molecule according to any one of claims 1 to 87 or an antigen binding domain according to any one of claims 88 to 100.

102. An expression vector comprising one or more isolated polynucleotides according to claim 101.

103. A host cell comprising one or more isolated polynucleotides according to claim 101 or an expression vector according to claim 102.

104. A method for producing an FcRn / antigen binding molecule or an antigen binding domain, the method comprising culturing the host cell of claim 103 under conditions that allow expression of the FcRn / antigen binding molecule or the antigen binding domain.

105. A pharmaceutical composition comprising the FcRn / antigen binding molecule according to any one of claims 1 to 87 or the antigen binding domain according to any one of claims 88 to 100 and at least one pharmaceutically acceptable carrier.

106. The FcRn / antigen binding molecule according to any one of claims 1 to 87, or the antigen binding domain according to any one of claims 88 to 100, or the pharmaceutical composition according to claim 105, for use as a medicament.

107. A method of 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 according to any one of claims 1 to 87, or an antigen binding domain according to any one of claims 88 to 100, or a pharmaceutical composition according to claim 105.

108. A method of treating an antibody-mediated disorder in a subject, the method comprising administering to a patient in need thereof a therapeutically effective amount of an FcRn / antigen binding molecule according to any one of claims 1 to 87, or an antigen binding domain according to any one of claims 88 to 100, or a pharmaceutical composition according to claim 105.

109. The method of claim 108, wherein the antibody-mediated disorder is an IgG-mediated disorder.

110. The method of claim 108 or 109, wherein the antibody-mediated disorder is an autoimmune disease.

111. The method of claim 110, wherein the autoimmune disease is selected from the group consisting of: allogeneic islet transplant rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANCA), adrenal autoimmune disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, immune-mediated thrombocytopenia or primary immune thrombocytopenia), autoimmune urticaria rash, Behcet's disease, bullous pemphigoid (BP), cardiomyopathy, Castleman syndrome, celiac sprue, chronic fatigue immune dysfunction syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), Chargar-Strauss syndrome, cicatricial pemphigoid, CREST syndrome, cold agglutinin disease, Crohn's disease, dilated cardiomyopathy, discoid lupus, epidermolysis bullosa acquisita, essential mixed cryoglobulinemia, factor VIII 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, atrophic lichen sclerosus, lupus erythematosus, lupus nephritis, Meniere's disease, mixed connective tissue disease, mucosal pemphigoid, multiple sclerosis, type 1 diabetes, multifocal motor neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), myositis, paraneoplastic bullous pemphigoid, pemphigoid gestationis, pemphigus 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, psoriatic arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis, scleroderma, Sjögren's syndrome, solid organ transplant rejection, stiff-person 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.

112. The method of any one of claims 107 to 111, wherein the FcRn / antigen binding molecule or antigen binding domain is administered to the subject simultaneously or sequentially with an additional therapeutic agent.

113. The FcRn / antigen binding molecule according to any one of claims 1 to 87, or the antigen binding domain according to any one of claims 88 to 100, or the pharmaceutical composition according to claim 105, for use in the treatment of an antibody-mediated disorder.

114. An FcRn / antigen binding molecule according to any one of claims 1 to 87 or an antigen binding domain according to any one of claims 88 to 100 for use in the manufacture of a medicament for the treatment of an antibody-mediated disorder.

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