FCRN / HSA binding molecule and method of use

Abstract

The present invention provides an improved agent for use in the treatment of antibody-mediated disorders, which antagonistizes FcRn binding to IgG, resulting in a longer half-life, lower doses, less frequent administration, better maintenance of albumin levels, and / or reduced or eliminated FcRn degradation. [Solution] A binding molecule is provided for treating antibody-mediated disorders with an FcRn / antigen binding molecule, comprising a human neonatal Fc receptor (FcRn) binding molecule and at least one antigen-binding domain linked to the FcRn binding molecule. In one embodiment, an FcRn / antigen binding molecule is provided, comprising an FcRn binding molecule and a first antigen-binding domain, wherein the first antigen-binding domain is linked to the C-terminus of the FcRn binding molecule, and the first antigen-binding domain specifically binds to human serum albumin (HSA).

Description

Technical Field

[0001] The present disclosure relates to human neonatal Fc receptor (FcRn) / HSA binding molecules and methods of using them. It relates to.

Background Art

[0002] Immunoglobulin gamma (IgG) antibodies play an important role in the pathology of many diseases, such as autoimmune diseases, inflammatory diseases, and disorders where the pathology is characterized by overexpression of IgG antibodies. In the pathology of diseases characterized by overexpression of IgG antibodies, it plays an important role. It plays an important role.

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

[0004] When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from lysosomal degradation and thus has a reduced serum half-life. When the serum concentration of IgG reaches a level that exceeds the available FcRn molecules, unbound IgG is not protected from lysosomal degradation and thus has a reduced serum half-life. Therefore, inhibition of IgG binding to FcRn reduces 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, are useful for modulating, treating, or preventing antibody-mediated disorders, such as autoimmune diseases or inflammatory diseases. Therefore, inhibition of IgG binding to FcRn reduces 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, are useful for modulating, treating, or preventing antibody-mediated disorders, such as autoimmune diseases. Or inflammatory diseases.

[0005] Efgultigimod is a modified human immunoglobulin that binds to human FcRn with nanomolar affinity. This is the Fc allotype of za derived from globulin (Ig) gamma (IgG) 1. Tigimod encapsulates the IgG1 Fc region and uses ABDEG technology to analyze physiological and acidic processes. It has been manipulated to increase its affinity for FcRn at both acidic and acidic pH levels. The increased affinity of efgultigimod for FcRn at both physiological pH levels indicates that IgG It causes blockage of FcRn-mediated recirculation. Efgaltigimod is used in the treatment of generalized myasthenia gravis. It is approved in the United States and Japan as a weekly intravenous injection for therapeutic use. It is under development for the treatment of several other antibody-mediated disorders.

[0006] FcRn also binds to serum albumin, a regulator of serum cholesterol levels. , and then recirculate it. Efgultigimod is advantageous in serum albumin in human subjects. It does not negatively affect the level. However, recently, anti-FcRn antibodies have been shown in human subjects. A decrease in serum albumin levels and an associated increase in serum cholesterol levels. It has been shown that this can cause both, and neither is desirable.

[0007] Therefore, it antagonistizes FcRn binding to IgG, resulting in a longer half-life and lower Dosage, less frequent administration, better maintenance of albumin levels, and / or FcRn Improved for use in the treatment of antibody-mediated disorders, having reduced or eliminated degradation. There is a need for such drugs in the field of this technology. [Overview of the project]

[0008] This disclosure broadly describes one or more antigen-binding domains that specifically bind to human serum albumin. A neonatal Fc receptor (FcRn) binding molecule linked to the ion (FcRn / antigen binding molecule or This paper covers FcRn / HSA binding molecules and their methods of use. Unexpectedly, HSA binding Including the binding portion means linking to one or more antigen-binding domains that specifically bind to HSA. The initial goal was to increase the stability (long lifespan) and FcRn occupancy rate of the FcRn-binding molecule. This is shown in the present application.

[0009] In one embodiment, an FcRn / anti- The primary binding molecule is one in which the first antigen-binding domain is linked to the C-terminus of the FcRn-binding molecule. The first antigen-binding domain specifically binds to human serum albumin (HSA). FcRn / antigen-binding molecules are provided herein.

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

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

[0012] In some embodiments, the FcRn / antigen binding molecule is attached to FcRn at pH 5.5 and / Alternatively, it binds at pH 6.0 and to FcRn at pH 5.5 and / or pH 6.0. It binds with a higher affinity than gimodo. In some embodiments, several implementations Morphologically, the FcRn / antigen-binding molecule is attached to FcRn at pH 5.5 and / or pH 6.0. The affinity of efgartigimodo to FcRn at pH 5.5 and / or pH 6.0 is due to its binding and affinity for Fgartigimodo. It binds with even lower affinity.

[0013] In any of the embodiments described above, the bonding affinity is optionally the same as the surface plasmon. It can be measured by sound.

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

[0015] In some embodiments, the first Fc domain and / or the second Fc domain is EU At positions 252, 254, 256, 433, and 434, amino acids Y, T, and E are present, respectively. Includes K and F. In some embodiments, a first Fc domain and / or a second Fc The domains are located at EU locations 252, 254, 256, 433, 434, and 436 respectively. This contains amino acids Y, T, E, K, F, and Y.

[0016] In some embodiments, both the first Fc domain and the second Fc domain are ami Acids Y, T, E, K, and F are located at EU positions 252, 254, 256, and 433, respectively. and 434 include. In some embodiments, the first Fc domain and the second Fc Both domains contain amino acids Y, T, E, K, F, and Y at EU position 252, respectively. , including in 254, 256, 433, 434, and 436.

[0017] In some embodiments, the first Fc domain and / or the second Fc domain is Ig A G Fc domain, for example, an IgG1 Fc domain. In some embodiments, The first Fc domain and / or the second Fc domain is a human IgG Fc domain, for example It is the human IgG1 Fc domain.

[0018] In some embodiments, both the first Fc domain and the second Fc domain are Ig G Fc domains, for example, human IgG1 Fc domains. In some embodiments Both the first and second Fc domains are human IgG Fc domains. For example, the human IgG1 Fc domain.

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

[0020] In some embodiments, the N-terminus of the first antigen-binding domain is the first Fc domain It is fused to the C-terminus. In some embodiments, the N-terminus of the first antigen-binding domain is It is fused to the C-terminus of the second Fc domain. In some embodiments, the first antigen binding The domain merges with the first or second Fc domain via a linker. In some embodiments, the linker is an uncuttable linker. In some embodiments, the linker is a peptide linker. The drinker is a GS linker, optional, and has a length of 8-40 amino acids. And it is 20 or 30 amino acids long.

[0021] In some embodiments, the first Fc domain and / or the second Fc domain are sequence It includes an amino acid sequence independently selected from the amino acid sequences described in number 1, 2, or 3. In some embodiments, the first Fc domain and / or the second Fc domain are sequence numbers Contains the amino acid sequence of No. 2.

[0022] In some embodiments, both the first Fc domain and the second Fc domain are sequence It includes an amino acid sequence independently selected from the amino acid sequences described in number 1, 2, or 3. In some embodiments, both the first Fc domain and the second Fc domain are sequence numbers Contains the amino acid sequence of No. 2.

[0023] In some embodiments, the amino acids of the first Fc domain and the second Fc domain The acid sequence is an amino acid sequence independently selected from the amino acid sequences described in SEQ ID NOs: 1, 2, or 3. It consists of an acid sequence. In some embodiments, the amino acid sequence of the first Fc domain or the second The amino acid sequence of the Fc domain is as shown in SEQ ID NO: 2.

[0024] In some embodiments, both the first Fc domain and the second Fc domain are amino The acid sequence consists of sequence number 2.

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

[0026] In some embodiments, the amino acid sequence of the first Fc domain is such that amino acid W is EU Further includes at position 366.

[0027] In some embodiments, the amino acid sequence of the first Fc domain is sequence numbers 4, 5, and This includes an amino acid sequence selected from the amino acid sequences described in 6. In some embodiments, The amino acid sequence of the first Fc domain includes the amino acid sequence of SEQ ID NO: 5.

[0028] In some embodiments, the amino acid sequence of the first Fc domain is sequence numbers 4, 5, and This consists of an amino acid sequence selected from the amino acid sequences described in 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 is amino acids S, A, and The following further include V at EU positions 366, 368, and 407, respectively.

[0030] In some embodiments, the amino acid sequence of the second Fc domain is sequence numbers 7, 8, or This includes an amino acid sequence selected from the amino acid sequences described in 9. In some embodiments, The amino acid sequence of the second Fc domain includes the amino acid sequence of SEQ ID NO: 8.

[0031] In some embodiments, the amino acid sequence of the second Fc domain is sequence numbers 7, 8, or This consists of an amino acid sequence selected from the amino acid sequences described in 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 Fab fragment, sdAb, scF v is selected from an antibody mimetic, HSA, or an HSA-binding fragment thereof. Several embodiments The antibody mimetic is anticalin or DARPin. Several embodiments Therefore, sdAb is a VHH fragment.

[0033] In some embodiments, the first antigen-binding domain is any of the domains described herein. This is the antigen-binding domain. In some embodiments, the first antigen-binding domain is VH H fragment, and VHH fragment is any of the VHH fragments disclosed herein. Includes R1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence. In this embodiment, the first antigen-binding domain is a VHH fragment, and the VHH fragment is sequence number VH containing amino acid sequences selected from numbers 43-74, 84-90, and 120-127 Includes the CDR1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence of the H fragment. nothing.

[0034] In some embodiments, the first antigen-binding domain is a VHH fragment, and the VHH fragment This is an amino acid sequence selected from sequence numbers 43-74, 84-90, and 120-127. and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% It contains amino acid sequences that are % or 99% identical. In some embodiments, the first antigenic linkage The combined domain is a VHH fragment, and the VHH fragment has the amino acid sequence described in SEQ ID NO: 44. At least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% , or containing amino acid sequences that are 99% identical. In some embodiments, the first antigen binding The domain is selected from sequence numbers 43-74, 84-90, and 120-127. It contains an acid sequence. In some embodiments, the first antigen-binding domain is located in SEQ ID NO 44. Contains the amino acid sequence described.

[0035] In some embodiments, the FcRn / antigen-binding molecule is, for example, the first antigen-binding domain. When the molecule is a VHH fragment, one or more additional amino acids are added to the first antigen-binding domain. It further contains at the C-terminus. In some embodiments, one or more additional amino acids are a) The group is selected from 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. include.

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

[0038] In some embodiments, the second antigen-binding domain is the first Fc domain or the second It is fused to the Fc domain via a linker. In some embodiments, the linker is , an inseparable linker. In some embodiments, the linker is a peptide linker —In some embodiments, the peptide linker is a GS linker, and optionally The length is 8-40 amino acids by choice, and 20 or 30 amino acids by choice.

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

[0040] In some embodiments, the first antigen-binding domain is fused to the first Fc domain. Furthermore, the second antigen-binding domain is fused to the second Fc domain. Several implementations Morphologically, 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. They are doing it.

[0041] In some embodiments, the first antigen-binding domain is fused to the second Fc domain. Furthermore, the second antigen-binding domain is fused to the first Fc domain. Several implementations Morphologically, 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. They are doing it.

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

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

[0044] In some embodiments, the second antigen-binding domain is any of the domains described herein. This is the antigen-binding domain. In some embodiments, the second antigen-binding domain is VH H fragment, and VHH fragment is any of the VHH fragments disclosed herein. Includes R1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence. In this embodiment, the second antigen-binding domain is a VHH fragment, and the VHH fragment is sequence number VH containing amino acid sequences selected from numbers 43-74, 84-90, and 120-127 Includes the CDR1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence of the H fragment. nothing.

[0045] In some embodiments, the second antigen-binding domain is a VHH fragment, and the VHH fragment This is an amino acid sequence selected from sequence numbers 43-74, 84-90, and 120-127. and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% It contains amino acid sequences that are % or 99% identical. In some embodiments, a second antigenic linkage The combined domain is a VHH fragment, and the VHH fragment has the amino acid sequence described in SEQ ID NO: 44. At least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% , or containing amino acid sequences that are 99% identical. In some embodiments, a second antigen binding The domain is selected from sequence numbers 43-74, 84-90, and 120-127. It contains an acid sequence. In some embodiments, the second antigen-binding domain is located in Sequence ID No. 44. Contains the amino acid sequence described.

[0046] In some embodiments, the FcRn / antigen-binding molecule is, for example, a second antigen-binding domain. When the molecule is a VHH fragment, one or more amino acids are attached to the C-terminus of the second antigen-binding domain. In some embodiments, one or more amino acids are a) A, b) A The group is selected from c)GG, d)PP, and e)AA.

[0047] In some embodiments, the first antigen-binding domain and the second antigen-binding domain are the same It is one.

[0048] In some embodiments, the FcRn / antigen binding molecule consists of an FcRn binding molecule and FcRn It contains only one antigen-binding domain linked to the binding molecule.

[0049] In one embodiment, an FcRn / antigen-binding molecule comprising a first heavy chain, wherein the first heavy chain is sequence At least 70% of one of the amino acid sequences numbered 137-176 and 180 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical FcRn / antigen-binding molecules containing the following amino acid sequence are provided herein. In that embodiment, the first heavy chain is at least 70% of the amino acid sequence of SEQ ID NO: 180. 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical It contains a certain amino acid sequence. In some embodiments, the first heavy chain is sequence numbers 137-1 It contains or consists of one of the amino acid sequences of 76 and 180. In some embodiments, the first heavy chain contains the amino acid sequence of SEQ ID NO: 180, or the same It consists of. In some embodiments, the first heavy chain has a further added at the C-terminus. It further contains one of the amino acids, and one of the further amino acids is optionally A, AG. Selected from GG and PP.

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

[0051] In one embodiment, a selection from sequence numbers 43-74, 84-90, and 120-127 is used. The CDR1 amino acid sequence, CDR2 amino acid sequence, and CD of the VHH fragment containing the amino acid sequence. An antigen-binding domain containing the R3 amino acid sequence is provided herein.

[0052] In some embodiments, the first and / or second antigen-binding domains are a) Sequence ID 13 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, b) Sequence ID 14 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, c) Sequence ID 15 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, d) Sequence ID 16 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, e) Sequence ID 17 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, f) Sequence ID 10 (CDR1), Sequence ID 18 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, g) Sequence ID 10 (CDR1), Sequence ID 19 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, h) Sequence ID 10 (CDR1), Sequence ID 20 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, i) Sequence ID 10 (CDR1), Sequence ID 21 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, j) Sequence ID 10 (CDR1), Sequence ID 22 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, k) Sequence ID 10 (CDR1), Sequence ID 23 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, l) Sequence ID 10 (CDR1), Sequence ID 24 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, m) Sequence ID 10 (CDR1), Sequence ID 25 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, n) Sequence ID 10 (CDR1), Sequence ID 26 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, o) Sequence ID 10 (CDR1), Sequence ID 27 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, p) Sequence ID 10 (CDR1), Sequence ID 28 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, q) Sequence ID 10 (CDR1), Sequence ID 29 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, r) Sequence ID 10 (CDR1), Sequence ID 30 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, s) Sequence ID 10 (CDR1), Sequence ID 31 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, t) Sequence ID 10 (CDR1), Sequence ID 32 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, u) Sequence ID 10 (CDR1), Sequence ID 33 (CDR2), and Sequence ID 12 (CDR 3) Amino acid sequence including, v) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 34 (CDR 3) Amino acid sequence including, w) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 35 (CDR 3) Amino acid sequence including, x) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 36 (CDR 3) Amino acid sequence including, y) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 37 (CDR 3) Amino acid sequence including, z) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 38 (CDR 3) Amino acid sequence including, aa) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 39 (CD Amino acid sequence including R3, bb) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 40 (CD Amino acid sequence including R3, cc) Sequence ID 15 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 36 (CD Amino acid sequence including R3, dd) Sequence ID 15 (CDR1), Sequence ID 21 (CDR2), and Sequence ID 12 (CD Amino acid sequence including R3, ee) Sequence ID 10 (CDR1), Sequence ID 41 (CDR2), and Sequence ID 12 (CD Amino acid sequence including R3, ff) Sequence ID 10 (CDR1), Sequence ID 20 (CDR2), and Sequence ID 36 (CD Amino acid sequence including R3, gg) Sequence ID 111 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (C Amino acid sequence including DR3, hh) Sequence ID 112 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 12 (C Amino acid sequence including DR3, ii) Sequence ID 10 (CDR1), Sequence ID 113 (CDR2), and Sequence ID 12 (C Amino acid sequence including DR3, jj) Sequence ID 10 (CDR1), Sequence ID 114 (CDR2), and Sequence ID 12 (C Amino acid sequence including DR3, kk) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 115 (C Amino acid sequence including DR3, ll) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 116 (C Amino acid sequence including DR3, mm) Sequence ID 10 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 117 (C Amino acid sequence including DR3, nn) Sequence ID 118 (CDR1), Sequence ID 11 (CDR2), and Sequence ID 119 ( Amino acid sequence including CDR3, oo) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 77 (CD Amino acid sequence including R3, pp) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 78 (CD Amino acid sequence including R3, qq) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 79 (CD Amino acid sequence including R3, rr) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 80 (CD Amino acid sequence including R3, ss) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 81 (CD Amino acid sequence including R3, tt) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 82 (CD Amino acid sequences including R3), and uu) Sequence ID 75 (CDR1), Sequence ID 76 (CDR2), and Sequence ID 83 (CD It includes an amino acid sequence selected from the group consisting of amino acid sequences containing R3).

[0053] In some embodiments, the antigen-binding domain is sequence number 14 (CDR1), sequence number It contains amino acid sequences including 11 (CDR2) and SEQ ID NO: 12 (CDR3).

[0054] In some embodiments, the first and / or second antigen-binding domains are sequence numbers 43- The amino acid sequences described in 74, 84-90, and 120-127, and at least 70%, 75 They are identical by %, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. It contains an amino acid sequence. In some embodiments, the antigen-binding domain is described in SEQ ID NO: 44. The listed amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96% It contains amino acid sequences that are 97%, 98%, or 99% identical. In some embodiments, The first and / or second antigen-binding domains are SEQ ID NOs: 43-74, 84-90, and It includes an amino acid sequence selected from the amino acid sequences described in 120-127. In the application form, the first and / or second antigen-binding domains are the amino acids described in SEQ ID NO: 44. Includes arrays.

[0055] In some embodiments, the antigen-binding domain is sdAb. So, sdAb is a VHH fragment. In some embodiments, the antigen-binding domain is The VHH fragment further contains one or more additional amino acids at its C-terminus. Several implementations In this state, one or more additional amino acids are a) A, b) AG, c) GG, d) PP, and e Selected from the group consisting of )AA.

[0056] In some embodiments, the antigen-binding domain specifically binds to HSA. In the application form, the antigen-binding domain is the VHH fragment, and the VHH fragment is acidic to HSA. It binds with stronger affinity than H at a neutral pH. In some embodiments, the antigen-binding domain When coupled to HSA and optionally measured by surface plasmon resonance, HSA It binds to Alb23 (sequence number 42) with a lower affinity than Alb23 binds to it.

[0057] Furthermore, any of the FcRn / antigen binding molecules described herein or the One or more isolated polynucleotides encoding one of the antigen-binding domains It will be provided.

[0058] Furthermore, it includes one or more isolated polynucleotides as described herein. An expression vector is provided.

[0059] Furthermore, one or more isolated polynucleotides described herein or Host cells containing either expression vector are provided.

[0060] Furthermore, a method for producing an FcRn / antigen-binding molecule or antigen-binding domain, The host cells described herein express the expression of FcRn / antigen-binding molecules or antigen-binding domains. A method is provided which includes culturing under conditions that enable this.

[0061] Furthermore, the FcRn / antigen binding molecule or the antigen binding molecule described herein A pharmaceutical composition comprising a composite domain and at least one pharmaceutically acceptable carrier is proposed. To be served.

[0062] Furthermore, the FcRn / antigen-binding molecules described herein for use as pharmaceuticals, This specification provides for antigen-binding domains or pharmaceutical compositions thereof.

[0063] Furthermore, a method for reducing serum IgG in a subject, which is necessary for the subject. , a therapeutically effective amount of the FcRn / antigen-binding molecule described herein (for example, as described herein) The FcRn / HSA binding molecule described herein, or the antigen-binding domain described herein, A method is provided which includes administering the pharmaceutical composition.

[0064] Furthermore, a method for treating antibody-mediated disorders in the subject, which is in need of the subject In the elephant, a therapeutically effective amount of the FcRn / antigen-binding molecule described herein (for example, as described herein). FcRn / HSA binding molecule as described herein, or antigen-binding domain as described herein. A method is provided which includes administering, or a pharmaceutical composition thereof.

[0065] In some embodiments, antibody-mediated injury is IgG-mediated injury. In the context of application, antibody-mediated disorders are autoimmune diseases. In some embodiments, auto Immunological diseases include allograft rejection, alopecia areata, ankylosing spondylitis, antiphospholipid syndrome, and autologous grafts. Immunotherapy-induced Addison's disease, Alzheimer's disease, anti-neutrophil cytoplasmic autoantibodies (ANCA), adrenal autoimmune disease Autoimmune diseases, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune myocarditis, autoimmune Neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (ITP or idiopathic) idiopathic thrombocytopenic purpura urpura), idiopathic thrombocytopenic purpura (idiopathic thrombocytopenic purpura) ytopenia purpura), immune-mediated thrombocytopenia, or primary immune thrombocytopenia (Platelet palsy), autoimmune urticaria, Behçet's disease, bullous pemphigoid (BP), cardiomyopathy, Jasslemann's disease, celiac plue dermatitis, chronic fatigue immune deficiency syndrome, chronic inflammatory Demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, scarring pemphigoid CREST syndrome, cold agglutination disorder, Crohn's disease, dilated cardiomyopathy, discoid lupus erythematosus Acquired epidermolysis bullosa, essential mixed cryoglobulinemia, factor VIII deficiency, Fibromyalgia - Fibromyalgia, Glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Goodpasti Jerk syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, idiopathic inflammatory myocardial infarction Idiopathic membranous neuropathy (IIM), idiopathic pulmonary fibrosis, IgA neuropathy IgM-dependent neuropathy, immune-mediated necrotizing myopathy (IMNM), juvenile arthritis Kawasaki disease, lichen planus, lichen sclerosing, 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 of pregnancy, pemphigus vulgaris (PV), pemphigus foliaceus (PF), malignant Anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polymyalgia rheumatica, polymyalgia Myositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), anti-synthetase syndrome Group (ASyS), primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic-related conditions Arthritis, relapsing polychondritis, Raynaud's phenomenon, Reiter's syndrome, rheumatoid arthritis, sarcoidosis Cis, scleroderma, Sjögren's syndrome, parenchymal organ transplant rejection, generalized rigidity syndrome, systemic lupus erythema Matositis, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson disease Syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura, ulcerative colitis uveitis, herpetiform dermatitis vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, vitiligo, and uveitis The group is selected from those with Gener's granulomatosis.

[0066] In some embodiments, the FcRn / antigen-binding molecule or antigen-binding domain is applied to the target. It is administered simultaneously with or sequentially with additional therapeutic agents.

[0067] Furthermore, for use in the treatment of antibody-mediated disorders, FcRn / as described herein An antigen-binding molecule or an antigen-binding domain as described herein is provided.

[0068] Furthermore, F described herein for the manufacture of pharmaceuticals for the treatment of antibody-mediated disorders cRn / antigen binding molecule (e.g., FcRn / HSA binding molecule as described herein) or The use of antigen-binding domains described herein is provided. [Brief explanation of the drawing]

[0069] [Figure 1] This is a schematic diagram of a typical two-armed (TA)Fc-ABDEG molecule that possesses anti-HSAVHH fused at the N-terminus of both Fc domains.

[0070] [Figure 2] The pharmacokinetic profiles of individual cynomolgus monkeys treated with a single intravenous (IV) dose of the Fc-ABDEG molecule (TA-Alb23-Fc-ABDEG), each containing one anti-HSAVHH(Alb23) fused at the N-terminus of each Fc domain, are shown; C1-3: 20 mg / kg, C4-6: 5 mg / kg. TA-Alb23-Fc-ABDEG concentrations are plotted over time. Data points are shown as the mean ± SD of two pairs (n = two pairs, 2x study sample dilution in each pair) as the result per post-dose time point.

[0071] [Figure 3A] This shows the pharmacodynamic profiles of individual cynomolgus monkeys treated with a single IV dose of TA-Alb23-Fc-ABDEG; -C1~3: 20 mg / kg. % total serum IgG levels of cynomolgus monkeys compared to pre-dose are plotted over time. Data points are shown as the mean ± SD of two pairs (n=2 pairs, 2x study sample dilution in each pair) as the result per post-dose time point. [Figure 3B] This shows the pharmacodynamic profiles of individual cynomolgus monkeys treated with a single IV dose of TA-Alb23-Fc-ABDEG; -C4~6: 5 mg / kg. % total serum IgG levels of cynomolgus monkeys compared to pre-dose were plotted over time. Data points are shown as the mean ± SD of two pairs (n=2 pairs, 2x study sample dilution in the pairs) as the result per post-dose time point.

[0072] [Figure 4] This shows the TA-Alb23-Fc-ABDEG ADA development profiles of individual cynomolgus monkeys treated with a single IV dose of TA-Alb23-Fc-ABDEG; C1-3: 20 mg / kg, C4-6: 5 mg / kg. The immune response that occurred was plotted over time. Data points are shown as the mean ± SD of one pair (n=1 pair, 1x study sample dilution in the pair) as the result per time point after one dose.

[0073] [Figure 5] This is a schematic diagram of a typical TA Fc-ABDEG molecule that possesses anti-HSAVHH(Alb23) fused at the C-terminus of both Fc domains.

[0074] [Figure 6A]This graph shows the total circulating IgG levels of individual cynomolgus monkeys after a single IV bolus injection of the Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) containing anti-HSAVHH(Alb23) fused via a 20GS linker at the C-terminus of both Fc domains. On day 0, monkeys in group 1 (G1-1, G1-2, and G1-3) received a dose of TA-Fc-ABDEG-Alb23 at 30 mg / kg. The percentage relative to baseline at -5 minutes on day 0 was 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 minutes) 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 study samples analyzed in pairs (technical replicates). [Figure 6B] This graph shows the total circulating IgG levels of individual cynomolgus monkeys after a single IV bolus injection of the Fc-ABDEG molecule (TA-Fc-ABDEG-Alb23) containing anti-HSAVHH(Alb23) fused via a 20GS linker at the C-terminus of both Fc domains. On day 0, monkeys in group 2 (G2-1, G2-2, and G2-3) received a dose of 75 mg / kg of TA-Fc-ABDEG-Alb23. The percentage relative to baseline at -5 minutes on day 0 was 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 minutes) 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 study samples analyzed in pairs (technical replicates).

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

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

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

[0078] [Figure 10A]This shows normalized tracer IgG1 after a single IV dose of TA-Fc-ABDEG molecules (TA-Fc-ABDEG-Alb23, TA-Fc-ABDEG-Alb23(modified), and TA-Fc-ABDEG-0GS-Alb23(modified); see Table S15 for construct descriptions) at a dose of 30 mg / kg in AlbuMus mice. Normalized hIgG1 (pre-dosage %) after injection is shown per group. Changes in hIgG1 concentration are plotted over time (days after injection) as % relative to pre-dosage at -1 hour on day 0. Data points represent the mean ± SEM per time point for 4 mice per group. Dashed lines represent LLOQ from ELISA readout. [Figure 10B] This shows normalized tracer IgG1 after a single IV dose of TA-Fc-ABDEG molecules (TA-Fc-ABDEG-Alb23, TA-Fc-ABDEG-Alb23(modified), and TA-Fc-ABDEG-0GS-Alb23(modified); see Table S15 for construct descriptions) at a dose of 30 mg / kg in AlbuMus mice. Normalized total serum IgG (hVIg, pre-dosage %) after injection is shown per group. Changes in hVIg concentration are plotted over time (days after injection) as % relative to pre-dosage at -1 hour on day 0. Data points show the mean ± SEM per time point for 4 mice per group.

[0079] [Figure 11]This study shows the serum pharmacokinetics (PK) of TA-Fc-ABDEG-Alb23(modified), TA-Fc-ABDEG-Alb23, and TA-Fc-ABDEG-0GS-Alb23(modified) after a single IV injection. Three groups of AlbuMus mice received a single dose of 30 mg / kg of either TA-Fc-ABDEG-Alb23(modified), TA-Fc-ABDEG-Alb23, or TA-Fc-ABDEG-0GS-Alb23(modified). Serum concentrations of the test substance were plotted over time during the study as the mean per group. Data points represent the mean ± SEM of four animals per group.

[0080] [Figure 12] This study shows the ADA response in individual Albumus mice after a single IV injection of TA-Fc-ABDEG-Alb23 (modified), TA-Fc-ABDEG-Alb23, or TA-Fc-ABDEG-0GS-Alb23 (modified). On day 0, mice received TA-Fc-ABDEG-Alb23 (modified) (30 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), or TA-Fc-ABDEG-0GS-Alb23 (modified) (30 mg / kg). The ADA response (OD450, right Y-axis) is overlaid with the PK profile (μg / mL, left Y-axis) and the time course per mouse group (days after injection, X-axis). Each data point (PK and ADA) represents the mean of the study samples analyzed in pairs (technical replicates).

[0081] [Figure 13] This shows the normalized albumin levels (pre-dose %) after a single IV injection of TA-Fc-ABDEG-Alb23(modified) (30 mg / kg), TA-Fc-ABDEG-Alb23(30 mg / kg), or TA-Fc-ABDEG-0GS-Alb23(modified) (30 mg / kg) in AlbuMus mice. Albumin levels are plotted over time (days after injection) as a percentage of the average pre-dose level (day 0, -1 hour) per group. Data points represent the mean ± SEM per time point for 4 mice per group.

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

[0083] [Figure 15] Schematic diagrams of typical two-arm and one-arm albumin-binding VHH Fc-ABDEG molecules according to the present invention are shown.

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

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

[0086] [Figure 18] This study demonstrates the effect of the one-armed Fc-ABDEG-2H11 molecule on FcRn degradation in the presence or absence of HSA. Furthermore, the pH-dependent HSA binding profiles of each molecule are shown to illustrate that the use of VHH with reduced albumin-binding affinity reduces 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. Bars represent the mean ± SD of two independent experiments performed in pairs.

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

[0088] [Figure 19B] Serum pharmacokinetics (PK) of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IP injection are shown. Tg32-hFc mice received 30 mg / kg of TA-Fc-ABDEG-Alb23, 30 mg / kg of TA-Alb23-Fc-ABDEG, or 25 mg / kg of OA-Fc-ABDEG-Alb23 (equimolar doses). Serum concentrations of the test substance were plotted over time during the study as the mean per group. Data points represent the mean ± SEM of 5 animals per group.

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

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

[0091] [Figure 22A]This study demonstrates 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 either 30 mg / kg of TA-Fc-ABDEG-Alb23, 30 mg / kg of TA-Alb23-Fc-ABDEG, 25 mg / kg of OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for 5 mice per group. Normalized tracer IgG levels (pre-administration %) after injection per group are shown. Changes in tracer IgG levels were plotted over time (days after injection) as % relative to pre-administration at -2 hours on day 0. [Figure 22B] This study demonstrates 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 either 30 mg / kg of TA-Fc-ABDEG-Alb23, 30 mg / kg of TA-Alb23-Fc-ABDEG, 25 mg / kg of OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for 5 mice per group. Serum PK of TA-Fc-ABDEG-Alb23, TA-Alb23-Fc-ABDEG, and OA-Fc-ABDEG-Alb23 after a single IV injection is also shown. The serum concentration of the test substance was plotted over time as the mean per group during the course of the study. [Figure 22C]This study demonstrates 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 either 30 mg / kg of TA-Fc-ABDEG-Alb23, 30 mg / kg of TA-Alb23-Fc-ABDEG, 25 mg / kg of OA-Fc-ABDEG-Alb23 (equimolar to 30 mg / kg of the two-arm construct), or PBS on day 0. Data points represent the mean ± SEM per time point for 5 mice per group. Normalized albumin levels (pre-dose %) after injection per group are shown. Albumin levels are plotted over time (days after injection) as a percentage of the average pre-dose (day 0, -2 hours) per group.

[0092] [Figure 23] This study demonstrates the effect of a one-armed Fc-ABDEG-Alb23 variant molecule 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 bar) or in the presence of 50,000 nM HSA (striped bar). The bars represent the mean ± SEM of wells in pairs and are the results of two independent runs.

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

[0094] [Figure 25A]This study shows the PD / PK effects of OA-Fc-ABDEG-Alb23-F32A with a 20GS linker, OA-Fc-ABDEG-Alb23-F32A with a 30GS linker, and OA-Fc-ABDEG-3Rab. Data points represent the mean ± SD of 3-4 animals per group. Pharmacokinetic profiles of OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg) after single IP injection in AlbuMus Rag1KO mice are shown. Serum concentrations of the test substances are plotted over time during the study as the mean per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph. [Figure 25B] This study shows the PD / PK effects of OA-Fc-ABDEG-Alb23-F32A with a 20GS linker, OA-Fc-ABDEG-Alb23-F32A with a 30GS linker, and OA-Fc-ABDEG-3Rab. Data points represent the mean ± SD of 3-4 animals per group. Normalized levels (pre-dosage %) of total preload human IgG in Albumus Rag1 KO after a single IP administration of OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23-F32A (25 mg / kg) are shown. Changes in total IgG concentration are plotted over time (days after injection) as a percentage of pre-dosage at -2 hours on day 0.

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

[0096] [Figure 26C]This shows the pharmacokinetic profiles of ARGX-113 (efgartigimod; 20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg) in Albumus Rag1 KO mice after a single IP injection. Serum concentrations of the test substances are plotted over time during the study as the mean per group. Data points represent the mean ± SD of 4-5 animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph.

[0097] [Figure 26D] This report shows the levels of human serum albumin (%) relative to pre-dose levels in Albuminus Rag1 KO mice after a single IP administration of ARGX-113 (efgartigimod; 20 mg / kg), TA-Fc-ABDEG-Alb23 (30 mg / kg), OA-Fc-ABDEG-Alb23 (25 mg / kg), OA-Fc-ABDEG-3Rab (25 mg / kg), OA-Fc-ABDEG-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-Alb23-M34A (25 mg / kg). Albumin levels are plotted over time (days after injection) as a percentage of pre-dose levels (day 0, -2 hours) averaged per group. Data points represent the mean ± SEM per time point for 4-5 mice per group.

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

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

[0100] [Figure 29A] This shows the pharmacokinetic profiles in cynomolgus monkeys treated with a single intravenous (IV) dose of ABDEG-30GS-Alb23-SM. ABDEG-30GS-Alb23-SM concentrations are plotted over time. Data points represent the mean ± SD of three individual monkeys (n=3) administered 10 mg / kg of ABDEG-30GS-Alb23-SM. Data points with results for only one individual monkey are marked with an asterisk. For comparison, PK profiles in cynomolgus monkeys of equimolar doses of ephgartigimod (model simulation), as well as nearly equimolar doses of OA-HEL-ABDEG (experimental data) and TA-ABDEG-Alb23 (experimental data) are plotted. Points in time where the presence of ADA is detected and there is a steep decrease in concentration in the PK curve are excluded from the graph. [Figure 29B]This shows the pharmacokinetic profiles in cynomolgus monkeys treated with a single intravenous (IV) dose of ABDEG-30GS-Alb23-SM. ABDEG-30GS-Alb23-SM concentrations are plotted over time. Data points represent the mean ± SD of five individual monkeys (n=5) administered 60 mg / kg of ABDEG-30GS-Alb23-SM. Data points with results for only one individual monkey are marked with an asterisk. For comparison, PK profiles in cynomolgus monkeys for equimolar doses of ephgartigimod (model simulation), as well as nearly equimolar doses of OA-HEL-ABDEG (experimental data) and TA-ABDEG-Alb23 (experimental data) are plotted. Points in time where the presence of ADA is detected and there is a steep decrease in concentration in the PK curve are excluded from the graph.

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

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

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

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

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

[0106] [Figure 33B] This study demonstrates 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 the test molecules in the absence of HSA or in the presence of 50,000 nM HSA. Each bar represents the mean ± SD of at least three independent experiments performed on two technical replicates.

[0107] [Figure 34A] This shows the normalized levels (pre-dose %) of tracer human IgG in Albuminus Rag1 KO mice after a single IP injection of PBS (placebo), fgultigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). Changes in tracer hIgG concentration are plotted over time (days after injection) as a percentage of pre-dose at -2 hours on day 0. Data points represent the mean ± SEM per time point for 5 mice per group.

[0108] [Figure 34B] This shows the normalized levels (pre-dose %) of total preloaded human IgG in Albumus Rag1 KO after a single IP administration of PBS (placebo), fgultigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg). Changes in total IgG concentration are plotted over time (days after injection) as a percentage of pre-dose at -2 hours on day 0. Data points represent the mean ± SEM of 5 animals per group.

[0109] [Figure 34C] This graph shows the pharmacokinetic profiles of fgultigimod (20 mg / kg), OA-Fc-ABDEG-30GS-Alb23-F32A (25 mg / kg), and OA-Fc-ABDEG-20GS-Alb23 (25 mg / kg) after a single IP injection in AlbuMus Rag1KO mice. Serum concentrations of the test substances are plotted over time during the study as the mean per group. Data points represent the mean ± SD of 5 animals per group. Values ​​below the lower limit of quantification (LLOQ) are excluded from the graph. [Modes for carrying out the invention]

[0110] This disclosure relates to an engineered FcRn-binding molecule (F) linked to one or more antigen-binding domains. The invention provides a cRn / antigen-binding molecule. In one embodiment, the anti-HSA antigen-binding domain is C-terminal , or FcRn links linked at the N-terminus, C-terminus, or positions other than the N-terminus FcRn / antigen-binding molecules containing the child are provided. In some embodiments, FcRn / The antigen-binding molecule contains an FcRn-binding molecule and a single antigen-binding domain. Nucleic acids encoding such FcRn / antigen-binding molecules, vectors, host cells, and manufacturing methods. Methods for their use in the treatment of antibody-mediated disorders are provided herein. .

[0111] definition As used herein, the term "FcRn" refers to the neonatal Fc receptor. An exemplary FcRn molecule is FCGR, as shown in RefSeq NM 004107. One example is the human FcRn encoded by the T gene. The corresponding amino acids of the protein The acid sequence is shown in RefSeq NP_004098.

[0112] As used herein, the term "FcRn-binding molecule" specifically refers to a molecule that binds FcRn. Refers to any of the drugs that bind to it. As used herein, "FcRn antagonist" The term "fcRn" refers to a substance that specifically binds to FcRn and inhibits immunity against FcRn (e.g., human FcRn). This refers to any drug that inhibits the binding of globulin. In one embodiment, FcRn ant The gonist includes an Fc region (for example, a variant Fc region disclosed herein), F It specifically binds to cRn via the Fc region and inhibits the binding of immunoglobulin to FcRn. In one embodiment, the FcRn antagonist is not a full-length IgG antibody. In this state, the FcRn antagonist has an antigen-binding domain that binds to the target antigen, and a Varian The Fc region and includes. In one embodiment, the term "FcRn antagonist" is used to mean an anti- A body or its antigen-binding fragment, wherein the antigen-binding domain or its Fc region is attached to the FcRn. It specifically binds to the FcRn of immunoglobulins (e.g., IgG autoantibodies). This refers to an antibody or its antigen-binding fragment that inhibits binding to a region. 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. or HSA. In some embodiments, the antigen is HSA. or HSA. In some embodiments, the antigen is HSA.

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

[0114] As used herein, the term "specifically binds" 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 can bind to other molecules, for example, in an immunoassay, BIAcore™, K inExA 3000 instrument (Sapidyne Instruments, Boise, Id.), or other assays known in the art, generally bind with a much lower affinity. In a specific embodiment, a molecule that specifically binds to a given target binds to the antigen with at least 2 logs, 2.5 logs, 3 logs, 4 logs less K Id.) or other assays known in the art, generally bind with a much lower affinity. In a specific embodiment, a molecule that specifically binds to a given target binds to the antigen with at least 2 logs, 2.5 logs, 3 logs, 4 logs less K or K when the molecule binds non-specifically to another target. D or K D less than.[[ID=4))

[0115] As used herein, the term "operatively linked" refers to the linkage of polynucleotide sequence elements that are in a functional relationship. For example, a polynucleotide sequence is separate refers to the linkage of polynucleotide sequence elements that are in a functional relationship. For example, a polynucleotide sequence is separate operatively linked when in a functional relationship with a polynucleotide sequence . In some embodiments, a transcriptional regulatory polynucleotide sequence, e.g., a promoter, an enhancer, or other expression control element, is operatively linked to a polynucleotide sequence encoding a protein when it affects the transcription of the polynucleotide sequence encoding the protein. The operatively linked elements can be continuous or

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

[0117] a non-covalent bond. As used herein, the term "covalently linked" refers to the linkage of two molecules or chemical moieties by a covalent bond. In some embodiments, the covalent bond is a peptide bond or a disulfide bond. As used herein, the term "fused" refers to the linkage 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 discontinuously fused via a peptide linker. In some It is fused to the linker at the first position by a peptide bond, and the second protein It is fused to the peptide linker at a second position by a peptide bond. When used in detail, the term "non-covalently linked" means non-covalently linked This refers to the linking of two molecules or chemical moieties by action or non-covalent bonding. In some embodiments, Non-covalent interactions or non-covalent bonds are hydrogen bonds, electrostatic bonds or interactions, halogens This includes genuity bonding, pi-stacking, and van der Waals interactions.

[0118] Determining the "percentage of identity" between two sequences (e.g., amino acid sequence or nucleic acid sequence) is This can be achieved using mathematical algorithms. Used for comparing two arrays. A concrete, non-restrictive example of a mathematical algorithm is found in Karlin S & Altsch. Modified as in ul SF, (1993) PNAS 90:5873-5877 Karlin S & Altschul SF, (1990) PNAS 87:22 The algorithms 64-2268, each of which is described herein by reference in its entirety. It is incorporated. Such an algorithm is described by Altschul SF et al., (19 90) NBLAST and XBLAST programs of J Mol Biol 215:403 Incorporated into this document, this document is incorporated herein by reference in its entirety. BLAS T nucleotide search uses the NBLAST nucleotide program parameter set, for example. , performed with a score of 100 and a word length of 12, homologous to the nucleic acid molecules described herein. The nucleotide sequence can be obtained. BLAST protein search is XBLAST The program parameter set, for example, score=50, word length=3, is used to run this statement. It is possible to obtain an amino acid sequence homologous to the protein molecule described in the book. To obtain alignment for comparison purposes, gapped BLAST is used in Altschul SF et al.,(1997)Nuc Acids Res 25:3389-3402 As described, Gapped BLAST can be used. Alternatively, PSI BLAST is used to perform iterative searches to detect distance relationships between molecules. Obtain. Same as above. BLAST, gapped BLAST, and PSI BLAST programs. When using them, the data of each program (for example, XBLAST and NBLAST) Fault parameters may be used (for example, National Center for Biotechnology Information(NCBI) on the w See the Worldwide Web, ncbi.nlm.nih.gov. Array Another specific non-restrictive example of a mathematical algorithm used for comparison is Myers and Miller, (1988) CABIOS 4:11-17 algorithm Yes, and this document is incorporated herein by reference in its entirety. Zum is part of the ALIGN program, which is part of the GCG sequence alignment software package. It will be incorporated into RAM (version 2.0). ALIGN will be used to compare amino acid sequences. When using the program, the PAM120 weight residue table, gap length penalty 12, and G A cap penalty of 4 may be used.

[0119] Percent identity between two sequences can be calculated using a similar technique to the one described above, by checking the gap. can be determined with or without allowing a tolerance or a gap. In the calculation of percent identity, typically, only exact matches are counted.

[0120] As used herein, the terms “antibody” and “antibodies” include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules that include 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 that include two heavy chains and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies (sdAbs), monovalent antibodies, single chain antibodies or single chain Fvs (scFvs), camelid antibodies, affibody molecules, VHH fragments, Fab fragments, F(ab’)2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotype ( anti-Id) antibodies (e.g., including anti-anti-Id antibodies), and antigen-binding fragments of any of the above. Antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or species (e.g., mouse IgG or IgG ) of an immunoglobulin molecule. 2a 2b )

[0121] As used herein, “antigen-binding domain” "domain)" (or "antigen binding domain)" The term "antinucleotide" refers to any polypeptide that specifically binds to an antigen. Examples of primordial binding domains include antibodies, such as Fab fragments, F(ab')2 fragments, and disulfide. Fido-linked Fv (sdFv), single-stranded Fv (scFv), CDR, VH domain (VH), VL domain (VL), single-domain antibody (sdAb), VHH fragment, camel antibody, and Examples include polypeptides derived from any of the antigen-binding fragments listed above. Also, synthetic antigen-binding proteins or antibody-mimicking proteins, such as anticalin and It includes DARPin.

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

[0123] As used herein, the term “Fc region” refers to the Fc domain of its two heavy chains. This refers to the portion of immunoglobulin formed by the nucleotide. The Fc region is the wild-type Fc region (natural It may be an Fc region or a variant Fc region. The natural Fc region is a homodimer. The c region may originate from any natural immunoglobulin. In some embodiments, the Fc region The region is formed from the constant region of the IgA, IgD, IgE, or IgG heavy chain. In some embodiments, the Fc region is formed from the IgG heavy chain constant region. Therefore, the IgG heavy chain is the constant region of the IgG1, IgG2, IgG3, or IgG4 heavy chain. In some embodiments, the Fc region is formed from the IgG1 heavy chain constant region. In that embodiment, the IgG1 heavy chain constant region is G1m1(a), G1m2(x), G1m Includes 3(f) or G1m17(z) allotypes. For example, Jefferis and Lefranc (2009) mAbs 1(4):332-338, and de Tae See Ye et al., (2020) Front Immunol. 11:740. Therefore, these documents are incorporated herein by reference in their entirety.

[0124] As used herein, the term “variant Fc region” refers to a region that is different from a natural Fc region. This refers to a variant of the Fc region that has one or more changes. Modifications include amino acid substitutions and additions. This may include addition and / or deletion, linking of additional parts, and / or modification of natural glycans. This term encompasses each of the constituent Fc domains, each representing a different heterodimeric Fc region. The term also refers to a single-stranded Fc whose constituent Fc domains are linked together by a linker portion. To encompass a region.

[0125] As used herein, the term "Fc domain" refers to the CH2 and CH3 of an antibody. This refers to a portion of a single immunoglobulin heavy chain that includes both domains. In some embodiments, The Fc domain is the hinge region (e.g., upper, middle, and / or lower hinge regions), C It includes an H2 domain and at least a portion of the CH3 domain. In some embodiments, The Fc domain does not contain a hinge region.

[0126] As used herein, the term "hinge region" refers to the CH1 domain being a CH2 domain This refers to the portion of the heavy chain molecule that is bonded to the main body. In some embodiments, the hinge region is the largest It is the length of 70 amino acid residues. In some embodiments, this hinge region is approximately It contains 11-17 amino acid residues, is mobile, and therefore has two N-terminal antigenic bonds. This allows the joint region to move independently. In some embodiments, the hinge region is The length is 12 amino acid residues. In some embodiments, the hinge region is 15 This is the length of an amino acid residue. In some embodiments, the hinge region consists of 62 amino acids. This refers to the length of the residue. The hinge region consists of three distinct hinge domains: upper, middle, and lower. It can be subdivided into domains. The FcRn / antigen-binding molecule of this disclosure has a hinge region. This may include all or any part of it. In some embodiments, the hinge region is , derived from IgG1 antibody. In some embodiments, the hinge region is EPKSCDKT Contains the amino acid sequence of HTCPPCP (SEQ ID NO: 179).

[0127] As used herein, the term “FcRn bond fragment” means a fragment that confers FcRn bonds. It refers to a portion of the FcRn binding molecule, for example, a portion of the Fc region, which is sufficient for this purpose.

[0128] As used herein, "one-armed" and "one-armed" are used in this specification. "one armed)", "1 arm (one-arm)", "1 arm (one ar The terms "m)" or "OA" refer to FcRn linked to only one antigen-binding domain. This refers to an FcRn / antigen binding molecule that includes a binding molecule. In some embodiments, it is described as "one-arm type". (one-armed)", "1-armed type (one armed)", "1-arm (on e-arm), "one arm", or "OA" refers to two heavy chains of F An FcRn / antigen-binding molecule containing an Fc region including a c domain, wherein the two heavy chains of Fc domains One of the main chains is linked to the antigen-binding domain, and the other of the two heavy chains is linked to the Fc domain. The main term refers to FcRn / antigen-binding molecules that are not linked to an antigen-binding domain. In several embodiments, the antigen-binding domain is one of the Fc domains of the two heavy chains. It is linked at the end. In some embodiments, the antigen-binding domain is F of the two heavy chains. It is linked to one of the N-terminuses of the c-domain. In some embodiments, antigen binding occurs. The domain is attached to one of the two heavy chain Fc domains at a position other than the N-terminus or C-terminus. They are connected. The connection can be covalent or non-covalent. Several implementation forms In this state, the antigen-binding domain is fused to the C-terminus of one of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is the Fc domain of the two heavy chains. It is fused to one of the N-terminuses. In some embodiments, the antigen-binding domain is two It is fused to one of the Fc domains of the heavy chain at a position other than the N-terminus or C-terminus.

[0129] As used herein, "two-armed" and "two-armed" are used. "two-armed"), "two-arm", "two ar The term "m)" or "TA" refers to FcRn binding linked to two antigen-binding domains. This refers to an FcRn / antigen-binding molecule containing the molecule. In some embodiments, it is described as a "two-armed (t "two-armed"), "two-armed", "two-armed" "Two-arm" or "TA" refers to a combination of two heavy-chain Fc units. An FcRn / antigen-binding molecule containing a main Fc domain, with two heavy chain Fc domains. Each of these refers to an FcRn / antigen-binding molecule, which is linked to an antigen-binding domain. In several embodiments, the antigen-binding domain is located at the C-terminus of each of the two heavy chain Fc domains. They are linked. In some embodiments, the antigen-binding domain is the Fc domain of the two heavy chains. It is ligated to the N-terminus of each of the in. In some embodiments, the antigen-binding domain is It is ligated to a position other than the N-terminus or C-terminus of each of the two heavy chain Fc domains. In several embodiments, one of the antigen-binding domains is the Fc domain of the two heavy chains. It is linked to the N-terminus of one of the two heavy chains, and the antigen-binding domain on the other side is the F of the other heavy chain. It is linked to the C-terminus of the c-domain. In some embodiments, the antigen-binding domain One of the two heavy chains is attached to a position other than the N-terminus or C-terminus of one of the Fc domains. The two heavy chains are linked, and the antigen-binding domain on the other side is at the N-terminus of the other Fc domain. They are linked. In some embodiments, one of the antigen-binding domains is two heavy It is ligated to one of the Fc domains of the chain at a position other than the N-terminus or C-terminus, and the other The antigen-binding domain is ligated to the C-terminus of the other Fc domain of the two heavy chains. The bond can be covalent or non-covalent. In some embodiments, the antigen-bound bond The main component is fused to the C-terminus of each of the two heavy chain Fc domains. Several implementations In this state, the antigen-binding domain is fused to the N-terminus of each of the two heavy chain Fc domains. In some embodiments, the antigen-binding domain is the N of each of the two heavy chain Fc domains. It is fused at a position other than the terminal or C-terminus. In some embodiments, the antigen-binding domain One of them is fused to the N-terminus of one of the two heavy chain Fc domains, and the other The antigen-binding domain is fused to the C-terminus of the other Fc domain of the two heavy chains. In several embodiments, one of the antigen-binding domains is the Fc domain of the two heavy chains. One of the antigen-binding domains is fused to a position other than the N-terminus or C-terminus, and the other antigen-binding domain is 2 It is fused to the N-terminus of the other Fc domain of one heavy chain. In some embodiments, the antigen One of the binding domains is the N-terminus or C-terminus of one of the Fc domains of the two heavy chains. It is fused at a position other than the end, and the other antigen-binding domain is the other Fc domain of the two heavy chains. It is fused to the C-terminus of the y-in molecule.

[0130] As used herein, the term “EU location” refers to Edelman, GM et al. al. Proc. Natl. Acad. USA, 63, 78-85 (1969), and Rabat et al., “Sequences of Proteins of I mmunological Interest,”USDept.Health a nd Human Services, 5 th Edition, 1991 This refers to the amino acid position in the EU numbering convention for the Fc region.

[0131] As used herein, the term “antibody-mediated disorder” means that the symptoms of the disorder are related to the subject This refers to any disorder caused by abnormal levels of one or more antibodies in this condition. When used in a specification, the term "autoantibody-mediated disorder" means that the underlying pathology is pathogenic to I This refers to any disease or disorder that is at least partially caused by IgG autoantibodies. vinegar.

[0132] As used herein, the terms “to treat,” “to treat,” and “treatment” are used in this specification. The term “treatment” refers to a therapeutic or preventive measure as described herein. The method of “treatment” is a disease To prevent, cure, or delay one or more symptoms of a disorder or recurrent illness or disorder. To prolong, reduce or improve its severity, or in the absence of such treatment In order to extend the lifespan of the subject beyond the expected lifespan, the disease or disability Administration of polypeptides to subjects who have or are susceptible to such diseases or disorders. To use. In some embodiments, the “treatment” method is used to treat a disease or disorder. or administer polypeptides to subjects predisposed to such diseases or disorders. To prevent or cure a disease or disorder, or a recurrent disease or disorder. Or, to delay it, reduce its severity, or use it to bring it into remission. Yes, they are.

[0133] As used herein, in the context of therapy, the term “effective dose” means This refers to the amount of therapy used to achieve the desired preventive or therapeutic effect.

[0134] As used herein, the terms “dosage” or “administration” refer to a single dose administered to a target. This refers to the amount of medication administered.

[0135] As used herein, the terms “fixed dose” or “uniform dose” both refer to the same thing. Elephant characteristics (e.g., weight, e.g., within a set range; sex; age, e.g., set) This refers to a dosage that does not change based on factors such as being within a certain range.

[0136] As used herein, the term "equivalent dose" refers to the doses of the first and second therapeutic agents. This refers to a dose in which the number of molecules of the first and second therapeutic agents are approximately the same. In the embodiment, the equivalent dose is an equimolar dose. When used herein, "equomolar dose" refers to an equimolar dose. The term "quantity" refers to the dose of the first and second therapeutic agents, and the number of moles of the first and second drugs. However, it refers to the same dose. In some embodiments, the first drug is FcRn / antigen The binding molecule, and the second drug, is efgaltigimod. In some embodiments, etc. The valence dose is calculated using the observed molecular weights of the first and second drugs. Several embodiments Then, the equivalent dose is calculated using the predicted molecular weights of the first and second drugs. In this embodiment, the equivalent dose is determined using the observed molecular weight of the first drug and the predicted molecular weight of the second drug. It is calculated as follows. In some embodiments, the equivalent dose is calculated based on the predicted molecular weight of the first drug and It is calculated using the observed molecular weight of the two drugs.

[0137] As used herein, the terms "pharmacodynamics" and "PD" refer to the interaction of therapeutic agents with living organisms. This refers to biological effects. In some embodiments, biological effects are those of a person who has been administered a therapeutic agent. This involves regulating the amount of circulating IgG in the substance. In some embodiments, the biological effect is therapeutic. This refers to the regulation of the amount of circulating albumin in organisms administered a therapeutic agent. In this case, the terms "improved pharmacodynamics" or "improved PD" refer to the treatment of patients who have been administered a therapeutic agent. This refers to the improvement of a desired biological effect in a living organism. In some embodiments, this refers to an improved drug. The mechanics include reducing the amount of circulating IgG in the subject. In some embodiments, improvements are made. The pharmacodynamics include maintaining the amount of circulating albumin in the subject. In some embodiments, Improved pharmacodynamics include a reduction in the amount of circulating IgG in the subject, and a reduction in circulating albuginea in the subject. This includes maintaining the amount of mine. In some embodiments, the therapeutic agent is an FcRn / antigen binding molecule. be.

[0138] As used herein, the terms "pharmacokinetics" and "PK" refer to the effects of administering pharmacokinetics to an organism. This refers to the biological effect on the therapeutic agent. In some embodiments, the effect is due to the metabolism of the therapeutic agent and / or clearance. In some embodiments, PK refers to the metabolism and / or of the therapeutic agent. Refers to the rate of clearance. When used herein, this may be referred to as "improved pharmacokinetics" or " The term "improved PK" refers to an improvement in the desired effect on an organism of a therapeutic agent administered to that organism. It refers to. In some embodiments, improved pharmacokinetics result in a reduced half-life of the therapeutic agent in the subject. T 1 / 2 ), including an increase in clearance or area under the curve (AUC). Several implementations In this context, the therapeutic agent is an FcRn / antigen-binding molecule.

[0139] As used herein, the terms “subject,” “patient,” or “participant” are, Includes any human or non-human animal. In one embodiment, the subject, patient, or participant is a human It is a human or non-human mammal. In one embodiment, the subject, patient, or participant is human. be.

[0140] As used herein, the terms "about" or "approximately" refer to measurable quantities such as dosage. When referring to a possible value, given A variation of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of the value or range. To include.

[0141] As used herein, the term "molecular weight" refers to "predicted molecular weight" or "observed molecular weight." It can refer to the "quantity". The "predicted molecular weight" of a protein is the total amount of all amino acids in the protein. It is the sum of molecular weights. In certain situations, the "predicted molecular weight" is the "observed molecular weight" of the molecules. This may differ from the following. In some embodiments, these differences may be due to the protein or a given protein Glycosylation, glycanization, ubiquitination, and phosphate formation of the complex with additional proteins. This can occur in proteins due to changes in chemicalization or protein cleavage.

[0142] FcRn / antigen binding molecule This disclosure provides FcRn / antigen-binding molecules or fragments thereof. Several embodiments Therefore, the FcRn / antigen-binding molecules disclosed herein are FcRn-binding molecules and at least It also contains one antigen-binding domain. The FcRn binding molecule is as described herein. It may be any of the FcRn binding molecules. Similarly, the antigen-binding domain is as described herein. It may be any of the antigen-binding domains. In some embodiments, FcRn / antigen binding The synthetic molecule contains only one antigen-binding domain (e.g., a single-arm FcRn / antigen binding molecule). (Molecule). In some embodiments, the FcRn / antigen-binding molecule has two antigen-binding domains. Includes (e.g., two-armed FcRn / antigen-binding molecules).

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

[0144] In some embodiments, the antigen-binding domain is fused to the C-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is fused to the N-terminus of the FcRn-binding molecule. In some embodiments, the antigen-binding domain is attached to the FcRn-binding molecule at the C-terminus. Alternatively, fusion occurs at a location other than the N-terminus.

[0145] In some embodiments, one antigen-binding domain is linked to the N-terminus of the FcRn-binding molecule. It is either bound or fused, and another antigen-binding domain is at the C-terminus of the FcRn-binding molecule. It is linked to or fused to. In some embodiments, one antigen-binding domain Is the FcRn-binding molecule linked to a position other than the N-terminus or C-terminus? Alternatively, they are fused, and another antigen-binding domain is linked to the N-terminus of the FcRn-binding molecule. They are either or fused. In some embodiments, one antigen-binding domain is FcRn One of the binding molecules is linked or fused at a position other than the N-terminus or C-terminus. Furthermore, another antigen-binding domain is either ligated to or fused to the C-terminus of the FcRn-binding molecule. It is.

[0146] In some embodiments, the FcRn binding molecule is an Fc region, for example, a variant Fc region. This is the region. In some embodiments, the antigen-binding domain is the Fc region of the variant Fc region. It is attached to or fused to one of the C-terminuses of the main. So, the antigen-binding domain is located at the N-terminus of one of the Fc domains in the variant Fc region. They are linked or fused. In some embodiments, the antigen-binding domain is F The cRn binding molecule is linked to or fused to at a position other than the C-terminus or N-terminus. Yes, they are.

[0147] In some embodiments, one antigen-binding domain is the Fc domain of the variant Fc region. It is linked to or fused to one of the C-terminuses, and another antigen-binding domain It is either ligated to or fused with the C-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is located in the variant Fc region. It is linked to or fused to one of the N-terminuses of the domain, and another antigen-binding domain The in is either ligated to or fused to the N-terminus of the other Fc domain of the variant Fc region. In some embodiments, one antigen-binding domain is located in the variant Fc region. It is linked to or fused to one of the N-terminuses of the Fc domain, and binds to another antigen. The domain is either ligated to the C-terminus of the other Fc domain in the variant Fc region or They are fused. In some embodiments, one antigen-binding domain is located in the variant Fc region. It is either ligated to a position other than the N-terminus or C-terminus of one of the Fc domains of the region, or fused. The antigen-binding domain is located at the N-terminus of the other Fc domain in the variant Fc region. It is linked or fused at the end. In some embodiments, one antigen-binding domain The in is located at a position other than the N-terminus or C-terminus of one of the Fc domains in the variant Fc region. It is linked to or fused to the variant Fc region, and another antigen-binding domain is located in the variant Fc region. It is either ligated to or fused with the C-terminus of the other Fc domain.

[0148] In some embodiments, the antigen-binding domain is the N-terminus or C of the FcRn-binding molecule. They may be directly connected to the ends, or directly fused to them. In some embodiments, The antigen-binding domain is linked to the N-terminus or C-terminus of the FcRn-binding molecule via a linker. In some embodiments, the linker is an uncuttable linker.

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

[0150] FcRn binding molecule The FcRn-binding molecules disclosed herein include any molecule that binds to FcRn. The molecule consists of either an anti-FcRn antibody, either an anti-FcRn binding region, or either It includes, but is not limited to, an Fc domain or Fc region.

[0151] In some embodiments, the FcRn binding molecule binds to FcRn and inhibits it. It is an FcRn antagonist containing one of the molecules, and the molecule is one of the anti-FcRn antibodies. The anti-FcRn binding region, or the Fc domain or Fc region, is included in either of these regions. , but not limited to these.

[0152] In some embodiments, the FcRn binding molecules disclosed herein are 2, 3, or 4 It includes two FcRn binding regions, for example, an Fc region.

[0153] In some embodiments, the FcRn binding molecule disclosed herein is one or more Fc The region or its FcRn binding fragment is connected to one or more antigen-binding domains (e.g., sdAb This includes combinations with Fab fragments, scFv, or antibody mimics.

[0154] Any of the Fc regions are modified to produce the variant Fc region disclosed herein. It can be converted. Generally, the Fc region or its FcRn binding fragment is human immunoglobulin It originates from [unclear]. However, the Fc region includes, for example, camelid species, rodents (for example) (For example, mice, rats, rabbits, guinea pigs) or non-human primates (e.g., chimpanzees) It is understood that this may originate from immunoglobulins of any other mammalian species, including macaques. Furthermore, the Fc region or its FcRn binding portion is linked to IgM, IgG, IgD, IgA, and Any immunoglobulin class including IgE, as well as IgG1, IgG2, IgG3, And may be derived from any immunoglobulin isotype, including IgG4. In one embodiment, In one embodiment, the Fc region is an IgG Fc region (for example, a human IgG region). The Fc region is the IgG1 Fc region (for example, the human IgG1 region). In one embodiment, The Fc region is a chimeric Fc region that contains parts of several different Fc regions. A preferred example of the Fc region is described in US2011 / 0243966A1, which is by reference. The entire sequence is incorporated herein. Various Fc region gene sequences (e.g., human stationary region) The regional gene sequences are available in the form of publicly available deposits.

[0155] The Fc region may be further cleaved to produce its smallest FcRn binding fragment, and The internal deletion may be possible. The ability of an Fc region fragment to bind to FcRn is any such technology. This can be determined using field-recognized binding assays, such as ELISA.

[0156] FcRn binding molecules and FcRn / antigen binding molecules containing them disclosed herein. To enhance the manufacturability, the constituent Fc region is a non-disulfide bond. It is preferable that it does not contain cysteine ​​residues. Therefore, in one embodiment, the Fc region is It does not contain free cysteine ​​residues.

[0157] In some embodiments, FcRn has increased affinity and reduced affinity for the natural Fc region. Either any Fc variant that specifically binds in a pH-dependent manner, or its FcRn bond cleavage. A variant may be used herein. In one embodiment, the variant Fc region has a desired feature. This includes the conferred amino acid changes, substitutions, insertions, and / or deletions. In some embodiments, The FcRn binding molecule includes a variant Fc region or its FcRn binding fragment, The Fc region or its FcRn binding fragment is connected to FcRn at pH 5.5, corresponding to wild-type Fc It binds with higher affinity compared to the region. In some embodiments, the FcRn binding molecule This includes a variant Fc region or its FcRn binding fragment, and the variant Fc region or its The FcRn binding fragment is attached to FcRn at pH 6.0 and / or pH 7.4, corresponding to the wild type. It binds with higher affinity compared to the Fc region. In some embodiments, FcRn binding occurs. The molecule includes a variant Fc region or its FcRn binding fragment, and the variant Fc region or The FcRn binding fragment is linked to FcRn, and in both acidic and neutral pH, it corresponds to the wild-type FcRn. It binds with higher affinity compared to other regions.

[0158] In some embodiments, the variant Fc region is the Fc region of any innate immunoglobulin. It originates from the region. In some embodiments, natural immunoglobulins are derived from human immunoglobulins. Yes. In some embodiments, the immunoglobulin is IgA, IgD, IgE, or Ig It is G. In some embodiments, the immunoglobulin is IgG. In some embodiments Morphologically, immunoglobulins are human IgA, human IgD, human IgE, or human IgG. Yes. In some embodiments, the immunoglobulin is human IgG. Morphologically, IgG can be IgG1, IgG2, IgG3, or IgG4. In this embodiment, human IgG is human IgG1, human IgG2, human IgG3, or human I It is gG4. In some embodiments, the variant Fc region is the human IgG1 Fc region. It changes from the region. In some embodiments, the human IgG1 Fc region is G1m1(a) This includes allotypes G1m2(x), G1m3(f), or G1m17(z).

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

[0160] In some embodiments, the variant Fc region or its FcRn binding fragment is at least It also contains or consists of one Fc domain. In some embodiments, Varian The Fc region contains or consists of two Fc domains. Several embodiments Therefore, the Fc domain is the same. In some embodiments, the Fc domain is different. In certain embodiments, the variant Fc domain or FcRn described herein may be used. At least one of the binding fragments is, below, 237M, 238A, 239K, 248I, 250A, 250F, 250I, 250M, 250Q, 250S, 250V, 250W, 250Y, 252F, 252W, 252Y, 254T, 255E, 256D, 256E, 256Q, 257A, 257G, 257I, 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, 314K, 314R, 315A, 315H, 317A, 325G, 332V, 334L, 360H, 376A, 378V, 380A, 382A, 384A, 385D, 385H, 386P, 387E, 389A, 389S, 424A, 428A, 428D, 428F, 428G, 428H, 428I, 428K, 428L, 428N, 428P, 428Q, 428S, 428T, 428V, 428W, 428Y, 433K, 434A, 434F, 434H, A small selection is available from 434S, 434W, 434Y, 436H, 436I, and 436F. It contains at least one amino acid or at least two amino acids, and its position follows the EU numbering system. is defined as. EU numbering refers to the convention for the Fc region as described in Edelman, G.M. et al., Proc Natl. Acad. Sci. USA, 63: 78 - 85 (1969), and Kabat et al., “Sequences of Proteins of Immun ological Interest”, U.S. Dept. Health and H uman Services, 5 th edition, 1991. In some embodiments, at least one of the variant Fc domains or FcRn binding fragments described herein is hereinafter 237M, 238 A, 239K, 248I, 250A, 250F, 250I, 250M, 250Q, 250 S, 250V, 250W, 250Y, 252F, 252W, 252Y, 254T, 255 E, 256D, 256E, 256Q, 257A, 257G, 257I, 257L, 257 M, 257N, 257S, 257T, 257V, 258H, 265A, 270F, 286 A, 286E, 289H, 297A, 298G, 303A, 305A, 307A, 307 D, 307F, 307G, 307H, 307I, 307K, 307L, 307M, 307 N, 307P, 307Q, 307R, 307S, 307V, 307W, 307Y, 308 A, 308F, 308I, 308L, 308M, 308P, 308Q, 308T, 309 A, 309D, 309E, 309P, 309R, 311A, 311H, 311I, 312 A, 312H, 314K, 314R, 315A, 315H, , 325G, 332 V, 334L, 360H, 376A, 378V, 380A, 382A, 384A, 385 ​D, 385H, 386P, 387E, 389A, 389S, 424A, 428A, 428 D, 428F, 428G, 428H, 428I, 428K, 428L, 428N, 428 P, 428Q, 428S, 428T, 428V, 428W, 428Y, 433K, 434 A, 434F, 434H, 434S, 434W, 434Y, 436H, 436I, Reg4 It contains 2, 3, 4, or 5 amino acids selected from 36F, and its position is determined by the EU numbering. Therefore, they are defined, and any combination is intended.

[0161] In certain embodiments, the variant Fc domain or FcRn described herein may be used. At least one of the combined fragments is numbered by the EU index listed in Kabat. If added, then 234, 235, 236, 239, 240, 241, 243, 2 44, 245, 247, 252, 254, 256, 262, 263, 264, 265, 2 66, 267, 269, 296, 297, 298, 299, 313, 325, 326, 3 At least selected from 27, 328, 329, 330, 332, 333, and 334 Contains one non-spontaneous amino acid or at least two non-spontaneous amino acids. (Optional) In the selection, at least one of the variant Fc domains contains non-spontaneously occurring amino acid residues. , may be included in additional and / or alternative positions known to those skilled in the art (e.g., U.S. Article 5, No. 624,821, No. 6,277,375, No. 6,737,056, PCT Patent Publication No. 01 / 58957, Publication No. 02 / 06919, Publication No. 04 / 016750, Publication No. See issues 04 / 029207, 04 / 035752, and 05 / 040217. Please note that the contents of these documents are incorporated herein by reference in their entirety. ).

[0162] In a particular embodiment, at least one of the variant Fc domains is Kab If numbered according to the EU index listed at, then 234D, 234E, 23 4N, 234Q, 234T, 234H, 234Y, 234I, 234V, 234F, 23 5A, 235D, 235R, 235W, 235P, 235S, 235N, 235Q, 23 5T, 235H, 235Y, 235I, 235V, 235F, 236E, 239D, 23 9E, 239N, 239Q, 239F, 239T, 239H, 239Y, 240I, 24 0A, 240T, 240M, 241W, 241L, 241Y, 241E, 241R, 24 3W, 243L, 243Y, 243R, 243Q, 244H, 245A, 247V, 24 7G, 252Y, 254T, 256E, 262I, 262A, 262T, 262E, 26 3I, 263A, 263T, 263M, 264L, 264I, 264W, 264T, 26 4R, 264F, 264M, 264Y, 264E, 265G, 265N, 265Q, 26 5Y, 265F, 265V, 265I, 265L, 265H, 265T, 266I, 26 6A, 266T, 266M, 267Q, 267L, 269H, 269Y, 269F, 26 9R, 296E, 296Q, 296D, 296N, 296S, 296T, 296L, 29 6I, 296H, 269G, 297S, 297D, 297E, 298H, 298I, 29 8T, 298F, 299I, 299L, 299A, 299S, 299V, 299H, 29 9F, 299E, 313F, 325Q, 325L, 325I, 325D, 325E, 32 5A, 325T, 325V, 325H, 327G, 327W, 327N, 327L, 32 8S, 328M, 328D, 328E, 328N, 328Q, 328F, 328I, 32 8V, 328T, 328H, 328A, 329F, 329H, 329Q, 330K, 33 0G, 330T, 330C, 330L, 330Y, 330V, 330I, 330F, 33 0R, 330H, 332D, 332S, 332W, 332F, 332E, 332N, 33 At least one selected from the group consisting of 2Q, 332T, 332H, 332Y, and 332A It also contains one or at least two non-spontaneous amino acids. Optional In the selection, at least one of the variant Fc domains is an additional and / or a variant known to those skilled in the art. Or it may include alternative non-naturally occurring amino acid residues (e.g., U.S. Patent No. 5,624,82) No. 1, No. 6,277,375, No. 6,737,056, PCT Patent Publication No. 01 / No. 58957, No. 02 / 06919, No. 04 / 016750, No. 04 / 029 Please refer to issues 207, 04 / 035752, and 05 / 040217. The contents of these documents are incorporated herein by reference in their entirety.

[0163] Other known Fc domain variants that may be used in the compositions disclosed herein are: Ghetie et al, 1997, Nat. Biotech. 15:637-40, Duncan et al, 1988, Nature 332:563-564, Lun d et al, 1991, J. Immunol, 147:2657-2662, Lun d 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,I mmunol Lett.,44:111-117, Lund et al,1995, Faseb J.,9:115-119、Jefferis et al,1996,I mmunol Lett.,54:101-104, Lund et al,1996, J.Immunol,157:4963-4969, Armor et al,199 9, Eur J Immunol 29:2613-2624, Idusogie et al. al,2000,J.Immunol,164:4178-4184、Reddy e t al,2000,J.Immunol,164:1925-1933,Xu et al al,2000,Cell Immunol,200:16-26、Idusogie et al,2001,J.Immunol,166:2571-2575、Shiel ds 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 No. 5,624,821, Same as No. 5,885,573 Number, same as No. 5,677,425, same as No. 6,165,745, same as No. 6,277,375 Same as No. 5,869,046, Same as No. 6,121,022, Same as No. 5,624,821. Same as No. 5,648,260, same as No. 6,528,624, same as No. 6,194,551, same as Nos. 6,737,056, 6,821,505, and 6,277,375, United States Patent Publication No. 2004 / 0002587, and PCT Patent Publication No. 94 / 29351, the same No. 99 / 58572, No. 00 / 42072, No. 02 / 060919, No. 04 Disclosed in / 029207, No. 04 / 099249, and No. 04 / 063351 This includes, but is not limited to, those mentioned, and the content of these documents as a whole is referenced. This specification is more fully incorporated here.

[0164] In one embodiment, the variant Fc region or its FcRn binding fragment consists of two Fc domains. It includes or consists of. In one embodiment, the variant Fc region or its FcR The n-binding fragment contains at least one Fc domain, and at least one Fc domain is , amino acids Y, T, E, K, and F are located at EU positions 252, 254, 256, and 4, respectively. This includes in 33 and 434. In one embodiment, the variant Fc region or its FcRn The binding fragment contains at least one Fc domain, and at least one Fc domain is The amino acids Y, T, E, K, F, and Y are located at EU positions 252, 254, and 256, respectively. This includes in 433, 434, and 436. In one embodiment, the variant Fc region or The FcRn binding fragments bind amino acids Y, T, E, K, and F at EU position 252, respectively. , 254, 256, 433, and 434 contain one Fc domain and amino acid K and F are included in a second Fc domain at EU positions 433 and 434, respectively. Includes. In one embodiment, the variant Fc region or its FcRn binding fragment is amino acid Y, T, E, K, F, and Y are assigned to EU positions 252, 254, 256, 433, and 43, respectively. In 4 and 436, one Fc domain and amino acids K and F are respectively represented as E It includes a second Fc domain located at positions U 433 and 434. In one embodiment, The variant Fc region or its FcRn binding fragment consists of two Fc domains, and Both have amino acids Y, T, E, K, and F at EU positions 252, 254, and 2, respectively. This includes in 56, 433, and 434. In one embodiment, the variant Fc region or its The FcRn binding fragment consists of two Fc domains, both of which contain amino acids Y and T. E, K, F, and Y are assigned to EU positions 252, 254, 256, 433, and 434, respectively. and included in 436.

[0165] In certain embodiments, the variant Fc domain or FcRn described herein may be used. At least one of the combined fragments is as follows:

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

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

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

[0169] (iv) Y, E, and Y at EU locations 252, 286, and 434 respectively It includes a combination of amino acids selected from among them.

[0170] In certain embodiments, the variant Fc domain or FcRn described herein may be used. At least one of the binding fragments is G237M, P238A, S239K, K248I , T250A, T250F, T250I, T250M, T250Q, T250S, T25 0V, T250W, T250Y, M252F, M252W, M252Y, S254T, R 255E, T256D, T256E, T256Q, P257A, P257G, P257I , P257L, P257M, P257N, P257S, P257T, P257V, E25 8H, D265A, D270F, N286A, N286E, T289H, N297A, S 298G, V303A, V305A, T307A, T307D, T307F, T307G , T307H, T307I, T307K, T307L, T307M, T307N, T30 7P, T307Q, T307R, T307S, T307V, T307W, T307Y, V 308A, V308F, V308I, V308L, V308M, V308P, V308Q , V308T, V309A, V309D, V309E, V309P, V309R, Q31 1A, Q311H, Q311I, D312A, D312H, L314K, L314R, N 315A, N315H, K317A, N325G, I332V, K334L, K360H , D376A, A378V, E380A, E382A, N384A, G385D, G38 5H, Q386P, P387E, N389A, N389S, S424A, M428A, M 428D, M428F, M428G, M428H, M428I, M428K, M428L , M428N, M428P, M428Q, M428S, M428T, M428V, M42 8W, M428Y, H433K, N434A, N434F, N434H, N434S, N Select from 434W, N434Y, Y436H, Y436I, and Y436F. Each contains one amino acid substitution, and its position is defined according to EU numbering. In embodiments, the variant Fc domain or FcRn binding fragment described herein At least one of them is: G237M, P238A, S239K, K248I, T2 50A, T250F, T250I, T250M, T250Q, T250S, T250V, T250W, T250Y, M252F, M252W, M252Y, S254T, R255 E, T256D, T256E, T256Q, P257A, P257G, P257I, P2 57L, P257M, P257N, P257S, P257T, P257V, E258H, D265A, D270F, N286A, N286E, T289H, N297A, S298 G, V303A, V305A, T307A, T307D, T307F, T307G, T3 07H, T307I, T307K, T307L, T307M, T307N, T307P, T307Q, T307R, T307S, T307V, T307W, T307Y, V308 A, V308F, V308I, V308L, V308M, V308P, V308Q, V3 08T, V309A, V309D, V309E, V309P, V309R, Q311A, Q311H, Q311I, D312A, D312H, L314K, L314R, N315 A, N315H, K317A, N325G, I332V, K334L, K360H, D3 76A, A378V, E380A, E382A, N384A, G385D, G385H, Q386P, P387E, N389A, N389S, S424A, M428A, M428 D, M428F, M428G, M428H, M428I, M428K, M428L, M4 28N, M428P, M428Q, M428S, M428T, M428V, M428W, M428Y, H433K, N434A, N434F, N434H, N434S, N434 2, 3, 4 are selected from W, N434Y, Y436H, Y436I, and Y436F. or containing five amino acid substitutions, the position of which is defined according to EU numbering, and any of the substitutions Combinations are also being considered.

[0171] In certain embodiments, the variant Fc domain or FcRn described herein may be used. At least one of the combined fragments is as follows:

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

[0173] (ii) T250Q and M428L,

[0174] (iii) V308P and N434A,

[0175] (iv) V308P and N434Y, or

[0176] (v) Combinations of amino acid substitutions selected from M252Y, N286E, and N434Y Includes

[0177] In one embodiment, one, two, or more mutations (e.g., amino acid substitutions) are described in this specification. It is introduced into the hinge region of the polypeptide described in the book, thereby the hinge region The number of cysteine ​​residues in is, for example, as described in U.S. Patent No. 5,677,425. It is changing (for example, increasing or decreasing), and this document is by reference in its entirety. Incorporated herein, the number of cysteine ​​residues in the hinge region is, for example, the light chain and The structure may be modified to facilitate the assembly of the heavy chain, or to alter the stability of the polypeptide. It may change to (for example, increase or decrease).

[0178] In one embodiment, one, two, or more amino acid mutations (e.g., substitution, insertion, or The deletion is introduced within the Fc region, Fc domain, or its FcRn binding fragment. To alter (e.g., decrease or increase) the half-life of a polypeptide in vivo. Examples of mutations that alter the half-life of antibodies (e.g., decrease or increase) are, for example, internationally publicly disclosed. Publications No. 02 / 060919, No. 98 / 23289, and No. 97 / 34631, U.S. Patent No. 5,869,046, No. 6,121,022, No. 6,277,3 Please refer to issues 75 and 6,165,745, all of which are related to those publications. The entirety of this is incorporated herein by reference. In certain embodiments, one, two, or Further amino acid mutations (e.g., substitutions, insertions, or deletions) affect the Fc region, Fc domain. , or introduced within its FcRn binding fragment, the half-life of the polypeptide in vivo is To reduce. In other embodiments, one, two, or more amino acid mutations (e.g., substitutions) An insertion or deletion is introduced into the Fc region, Fc domain, or its FcRn binding fragment. This increases the half-life of the antibody in vivo. In one embodiment, the Fc region or Fc The domain has one or more amino acid mutations (e.g., substitutions) that create a second constant (CH2) domain. (Human IgG1 residues 231-340) and / or a third constant (CH3) domain (H) These may be present in residues 341-447 of IgG1, and these are included in the EU numbering system. Therefore, they are numbered. In one embodiment, the polypeptide described herein is IgG1 The steady-state region includes a substitution from methionine (M) to tyrosine (Y) at position 252. The substitution of serine (S) to threonine (T) at position 254 is included, and threonine The substitution of n(T) to glutamic acid(E) at position 256 is included, and these are EU Numbered according to the numbering system. See U.S. Patent No. 7,658,921. This document is incorporated herein by reference in its entirety. "YTE variant" This type of mutant Fc domain, referred to as [name of mutant], is compared to the wild-type version of the same antibody. It has been shown to exhibit a four-fold increase in half-life (Dall'Acqua WF et a Please refer to l., (2006) J Biol Chem 281:23514-24. (This document is incorporated herein by reference in its entirety). In one embodiment, poly Peptides contain an IgG constant region, which consists of 1, 2, or 3 amino acid residues. Or more amino acid substitutions at positions 251-257, 285-290, 308-314 This includes 385-389 and 428-436, which are part of the EU numbering system. They are numbered according to the following criteria.

[0179] In one embodiment, one, two, or more mutations (e.g., amino acid substitutions) are described in this specification. Fc region, Fc domain, or FcRn binding fragment of polypeptide described in the document (e.g.) For example, the CH2 domain (residues 231-340 of human IgG1) and / or the CH3 domain (Residues 341-447 of human IgG1, numbered according to the EU numbering system) , and / or hinge region (residues 216-2 numbered according to the EU numbering system) 30)) It is introduced into the Fc receptor on the surface of effector cells (e.g., activated To increase or decrease the affinity of antibodies to Fc receptors. Mutations in the Fc region, Fc domain, or its FcRn binding fragment, which reduce or increase the amount of mutations. Techniques for introducing such mutations into the Fc receptor or fragments thereof are known to those skilled in the art. This alters the affinity of the variant Fc region or its FcRn binding fragment to the Fc receptor. Fc regions, Fc domains, or their FcRn binding fragments can be fabricated in such a manner. An example of the mutation is, for instance, Smith P et al., (2012) PNAS 109: 6181-6186, U.S. Patent No. 6,737,056, and International Publication No. 02 / 060 This is described in issues 919, 98 / 23289, and 97 / 34631. All of these documents are incorporated herein by reference in their entirety.

[0180] In one embodiment, one, two, or more amino acid substitutions constitute the Fc region, Fc domain. , or introduced within its FcRn binding fragment, which has the effector function of polypeptides (multiple Changes the number of amino acids. For example, amino acid residues numbered according to the EU numbering system. Groups 234, 235, 236, 237, 239, 243, 267, 292, 297, 300 Select one from 318, 320, 322, 328, 330, 332, and 396. The amino acids above can be replaced with different amino acid residues, thereby changing the polypeptide. It has altered affinity for the effector ligand, but the antigen-binding ability of the parent polypeptide is altered. It retains. Effector ligands whose affinity has changed are, for example, Fc receptors. This approach is based on U.S. Patent Nos. 5,624,821 and 5,648. Further details are provided in issue 260, each of which is referred to herein by reference. It is incorporated into. In one embodiment, one or more amino acid substitutions are incorporated into the port described herein. It is introduced into the Fc region or Fc domain of the lipeptide, and on the Fc region or Fc domain Removing potential glycosylation sites can reduce Fc receptor binding (e.g., S shields RL et al.,(2001)J Biol Chem 276:6 Please refer to 591-604, which is incorporated herein by reference in its entirety. (to be shown). In one embodiment, the following in the steady region of the polypeptide described herein Mutation, N297A substitution, N297Q substitution, L234A substitution, L234F substitution, L235A Replacement, L235F replacement, L235V replacement, L237A replacement, S239D replacement, E233P Replacement, L234V replacement, L235A replacement, C236 deletion, P238A replacement, S239D placement replacement, F243L replacement, D265A replacement, S267E replacement, L328F replacement, R292P replacement replacement, Y300L replacement, A327Q replacement, P329A replacement, A330L replacement, I332E replacement One or more of the following may be produced: replacement, or P396L replacement, and these may be produced by the EU numbering system They are numbered according to the m.

[0181] In one embodiment, D265A, P329 are numbered according to the EU numbering system. A mutation selected from the group consisting of A and combinations thereof is described herein. It can be produced in the constant region of the lipeptide. In one embodiment, the EU numbering system Therefore, from the group consisting of L235A, L237A, and combinations thereof, which are numbered as follows The selected mutations can be generated in the constant region of the polypeptides described herein. In one embodiment, S267E, L328 are numbered according to the EU numbering system. The mutations selected from the group consisting of F and combinations thereof are described herein. It can be produced in the constant region of the lipeptide. In one embodiment, the EU numbering system Therefore, the numbers S239D, I332E, optionally A330L, and their The mutations selected from the group of combinations are the constant state of the polypeptides described herein. It can be manufactured in the region. In one embodiment, it is numbered according to the EU numbering system. L235V, F243L, R292P, Y300L, P396L, and combinations thereof. The mutations selected from the combined group are the constant region of the polypeptide described herein. It can be manufactured in one embodiment. In one embodiment, it is numbered according to the EU numbering system. Mutations selected from the group consisting of S267E, L328F, and combinations thereof are... It can be prepared in the steady-state region of the polypeptide described in the specification.

[0182] In one embodiment, the Fc region, Fc domain, or FcRn network described herein is used. The combined fragment is numbered N297Q or N297A according to the EU numbering system. It includes a constant region of IgG1 having an acid substitution. In one embodiment, F described herein The c region, Fc domain, or its FcRn binding fragment is numbered according to the EU numbering system. Selected from the group consisting of D265A, P329A, and combinations thereof, It includes the constant region of IgG1 having a mutation. In one embodiment, Fc as described herein A region, Fc domain, or its FcRn binding fragment is numbered according to the EU numbering system. Selected from the group consisting of L234A, L235A, and combinations thereof. It includes the constant region of IgG1 having a mutation. In another embodiment, Fc as described herein A region, Fc domain, or its FcRn binding fragment is numbered according to the EU numbering system. The group consists of L234F, L235F, N297A, and combinations thereof. It includes a constant region of IgG1 having selected mutations. In one embodiment, as described herein In the constant region of the Fc region, Fc domain, or its FcRn binding fragment, the EU number Positions L234 and L2 in the human IgG1 heavy chain are numbered according to the numbering system. The amino acid residues at positions 35 and D265 are L, L, and D, respectively. No. This approach is described in detail in International Publication No. 14 / 108483. This is incorporated herein by reference in its entirety. In one embodiment, human IgG1 The amino acids corresponding to positions L234, L235, and D265 in the heavy chain are, respectively, F, E, and A, or A, A, and A, and these are according to the EU numbering system. They will be numbered.

[0183] In one embodiment, positions 433, 434 of the heavy chain steady region, according to the EU numbering system, The amino acids in and 436 are K, F, and Y, respectively. In one embodiment, E According to the U numbering system, at positions 252, 254, and 256 in the heavy chain steady region The amino acids are Y, T, and E, respectively. In one embodiment, the EU numbering system Therefore, the amino acids at positions 428 and 434 in the heavy chain constant region are L and S, respectively. Yes. In one embodiment, according to the EU numbering system, positions 309, 31 of the heavy chain steady region. The amino acids in 1 and 434 are D, H, and S, respectively.

[0184] In one embodiment, the polypeptide comprises amino acids Y, T, E, K, and F, respectively, E U is not present at positions 252, 254, 256, 433, and 434.

[0185] In one embodiment, the constant region of the polypeptide described herein is EU numbered Selected from amino acid residues 329, 331, and 322, which are numbered according to the system. One or more amino acids can be replaced with different amino acid residues, thereby the antibody , altered C1q binding, and / or reduced or absent complement-dependent cytotoxicity (C This approach has U.S. Patent No. 6,194,551 (Idusogi). Further details are provided in (e et al.), and this entire document is referenced in this book. It is incorporated into the specification. In one embodiment, the CH2 of the polypeptide described herein One or more amino acid residues within amino acid positions 231-238 in the main N-terminal region are , it is changing, and thereby altering the ability of antibodies to fix complement, and these are EU It is numbered according to the numbering system. This approach is entirely by reference. Further details are included in the specification and in International Publication No. 94 / 29351. One implementation In this state, the Fc region or Fc domain of the polypeptide described herein is antibody-dependent. To increase the ability of antibodies to mediate cytotoxicity (ADCC) and / or Fc receptor To increase the affinity of polypeptides to the body, the following positions, 238, 239, 248 ,249,252,254,255,256,258,265,267,268,269 , 270, 272, 276, 278, 280, 283, 285, 286, 289, 290 , 292, 293, 294, 295, 296, 298, 301, 303, 305, 307 ,309,312,315,320,322,324,326,327,328,329 ,330,331,333,334,335,337,338,340,360,373 ,376,378,382,388,389,398,414,416,419,430 , by mutating one or more amino acids in 434, 435, 437, 438, or 439 They are modified by (for example, by introducing amino acid substitutions), and these are EU number It is numbered according to the numbering system. This approach is entirely based on reference. Further details are included in International Publication No. 00 / 42072, which is incorporated into the detailed document.

[0186] In one embodiment, any of the constant region mutations or modifications described herein are 2 One or both heavy chain steady regions of the polypeptide described herein having two heavy chain steady regions It can be introduced into the region. In one embodiment, the constant regional mutation or modification described herein One of these is the heavy chain constant region of the polypeptide described herein. It can be introduced into the chain's steady-state region.

[0187] In one embodiment, the disclosure relates to a poly(P) comprising one, two, or three binding sites to human FcRn. A peptide that specifically binds to FcRn and functions as an antagonist. We offer Petit Do.

[0188] In one embodiment, the amino acid sequence of the Fc domain in the variant Fc region is as shown in SEQ ID NO: 1 Includes an amino acid sequence. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region The column consists of the amino acid sequence of SEQ ID NO: 1. In one embodiment, the Fc region of the variant Fc The amino acid sequence of the domain includes the amino acid sequence of SEQ ID NO: 2. In one embodiment, a barrier The amino acid sequence of the Fc domain in the Fc region consists of the amino acid sequence of SEQ ID NO: 2. In this embodiment, the amino acid sequence of the Fc domain in the variant Fc region is the amino acid sequence of SEQ ID NO: 3 It contains an acid sequence. In one embodiment, the amino acid sequence of the Fc domain of the variant Fc region is It consists of the amino acid sequence of SEQ ID NO: 3.

[0189] In one embodiment, the FcRn binding molecule includes a variant Fc region, and the variant Fc region The region contains two Fc domains, and the amino acid sequence of each Fc domain is as follows: It is selected independently of sequence number 2 or sequence number 3.

[0190] In a particular embodiment, the variant Fc region is a heterodimer, and the constituent Fc domain The compounds are different from each other. Methods for producing Fc heterodimers are known in the art (e.g., For example, please refer to US8,216,805, which is entirely based on references. (To be incorporated into the details). In one embodiment, the FcRn binding molecule is from the variant Fc region. The variant Fc region consists of two Fc domains that form a heterodimer, F Each amino acid sequence in the c domain is independent of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3. Selected by the above. In one embodiment, the FcRn binding molecule consists of a variant Fc region. , or including the same, the variant Fc region consists of two Fc domains that form a heterodimer. It consists of or includes the first Fc domain, and the amino acid sequence of the first Fc domain is the same as in SEQ ID NO: 1. It consists of or contains a amino acid sequence, and the amino acid sequence of the second Fc domain is sequence number It consists of or contains the amino acid sequence of No. 2 or SEQ ID NO: 3. In one embodiment, FcRn binding molecules consist of or contain a variant Fc region. The region consists of two Fc domains that form a heterodimer, or contains them, The amino acid sequence of the Fc domain of 1 consists of the amino acid sequence of SEQ ID NO: 2, or it is the same as that sequence. The amino acid sequence of the second Fc domain is the same as the amino acids in SEQ ID NO: 1 or SEQ ID NO: 3. Consists of or includes a sequence. In one embodiment, the FcRn binding molecule is variant F The c region consists of or includes the c region, and the variant Fc region forms a heterodimer. It consists of or contains two Fc domains, and the amino acid sequence of the first Fc domain is , consisting of or containing the amino acid sequence of SEQ ID NO: 3, and the amino acid of the second Fc domain The acid sequence consists of, or includes, the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2.

[0191] In one embodiment, the FcRn binding molecule includes a variant Fc region, and the variant Fc region The region consists of two Fc domains that form a homodimer, or contains them, and Fc domain Each main amino acid sequence consists of or contains the amino acid sequence of Sequence ID No. 1. .

[0192] In one embodiment, the FcRn binding molecule includes a variant Fc region, and the variant Fc region The region consists of two Fc domains that form a homodimer, or contains them, and Fc domain Each main amino acid sequence consists of or contains the amino acid sequence of Sequence ID No. 2. .

[0193] In one embodiment, the FcRn binding molecule includes a variant Fc region, and the variant Fc region The region consists of two Fc domains that form a homodimer, or contains them, and Fc domain Each main amino acid sequence consists of or contains the amino acid sequence of Sequence ID No. 3. .

[0194] In one embodiment, the FcRn binding molecule includes a variant Fc region, and the variant Fc region The region is Evgarchigimodo (CAS Registry No. 1821402-21-4) ) contains or consists of ). When used herein, "Evgarchigimodo" The terminology is interchangeable with "Efgarchigimodo Alpha" and "ARGX-113". In some embodiments, efgarchigimod is efgarchigimod alpha-fcab. ru.

[0195] In one embodiment, the variant Fc region is modified to promote heterodimerization. Such modifications are known in the art and are intended to promote heterodimerization. Any preferred means for generating the FcRn / antigen-binding molecule described herein It can be used for the following. In some embodiments, the variant Fc region is the CH of the Fc domain. It includes one or more mutations in amino acid residues that form the interface of the three domains. Several implementations In this state, the variant Fc region contains a knob-into-hole mutation (e.g., International Publication No. 2) Please refer to issue 006 / 028936, which is incorporated in its entirety by reference. (This refers to mispairing of the Ig heavy chain, in this technique, at the interface of the CH3 domain in IgG.) This is reduced by mutating the selected amino acids that form the chain. The two heavy chains directly At the interacting CH3 domain, one or more small side chains (holes) The above amino acid is introduced into the sequence of one of the heavy chains and has a large side chain (knob) One or more amino acids are introduced into the corresponding interaction residue position(s) on the other heavy chain. The Fc domains in the Fc region belong to the same subclass (e.g., IgG1 or IgG3). Or different subclasses (e.g., IgG1 and IgG3, or IgG3 and IgG4) It may be composed of immunoglobulin chains.

[0196] In some embodiments, the variant Fc region includes two Fc domains, or It consists of these, and one of the Fc domains contains amino acid W at EU position 366. Includes. In some embodiments, the variant Fc region includes two Fc domains, Or consisting of them, one of the Fc domains contains amino acids S, A, and V, respectively This includes EU locations 366, 368, and 407. In some embodiments, The AntFc region contains or consists of two Fc domains, one of which is... The first domain contains amino acid W at EU position 366, and the other Fc domain contains amino acid S, A, and V are included in EU positions 366, 368, and 407, respectively.

[0197] In some embodiments, the variant Fc region includes two Fc domains, or It consists of these, and one of the Fc domains contains amino acids E and D at EU position 37, respectively. It contains at positions 0 and 409, and the other Fc domain contains amino acid K at EU position 357 and 399 includes. In some embodiments, the variant Fc region is two Fc domains. It contains or consists of , and one Fc domain contains H and A, respectively, and E The U domain contains amino acids T and F at positions 364 and 405, and the other Fc domain contains amino acids T and F. These are included in EU positions 349 and 394, respectively. In some embodiments, variants The Fc region contains or consists of two Fc domains, one of which is , amino acids V, Y, A, and V are located at EU positions 350, 351, 405, and 4 respectively. In 07, the other Fc domain contains amino acids V, L, L, and W, respectively. This includes EU positions 350, 366, 392, and 394. In some embodiments, The variant Fc region contains or consists of two Fc domains, one of which is Fc The domain contains amino acids D, M, and A at EU positions 360, 399, and 40, respectively. In 7, the other Fc domain contains amino acids R, R, V, and V, respectively, E U positions 345, 347, 366, and 409 are included. In some embodiments, The rian Fc region contains or consists of two Fc domains, one of which is an Fc domain The main component contains amino acid D at EU positions 409 and 392, while the other Fc domain... It contains amino acid K at EU positions 399 and 356. In some embodiments, The variant Fc region contains or consists of two Fc domains, one of which is Fc The domain contains amino acids E, W, and C at EU positions 360, 409, and 34, respectively. In 9, the other Fc domain contains amino acids R, V, T, and C, respectively, and E U positions 347, 399, 405, and 354 are included. In some embodiments, The rian Fc region contains or consists of two Fc domains, one of which is an Fc domain The main component contains amino acids E and W at EU positions 370 and 409, respectively, and others The Fc domain of this type has amino acids N, V, and T at EU positions 357 and 399, respectively. and included in 405.

[0198] In one embodiment, the FcRn binding molecule consists of a variant Fc region, and variant Fc The region contains or consists of two Fc domains that form a heterodimer, The amino acid sequence of the Fc domain of 1 includes SEQ ID NOs. 4, 5, and 6. or selected from amino acid sequences consisting thereof, and / or the second Fc domain The amino acid sequence includes or contains SEQ ID NOs. 7, 8, and 9. Selected from the following amino acid sequences. In one embodiment, the FcRn binding molecule is a variant It consists of an Fc region, and the variant Fc region has two Fc domains that form a heterodimer. It contains or consists of the first Fc domain, and the amino acid sequence of the first Fc domain is SEQ ID NO: 7, Selected from amino acid sequences including or consisting of sequence number 8 and sequence number 9. , and / or the amino acid sequence of the second Fc domain is as shown in SEQ ID NO: 4, SEQ ID NO: 5, and sequence The amino acid sequence is selected from those containing or consisting of number 6. In one embodiment, The FcRn binding molecule consists of a variant Fc region, and the variant Fc region is heterodiplex. It contains or consists of two Fc domains that form a mer, and the first Fc domain The amino acid sequence of the second Fc domain contains or consists of SEQ ID NO: 4. The no-acid sequence includes or consists of SEQ ID NO 7. In one embodiment, the FcRn binding component The child consists of a variant Fc region, and the variant Fc region forms a heterodimer. It contains or consists of two Fc domains, and the amino acid sequence of the first Fc domain is , containing or consisting of Sequence ID No. 5, the amino acid sequence of the second Fc domain is sequence It includes or consists of number 8. In one embodiment, the FcRn binding molecule is a variant It consists of an Fc region, and the variant Fc region has two Fc domains that form a heterodimer. It contains or consists of the first Fc domain, and the amino acid sequence of the first Fc domain contains SEQ ID NO: 6 The amino acid sequence of the second Fc domain is either the same as or derived from the second Fc domain, and includes sequence number 9. or consists of the same. In some embodiments, the FcRn binding molecule is an FcRn antagonist. It's a strike. Table 1. Amino acid sequence of the variant Fc region. [Table 1]

[0199] In some embodiments, the variant Fc region comprises amino acids Y, T, E, K, and F The first includes in EU locations 252, 254, 256, 433, and 434, respectively. The Fc domain contains amino acids K and F at EU positions 433 and 434, respectively. It includes a second Fc domain. In some embodiments, the first Fc domain is distributed It contains the amino acid sequence of column number 1. In some embodiments, the first Fc domain is sequence It contains amino acid sequence number 2. In some embodiments, the first Fc domain is sequence number 2. Contains the amino acid sequence of No. 3.

[0200] In some embodiments, the variant Fc region is amino acids Y, T, E, W, K, and F is located at EU positions 252, 254, 256, 366, 433, and 434, respectively. The first Fc domain, which contains amino acids S, A, V, K, and F, is located at the EU position, respectively. The second Fc domain included in 366, 368, 407, 433, and 434, and 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 includes the amino acid sequence of SEQ ID NO: 6.

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

[0202] In one embodiment, the anti-FcRn antibody is rozanolixizumab (UCB7665), Nipoka Rimab (M281), olilanorimab (ALXN1830 / SYNT001), or bat It is climab (IMVT-1401 / RVT1401 / HBM9161).

[0203] In one embodiment, the immunoglobulin specifically binds to FcRn and to the Fc region of FcRn. The antibody that inhibits the binding of is nipocalimab, also known as M281. Nipocalimab is It is a full-length "Fc dead" IgG1 monoclonal antibody. Nipocalimab is administered intravenously. As an entry point, the treatment of myasthenia gravis (MG) and warm-type antibody autoimmune hemolytic anemia (WAIHA) In a Phase 2 / 3 clinical trial for the treatment of fetal and neonatal hemolytic disease (HDFN), Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome It is being administered in a Phase 2 clinical trial for the treatment of (SS). Nipocalimab is used in the following Includes the light chain (Sequence No. 128) and heavy chain (Sequence No. 129) sequences listed in Table 2 (Sequence No. (VL in sequence number 128 and VH in sequence number 129 are underlined.) Table 2. Heavy and light chain sequences of nipocalimab [Table 2]

[0204] In one embodiment, the immunoglobulin specifically binds to FcRn and to the Fc region of FcRn. The antibody that inhibits its binding is rozanolixizumab, also known as UCB 7665. Rozanolixizumab is a full-length humanized IgG4 monoclonal antibody. Zumab is administered subcutaneously for the treatment of myasthenia gravis (MG), immune thrombocytopenia (ITP), and chronic inflammatory demyelinating polycythemia. CIDP (Chronic Illegible Neuropathy), Autoimmune Encephalitis (AIE), and Myelin Oligodendrosis In clinical trials for locytic glycoprotein-associated disease (MOG-AD), it was administered. Rozanolixizumab contains the light chain (SEQ ID NO: 130) and heavy chain (PLA) listed in Table 3 below. Column number 131) Contains the array (VL of sequence number 130 and VH of sequence number 131 are underlined) (It is.) Table 3. Heavy and light chain sequences of rozanolixizumab. [Table 3]

[0205] In one embodiment, the immunoglobulin specifically binds to FcRn and to the Fc region of FcRn. The antibody that inhibits the binding of is also known as SYNT001 / ALXN1830. It is olilanolimab. Orilanolimab is another full-length humanized IgG4 monoclonal antibody. Orilan-olimab is administered intravenously as part of a Phase 2 drug for the treatment of WAIHA and pemphigus. It is administered in clinical trials. Orilanolimab is a light chain (sequence) as shown in Table 4 below. (Sequence number 132) and heavy chain (Sequence number 133) sequence (VL and sequence number of Sequence number 132) (VH in train number 133 is underlined.) Table 4. Heavy and light chain sequences of olilanorimab [Table 4]

[0206] In one embodiment, the immunoglobulin specifically binds to FcRn and to the Fc region of FcRn. Antibodies that inhibit binding are also known as IMVT1401 / RVT1401 / HBM9161. It is a known batoclimab. Batoclimab is another full-length "Fc-dead" IgG1 monoclean. It is a ronal antibody. Batoclimab is administered by subcutaneous injection for MG, ITP, and Graves' ophthalmopathy. Phase 2 for the treatment of thyroid eye diseases and neuromyelitis optica spectrum disorder (NMOSD) It is administered in clinical trials. Batoclimab is a light chain (SEQ ID NO:) as described in Table 5 below. 134) and heavy chain (SEQ ID NO: 135) sequence (VL of SEQ ID NO: 134 and SEQ ID NO: 1 (VH 35 is underlined.) Table 5. Heavy and light chain sequences of batoclimab [Table 5]

[0207] antigen-binding domain In one embodiment, an antigen-binding domain is provided by this disclosure. In several embodiments, The FcRn / antigen-binding molecules disclosed herein contain one or more FcRn-binding molecules. It comprises one or more antigen-binding domains in combination. In some embodiments, as specified herein The FcRn / antigen-binding molecules disclosed herein are one or more Fc regions or their FcRn bindings. The fragment comprises a combination of one or more antigen-binding domains. In some embodiments, The antigen-binding domain is a polypeptide derived from the antibody, and the antibody is an sdAb (for example, This includes, but is not limited to, VHH fragments, Fab fragments, scFv, VH, or VL. In some embodiments, the antigen-binding domain is a synthetic antigen-binding protein or an antibody mimic. Antigenic proteins are synthetic antigen-binding proteins or antibody-mimicking proteins. This includes, but is not limited to, alin or DARPin.

[0208] In some embodiments, the antigen-binding domain is one or more added at its C-terminus. It further contains the above amino acids. In some embodiments, the antigen-binding domain is located at the C-terminus. It further contains one or more amino acids that have been added, and one or more amino acids are A, AG, GG, and PP are selected. In some embodiments, the C-terminus of VHH is the amino acid sequence V This is TVSS (SEQ ID NO: 91). In some embodiments, the C-terminus of VHH is amino It consists of the acid sequence VTVSS (SEQ ID NO: 91).

[0209] The antigen-binding domain can bind to any antigen. In some embodiments, the antigen is Non-human antigens, for example, antigens that are not normally expressed by humans and are not normally found in humans. It is an protein or a fragment thereof. In some embodiments, the non-human antigen is transmitted by humans. It is a protein or fragment thereof that is not normally expressed but can be found in humans. Examples of non-human antigens that may be found include proteins expressed by pathogens or other substances. These fragments include, for example, bacterial or viral proteins or fragments thereof. These pathogenic proteins or fragments thereof, in humans, result from infection and / or immunization. Therefore, in some embodiments, non- Human antigens are viral antigens. In some embodiments, non-human antigens are human odors. It is a non-human antigen that is not found in humans. Examples of non-human antigens not found in humans include: Proteins or fragments thereof that are not pathogenic and do not have human counterparts, for example, chicken eggs. Examples include white lysozyme (HEL) or ovalbumin.

[0210] In some embodiments, the antigen is a human antigen, for example, a tadactyl that is normally expressed by humans. It is an protein or a fragment thereof. In some embodiments, the human antigen is HSA or IgE Selected from.

[0211] In some embodiments, the antigen-binding domain specifically binds to HSA. In this embodiment, the antigen-binding domain specifically binds to HSA, and the Fab fragment, scFv Selected from sdAb, HSA, and its HSA-binding fragment. In some embodiments, The antigen-binding domain specifically binds to HSA and is an sdAb, such as a VHH fragment. In some embodiments, the HSA is assigned GenBank acceptance number AAA98797.1. It contains an amino acid sequence that is at least 95% identical to the amino acid sequence provided. In one embodiment, the HSA is in GenBank acceptance number AAA98797.1 Includes the provided amino acid sequence.

[0212] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment is distributed Includes amino acid sequences selected from column numbers 43-74, 84-90, and 120-127. CDR1 amino acid sequence, CDR2 amino acid sequence, and CDR3 amino acid sequence of the VHH fragment Includes.

[0213] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment is C Includes or consists of a combination of DR1, CDR2, and CDR3, and 1, 2, 3 , 4 or 5 amino acids, SEQ ID NOs: 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 11, and 12; 16, 11, and 12; 17, 11, and 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 3 5;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;1 0, 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 8 0; 75, 76, and 81; 75, 76, and 82; and selected from 75, 76, and 83. At least one of the selected amino acid sequences is different.

[0214] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment is distributed Column numbers 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 1 1, 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 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 4 0;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 1 2;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 CDR1, CDR2, and selected from 75, 76, and 83. A combination of CDR3 and one or more CDRs The above amino acids are substituted with alanine or histidine.

[0215] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment is distributed Column numbers 10, 11, and 12; 13, 11, and 12; 14, 11, and 12; 15, 1 1, 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 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 4 0;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 1 2;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 CDR1, CDR2, and selected from 75, 76, and 83. It includes or consists of a combination of CDR3.

[0216]

[0217] In some embodiments, the antigen-binding domain is a VHH fragment, and the VHH fragment is distributed The amino acid sequence selected from row numbers 42-74, 84-90, and 120-127 is a small number of... At least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, young Or it contains or consists of an amino acid sequence that is 99% identical. Several embodiments The antigen-binding domain is the VHH fragment, and the VHH fragment is sequence numbers 42-74, 8 It contains or consists of an amino acid sequence selected from 4-90 and 120-127. .

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

[0219] In some embodiments, the antigen-binding domain is noncovalently attached to the FcRn-binding molecule. It can be bonded. In some embodiments, the antigen-binding domain is covalently bonded to the FcRn-binding molecule. They can be linked together.

[0220] In some embodiments, the antigen-binding domain is the N-terminus or C-terminus of the FcRn-binding molecule. It can be directly linked (for example, fused) to the antigen-binding domain. In some embodiments, the antigen-binding domain The FcRn is linked to the N-terminus or C-terminus of the FcRn-binding molecule via a linker. In one embodiment, the linker is an inseparable linker.

[0221] In some embodiments, the antigen-binding domain is directly attached to the N-terminus or C-terminus of the Fc domain. They can be linked (for example, fused). In some embodiments, the antigen-binding domain is It is linked to the N-terminus or C-terminus of the Fc domain via a linker. In this application, the linker is an inseparable linker. When used herein, The term "uncleavable linker" refers to a linker that is cleaved by one of the following: a given enzyme, chemical agent, or light irradiation. The above refers to a linker that is not easily cleaved. In some embodiments, the enzyme is p It is a rotease.

[0222] In some embodiments, the linker is a synthetic compound linker, such as a chemical crosslinking agent. A non-limiting example of a suitable commercially available crosslinking agent is N-hydroxysuccinate. Imide (NHS), disuccinimidylsberate (DSS), bis(sulfosuccini) Mizyl) Sverate (BS3), Dithiobis (Succinimidylpropionate) (DS P), dithiobis(sulfosuccinimidylpropionate) (DTSSP), ethylene Glycol bis(succinimidyl succinate) (EGS), ethylene glycol bis (Sulfosuccinimidyl succinate) (Sulfo-EGS), Disuccinimidyl Talate (DST), disulfosuccinimidyl tartalate (sulfo-DST), bis [2-(succinimidooxycarbonyloxy)ethyl]sulfone (BSOCOES) , and bis[2-(sulfosuccinimideoxycarbonyloxy)ethyl]sulfone ( Examples include sulfo-BSOCOES.

[0223] As described above, the Fc domains disclosed herein may include a portion of the hinge region. Therefore, the antigen-binding domain is located at the N-terminus of the Fc domain via this hinge region. They can be linked. In some embodiments, one or more amino acids are the C of the antigen-binding domain. It is contained between the terminal and the N-terminus of the Fc domain. In some embodiments, the antigen-binding domain One or more amino acids located between the C-terminus of the protein and the N-terminus of the Fc domain are native to the protein. It is an amino acid in the di region. In some embodiments, the C-terminus of the antigen-binding domain is Fc It is fused to the N-terminus of the domain via a hinge region or a portion thereof. Several implementations Morphologically, the hinge region is the IgG hinge region, for example, the human IgG hinge region. .

[0224] In some embodiments, the linker is a peptide linker. Examples are well known, and those skilled in the art can identify FcRn binding molecules, for example, antigen-binding molecules to the Fc domain. A suitable peptide linker can be selected for use in the main linking process.

[0225] The peptide linker can be of any length. In some embodiments, The length and amino acid composition of the kernel peptide sequence are determined by the orientation of the polypeptide domains relative to each other. / or vary the proximity to optimize for achieving the desired activity of the FcRn / antigen binding molecule. It is possible. In some embodiments, the peptide linker is about 1 to about 100 amino acids long. The length is approximately 8 to 40 amino acids, or approximately 15 to 25 amino acids. In the application form, the peptide linker is 1-100 amino acid length, 8-40 amino acid length, or 1 The length is 5 to 25 amino acids. In some embodiments, the peptide linker is about 8 amino acids. Acid length, approximately 9 amino acid length, approximately 10 amino acid length, approximately 11 amino acid length, approximately 12 amino acid length, approximately 1 3 amino acid length, approximately 14 amino acid length, approximately 15 amino acid length, approximately 16 amino acid length, approximately 17 amino acids Acid length, approximately 18 amino acid length, approximately 19 amino acid length, approximately 20 amino acid length, approximately 21 amino acid length, approximately 22 amino acid length, approximately 23 amino acid length, approximately 24 amino acid length, approximately 25 amino acid length, approximately 26 amino acids No amino acid length, approximately 27 amino acid length, approximately 28 amino acid length, approximately 29 amino acid length, approximately 30 amino acid length, Approximately 31 amino acid length, approximately 32 amino acid length, approximately 33 amino acid length, approximately 34 amino acid length, approximately 35 amino acid length Minoic acid length, approximately 36 amino acid length, approximately 37 amino acid length, approximately 38 amino acid length, approximately 39 amino acid length , or about 40 amino acid length. In some embodiments, the peptide linker is 8 amino acids long. No amino acid length, 9 amino acid length, 10 amino acid length, 11 amino acid length, 12 amino acid length, 13 amino acid Acid length, 14 amino acid length, 15 amino acid length, 16 amino acid length, 17 amino acid length, 18 amino Acid length, 19 amino acid length, 20 amino acid length, 21 amino acid length, 22 amino acid length, 23 amino Acid length, 24 amino acid length, 25 amino acid length, 26 amino acid length, 27 amino acid length, 28 amino Acid length, 29 amino acid length, 30 amino acid length, 31 amino acid length, 32 amino acid length, 33 amino Acid length, 34 amino acid length, 35 amino acid length, 36 amino acid length, 37 amino acid length, 38 amino The acid length is 39 amino acid length, or 40 amino acid length.

[0226] In some embodiments, the peptide linker is a glycine residue and / or serine residue It contains (for example, glycine-serine linker or GS linker). Examples of Chidrinker include Gly(x)Ser (where x is 0-6) or Ser Gly(x) (where x is between 0 and 6), (Gly Gly Gly Gly Ser)n (n is an integer greater than or equal to 1), and (Ser Gly Gly Gly Gly)n( Examples include n being an integer greater than or equal to 1. In some embodiments, a peptide linker This includes an amino acid sequence selected from the group consisting of (GGGGS)n and (SGGGG)n. n is 1 to 8. In some embodiments, the linker peptide is an amino acid sequence There is no GSG (which occurs at the junction of conventional Gly / Ser linker peptide repeats). It is modified to (GGGXX). For example, in some embodiments, the peptide linker is (GGGXX )nGGGGS and GGGGS(XGGGS)n(X can be inserted into the array, Any amino acid that does not result in a polypeptide containing the sequence GSG, where n is 0-4. It includes an amino acid sequence selected from the group consisting of (a). In some embodiments, the linker The peptide sequence is (GGGX1X2)nGGGGS, where X1 is P and X2 is S, and n is 0-4. In some other embodiments, the linker peptide is The array is (GGGX1X2)nGGGGS, where X1 is G and X2 is Q. n is 0 to 4. In some other embodiments, the linker peptide sequence is (G GGX1X2)nGGGGS, where X1 is G, X2 is A, and n is 0~ 4. In yet another embodiment, the linker peptide sequence is GGGGS(XGGGS )n, where X is P, and n is 0 to 4. In some embodiments of this disclosure Linker peptides contain or are derived from the amino acid sequence (GGGGA)2GGGGS. In some embodiments, the linker peptide has the amino acid sequence (GGGGQ)2GG. It contains or consists of GGS. In another embodiment, the linker peptide is an amino acid compound The column (GGGPS) includes or consists of 2GGGGS. In another embodiment, the linker The peptide contains or consists of the amino acid sequence GGGGS(PGGGS)2. In another embodiment, the linker peptide comprises the amino acid sequence GSGGS or SGGSGS. It consists of or. In some embodiments, the linker peptide is an amino acid sequence G GGGSGGGGSGGGGSGGGGS( EQ136 ), GGGGSGGGGS( Array 181), or GGGGSGGGGSGGGGSGGGGSGGGGGSGGGG It contains or consists of S (sequence number 182).

[0227] In some embodiments, the peptide linker is a GS linker with a length of about 20 or about 30 amino acids. It is a linker. In some embodiments, the peptide linker is 20 or 30 amino acids long. This is the GS linker.

[0228] Heavy chain molecules In some embodiments, the FcRn / antigen-binding molecule is the first heavy molecule described herein. It may include chains. In some embodiments, the first heavy chain is linked by a linker. It includes an Fc domain and an antigen-binding domain. In some embodiments, FcRn / The antigen-binding molecule may further comprise a second heavy chain as described herein. In this embodiment, the second heavy chain is linked by a linker and comprises an Fc domain and an antigen-binding domain. Includes the main. In some embodiments, the second heavy chain includes an Fc domain. In some embodiments, the first and second heavy chains are the same. In some embodiments, the first and The second heavy chain is different.

[0229] In some embodiments, the first and second heavy chains have the same Fc domain. In one embodiment, the first and second heavy chains have different Fc domains. In the embodiment, both the first and second heavy chains include antigen-binding domains. Several embodiments Therefore, the antigen-binding domains in the first and second heavy chains are the same. Several implementations In this configuration, the antigen-binding domains in the first and second heavy chains are different. Several embodiments The first heavy chain contains an Fc domain and an antigen-binding domain, and the second heavy chain contains an Fc It contains but does not contain the antigen-binding domain. In some embodiments, the first heavy chain is Fc The main and antigen-binding domains are included, and the second heavy chain includes an Fc domain, but the antigen-binding domain It does not contain a main or linker. In some embodiments, the first heavy chain is an Fc domain. The second heavy chain includes an antigen-binding domain and a linker, and the antigen-binding domain is included in the second heavy chain, which includes an Fc domain. It does not contain a linking domain or linker.

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

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

[0232] In some embodiments, the antigen-binding domain is located at the N-terminus of the Fc domain, and the linker is located at the linker. Therefore, they are linked. In some embodiments, the antigen-binding domain is the Fc domain It is linked at the C-terminus by a linker. In some embodiments, antigen-binding domain The linker is attached to a position other than the N-terminus or C-terminus of the Fc domain. .

[0233] In some embodiments, the antigen-binding domain has a peptide at the N-terminus of the Fc domain. It is fused by an inker. In some embodiments, the antigen-binding domain is Fc domain It is fused to the C-terminus of the molecule by a peptide linker. In some embodiments, the anti The primordial binding domain is located at a position other than the N-terminus or C-terminus of the Fc domain, and is linked to the peptide linker. Therefore, they are fused together.

[0234] In some embodiments, the Fc domain is one of the sequence numbers 1 to 9. Mino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 9 It contains amino acid sequences that are 7%, 98%, or 99% identical. In some embodiments, F The c domain contains at least 70% of one of the amino acid sequences from sequence numbers 1-9. 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical It consists of the following amino acid sequence.

[0235] In some embodiments, the Fc domain is one of the sequence numbers 1 to 9. It contains a mino acid sequence. In some embodiments, the Fc domain is one of the sequences 1-9. It consists of any one of the amino acid sequences.

[0236] In some embodiments, the first and second heavy chains contain the same Fc domain. In this embodiment, both the first and second heavy chains are one of the sequence numbers 1 to 3. Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, It contains an Fc domain with an amino acid sequence that is 97%, 98%, or 99% identical. In that embodiment, both the first and second heavy chains are any one of sequence numbers 1-3 The amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96% It contains an Fc domain consisting of an amino acid sequence that is 97%, 98%, or 99% identical. In some embodiments, both the first and second heavy chains are any of SEQ ID NOs: 1-3 It contains an Fc domain comprising a single amino acid sequence. In some embodiments, the first and second Both heavy chains consist of an Fc dome consisting of one of the amino acid sequences from sequence numbers 1-3. Includes "in".

[0237] In some embodiments, the first and second heavy chains contain different Fc domains. In that embodiment, the first heavy chain is one of the amino acid sequences from SEQ ID NOs: 4-6 and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% It contains an Fc domain that has an amino acid sequence that is % or 99% identical, and the second heavy chain is sequence One amino acid sequence from numbers 7 to 9 and at least 70%, 75%, or 80% Amino acid sequences that are 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical. It includes an Fc domain containing the following. In some embodiments, the first heavy chain is the same as sequence numbers 4-6. One of the amino acid sequences and at least 70%, 75%, 80%, 85%, 90% Fc consists of amino acid sequences that are identical by %, 95%, 96%, 97%, 98%, or 99%. The second heavy chain contains the domain and one of the amino acid sequences from sequence numbers 7-9. At least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% , or comprising an Fc domain consisting of an amino acid sequence that is 99% identical. Several embodiments So, the first heavy chain is an Fc-type containing one of the amino acid sequences from sequence numbers 4-6. The main chain is included, and the second heavy chain contains one of the amino acid sequences from sequence numbers 7-9. It contains an Fc domain. In some embodiments, the first heavy chain is the amino acid of SEQ ID NO: 4. When the second heavy chain contains an Fc domain containing the sequence or a variant thereof, the sequence number 7 or It includes an Fc domain containing that variant. In some embodiments, the first heavy chain is When the Fc domain contains the amino acid sequence of SEQ ID NO: 5 or a variant thereof, the second The heavy chain includes an Fc domain containing SEQ ID NO: 8 or a variant thereof. Several embodiments So, the first heavy chain is an Fc domain containing the amino acid sequence of SEQ ID NO: 6 or a variant thereof. When it includes, the second heavy chain includes an Fc domain containing SEQ ID NO: 9 or a variant thereof. .

[0238] In some embodiments, the first and second heavy chains further comprise peptide linkers. In some embodiments, the first and second heavy chains further comprise the same peptide linker. In that embodiment, the first and second heavy chains further comprise different peptide linkers. In that embodiment, the first heavy chain comprises an Fc domain, a peptide linker, and an antigen-binding domain. It contains a second heavy chain containing an Fc domain, but a peptide linker or antigen-binding domain It does not contain yin. The peptide linkers encoded by the first and heavy chains are described herein. It can be any of the ones listed. In some embodiments, the linker is It contains the amino acid sequence of column number 136, 180, or 181.

[0239] In some embodiments, the FcRn / antigen-binding molecule is composed of amino acids selected from Table 6. Includes a column or its variant. [Table 6] TIFF2026048773000008.tif249170TIFF2026048773000009.tif248170TIFF2026048773000010.tif245170 TIFF2026048773000011.tif248170TIFF2026048773000012.tif244170TIFF2026048773000013.tif244170

[0240] In some embodiments, the FcRn / antigen binding molecule is sequence numbers 137-176 and 1 Any one of the 80 amino acid sequences and at least 70%, 75%, 80%, 85% , amino acid sequences that are 90%, 95%, 96%, 97%, 98%, or 99% identical It includes or consists of. In some embodiments, the FcRn / antigen-binding molecule is sequence It contains one of the amino acid sequences from numbers 137-176 and 180, or It consists of.

[0241] In some embodiments, the FcRn / antigen binding molecule is sequence numbers 137-176 and 1 One of the 80 amino acid sequences or a variant thereof, with an addition at the C-terminus It contains one or more amino acids, and in some embodiments, an FcRn / antigen-binding molecule. This refers to any one of the amino acid sequences from sequence numbers 137-176 and 180, or their variants. It comprises a riant and one or more amino acids added at the C-terminus, and one or more amino acids The no acids are selected from A, AG, GG, and PP.

[0242] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 137~ One of the amino acid sequences from 176 and 180 and at least 70%, 75%, 8 A is identical at 0%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. The second heavy chain of the FcRn / antigen-binding molecule contains or consists of a mino acid sequence, and the antigen is the antigen. It does not contain a binding domain. In some embodiments, the second weight of the FcRn / antigen binding molecule The chain contains an Fc domain but does not contain an antigen-binding domain. Optionally, FcRn / anti- The second heavy chain of the original bond molecule has at least 70%, 75%, and 8 amino acids in the amino acid sequence of SEQ ID NO: 8. A is identical at 0%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%. It contains or consists of a mino acid sequence.

[0243] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 137~ It contains or consists of one of the amino acid sequences 176 and 180, F The second heavy chain of the cRn / antigen-binding molecule does not contain the antigen-binding domain. Several implementations In this state, the second heavy chain of the FcRn / antigen-binding molecule contains an Fc domain, but the antigen-binding domain It does not contain .Optionally, the second heavy chain of the FcRn / antigen-binding molecule is the α of SEQ ID NO: 8. It contains or consists of a mino acid sequence.

[0244] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 137 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 137 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0245] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 137 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0246] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 138 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 138 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0247] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 138 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0248] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 139 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 139 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0249] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 139 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0250] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 140 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 140 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0251] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 140 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0252] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 141 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 141 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0253] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 141 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0254] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 142 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 142 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0255] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 142 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0256] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 143 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 143 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0257] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 143 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0258] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 144 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 144 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0259] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 144 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0260] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 145 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 145 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0261] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 145 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0262] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 146 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 146 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0263] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 146 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0264] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 147 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 147 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0265] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 147 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0266] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 148 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 148 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0267] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 148 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0268] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 149 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 149 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0269] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 149 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0270] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 150 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 150 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0271] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 150 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0272] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 151 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 151 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0273] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 151 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0274] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 152 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 152 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0275] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 152 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0276] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 153 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 153 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0277] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 153 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0278] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 154 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 154 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0279] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 154 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0280] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 155 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 155 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0281] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 155 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0282] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 156 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 156 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0283] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 156 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0284] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 157 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 157 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0285] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 157 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0286] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 158 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 158 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0287] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 158 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0288] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 159 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 159 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0289] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 159 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0290] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 160 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 160 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0291] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 160 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0292] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 161 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 161 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0293] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 161 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0294] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 162 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 162 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0295] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 162 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0296] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 163 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 163 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0297] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 163 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0298] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 164 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 164 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0299] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 164 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0300] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 165 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 165 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0301] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 165 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0302] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 166 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 166 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0303] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 166 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0304] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 167 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 167 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0305] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 167 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0306] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 168 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 168 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0307] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 168 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0308] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 169 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 169 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0309] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 169 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0310] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 170 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 170 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0311] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 170 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0312] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 171 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 171 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0313] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 171 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0314] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 172 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 172 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0315] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 172 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0316] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 173 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 173 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0317] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 173 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0318] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 174 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 174 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0319] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 174 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0320] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 175 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 175 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0321] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 175 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0322] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 176 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 176 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0323] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 176 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0324] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 180 Amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, Containing amino acid sequences that are 97%, 98%, or 99% identical, the FcRn / antigen-binding molecule The second heavy chain contains an Fc domain with the amino acid sequence of SEQ ID NO: 8, but the antigen-binding domain It does not contain n. In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is sequence The amino acid sequence of number 180 and at least 70%, 75%, 80%, 85%, 90%, 95% Consists of amino acid sequences that are 96%, 97%, 98%, or 99% identical, and FcRn / The second heavy chain of the antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0325] In some embodiments, the first heavy chain of the FcRn / antigen-binding molecule is SEQ ID NO: 180 The second heavy chain of the FcRn / antigen-binding molecule contains the amino acid sequence of SEQ ID NO: 8. It contains an Fc domain that includes columns, but does not contain 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, F The second heavy chain of the cRn / antigen-binding molecule consists of the amino acid sequence shown in SEQ ID NO: 8.

[0326] In some embodiments, the FcRn / antigen binding molecule is the SEQ ID NO: described herein. One amino acid sequence or variant thereof from among 137-176 and 180, It comprises one or more amino acids added to the C-terminus. In some embodiments, F The cRn / antigen-binding molecules are those described in SEQ ID NOs. 137-176 and 180 as specified herein. One of the amino acid sequences or a variant thereof, and one added at the C-terminus The above amino acids are included, and one or more amino acids are selected from A, AG, GG, and PP. It will be done.

[0327] Polynucleotides, vectors, and methods for producing them This disclosure also relates to the FcRn / antigen binding molecules or fragments thereof disclosed herein. To provide polynucleotides. In some embodiments, the polynucleotides are The antigen-binding domain of the present disclosure is encoded. In some embodiments, the polynucleotide is , encoding the FcRn binding molecule of the present disclosure. In some embodiments, polynucleotides This encodes the Fc region of the present disclosure. In some embodiments, the polynucleotide is the The disclosure encodes the Fc domain. In some embodiments, the polynucleotide is an antigen. It encodes one or more of the following: a binding domain, an FcRn binding molecule, and a linker. In one embodiment, the polynucleotide coats the antigen-binding domain and the FcRn-binding molecule. And optionally, a linker is encoded. In some embodiments, a polynucleotide It encodes one or more of the antigen-binding domain, Fc region, and linker. In that embodiment, the polynucleotide encodes an antigen-binding domain and an Fc region, Selectively encodes a linker. In some embodiments, one polynucleotide This encodes an FcRn / antigen-binding molecule containing the antigen-binding domain and the Fc region described above. In some embodiments, the polynucleotide comprises an antigen-binding domain, an Fc domain, and Encodes one or more bilinkers. In some embodiments, polynucleotides. It encodes the antigen-binding domain and the Fc domain, and optionally encodes the linker. In some embodiments, the polynucleotide has one or more antigen-binding domains and one The above Fc domains and the FcRn / antigen-binding molecules are encoded. Several implementations In terms of form, polynucleotides encode one or more heavy chains of the present disclosure.

[0328] As used herein, “isolated” polynucleotide or nucleic acid molecule means nucleic acid From other nucleic acid molecules present in the natural source of this child (for example, in mice or humans) It is a separated molecule. Also, "isolated" nucleic acid molecules, such as cDNA molecules, are recombinant. When produced by this technique, it substantially contains no other cell material or culture medium. Also, when chemically synthesized, it is substantially free of chemical precursors or other chemical substances. It is not necessary. For example, the expression "substantially does not contain" means that polynucleotides or nucleic acids The preparation contains approximately 15%, 10%, 5%, 2%, 1%, 0.5%, or less than 0.1% (special In addition, other materials (less than approximately 10%), such as cell materials, culture media, other nucleic acid molecules, and chemical precursors. This includes having a body and / or other chemical substances. In one embodiment, as described herein The nucleic acid molecule(s) encoding the polypeptide has been isolated or purified.

[0329] In one embodiment, the FcRn binding molecule or FcRn / antigen binding molecule described herein is used A polynucleotide containing a nucleotide sequence is provided herein. The following includes a nucleotide sequence encoding the antigen-binding domain described herein: Polynucleotides are provided herein. In another embodiment, Fc A polynucleotide containing a nucleotide sequence encoding an Rn / antigen-binding molecule is described in this specification. Provided in writing. In another embodiment, the FcRn / HSA binding molecule described herein is coated A polynucleotide containing a nucleotide sequence is provided herein.

[0330] The polynucleotide comprises the FR and CDR antigen-binding domains described herein. Encoding sdAb (e.g., VHH fragment), Fab fragment, scFv, VH, or VL. It may contain a nucleotide sequence. Polynucleotides are also described herein. It may include a nucleotide sequence encoding an antibody mimetic. In some embodiments, The polynucleotide comprises the FR and CDR of the antigen-binding domain as described herein. It may include a nucleotide sequence encoding a VHH fragment. In some embodiments, it may include a nucleotide sequence that encodes a VHH fragment. The polynucleotides are the VL FR and CD of the antigen-binding domain described herein. A nucleotide sequence encoding a light chain containing R, or an antigen-binding domain as described herein. VH FR and CDR of the Fc domain described herein and / or It may include a nucleotide sequence that codes for a chain. In one embodiment, a polynucleotide sequence may be included. The do is the VH, VL, heavy chain, and / or light chain of the antigen-binding domain described herein. In one embodiment, the polynucleotide is an antigen-binding domain as described herein. It encodes the first VH and first VL of n. In one embodiment, the polynucleotide is This encodes the second VH and second VL of the antigen-binding domain described in the specification. Morphologically, the polynucleotide is the first heavy chain of the antigen-binding domain described herein and And encodes the first light chain. In one embodiment, the polynucleotide is as described herein. It encodes the second heavy chain and second light chain of the antigen-binding domain. In one embodiment, polynu Cleotide is the VH and / or VL of the antigen-binding domain described herein, or This code codes for heavy chains and / or light chains.

[0331] In some embodiments, the polynucleotide is a first heavy chain as described herein. It may include a nucleotide sequence that runs. In some embodiments, the first heavy chain is It includes an Fc domain and an antigen-binding domain, which are linked by a linker. In the application form, the polynucleotide encodes the nucleus of the second heavy chain as described herein. It may include an ocidal sequence. In some embodiments, the second heavy chain is linked by It contains an Fc domain and an antigen-binding domain that are bound together. In some embodiments, The first and second heavy chains are the same. In some embodiments, the first and second heavy chains are different. Yes.

[0332] In some embodiments, the first and second heavy chains have the same Fc domain. In one embodiment, the first and second heavy chains have different Fc domains. In the embodiment, both the first and second heavy chains include antigen-binding domains. Several embodiments Therefore, the antigen-binding domains in the first and second heavy chains are the same. Several implementations In this configuration, the antigen-binding domains in the first and second heavy chains are different. Several embodiments So, the second heavy chain contains an Fc domain but does not contain an antigen-binding domain, and the first heavy chain is , comprising an Fc domain and an antigen-binding domain. In some embodiments, the second heavy chain is It contains an Fc domain but does not contain an antigen-binding domain or linker, and the first heavy chain is an Fc domain. It includes a main and antigen-binding domain. In some embodiments, the second heavy chain is an Fc domain. It contains a yin but does not contain an antigen-binding domain or a linker, and the first heavy chain has an Fc domain and It includes an antigen-binding domain and a linker.

[0333] In some embodiments, the polynucleotide is one of sequence numbers 1-9 The amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96% , encoding an Fc domain containing an amino acid sequence that is 97%, 98%, or 99% identical. It contains a nucleotide sequence. In some embodiments, the polynucleotide is sequence number 1- One of the 9 amino acid sequences and at least 70%, 75%, 80%, 85%, F containing amino acid sequences that are 90%, 95%, 96%, 97%, 98%, or 99% identical. It consists of a nucleotide sequence that codes for the c domain.

[0334] In some embodiments, the polynucleotide is one of sequence numbers 1-9 It contains a nucleotide sequence that encodes an Fc domain containing the amino acid sequence of several real In the application form, the polynucleotide is one of the amino acid sequences from SEQ ID NOs: 1 to 9. It contains a nucleotide sequence that codes for an Fc domain consisting of [a specific component].

[0335] In some embodiments, the polynucleotide encodes two or more Fc domains. It contains a nucleotide sequence. In some embodiments, the polynucleotide consists of two Fc units. Includes a nucleotide sequence that codes for the main component. In some embodiments, polynucleotides The first nucleotide sequence encodes the first Fc domain, and the second Fc domain It includes a second nucleotide sequence that codes for . In some embodiments, the first nucleotide The nucleotide sequence and the second nucleotide sequence are contained within different nucleic acid molecules. In this application, the first nucleotide sequence and the second nucleotide sequence are within the same nucleic acid molecule. It is included.

[0336] In some embodiments, the first and second nucleotide sequences share the same Fc domain. In some embodiments, both the first and second nucleotide sequences are sequence numbers. One of the amino acid sequences from numbers 1-3 and at least 70%, 75%, 80%, 8 Amino acid sequences that are 5%, 90%, 95%, 96%, 97%, 98%, or 99% identical Encodes the Fc domain, including the first and second nucleotides. Both sequences are at least 70% of one of the amino acid sequences from sequence numbers 1-3. 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical It encodes an Fc domain consisting of the amino acid sequence. In some embodiments, the first Both the first and second nucleotide sequences are one of the amino acids from sequence numbers 1-3. Encodes an Fc domain containing a sequence. In some embodiments, first and second nuclei Both Otid sequences consist of one amino acid sequence from sequence numbers 1-3. Code the domain.

[0337] In some embodiments, the first and second nucleotide sequences have different Fc domains. To encode. In some embodiments, the first nucleotide sequence is the sequence of SEQ ID NOs. 4-6. One of the amino acid sequences and at least 70%, 75%, 80%, 85%, 90% Fc domains containing amino acid sequences that are 95%, 96%, 97%, 98%, or 99% identical. The second nucleotide sequence codes for one of the sequence numbers 7-9. Mino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 9 It encodes an Fc domain containing an amino acid sequence that is 7%, 98%, or 99% identical. In some embodiments, the first nucleotide sequence is any one of sequence numbers 4 to 6. One amino acid sequence and at least 70%, 75%, 80%, 85%, 90%, 95%, 96% Encoding an Fc domain consisting of amino acid sequences that are 97%, 98%, or 99% identical. The second nucleotide sequence is one of the amino acid sequences from sequence numbers 7-9 and At least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% It encodes an Fc domain consisting of an amino acid sequence that is 99% identical. In the application form, the first nucleotide sequence is one of the amino acids from sequence numbers 4-6. The Fc domain, which contains the acid sequence, is encoded, and the second nucleotide sequence is the sequence of SEQ ID NOs. 7-9. Encodes an Fc domain containing any one of the amino acid sequences. Several embodiments So, the first nucleotide sequence is one of the amino acid sequences from sequence numbers 4-6. It encodes an Fc domain consisting of the following, and the second nucleotide sequence is one of the sequences 7-9. It encodes an Fc domain consisting of any one amino acid sequence. In some embodiments, The first nucleotide sequence codes for the amino acid sequence of SEQ ID NO: 4 or a variant thereof. At that time, the second nucleotide sequence encodes SEQ ID NO: 7 or a variant thereof. In some embodiments, the first nucleotide sequence is the amino acid sequence of SEQ ID NO: 5 or When encoding a variant of , the second nucleotide sequence is , Encodes an ant. In some embodiments, the first nucleotide sequence is sequence number 6. When encoding the amino acid sequence or a variant thereof, the second nucleotide sequence is Code column number 9 or its variant.

[0338] In some embodiments, the first and second nucleotide sequences also include antigen-binding domains. It codes for the same antigen. In some embodiments, the first and second nucleotide sequences are the same antigen. Encodes the binding domain. In some embodiments, the first and second nucleotide sequences These encode different antigen-binding domains. In some embodiments, the first nucleoti The first nucleotide sequence encodes the Fc domain and the antigen-binding domain, and the second nucleotide sequence is, It codes for the Fc domain but not the antigen-binding domain. First and / or second The antigen-binding domain encoded by the nucleotide sequence is described herein. It can be any of the following.

[0339] In some embodiments, the first and second nucleotide sequences also function as peptide linkers. It codes for. In some embodiments, the first and second nucleotide sequences are the same pep Encodes a tidlinker. In some embodiments, the first and second nucleotide sequences These encode different peptide linkers. In some embodiments, the first nucleoti The sequence encodes the Fc domain, peptide linker, and antigen-binding domain, and the second The nucleotide sequence encodes the Fc domain, but the peptide linker or antigen-binding domain In does not code. In some embodiments, the first nucleotide sequence is antigen-binding The main peptide linker and Fc domain are encoded, and the second nucleotide sequence is: It codes for the Fc domain, but not for the peptide linker or antigen-binding domain. The peptide linker encoded by the first and / or second nucleotide sequence is, It may be any of the details described in the document. In some embodiments, the linker - contains the amino acid sequence of SEQ ID NO: 136, 181, or 182.

[0340] In some embodiments, the polynucleotide is the same as in SEQ ID NOs. 137-176 and 180. One of the amino acid sequences and at least 70%, 75%, 80%, 85%, 90% Does it contain amino acid sequences that are identical by %, 95%, 96%, 97%, 98%, or 99%? , or a nucleotide sequence encoding a protein consisting thereof.

[0341] In some embodiments, the polynucleotide is the same as in SEQ ID NOs. 137-176 and 180. It codes for a protein that contains or consists of any one of the following amino acid sequences. Contains a nucleotide sequence.

[0342] In some embodiments, the first nucleotide sequence is sequence numbers 137-176 and 1 Any one of the 80 amino acid sequences and at least 70%, 75%, 80%, 85% , amino acid sequences that are 90%, 95%, 96%, 97%, 98%, or 99% identical It encodes a protein that contains or consists of, and the second nucleotide sequence is Fc-domed It codes for the nucleotide but does not code for the antigen-binding domain. Optionally, a second nucleotide is used. The sequence is at least 70%, 75%, 80%, 85%, 9% of the amino acid sequence of sequence number 8. Tans containing amino acid sequences that are 0%, 95%, 96%, 97%, 98%, or 99% identical. It codes for protein.

[0343] In some embodiments, the first nucleotide sequence is sequence numbers 137-176 and 1 It codes for a protein containing any one of the 80 amino acid sequences, and the second nucleo The cytoplasmic sequence codes for the Fc domain but not the antigen-binding domain. (Optional) The second nucleotide sequence codes for a protein containing the amino acid sequence of sequence number 8. In some embodiments, the first nucleotide sequence is sequence numbers 137-176 and Nucleotides that encode proteins consisting of any one of 180 amino acid sequences. It contains a do sequence, and the second nucleotide sequence encodes the Fc domain, but the antigen-binding domain It does not code for IN. Optionally, the second nucleotide sequence is the amino acid sequence of SEQ ID NO: 8. It codes for proteins that consist of rows.

[0344] Furthermore, a polynucleotide encoding the polypeptide provided above, for example Codon / RNA optimization, substitution with heterogeneous signal sequences, and mRNA instability elements Polynucleotides optimized by the elimination of certain components are provided herein. Therefore, the nucleic acid optimized for recombinant expression introduces codon changes in mRNA. Methods for generating by and / or elimination of inhibitory regions are, for example, described in U.S. Patent No. 5,966. No. 5,726, No. 6,174,666, No. 6,291,664, No. 6,414 The optimization methods described in No. 132 and No. 6,794,498 shall be conformed. This may be carried out by, and all of these documents are incorporated herein by reference in their entirety. It is incorporated. For example, potential splice sites and unstable elements within RNA (e.g., A / T or A / U rich elements are modified amino acids encoded by nucleic acid sequences. It can mutate without causing mutations, thereby increasing the stability of RNA for recombinant expression. The changes use the degeneracy of the genetic code, for example, alternative codes for the same amino acid. A don is used. In one embodiment, one or more codons are changed to create a conservative mutation, for example , similar amino acids having the same chemical structure, properties, and / or functions as the original amino acids It may be desirable to do so.

[0345] Polynucleotides can be obtained by any method known in the art, The nucleotide sequence of the creotide was determined by any method known in the art. This may be the case. Nucleotide sequences encoding proteins described herein, and these Modified versions of antibodies can be determined using methods well known in the art, that is, In other words, nucleotide codons, which are known to encode specific amino acids, are proteins. It is assembled to generate nucleic acids that code for proteins. Polynucleotides can be assembled from chemically synthesized oligonucleotides (for example) Kutmeier G et al., (1994) BioTechniques This is described in 17:242-6, and the entire document is incorporated herein by reference. (Included), in short, this is a duplicate oligo containing a portion of the sequence that codes for an antibody. Nucleotide synthesis, annealing and ligation of these nucleotides, Next, the process includes amplification of ligated oligonucleotides by PCR.

[0346] Alternatively, the polynucleotides encoding the proteins described herein are preferred. From nucleic acids from a suitable source (e.g., hybridoma), using methods well known in the relevant field (e.g., For example, known formulations can be produced using PCR and other molecular cloning methods. PCR amplification using synthetic primers that can hybridize to the 3' and 5' ends of the column, Using genomic DNA obtained from hybridoma cells that produce the target polypeptide Such PCR amplification methods can be performed. Such PCR amplification methods involve nucleic acids containing a sequence encoding a polypeptide. It can be used to obtain the amplified nucleic acid within the vector, which is then expressed in the host cell. It can be cloned for further cloning.

[0347] Although clones containing nucleic acids encoding specific polypeptides are not available, If the sequence of the peptide is known, the nucleic acid encoding the polypeptide is a suitable source (for example) If generated from any tissue or cell expressing the polypeptide described herein, A cDNA library, or nucleic acids isolated therefrom, preferably poly(A+RNA) ) Using synthetic primers that can hybridize to the 3' and 5' ends of the sequence, PC By R amplification, or by using oligonucleotide probes specific to a particular gene sequence. For example, a cDNA clone can be extracted from a cDNA library that encodes polypeptides. It may be chemically synthesized or obtained by a defined cloning process. Then, PC The amplified nucleic acids generated by R are placed in a replicable cloning vector, and the technique It can be cloned using any method known in the field.

[0348] The DNA encoding the proteins described herein can be easily obtained using conventional procedures. They can be isolated and sequenced. Hybridoma cells can serve as a source of such DNA. It is possible. When isolated, the DNA can be placed in an expression vector, and then These are host cells, such as E. coli cells, monkey COS cells, and Chinese ham cells. Star Ovarian (CHO) Cells (e.g., CHO GS System (trademark) (Lonza CHO cells from ) or otherwise producing the proteins described herein It is transfected into myeloma cells.

[0349] Also, high stringency, intermediate, or low stringency hybridization Under these conditions, the polynucleotide encoding the protein described herein is hybridized To enable this, polynucleotides are provided.

[0350] Hybridization conditions are described in the relevant art and are known to those skilled in the art. For example, hybridization under stringent conditions is 6 times more efficient at approximately 45°C. Hive to filter-bound DNA in sodium chloride / sodium citrate (SSC) Redization, followed by 0.2 times SSC / 0.1% SDS at approximately 50-65°C. This may include one or more washes and hybridize under highly stringent conditions. The hybridization of filter-bound nucleic acids in SSCs at approximately 45°C is 6 times more effective. Next, the process includes one or more washes in a 0.1x SSC / 0.2% SDS solution at approximately 68°C. It is possible to hybridize under other stringent hybridization conditions. The facilitation is known to those skilled in the art and is described, for example, in Ausubel FM. et al., eds. (1989)Current Protocols in Mo Lecular Biology,Vol.I,Green Publishing A ssociates, Inc. and John Wiley & Sons, Inc. Please refer to pages 6.3.1-6.3.6 and 2.10.3 of the New York edition. The references are incorporated herein by reference in their entirety.

[0351] In one embodiment, this specification expresses (for example, recombinant) the proteins described herein. Cells (e.g., host cells) that express (the polynucleotides and expression vectors) and related polynucleotides The proteins described herein are provided. A host cell, preferably a mammalian cell (for example, a polynucleotide containing a tide sequence) A vector for recombinant expression in CHO cells (e.g., an expression vector) is described in this specification. It is provided in writing. Also, the proteins described herein, including such vectors. Host cells for recombinant expression are provided herein. In one embodiment, as described herein A method for producing a protein, wherein a polypeptide is expressed from a host cell. Methods including the above are provided herein.

[0352] The recombinant expression of proteins described herein generally involves polypeptides. This includes constructing an expression vector containing polynucleotides. When a polynucleotide encoding tide is obtained, a vector for polypeptide production is used. However, it can be produced using recombinant DNA technology and techniques well known in the field. Therefore, the protein is a polypeptide containing a polypeptide that codes for a nucleotide sequence. A method for preparing by expressing nucleotides is described herein. A method well known to those skilled in the art involves a polypeptide coding sequence and appropriate transcription and translation control signals. These methods can be used to construct expression vectors containing [specific components]. For example, this includes in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Furthermore, it contains nucleotide sequences that encode polypeptides described herein. A replicable vector in which the nucleotide sequence is operablely linked to a promoter. A vector is provided. Such a vector is, for example, the first heavy chain of the disclosure. It may contain a nucleotide sequence that codes for (for example, International Publication No. 86 / 05807) See U.S. Patent No. 89 / 01036 and U.S. Patent No. 5,122,464. These documents (the whole of which is incorporated herein by reference) are the second of the disclosures. The heavy chains within such a vector are the first heavy chain, the second heavy chain, or the first and second heavy chains It can be cloned for the expression of both.

[0353] In one embodiment, the vector is the sdAb, Fab of the polypeptide described herein. Polynucleations encoding fragments, scFv, VHH fragments, VH, VL, heavy chains, and / or light chains. Contains a rheotide. In another embodiment, the vector is a polypeptide as described herein. The vector contains polynucleotides encoding VH and VL. In another embodiment, the vector The specification includes polynucleotides encoding the heavy and light chains of the polypeptide described in the specification.

[0354] Expression vectors can be transferred to cells (e.g., host cells) using conventional techniques, and then... The resulting cells are cultured using conventional techniques and then subjected to the polypeptide described herein. Polypeptide or fragments thereof can be produced. Therefore, the polypeptide described herein D or a fragment thereof, or its heavy or light chain, or a fragment thereof, or as described herein A host cell containing polynucleotides encoding a single-chain antibody, Polynucleotides are used by promoters for the expression of such sequences in host cells. A host cell that is operablely linked is provided herein.

[0355] In one embodiment, the host cell has one of the above first nucleotide sequences and the above It contains a polynucleotide that includes one of the second nucleotide sequences. In another embodiment, The host cell contains a first polynucleotide sequence containing one of the first nucleotide sequences described above. D, and a second polynucleotide containing one of the first nucleotide sequences described above, Includes. In another embodiment, the host cell has one of the first nucleotide sequences described above and Includes a first vector containing one of the second nucleotide sequences described above. Another embodiment So, the host cell has one of the first nucleotide sequences and the second nucleotide. A first vector containing one of the ocid sequences, and of the first nucleotide sequences mentioned above A second vector containing a second polynucleotide which includes one of the following.

[0356] In some embodiments, an FcRn / antigen-binding molecule expressed by a first host cell. It associates with the FcRn / antigen-binding molecule expressed by the second host cell, forming a two-armed structure. It forms an FcRn / antigen binding molecule by a first host cell. In some embodiments, it is formed by a first host cell. The expressed FcRn / antigen-binding molecule is FcRn-binding expressed by the second host cell. It associates with molecules to form a one-armed FcRn / antigen-binding molecule. In some embodiments, This is a collection of host cells, including such a first host cell and such a second host cell. The group is provided herein.

[0357] In some embodiments, the polynucleotide encoding the FcRn / antigen-binding molecule is included. The first vector contains a polynucleotide encoding an FcRn / antigen-binding molecule. A collection of vectors, including the vector of , is provided herein. Several embodiments So, the first vector contains a polynucleotide encoding an FcRn / antigen-binding molecule, A second vector containing a polynucleotide encoding an FcRn binding molecule, and a vector containing A group of ter is provided herein. In some embodiments, FcRn / antigen binding Polynucleotides that code for offspring and polynucleotides that code for FcRn / antigen-binding molecules A group of vectors, including a first vector containing tide, is provided herein. In this embodiment, the polynucleotide comprising two FcRn / antigen-binding molecules is used. A collection of vectors, including vector 1, is provided herein.

[0358] Various host expression vector systems are used to express the polypeptides described herein. It may be used (see, for example, U.S. Patent No. 5,807,715, this document is...) (The entirety of which is incorporated herein by reference). Such a host expression system is the desired code This represents a medium from which a sequence can be produced and subsequently purified, and also a suitable nucleotide code. When transformed or transfected in a sequence, the polypeptides described herein This represents cells that can express the phenotype in insights. These are microorganisms, for example, bacteria. For example, E. coli and B. subtilis), for example, FcRn / antigen-binding molecule Recombinant bacteriophage DNA, plasmid DNA, or cosmic sequences containing a cosmic sequence. Bacteria transformed with a DNA expression vector; yeast (e.g., Saccharomycetes) Recombinant yeast (e.g., s and Pichia), for example, containing an FcRn / antigen-binding molecular coding sequence Yeast transformed with a parent expression vector; insect cell line, e.g., FcRn / antigen-binding molecule Infection with a recombinant virus expression vector containing a code sequence (e.g., baculovirus) insect cell systems; plant cell systems (e.g., green algae, e.g., Chlamydomonas re (inhardtii), for example, recombinant U2 containing FcRn / antigen-binding molecular coding sequences Virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus) Plant cell lines infected with the cuvirus (TMV), or, for example, FcRn / antigen-binding molecules Recombinant plasmid expression vectors containing coding sequences (e.g., Ti plasmids) Converted plant cell lines; or mammalian cell lines (e.g., COS(e.g., COS1 or CO) S), CHO, BHK, MDCK, HEK 293, NS0, PER.C6, VERO, CRL7O3O, HsS78Bst, HeLa, NIH 3T3, HEK-293T, H epG2, SP210, R1.1, BW, LM, BSC1, BSC40, YB / 20 , and BMT10 cells), for example, promoters derived from the genome of mammalian cells (e.g., , metallothionein promoter) or promoters derived from mammalian viruses (e.g.) For example, the late promoter of adenovirus; the 7.5K promoter of vaccinia virus. This includes, but is not limited to, mammalian cell lines possessing recombinant expression constructs containing the constituent recombinant expression constructs. In the embodiments, cells for expressing the FcRn / antigen-binding molecule described herein are Chinese hamster ovary (CHO) cells, for example, CHO GS System ( These are CHO cells from (Lonza) (trademark). In one embodiment, CHO cells produce The resulting heavy and / or light chains are N-terminal glutamate replaced by pyroglutamate. It may have mine or glutamic acid residues. In one embodiment, the polypeptide described herein The cells used to express the cydo are human cells, for example, human cell lines. In one embodiment, The mammalian expression vector is pOptiVEC® or pcDNA3.3. In terms of application morphology, bacterial cells, e.g., Escherichia coli, or eukaryotic cells (e.g.) For example, mammalian cells are used for the expression of recombinant polypeptides. Cells, for example, CHO cells, are derived from vectors, for example, human cytomegalovirus. Along with the earliest gene promoter elements, it is an effective expression system for antibodies (Fo ecking MK & Hofstetter H(1986)Gene 45:10 1-5, and Cockett MI et al., (1990) Biotechnol ogy 8(7):662-7, each of these documents is referred to herein by reference in its entirety. (to be incorporated into). In one embodiment, the polypeptide described herein is incorporated into CHO cells or produced by NS0 cells. In one embodiment, 2, 3, or 4 are added to human FcRn. A nucleotide sequence encoding a polypeptide described herein, which includes two binding sites. Expression is controlled by a constitutive promoter, an inducible promoter, or a tissue-specific promoter. It is adjusted.

[0359] In bacterial systems, some expression vectors are used for purposes intended for molecular expression. They may exist and be advantageously selected. For example, large amounts of such polypeptides can be used in the pharmaceutical research of antibody molecules. High levels of fusion proteins that are easily purified when produced for the creation of target compositions. A vector that directs the expression of the product may be desirable. Such a vector is E. col i expression vector pUR278 (Ruether U & Mueller-Hill B (1983)EMBO J 2:1791-1794) and the code sequence is lac It can be individually ligated within a vector in a frame having a Z code region, and thus The fusion protein is produced, pUR278; and pIN vector (Inouye S & Inouye M(1985)Nuc Acids Res 13:3101- 3109, Van Heeke G & Schuster SM (1989) J Bi This includes, but is not limited to, ol Chem 24:5503-5509, etc. All of the literature cited is incorporated herein by reference in its entirety. Also, for example, The pGEX vector transfers the exogenous polypeptide to glutathione 5-transferase (GS). It can be used to express as a fusion protein with T). Generally speaking, such fusion Proteins are soluble, and from lysed cells, matrix glutathione agarose β Adsorption and binding to the substance, followed by elution in the presence of free glutathione, allows for easy purification. It is possible. The pGEX vector contains a thrombin or factor Xa protease cleavage site. It is designed in such a way that the cloned target gene product is either GST or They can be released.

[0360] In insects, for example, *Autographa californica* nuclear polyhedrosis The virus (AcNPV) can be used as a vector to express foreign genes. The virus replicates in Spodoptera frugiperda cells. The coding sequence is individually clawed within the non-essential regions of the virus (e.g., polyhedrin genes). It may be controlled under the control of the AcNPV promoter (e.g., the polyhedrin promoter). It can be placed there.

[0361] Several virus-based expression systems can be used in mammalian host cells. When a virus is used as an expression vector, the desired coding sequence is obtained through adenovirus transmutation. The translation / reactivity control complex, for example, the late promoter and the triplicate reader sequence, ligates This can then be done. Next, this chimeric gene is placed in the adenovirus genome in vitro or It can be inserted by in vivo recombination into non-essential regions of the viral genome (e.g., region E1). Insertion into E3) results in a recombinant virus, which then infects the host. In this context, it is possible to survive and express molecules (for example, Logan J See & Shenk T (1984) PNAS 81(12):3655-9. (This document is incorporated herein by reference in its entirety.) Also, specific beginning Signals may be required for the efficient translation of the inserted code sequence. The Gnar includes the ATG start codon and adjacent sequences. Furthermore, the start codon encompasses the entire insert. To ensure the translation is correct, the desired code array must be homeomorphic to the reading frame. These exogenous translational regulatory signals and start codons originate from a variety of natural and synthetic sources. It can be. Expression efficiency depends on the appropriate transcription enhancer element, transcription terminology. It can be enhanced by including components such as (for example, Bitter G et al.) See (1987) Methods Enzymol. 153:516-544. (Incidentally, this document is incorporated herein by reference in its entirety.)

[0362] In addition, it may regulate the expression of the inserted sequence or the gene product in a desired specific manner. Host cell lines for modification and processing may be selected. Such modifications of protein products (e.g., glycosylation) and processing (e.g., cleavage) are functions of proteins. This may be important for different host cells. It has characteristic and specific mechanisms for expression and modification. A suitable cell line or host system expresses it. It may be selected to ensure the correct modification and processing of the foreign protein being modified. For this purpose, proper processing of primary transcripts, glycosylation and phosphorylation of gene products are performed. Eukaryotic host cells with cellular mechanisms for this purpose may be used. Such mammalian host cells are CHO, VERO, BHK, HeLa, MDCK, HEK 293, NIH 3T3, W 138, BT483, Hs578T, HTB2, BT2O and T47D, NS0 (any of them) (A mouse myeloma cell line that does not endogenously produce immunoglobulin chains), CRL7O3O, CO S (e.g., COS1 or COS), PER.C6, VERO, HsS78Bst, HE K-293T, HepG2, SP210, R1.1, BW, LM, BSC1, BSC This includes, but is not limited to, cells 40, YB / 20, BMT10, and HsS78Bst. It is not possible. In one embodiment, the protein described herein is used in mammalian cells, for example, C It is produced in HO cells.

[0363] In one embodiment, the polypeptide described herein has a reduced fucose content. It includes a portion of the antibody that either contains or does not contain fucose. Such proteins They can be produced using techniques known to those skilled in the art. For example, a protein can be fucosylated. It can be expressed in cells that lack or have impaired ability. One example is α1,6-fucosyl Cell lines with knockout of both alleles of the transferase showed reduced fucoid Potelligent (registered trademark) can be used to produce antibodies containing [specific component]. The Lonza system is used to produce antibodies with reduced fucose content. This is an example of such a system.

[0364] Stable expression cells can be generated for long-term high-yield production of recombinant proteins. For example. If a cell line that stably expresses the protein described herein can be manipulated. Morphologically, the cells provided herein have an antigen-binding domain, FcRn / antigen-binding molecule, Alternatively, it stably expresses an FcRn binding molecule, and has an antigen-binding domain, FcRn / antigen-binding molecule, Alternatively, the FcRn binding molecule may associate with a one-arm or two-arm port as described herein. It forms lipeptides.

[0365] In certain embodiments, instead of using an expression vector containing a viral replication origin The host cell then expresses the appropriate regulatory elements (e.g., promoters, enhancers, sequences). Controlled by (transfer terminators, polyadenylation sites, etc.) and selectable markers. It can be transformed with the DNA being transformed. After the introduction of foreign DNA / polynucleotides, it is manipulated. The cells can grow in enriched medium for 1-2 days, and then are transferred to selective medium. It can be replaced. Selectable markers in recombinant plasmids can improve resistance to selection. The cells then stably incorporate the plasmid into their chromosomes and proliferate. This allows for the formation of sap, and then the focus can be cloned into a cell line. It can be propagated. This method is advantageous in that it uses human FcRn or as described herein. Manipulate cell lines that express polypeptides containing two, three, or four binding sites to the fragment. It can be used for the purpose of directly or indirectly transferring polypeptides to such manipulated cell lines. This may be particularly useful in screening and evaluating compositions that interact with each other.

[0366] Several selection systems may be used, and these selection systems are tk, hgprt, or apr, respectively. Herpes simplex virus thymidine kinase in T cells (Wigler M et al.) .,(1977)Cell 11(1):223-32), Hypoxanthine guanine phosphate Horibosyltransferase (Szybalska EH & Szybalski W(1962)PNAS 48(12):2026-2034), and adenine phosphoryl Bosyltransferase (Lowy I et al., (1980) Cell 22 (3):817-23) This includes, but is not limited to, genes, and all of these references are, All of these are incorporated herein by reference. Furthermore, antimetabolite resistance is as follows: The gene dhfr (Wigler M et al.) confers resistance to methotrexate. al., (1980) PNAS 77(6):3567-70, O'Hare K e t al., (1981) PNAS 78:1527-31); against mycophenolic acid GPT (Mulligan RC & Berg P(1981)P) provides resistance to [unclear] NAS 78(4):2072-6); Resistance to aminoglycoside G-418 Agreeing with neo(Wu GY & Wu CH (1991) Biotherapy 3:8 7-95, Tolstoshev P (1993) Ann Rev Pharmacol. Toxicol 32:573-596, Mulligan RC (1993) Sci. ence 260:926-932, and Morgan RA & Anderson WF (1993) Ann Rev Biochem 62:191-217, Nabel GJ & Felgner PL (1993) Trends Biotechnol 11(5):211-5); and hygro to confer resistance to hygromycin (Santerre RF et al.,(1984)Gene 30(1-3):1 47-56) can be used as the basis for selection, and all of these documents are The entire text is incorporated herein by reference. The law is usually applied so that the desired recombinant clone can be selected, in such a way For example, Ausubel FM et al., (eds.), Current Pro tocols in Molecular Biology,John Wiley & Sons, NY (1993), Kriegler M, Gene Transfer and Expression,A Laboratory Manual,Stock Ton Press, NY (1990), and Chapters 12 and 13, Dracopoli NC et al., (Eds.), Current Protocols in Hum an Genetics, John Wiley & Sons, NY (1994), C olbere-Garapin F et al., (1981) J Mol Biol It is described in 150:1-14, and all of these references are referenced in their entirety. This specification is incorporated herein.

[0367] Polypeptide expression levels can be increased by vector amplification (see overview). Bebbington CR & Hentschel CCG, The use of vectors based on gene amplification for the expression of cloned genes in ma mmalian cells in DNA cloning,p.163-188.D NA Cloning,Vol III,A Practical Approach. DMGlover (Editor) (Academic Press, New York, 1 See 987), which is incorporated herein by reference in its entirety. When the marker in the vector system is amplified, it is present in the host cell culture. An increase in the inhibitor level increases the number of copies of the marker gene, and also amplifies it. Because the affected region is related to the target gene, polypeptide production increases (Crous e GF et al., (1983) Mol Cell Biol 3:257-66 (This document is incorporated herein by reference in its entirety.)

[0368] Host cells are co-transfected with two or more expression vectors described herein. Obtain. The two vectors can contain the same selectable markers and the same selection. Possible markers include polypeptides, e.g., the first heavy chain and the second heavy chain polypeptide. Enables fine expression. Host cells cotransfer two or more expression vectors in different amounts. It can be applied to host cells using the first expression vector and the second expression vector. The ratios below are approximately 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, and 1:9. 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40 It can be transfected in one of the following timeframes: 1:45, 1:50, or 1:45.

[0369] Alternatively, a single polypeptide that encodes both polypeptides and can express them. A vector may be used. The coding sequence can be cDNA or genomic DNA. The expression vector can be monocistronic or multicistronic. The cystronic nucleic acid constructs can be 2, 3, 4, 5, 6, 7, 8, 9, 10, or so More than this number of gene / nucleotide sequences, or 2-5, 5-10, or 10-20 It can encode within the range of individual genes / nucleotide sequences. For example, bicyclo The nucleic acid construct includes, in the following order: promoter, first gene, and second gene. It is possible to do so. In such an expression vector, the transcription of both genes is promoted —can be driven by, translation of mRNA from the first gene is cap-dependent scanning This can be due to a capping mechanism, and the translation of mRNA from the second gene is capped. It can be an independent mechanism, such as one mediated by IRES.

[0370] The polypeptides described herein, when produced by recombinant expression, are proteins Any method known in the art for quality purification, for example, chromatography ( For example, ion exchange, affinity, in particular affinity to specific antigens after protein A, and cy (For Zing column chromatography), centrifugation, differential solubility, or protein purification It can be purified by any of the other standard techniques described herein. Furthermore, the polyp Buttido is a heterogeneous polypeptide sequence as described herein, or otherwise the technical component It can be fused to known heterologous polypeptide sequences in the field, making purification easier.

[0371] In one embodiment, the polypeptide described herein is isolated or purified. In this embodiment, the isolated polypeptide has different antigen specificity from the isolated polypeptide. It substantially does not contain other polypeptides having the same properties. For example, in a particular embodiment Therefore, the protein preparations described herein are used to provide cell materials and / or chemical precursors. It does not contain it qualitatively. The expression "substantially does not contain cell material" refers to polypeptide preparations. The polypeptide is a single polypeptide derived from the cellular components of the cell from which it was isolated or recombinantly produced. Separated, containing preparations. Therefore, polypeptides that substantially do not contain cell material are Approximately 30%, 20%, 10%, 5%, 2%, 1%, 0.5%, or 0.1% (dry weight) (by) foreign proteins (also referred to herein as "contamination proteins") and / or Polypeptide variants, for example, polypeptides with different post-translational modification forms or other different A polypeptide preparation having a different version of the polypeptide (e.g., polypeptide fragment). This includes the product. Also, when polypeptides are recombinantly produced, they generally substantially reduce the culture medium. It does not contain, that is, the culture medium is approximately 20%, 10%, and 2% of the volume of the protein preparation. This represents less than 1%, 0.5%, or 0.1%. Polypeptides are produced by chemical synthesis. When prepared, it generally contains substantially no chemical precursors or other chemical substances, i.e., protein It is isolated from chemical precursors or other chemical substances involved in the synthesis of the substance. Therefore, Such protein preparations contain approximately 30%, 20%, 10%, or 5% (by dry weight). It has a chemical precursor or compound other than the target molecule, which is less than ) The polypeptides described have been isolated or purified.

[0372] The polypeptides described herein are known in the art for the synthesis of antibodies. It can be produced by any of the following methods, for example, chemical synthesis or recombinant expression techniques. Unless otherwise specified, the methods described are molecular biology, microbiology, genetic analysis, and recombinant D. NA, organic chemistry, biochemistry, PCR, oligonucleotide synthesis and modification, nucleic acid hybridization The technology employs conventional techniques in related fields within the relevant technical area. The technique is described, for example, in the references cited herein and is fully explained in those references. For example, Maniatis T et al., (1982) Molecula r Cloning:A Laboratory Manual,Cold Sprin g Harbor Laboratory Press, Sambrook J et al.,(1989),Molecular Cloning: A Laboratory y Manual,Second Edition,Cold Spring Harb or Laboratory Press, Sambrook J et al.,(2 001)Molecular Cloning: A Laboratory Manual l,Cold Spring Harbor Laboratory Press,Co ld Spring Harbor, NY, Ausubel FM et al.,Cu. rrent Protocols in Molecular Biology,Joh n Wiley & Sons (1987 and annual updates), Current Pro tocols in Immunology,John Wiley & Sons(1 987 and annual updates), Gait (ed.) (1984) Oligonucleoti de Synthesis:A Practical Approach,IRL Pr Ess, Eckstein (eds.) (1991) Oligonucleotides a nd Analogues:A Practical Approach,IRL Pr ess, Birren B et al., (eds.) (1999) Genome Ana lysis:A Laboratory Manual,Cold Spring Ha Please refer to rbor Laboratory Press; all of these documents are, The entirety of these is incorporated herein by reference.

[0373] In one embodiment, the polypeptide described herein is used by any means including the preparation of Therefore, for example, DNA sequence synthesis, preparation, expression, production via genetic manipulation, or It is isolated. In one embodiment, such polypeptides are used in vivo in animals or mammals. Sequences that do not naturally exist in the antibody germline repertoire of animals (e.g., humans) (e.g., Includes (DNA sequence or amino acid sequence).

[0374] Pharmaceutical composition In one aspect, this disclosure relates to a method for treating antibody-mediated disorders (e.g., autoantibody-mediated disorders). Pharmaceuticals for use in law, including FcRn / antigen-binding molecules disclosed herein. The present invention provides compositions. In certain embodiments, these compositions include FcRn binding molecules and It contains an FcRn / antigen-binding molecule that includes an antigen-binding domain. In some embodiments, Fc The Rn-binding molecule is an FcRn antagonist. In some embodiments, FcRn The antagonist is variant F, which inhibits the binding of immunoglobulins to the Fc region of FcRn. It contains or consists of a c region or its FcRn binding fragment. Generally speaking, these F cRn antagonists are Fc-containing drugs (e.g., antibodies and i) that target FcRn in vivo. It inhibits the binding of munoadhecin, which results in an increased degradation rate of Fc-containing drugs. This, in turn, leads to reduced serum levels of these drugs.

[0375] In some embodiments, the FcRn / antigen-binding molecule of this disclosure is a full-length IgG (approximately 15 The molecular weight range of approximately 50 kDa to 140 kDa is about one-third of the molecular weight of 0 kDa (MW). It has a molecular weight. In some embodiments, the FcRn / antigen-binding molecule is about 60 kDa to about It has a molecular weight of 104 kDa. In some embodiments, the FcRn / antigen-binding molecule is It has a molecular weight of 60 kDa to 104 kDa. In some embodiments, FcRn / antigen The binding molecule has a molecular weight of approximately 60 kDa. In some embodiments, FcRn / antigen The binding molecule has a molecular weight of approximately 104 kDa. In some embodiments, FcRn / anti The original binding molecule has a molecular weight of 60 kDa. In some embodiments, FcRn / antigen The binding molecule has a molecular weight of 104 kDa.

[0376] The FcRn / antigen-binding molecule of this disclosure has a molecular weight of full-length IgG (approximately 150 kDa MW). It has a predicted molecular weight in the range of approximately 50 kDa to approximately 140 kDa, which is about one-third of the total. In that embodiment, the FcRn / antigen-binding molecule has a predicted range of approximately 60 kDa to approximately 104 kDa. It has a molecular weight. In some embodiments, the FcRn / antigen-binding molecule is 60kDa~10 It has a predicted molecular weight of 4 kDa. In some embodiments, the FcRn / antigen-binding molecule is It has a predicted molecular weight of approximately 60 kDa. In some embodiments, the FcRn / antigen-binding molecule It has a predicted molecular weight of approximately 104 kDa. In some embodiments, FcRn / antigen ligation The combined molecule has a predicted molecular weight of 60 kDa. In some embodiments, FcRn / antigen The binding molecule has a predicted molecular weight of 104 kDa.

[0377] The formulations disclosed herein are pharmaceutical compositions that can be used to prepare unit dosage forms (e.g., Includes bulk drug compositions useful for the manufacture of compositions suitable for administration to a target or patient. In this state, the composition of the present invention is a pharmaceutical composition. Such a composition is effective for prevention or treatment. A quantity of one or more prophylactic or therapeutic agents of the present invention (e.g., FcRn / antigen-binding molecule) (or others) It includes a preventive or therapeutic agent for [condition] and a pharmaceutically acceptable carrier.

[0378] In some embodiments, the pharmaceutical composition is administered to the subject via one of the preferred routes of administration. It is formulated for administration via intramuscular, intravenous, intradermal, intraperitoneal, subcutaneous, and epidural routes. This includes administration via the nasal cavity, oral, rectal, topical, inhalation, buccal (e.g., sublingual), and transdermal channels. The invention is not limited to these. In one embodiment, the pharmaceutical composition is suitable for intravenous administration to a subject. It is formulated in such a way. In one embodiment, the pharmaceutical composition is suitable for subcutaneous administration to a subject. It is formulated in a certain way.

[0379] Treatment method This disclosure also relates to the treatment of antibody-mediated disorders (e.g., autoantibody-mediated disorders) in subjects. A method for which a therapeutically effective amount of the FcRn / antigen-binding molecule according to this disclosure is provided to the target. The present invention provides a method comprising administering a pharmaceutical composition containing or the same.

[0380] In some embodiments, antibody-mediated disorders are autoimmune diseases. Morphologically, autoimmune diseases include allograft rejection, alopecia areata, ankylosing spondylitis, and antiphospholipid Addison's disease, autoimmune Addison's disease, Alzheimer's disease, antineutrophil cytoplasmic autoantibodies (ANC) A) Autoimmune diseases of the adrenal glands, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune cardiomyopathy inflammation, autoimmune neutropenia, autoimmune oophoritis and orchitis, immune thrombocytopenia (IT P or idiopathic thrombocytopenic purpura penic purpura), idiopathic thrombocytopenic purpura (idiopathic t hrombocytopenia purpura), immune-mediated thrombocytopenia, or original (Immune thrombocytopenia), autoimmune urticaria, Behçet's disease, bullous pemphigoid (BP) ), cardiomyopathy, Castleman disease, celiac plue dermatitis, chronic fatigue immune deficiency syndrome Group, chronic inflammatory demyelinating polyneuropathy (CIDP), Churg-Strauss syndrome, Scarring pemphigoid, CREST syndrome, cold agglutination disease, Crohn's disease, dilated cardiomyopathy, discoid Lupus erythematosus, acquired epidermolysis bullosa, essential mixed cryoglobulinemia, Class VIII Factor deficiency, fibromyalgia-fibromyositis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome Goodpasture syndrome, graft-versus-host disease (GVHD), Hashimoto's thyroiditis, hemophilia A, special Inflammatory myopathy (IIM), idiopathic membranous neuropathy, idiopathic pulmonary fibrosis, IgA Neuropathy, IgM-rich neuropathy, immune-mediated necrotizing myopathy (IMNM) Juvenile arthritis, Kawasaki disease, lichen planus, lichen sclerosing, lupus erythematosus, lupus nephritis, Nieille's disease, mixed connective tissue disease, mucosal pemphigoid, multiple sclerosis, type 1 diabetes, multifocal disease Animal neuropathy (MMN), myasthenia gravis (MG), generalized myasthenia gravis (gMG), Myositis, paraneoplastic bullous pemphigoid, pemphigoid of pregnancy, pemphigus vulgaris (PV), pemphigus foliaceus (PF), pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndrome, polyrheumatic polychondritis Myalgia, polymyositis, dermatomyositis (DM), necrotizing autoimmune myopathy (NAM), anti-syringopathy Centetase 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, parenchymal organ transplant rejection, generalized rigidity syndrome Systemic lupus erythematosus, Takayasu's arteritis, toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome Johnson syndrome (SJS), temporal arteritis / giant cell arteritis, thrombotic thrombocytopenic purpura Ulcerative colitis, uveitis, herpetiform dermatitis, vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis, white blood The group is selected from plaques and Wegener's granulomatosis.

[0381] In one embodiment, the FcRn / antigen binding molecule binds FcRn to the antibody Fc region. To gonize. In one embodiment, the FcRn / antigen binding molecule binds to albumin. Do not antagonize the combination.

[0382] This disclosure relates to a method for reducing serum IgG in a subject, wherein the subject is given a therapeutically effective amount of This disclosure includes administering an FcRn / antigen-binding molecule or a pharmaceutical composition containing the same. The method provides a method in which at least one of the IgG subtypes is In elephants, it is reduced after administration of the FcRn / antigen-binding molecule. In some embodiments, IgG1, IgG2, IgG3, IgG4, or any combination thereof is reduced. In some embodiments, administration of an FcRn / antigen binding molecule is performed. This is a single dose of the molecule (e.g., a single therapeutic dose). In one embodiment, the level of serum IgG is measured. In the subjects, after administration of FcRn / antigen-binding molecules, the baseline level of serum IgG was observed. It decreases compared to the previous version.

[0383] In one embodiment, at least about 40% of total blood IgG levels compared to baseline serum IgG levels. A reduction in serum IgG is obtained. In one embodiment, a small amount is obtained compared to the baseline serum IgG level. Even without this, a reduction of approximately 45% in total serum IgG can be achieved. In one embodiment, baseline serum I A reduction of at least approximately 50% in total serum IgG compared to the IgG level can be achieved. In one embodiment, This indicates a reduction of at least approximately 55% in total serum IgG compared to baseline serum IgG levels. Obtained. In one embodiment, at least about 60 compared to baseline serum IgG levels. A % reduction in total serum IgG is obtained. In one embodiment, the ratio of baseline serum IgG levels is obtained. Compared to the previous method, a reduction of at least 65%, 70%, 75%, or 80% in total serum IgG was achieved. In one embodiment, at least about 65% compared to baseline serum IgG levels. A reduction in total serum IgG is obtained. In one embodiment, compared with baseline serum IgG levels. This results in a total serum IgG reduction of at least approximately 70%. In one embodiment, baseline A reduction of at least approximately 75% in total serum IgG levels can be achieved compared to serum IgG levels. Morphologically, at least approximately 80% of total serum IgG levels compared to baseline serum IgG levels. A reduction can be achieved.

[0384] In one embodiment, serum IgG levels are used in the target to measure the administration of FcRn / antigen-binding molecules. After administration, serum IgG levels decrease compared to baseline levels. In one embodiment, base A reduction of approximately 40% in total serum IgG is achieved compared to the line serum IgG level. (One embodiment) Therefore, a total serum IgG reduction of approximately 45% can be obtained compared to baseline serum IgG levels. In one embodiment, total serum IgG levels are reduced by approximately 50% compared to baseline serum IgG levels. A reduction is obtained. In one embodiment, a total reduction of approximately 55% is obtained compared to baseline serum IgG levels. A reduction in serum IgG is achieved. In one embodiment, compared to baseline serum IgG levels, A reduction of approximately 60% in total serum IgG can be achieved. In one embodiment, the baseline serum IgG level Compared to [the previous method], a total serum IgG reduction of approximately 65%, 70%, 75%, or 80% can be achieved. In one embodiment, approximately 65% ​​of total serum IgG levels were observed compared to baseline serum IgG levels. A reduction is obtained. In one embodiment, approximately 70% compared to baseline serum IgG levels. A reduction in total serum IgG is obtained. In one embodiment, compared with baseline serum IgG levels This results in a reduction of approximately 75% in total serum IgG. In one embodiment, baseline serum IgG levels Compared to Bell, it achieves approximately 80% reduction in total serum IgG.

[0385] In one embodiment, the level of FcRn is determined by the administration of an FcRn / antigen-binding molecule to a subject. Later, it does not decrease compared to the baseline level of FcRn. In one embodiment, the baseline FcRn reduction of approximately 1%, 2%, 3%, 4%, or less than 5% compared to the in-FcRn level. This is observed. In one embodiment, it is less than 10% compared to the baseline FcRn level. A reduction in FcRn is observed.

[0386] In one embodiment, albumin levels were determined in the subject after administration of an FcRn / antigen-binding molecule. Subsequently, the albumin level does not decrease compared to the baseline level. In one embodiment, the baseline Albumin levels less than approximately 1%, 2%, 3%, 4%, or 5% compared to line albumin levels. A reduction is observed. In one embodiment, approximately 10% compared to baseline albumin levels. A reduction in albumin levels of less than 1% was observed.

[0387] In one embodiment, total IgG, FcRn / antigen-binding molecule, FcR in a patient's serum sample. n, or albumin, is analyzed using a bioanalysis method. In one embodiment, the patient's blood In clean samples, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin are EL The analysis is performed using an ISA or an automated diagnostic analyzer (IVD). In one embodiment, the patient's blood In clean samples, total IgG, FcRn / antigen-binding molecules, FcRn, or albumin are EL Analysis is performed using ISA. In one embodiment, total IgG, Fc in the patient's serum sample. Rn / antigen-binding molecules, FcRn, or albumin are analyzed using an automated diagnostic analyzer (IVD). It is analyzed. In one embodiment, the total FcRn in a patient's blood sample is analyzed using a bioanalysis method. Preferably, the analysis is performed using flow cytometry, microscopy, or immunoblotting. .

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

[0389] In some embodiments, total serum IgG clearance is measured in the subject as FcRn / It increases after administration of the antigen-binding molecule. In some embodiments, FcRn / antigen-binding molecule Total serum IgG clearance in subjects after a single therapeutic dose of efgaltigimod This is equivalent to the clearance of total serum IgG in subjects after therapeutic administration. Several implementations In this state, the clearance of total serum IgG in subjects after a single therapeutic administration of FcRn / antigen-binding molecule Lance is a study on the clearance of total serum IgG in subjects after a single dose of efgaltigimod. It is similar to or the same as S. In some embodiments, the clearance of total serum IgG is the same as In elephants, after a single dose of FcRn / antigen-binding molecule, a single dose of efgaltigimod was administered. It increases compared to the clearance of total serum IgG after administration. In some embodiments, total In the subjects, serum IgG clearance was observed after a single therapeutic administration of FcRn / antigen-binding molecules. In comparison to the clearance of total serum IgG after a single therapeutic administration of efgaltigimod, 5% each, at least 10%, at least 15%, at least 20%, at least 25% , at least 30%, at least 40%, at least 50%, at least 60%, less 70% each, at least 80%, at least 90%, at least 100%, at least 1 It will increase by 25%, at least 150%, or at least 200%.

[0390] In some embodiments, total serum of subjects after a single administration of the FcRn / antigen-binding molecule. IgG clearance was measured in total serum of subjects after a single dose of an equivalent amount of efgaltigimod. This is equivalent to IgG clearance. In some embodiments, FcRn / antigen-binding molecule The clearance of total serum IgG in subjects after a single dose of efgaltigimod was equivalent to that of efgaltigimod. The clearance of total serum IgG in subjects after a single dose is similar to or the same as that of the subject. In that embodiment, total serum IgG clearance is achieved in the subject by FcRn / antigen binding. Clearing of total serum IgG after a single dose of the molecule and an equivalent amount of efgaltigimod. It increases compared to the threshold. In some embodiments, the clearance of total serum IgG is compared to In elephants, a single dose of an equivalent amount of efgartigimod was administered after a single dose of FcRn / antigen-binding molecule. Compared to the clearance of total serum IgG after administration, at least 5%, at least 10%, less 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%, and It will increase by at least 200%.

[0391] In some embodiments, the clearance of the FcRn / antigen-binding molecule is performed in the subject. After a single therapeutic administration of FcRn / antigen-binding molecule, after a single therapeutic administration of fgultigimod, It decreases compared to the clearance of gultigimod. In some embodiments, FcRn / The clearance of antigen-binding molecules is achieved by a single therapeutic administration of FcRn / antigen-binding molecules in the target population. Later, compared with the clearance of efgartigimod after a single therapeutic dose of efgartigimod. At least 1x, at least 1.5x, at least 2x, at least 3x, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 A reduction of at least 10 times, at least 12 times, at least 15 times, or at least 20 times. Less.

[0392] In some embodiments, the clearance of the FcRn / antigen-binding molecule is performed in the subject. After a single administration of FcRn / antigen-binding molecule, an equivalent amount of efgaltigimod is administered. It decreases compared to the clearance of gultigimod. In some embodiments, FcRn / The clearance of the antigen-binding molecule occurred in the subjects after a single administration of FcRn / antigen-binding molecule. Compared to the clearance of efgartigimod after a single dose of an equivalent amount of efga...

Claims

1. (a) A first polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 180; and (b) A second polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 8; A heterodimeric protein containing [the specified element].

2. The heterodimer protein according to claim 1, wherein the amino acid sequence of the first polypeptide is at least 95% identical to the amino acid sequence of SEQ ID NO: 180, and the amino acid sequence of the second polypeptide is at least 95% identical to the amino acid sequence of SEQ ID NO:

8.

3. The heterodimer protein according to claim 2, comprising the first polypeptide and the second polypeptide.

4. A pharmaceutical composition comprising a heterodimer protein according to any one of claims 1 to 3.

5. A pharmaceutical composition comprising a heterodimer protein according to any one of claims 1 to 3, for use in the treatment of IgG-mediated disorders.

6. A pharmaceutical composition comprising the heterodimer protein according to any one of claims 1 to 3, for use in reducing serum IgG in subjects who require it.

7. One or more polynucleotides encoding a heterodimeric protein according to any one of claims 1 to 3.

8. One or more expression vectors comprising one or more polynucleotides as described in claim 7.

9. A host cell comprising one or more polynucleotides as described in claim 7.

10. A method for producing a heterodimer protein, comprising culturing the host cells described in claim 9 under conditions that enable the expression of the heterodimer protein.

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