Treatment methods for systemic lupus erythematosus

Abstract

The present application relates to the use of a drug combination in the manufacture of a medicament for preventing and / or treating systemic lupus erythematosus, wherein the drug combination comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R. The application further relates to the use of a bispecific antibody that targets IL-17A and IL-36R in the manufacture of the medicament.

Description

[Technical Field]

[0001] The present application relates to the biomedicine field, and in particular to a method for preventing and / or treating systemic lupus erythematosus by targeting IL-17A and IL-36R. [Background technology]

[0002] Systemic lupus erythematosus (SLE) is a rheumatic immune disease that can cause irreversible organ damage. Lupus nephritis, a major complication of SLE, manifests as proteinuria, hematuria, tubular urinary tract infection, and progressive decline in renal function, ultimately requiring kidney transplantation or long-term dialysis treatment, severely impacting patients' quality of life and earning the nickname "immortal cancer." Currently, treatment options are limited, and more therapeutic agents need to be developed to meet clinical demand.

[0003] IL-17A is the main pro-inflammatory factor of the IL17 family. IL-17A is produced by cells secreted by Th17, CD8+ (Tc17), γδT, NKT, and ILC3s. IL36 is a member of the IL1 superfamily and consists of three agonists, IL36α, IL36β, and IL36γ, and a natural receptor antagonist, IL-36Ra. Activation of this pathway promotes the production of multiple inflammatory factors. Literature reports indicate that IL17 is highly expressed in patients with active SLE. Animal model and clinical trial data suggest that IL17 inhibition may have therapeutic potential for treating SLE and lupus nephritis (LN). Nuohua and Hengrui are currently conducting a phase III clinical trial to investigate the efficacy of IL17 monoclonal antibody therapy for LN. Levels of IL36α and IL36γ in serum of SLE patients were significantly increased and positively correlated with the SLE Disease Activity Index (SLEDAI).

[0004] However, there is currently a need to develop more effective treatment strategies to reduce patient mortality and slow the rate of increase in urinary protein levels, while at the same time reducing pathological damage to the kidney. Summary of the Invention

[0005] The present application provides a method for preventing and / or treating systemic lupus erythematosus by targeting IL-17A and IL-36R. In the present application, co-administration of an antigen-binding protein targeting IL-17A and an antigen-binding protein targeting IL-36R, or administration of a bispecific antigen-binding protein targeting IL-17A and IL-36R, can exert a synergistic effect of the two targets, resulting in a more effective treatment of systemic lupus erythematosus than administration of a single target alone. Targeting IL-17A and IL-36R can have one or more of the following therapeutic effects on systemic lupus erythematosus or diseases and / or symptoms caused by systemic lupus erythematosus: (1) inhibiting an increase in urinary protein levels in a subject; (2) significantly improving pathological damage to the kidneys of a subject; and (3) inhibiting renal fibrosis in a subject.

[0006] According to one aspect, the present application provides the use of a drug combination in the manufacture of a medicament, said medicament being for preventing and / or treating systemic lupus erythematosus, wherein said drug combination comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R.

[0007] In some embodiments, the IL-17A is human IL-17A.

[0008] In some embodiments, the antigen binding protein that targets IL-17A is capable of inhibiting the associated action of IL-17A and IL-17R.

[0009] In some embodiments, the antigen binding protein targeting IL-17A comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0010] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:13.

[0011] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR2, wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:14.

[0012] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:15.

[0013] In some embodiments, the antigen binding protein that targets IL-17A comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0014] In some embodiments, the antigen binding protein that targets IL-17A comprises an antibody heavy chain constant region.

[0015] In some embodiments, the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

[0016] In some embodiments, the antibody heavy chain constant region is derived from an IgG1 or IgG4 heavy chain constant region.

[0017] In some embodiments, the antibody heavy chain constant region of an antigen binding protein that targets IL-17A comprises the amino acid sequence set forth in SEQ ID NO:21.

[0018] In some embodiments, the antigen binding protein that targets IL-17A comprises at least one CDR in an antibody light chain variable region, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0019] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:17.

[0020] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

[0021] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR1, wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:19.

[0022] In some embodiments, the antigen binding protein that targets IL-17A comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0023] In some embodiments, the antigen binding protein that targets IL-17A comprises a light chain constant region.

[0024] In some embodiments, the light chain constant region is derived from Igκ.

[0025] In some embodiments, the heavy chain constant region of the antigen binding protein that targets IL-17A comprises the amino acid sequence set forth in SEQ ID NO:21.

[0026] In some embodiments, the IL-36R is human IL-36R.

[0027] In some embodiments, the antigen binding protein that targets IL-36R comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0028] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:27.

[0029] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR2, wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:28.

[0030] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:29.

[0031] In some embodiments, the antigen binding protein that targets IL-36R comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0032] In some embodiments, the antigen binding protein that targets IL-36R comprises an antibody heavy chain constant region.

[0033] In some embodiments, the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

[0034] In some embodiments, the antibody heavy chain constant region is derived from an IgG1 heavy chain constant region.

[0035] In some embodiments, the antibody heavy chain constant region of the antigen binding protein of IL-36R comprises the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:35.

[0036] In some embodiments, the antigen binding protein that targets IL-36R comprises at least one CDR in an antibody light chain variable region, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0037] In some embodiments, the antigen binding protein that targets IL-36R comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:31.

[0038] In some embodiments, the antigen binding protein that targets IL-36R comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

[0039] In some embodiments, the antigen binding protein that targets IL-36R comprises LCDR1, wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:33.

[0040] In some embodiments, the antigen binding protein that targets IL-36R comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0041] In some embodiments, the antigen binding protein that targets IL-36R comprises a light chain constant region.

[0042] In some embodiments, the light chain constant region is derived from Igκ.

[0043] In some embodiments, the heavy chain constant region of the antigen binding protein that targets IL-36R comprises the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:35.

[0044] In some embodiments, the systemic lupus erythematosus comprises systemic lupus erythematosus nephritis.

[0045] On the other hand, the present application further provides use of the isolated antigen-binding protein in the manufacture of a medicament, wherein said isolated antigen-binding protein comprises a first binding domain that targets IL-17A and a second binding domain that targets IL-36R, and said medicament is used for preventing and / or treating systemic lupus erythematosus.

[0046] In some embodiments, the isolated antigen binding protein comprises: (1) binding to IL-36R with high affinity; (2) binding to IL-1Rrp2 with high affinity; (3) inhibiting the binding of IL-36α, IL-36β, and IL-36γ to IL-36R; and (4) inhibiting cytokine secretion mediated by IL-36α, IL-36β, and IL-36γ.

[0047] In some embodiments, the isolated antigen binding protein is selected from a monoclonal antibody, a chimeric antibody, a humanized antibody, or a combination thereof.

[0048] In some embodiments, the first binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0049] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:13.

[0050] In some embodiments, the first binding domain of the isolated antigen binding protein comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:14.

[0051] In some embodiments, the first binding domain of the isolated antigen binding protein comprises HCDR1, wherein said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:15.

[0052] In some embodiments, the first binding domain of the isolated antigen binding protein comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0053] In some embodiments, the first binding domain of the isolated antigen binding protein comprises at least one CDR in a light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0054] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:17.

[0055] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

[0056] In some embodiments, the first binding domain of the isolated antigen binding protein comprises LCDR1, wherein said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:19.

[0057] In some embodiments, the first binding domain of the isolated antigen binding protein comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0058] In some embodiments, the isolated antigen binding protein comprises a heavy chain constant region.

[0059] In some embodiments, the isolated antigen binding protein comprises a light chain constant region.

[0060] In some embodiments, the heavy chain constant region is derived from human IgG1 or human IgG4.

[0061] In some embodiments, the light chain constant region is derived from human IgG1 or human IgG4.

[0062] In some embodiments, the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:21.

[0063] In some embodiments, the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:10.

[0064] In some embodiments, the second binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0065] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:27.

[0066] In some embodiments, the second binding domain of the isolated antigen binding protein comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:28.

[0067] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:29.

[0068] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0069] In some embodiments, the second binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0070] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:31.

[0071] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

[0072] In some embodiments, the second binding domain of the isolated antigen binding protein comprises LCDR1, wherein said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:33.

[0073] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0074] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VH and a VL, wherein the VH and VL are connected by a connecting peptide.

[0075] In some embodiments, the amino acid sequence of the connecting peptide is (G4S)n, where n is a positive integer.

[0076] In some embodiments, the second binding domain of the isolated antigen binding protein is an scFv.

[0077] In some embodiments, the scFv of the second binding domain of the isolated antigen binding protein comprises the amino acid sequence set forth in SEQ ID NO:24.

[0078] In some embodiments, the isolated antigen binding protein comprises (a) a first binding domain of an anti-IL-17A antibody, and (b) a second binding domain that binds to the anti-IL-17A antibody.

[0079] In some embodiments, the second binding domain is a single chain variable region (scFv) of an anti-IL-36R antibody.

[0080] In some embodiments, the second binding domain is linked directly or indirectly to the first binding domain.

[0081] In some embodiments, the second binding domain is connected to the first binding domain by a linker.

[0082] In some embodiments, the ScFvs of the anti-IL-17A antibody and the anti-IL-36R antibody are linked by a linker sequence.

[0083] In some embodiments, the isolated antigen binding protein is a homodimer.

[0084] In some embodiments, the isolated antigen binding protein is a tetravalent antibody.

[0085] In some embodiments, the isolated antigen binding protein is a bispecific antibody.

[0086] In some embodiments, the bispecific antibody is a double-chain antibody or a single-chain antibody.

[0087] In some embodiments, the bispecific antibody has the structure shown in Formula I from N-terminus to C-terminus: [ka] where: VH represents the heavy chain variable region of the anti-IL-17A antibody; VL represents the light chain variable region of the anti-IL-17A antibody; CH1, CH2, and CH3 represent the heavy chain constant regions CH1, CH2, and CH3 of the anti-IL-17A antibody, respectively. CL represents the light chain constant region of the anti-IL-17A antibody; ScFv represents the ScFv of the anti-IL-36R antibody; L represents a linker element, "~" represents a disulfide bond, "-" represents a peptide bond; Here, the bispecific antibody has the activity of simultaneously binding to IL-17A and IL-36R.

[0088] In some embodiments, the bispecific antibody is formed by fusing the scFvs of the anti-IL-17A antibody and the anti-IL-36R antibody, and has two pairs of symmetrical peptide chains, each pair of peptide chains comprising a light chain (L chain) and a heavy chain (H chain), all of which are linked by disulfide bonds, and any pair of peptide chains has the H chain and L chain structure shown in Formula I from the N-terminus to the C-terminus.

[0089] In some embodiments, the bispecific antibody is a homodimer of peptide chains having the structure shown in Formula I.

[0090] In some embodiments, the linker element is a connecting peptide.

[0091] In some embodiments, the amino acid sequence of the connecting peptide is (G4S)n, where n is a positive integer. The heavy chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO: 25, and the light chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO: 23.

[0092] In some embodiments, the isolated antigen binding protein further comprises a detectable marker, a target marker, a drug, a toxin, a cytokine, a radionuclide, or an enzyme.

[0093] In some embodiments, the systemic lupus erythematosus comprises lupus erythematosus nephritis.

[0094] In some embodiments, the drug can attenuate elevated urinary protein levels caused by systemic lupus erythematosus.

[0095] In some embodiments, the drug can alleviate pathological damage to the kidney caused by systemic lupus erythematosus.

[0096] In some embodiments, the drug can attenuate and / or inhibit renal fibrosis due to systemic lupus erythematosus.

[0097] On the other hand, the present application further provides a method for preventing and / or treating systemic lupus erythematosus, which comprises administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

[0098] In some embodiments, the systemic lupus erythematosus comprises lupus erythematosus nephritis.

[0099] On the other hand, the present application further provides for alleviating elevated urinary protein levels due to systemic lupus erythematosus, which comprises administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

[0100] On the other hand, the present application further provides a method for alleviating kidney pathological damage caused by systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

[0101] On the other hand, the present application further provides a method for alleviating and / or inhibiting renal fibrosis due to systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

[0102] In some embodiments, the IL-17A is human IL-17A.

[0103] In some embodiments, the IL-36R is human IL-36R.

[0104] In some embodiments, the medicament comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R.

[0105] In some embodiments, the antigen binding protein that targets IL-17A is capable of inhibiting the associated action of IL-17A and IL-17R.

[0106] In some embodiments, the antigen binding protein targeting IL-17A comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0107] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:13.

[0108] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR2, wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:14.

[0109] In some embodiments, the antigen binding protein that targets IL-17A comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:15.

[0110] In some embodiments, the antigen binding protein that targets IL-17A comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0111] In some embodiments, the antigen binding protein that targets IL-17A comprises an antibody heavy chain constant region.

[0112] In some embodiments, the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

[0113] In some embodiments, the antibody heavy chain constant region is derived from an IgG1 heavy chain constant region.

[0114] In some embodiments, the antibody heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:21.

[0115] In some embodiments, the antigen binding protein that targets IL-17A comprises at least one CDR in an antibody light chain variable region, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0116] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:17.

[0117] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

[0118] In some embodiments, the antigen binding protein that targets IL-17A comprises an LCDR1, wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:19.

[0119] In some embodiments, the antigen binding protein that targets IL-17A comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0120] In some embodiments, the antigen binding protein that targets IL-17A comprises a light chain constant region.

[0121] In some embodiments, the light chain constant region is derived from Igκ.

[0122] In some embodiments, the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:10.

[0123] In some embodiments, the antigen binding protein that targets IL-36R comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0124] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:27.

[0125] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR2, wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:28.

[0126] In some embodiments, the antigen binding protein that targets IL-36R comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:29.

[0127] In some embodiments, the antigen binding protein that targets IL-36R comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0128] In some embodiments, the antigen binding protein that targets IL-36R comprises an antibody heavy chain constant region.

[0129] In some embodiments, the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

[0130] In some embodiments, the antibody heavy chain constant region is derived from an IgG1 heavy chain constant region.

[0131] In some embodiments, the antibody heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:35.

[0132] In some embodiments, the antigen binding protein that targets IL-36R comprises at least one CDR in an antibody light chain variable region, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0133] In some embodiments, the antigen binding protein that targets IL-36R comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:31.

[0134] In some embodiments, the antigen binding protein that targets IL-36R comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

[0135] In some embodiments, the antigen binding protein that targets IL-36R comprises LCDR1, wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:33.

[0136] In some embodiments, the antigen binding protein that targets IL-36R comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0137] In some embodiments, the antigen binding protein that targets IL-36R comprises a light chain constant region.

[0138] In some embodiments, the light chain constant region is derived from Igκ.

[0139] In some embodiments, the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:10 or SEQ ID NO:36.

[0140] In some embodiments, the agent comprises an isolated antigen binding protein, wherein the isolated antigen binding protein comprises a first binding domain that targets IL-17A and a second binding domain that targets IL-36R.

[0141] In some embodiments, the isolated antigen binding protein comprises: (1) binding to IL-36R with high affinity; (2) binding to IL-1Rrp2 with high affinity; (3) inhibiting the binding of IL-36α, IL-36β, and IL-36γ to IL-36R; and (4) inhibiting cytokine secretion mediated by IL-36α, IL-36β, and IL-36γ.

[0142] In some embodiments, the isolated antigen binding protein is selected from a monoclonal antibody, a chimeric antibody, a humanized antibody, or a combination thereof.

[0143] In some embodiments, the first binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0144] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:13.

[0145] In some embodiments, the first binding domain of the isolated antigen binding protein comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:14.

[0146] In some embodiments, the first binding domain of the isolated antigen binding protein comprises HCDR1, wherein said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:15.

[0147] In some embodiments, the first binding domain of the isolated antigen binding protein comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:16.

[0148] In some embodiments, the first binding domain of the isolated antigen binding protein comprises at least one CDR in a light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0149] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:17.

[0150] In some embodiments, the first binding domain of the isolated antigen binding protein comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

[0151] In some embodiments, the first binding domain of the isolated antigen binding protein comprises LCDR1, wherein said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:19.

[0152] In some embodiments, the first binding domain of the isolated antigen binding protein comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:20.

[0153] In some embodiments, the isolated antigen binding protein comprises a heavy chain constant region.

[0154] In some embodiments, the isolated antigen binding protein comprises a light chain constant region.

[0155] In some embodiments, the heavy chain constant region is derived from human IgG1 or human IgG4.

[0156] In some embodiments, the light chain constant region is derived from human IgG1 or human IgG4.

[0157] In some embodiments, the second binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0158] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:27.

[0159] In some embodiments, the second binding domain of the isolated antigen binding protein comprises HCDR2, wherein said HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:28.

[0160] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an HCDR1, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:29.

[0161] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:4 or SEQ ID NO:30.

[0162] In some embodiments, the second binding domain of the isolated antigen binding protein comprises at least one CDR in an antibody light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0163] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:31.

[0164] In some embodiments, the second binding domain of the isolated antigen binding protein comprises an LCDR2, wherein the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

[0165] In some embodiments, the second binding domain of the isolated antigen binding protein comprises LCDR1, wherein said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:33.

[0166] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:34.

[0167] In some embodiments, the second binding domain of the isolated antigen binding protein comprises a VH and a VL, wherein the VH and VL are connected by a connecting peptide.

[0168] In some embodiments, the amino acid sequence of the connecting peptide is (G4S)n, where n is a positive integer.

[0169] In some embodiments, the second binding domain of the isolated antigen binding protein is an scFv.

[0170] In some embodiments, the scFv of the second binding domain of the isolated antigen binding protein comprises the amino acid sequence set forth in SEQ ID NO:24.

[0171] In some embodiments, the isolated antigen binding protein comprises (a) a first binding domain of an anti-IL-17A antibody, and (b) a second binding domain that binds to the anti-IL-17A antibody.

[0172] In some embodiments, the second binding domain is a single chain variable region (scFv) of an anti-IL-36R antibody.

[0173] In some embodiments, the second binding domain is linked directly or indirectly to the first binding domain.

[0174] In some embodiments, the second binding domain is connected to the first binding domain by a linker.

[0175] In some embodiments, the scFvs of the anti-IL-17A antibody and the anti-IL-36R antibody are linked by a linker sequence.

[0176] In some embodiments, the isolated antigen binding protein is a homodimer.

[0177] In some embodiments, the isolated antigen binding protein is a tetravalent antibody.

[0178] In some embodiments, the isolated antigen binding protein is a bispecific antibody.

[0179] In some embodiments, the bispecific antibody is a double-chain antibody or a single-chain antibody.

[0180] In some embodiments, the bispecific antibody has the structure shown in Formula I from N-terminus to C-terminus: [ka] where: VH represents the heavy chain variable region of the anti-IL-17A antibody; VL represents the light chain variable region of the anti-IL-17A antibody; CH1, CH2, and CH3 represent the heavy chain constant regions CH1, CH2, and CH3 of the anti-IL-17A antibody, respectively. CL represents the light chain constant region of the anti-IL-17A antibody; ScFv represents the scFv of the anti-IL-36R antibody; L represents a linker element, "~" represents a disulfide bond, "-" represents a peptide bond; Here, the bispecific antibody has the activity of simultaneously binding to IL-17A and IL-36R.

[0181] In some embodiments, the bispecific antibody is formed by fusing the ScFv of the anti-IL-17A antibody and the anti-IL-36R antibody, and has two pairs of symmetrical peptide chains, each pair of peptide chains comprising a light chain (L chain) and a heavy chain (H chain), all of which are linked by disulfide bonds, and any pair of peptide chains has the H chain and L chain structure shown in Formula I from the N-terminus to the C-terminus.

[0182] In some embodiments, the bispecific antibody is a homodimer of peptide chains having the structure shown in Formula I.

[0183] In some embodiments, the linker element is a connecting peptide.

[0184] In some embodiments, the amino acid sequence of the connecting peptide is (G4S)n, where n is a positive integer.

[0185] In some embodiments, the heavy chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO:25, and the light chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO:23.

[0186] In some embodiments, the isolated antigen binding protein further comprises a detectable marker, a target marker, a drug, a toxin, a cytokine, a radionuclide, or an enzyme.

[0187] In some embodiments, the medicament optionally further comprises a pharmaceutically acceptable carrier.

[0188] In some embodiments, the medicament comprises a nucleic acid molecule encoding the antigen binding protein.

[0189] Those skilled in the art will readily appreciate other aspects and advantages of the present application from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. Those skilled in the art will appreciate that, with the teachings of the present application, they may make changes to the particular embodiments disclosed without departing from the spirit and scope of the invention to which the present application pertains. Accordingly, the drawings and descriptions herein are illustrative only and not restrictive. [Brief explanation of the drawings]

[0190] Particular features of the invention related to this application are set forth in the appended claims. The features and advantages of the invention contained in this application can be better understood by reference to the exemplary embodiments described in detail below and the accompanying drawings, which are briefly described as follows: [Figure 1] 1 shows a structural schematic of the HB0043 bispecific antibody. [Figure 2] 1 shows the inhibitory effect of the antibody of the present application on IL-6 under stimulation with IL-17A and IL-36α. [Figure 3] 1 shows the inhibitory effect of the antibody of the present application on IL-6 under stimulation with IL-17A and IL-36β. [Figure 4] 1 shows the inhibitory effect of the antibody of the present application on IL-6 under stimulation with IL-17A and IL-36γ. [Figure 5] 1 shows the inhibitory effect of the antibody of the present application on IL-8 under stimulation with IL-17A and IL-36α. [Figure 6] 1 shows the inhibitory effect of the antibody of the present application on IL-8 under stimulation with IL-17A and IL-36β. [Figure 7] 1 shows the inhibitory effect of the antibody of the present application on IL-8 under stimulation with IL-17A and IL-36γ. [Figure 8] The kidney index of the mouse UUO side (kidney index = kidney mass on the operated side / mouse body weight) is shown. [Figure 9] 1 shows the detection of serum creatinine content in mice. [Figure 10] 1 shows the detection of serum BUN content in mice. [Figure 11] This shows PAS staining of the kidney on the side of UUO in a mouse. [Figure 12] Quantitative results of glomerular fibrosis (***P<0.001, vs. normal control; ##P<0.01, ###P<0.001, vs. 900543) are shown. [Figure 13] Quantitative results of tubulointerstitial fibrosis are shown. [Figure 14] Masson staining of the kidney on the side of mouse UUO is shown. [Figure 15] 1 shows the results of FN immunohistochemistry of the kidney on the side of mouse UUO. [Figure 16] 1 shows changes in body weight of NZB / NZW F1 mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 17] 1 shows the detection of protein levels in urine of NZB / NZW F1 mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 18] 1 shows evaluation of pathological damage in the kidneys of NZB / NZW F1 mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 19] 1 shows the detection of renal fibrosis in NZB / NZW F1 mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 20] 1 shows detection of mortality in MRL / lpr mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 21] 1 shows the detection of protein levels in urine of MRL / lpr mice after combined administration of IL-17A antibody and IL-36R antibody. [Figure 22] 1 shows the detection of renal fibrosis in MRL / lpr mice after combined administration of IL-17A antibody and IL-36R antibody. DETAILED DESCRIPTION OF THE INVENTION

[0191] The present invention will be described below with reference to specific examples. Those skilled in the art will easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

[0192] Definition of Terms In this application, the term "isolated" generally refers to being obtained from a natural state by artificial means. When an "isolated" substance or component occurs in nature, the natural environment in which it exists may have been altered, the substance may have been separated from its natural environment, or both. For example, a non-isolated polynucleotide or polypeptide may naturally occur in a living animal, but the same polynucleotide or polypeptide in a highly purified state separated from this natural state is said to be isolated. The term "isolated" does not exclude the presence of artificial or synthetic substances, nor does it exclude the presence of other impurities that do not affect the activity of the substance.

[0193] In this application, the term "isolated antigen-binding protein" generally refers to a protein having antigen-binding ability that has been separated from its naturally occurring state. This "isolated antigen-binding protein" may comprise an antigen-binding portion and, optionally, a frame or framework portion that allows the antigen-binding portion to assume a conformation that facilitates binding of the antigen-binding portion to the antigen. The antigen-binding protein may comprise, for example, a protein frame region (FR) derived from an antibody, or a candidate protein frame region or artificial frame region with grafted CDRs or CDR derivatives. Such frames include, but are not limited to, antibody-derived frame regions containing mutations introduced to stabilize the three-dimensional structure of the antigen-binding protein, and completely synthetic frame regions containing, for example, biocompatible polymers. See, for example, Korndorfer et al., 2003, Proteins: Structure, Function, and Bioinformatics, 53(1):121-129 (2003); Roque et al., Biotechnol. Prog. 20:639-654 (2004). Examples of antigen binding proteins include, but are not limited to, human antibodies, humanized antibodies, chimeric antibodies, recombinant antibodies, single chain antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, Fab, Fab', Fv fragments, F(ab')2, F(ab)2, scFv, di-scFv, dAb, IgD antibodies, IgE antibodies, IgM antibodies, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, or IgG4 antibodies and fragments thereof.

[0194] In this application, the term "antibody" generally refers to an immunoglobulin molecule, which typically has a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The antigenicity of immunoglobulins varies due to differences in the amino acid composition and sequence of the immunoglobulin heavy chain constant regions. Based on this, immunoglobulins can be classified into five categories, or different types of immunoglobulins: IgM, IgD, IgG, IgA, and IgE. The heavy chain constant regions corresponding to different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively. IgG represents the most important class of immunoglobulins. Based on differences in chemical structure and biological function, they are divided into four subclasses: IgG1, IgG2, IgG3, and IgG4. Light chains are classified as κ or λ chains based on differences in their constant regions. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known to those skilled in the art. In this application, the term includes monoclonal antibodies, polyclonal antibodies, murine antibodies, humanized antibodies, chimeric antibodies, bispecific antibodies, multispecific antibodies, and the like.

[0195] In this application, the term "CDR," also known as "complementarity-determining region," generally refers to a region within the variable domain of an antibody whose sequence is highly variable and / or forms a structurally defined loop. Antibodies typically contain six CDRs: three in the VH (HCDR1, HCDR2, and HCDR3) and three in the VL (LCDR1, LCDR2, and LCDR3). In certain embodiments, naturally occurring camelid antibodies consisting only of heavy chains can function normally and stably in the absence of light chains. See, for example, Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996). Antibody CDRs can be determined by various coding systems, including CCG, Kabat, Chothia, IMGT, and the combined Kabat / Chothia approach. These coding systems are known in the art and can be found, for example, at http: / / www.bioinf.org.uk / abs / index.html#kabatnum. For example, the amino acid sequence of the antigen-binding protein can be numbered according to the IMGT numbering scheme (IMGT, the international ImMunoGeneTics information system@imgt.cines.fr, http: / / imgt.cines.fr; Lefranc et al., 1999, Nucleic Acids Res. 27:209-212; Ruiz et al., 2000 Nucleic Acids Res. 28:219-221; Lefranc et al., 2001, Nucleic Acids Res. 29:207-209; Lefranc et al., 2003, Nucleic Acids Res. 31:307-310; Lefranc et al., 2005, DevComp Immunol 29:185-203).For example, the CDRs of the antigen-binding protein can be determined based on the Kabat numbering system (see, for example, Kabat EA & Wu TT (1971) Ann NY Acad Sci 190:382-391 and Kabat EA et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242).

[0196] In this application, the term "FR" generally refers to the more highly conserved portions of antibody variable domains, called framework regions. Native heavy and light chain variable domains typically each contain four FR regions: four in the VH (H-FR1, H-FR2, H-FR3, and H-FR4) and four in the VL (L-FR1, L-FR2, L-FR3, and L-FR4).

[0197] In this application, the terms "variable domain" and "variable region" can be used interchangeably and typically refer to portions of an antibody heavy and / or light chain. The variable domains of the heavy and light chains are referred to as "V" and "V" respectively. H " and "V L " (or referred to as "VH" and "VL," respectively). These domains are usually the most variable parts of an antibody (relative to other antibodies of the same type) and contain the antigen-binding sites.

[0198] In this application, the term "variable" generally refers to the fact that the sequences of some segments of the variable domains can vary considerably among antibodies. The variable domains mediate antigen binding and determine the specificity of a particular antibody for a particular antigen. However, variability is not evenly distributed throughout the variable domains. It is usually concentrated in three segments called hypervariable regions (CDRs or HVRs) in the light and heavy chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). Native heavy and light chain variable domains each contain four FR regions, most of which adopt a β-sheet configuration and are connected by three CDRs, which form loops and, in some cases, part of the β-sheet structure. The CDRs of each chain are held in close proximity by the FR regions and, together with the CDRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health (1991)).

[0199] In this application, the term "antigen-binding fragment" generally refers to a Fab fragment, a Fab' fragment, a F(ab')2 fragment, or a single Fv fragment having antigen-binding activity. An Fv antibody contains an antibody heavy chain variable region and a light chain variable region but lacks a constant region, and is the minimum antibody fragment containing all of the antigen-binding site. Generally, an Fv antibody further contains a polypeptide linker between the VH and VL domains and is capable of forming the structure necessary for antigen binding.

[0200] In this application, the term "Fab" generally refers to an antigen-binding fragment of an antibody. As described above, intact antibodies can be digested with PAIN. PAIN digestion of an antibody produces two identical antigen-binding fragments: an "Fab" fragment and a residual "Fc" fragment (i.e., the Fc region, as described above). The Fab fragment can be composed of the complete light chain, the variable region of the heavy chain, and the first constant region (CH1) of the heavy chain (VH).

[0201] In this application, the term "Fab" fragment refers to a monovalent antigen-binding fragment of a human monoclonal antibody that is generally slightly larger than an Fab fragment. For example, an Fab' fragment may contain all of the light chain, all of the heavy chain variable region, and all or part of the first and second constant regions of the heavy chain. For example, an Fab' fragment may also contain part or all of 220-330 amino acid residues of the heavy chain.

[0202] In this application, the term "F(ab')2" refers to an antibody fragment typically generated by pepsin digestion of an intact antibody. The F(ab')2 fragment contains two Fab fragments linked by disulfide bonds and a portion of the hinge region. The F(ab')2 fragment retains bivalent antigen-binding activity and is capable of cross-linking antigens.

[0203] As used herein, the term "Fv fragment" generally refers to a monovalent antigen-binding fragment of a human monoclonal antibody, including all or part of the heavy and light chain variable regions, and lacking the heavy and light chain constant regions. The heavy and light chain variable regions include, for example, the CDRs. For example, an Fv fragment includes all or part of the approximately 110 amino acid amino-terminal variable regions of the heavy and light chains.

[0204] In the present application, the term "scFv" generally includes a fusion protein of at least one variable region antibody fragment comprising a light chain and at least one variable region antibody fragment comprising a heavy chain, wherein the light and heavy chain variable regions are contiguous (e.g., via a synthetic linker such as a short flexible polypeptide linker) and can be expressed in the form of a single polypeptide chain, and wherein the scFv maintains the specificity of the intact antibody from which it is derived. Unless otherwise specified, as used in the present application, an scFv can have the VL and VH variable regions listed in any order (e.g., relative to the N-terminus and C-terminus of the polypeptide), and can include a VL-linker-VH or a VH-linker-VL.

[0205] In this application, the term "dAb" generally refers to an antigen-binding fragment having a VH domain, a VL domain, or having a VH domain or a VL domain, see for example Ward et al. (Nature, 1989 Oct 12, 341(6242):544-6), Holt et al., Trends Biotechnol., 2003, 21(11):484-490, and see for example WO 06 / 030220, WO 06 / 003388 and other disclosed patent applications of Domantis Ltd.

[0206] The present application includes not only complete antibodies, but also immunologically active antibody fragments or fusion proteins formed from antibodies and other sequences, and therefore further includes fragments, derivatives and analogs of said antibodies.

[0207] In this application, the term "monoclonal antibody" refers to an antibody secreted by a clone derived from a single cell. Monoclonal antibodies are highly specific because they are directed against a single antigenic epitope. The cell may be a eukaryotic, prokaryotic, or phage clonal cell line.

[0208] In this application, the term "chimeric antibody" refers to an antibody molecule obtained by combining mouse antibody V region genes and human antibody C region genes into a chimeric gene, inserting it into a carrier, and then introducing it into host cells for expression. This not only maintains the high specificity and affinity of the parent mouse antibody, but also allows the humanized Fc segment to effectively mediate biological functions.

[0209] In this application, the term "humanized antibody" generally refers to a modified form of an antibody variable region, having CDR regions derived (or essentially derived) from a non-human antibody (which may be, for example, a murine monoclonal antibody) and FR and constant regions derived essentially from human antibody sequences, i.e., by grafting murine antibody CDR region sequences onto various types of human germline antibody framework sequences. Because the CDR sequences are responsible for the majority of antibody-antigen interactions, recombinant antibodies that mimic the properties of specific naturally occurring antibodies can be expressed by constructing expression vehicles.

[0210] In this application, antibodies may be monospecific, bispecific, trispecific, or of greater multispecificity.

[0211] In the present application, the antibody of the present application further includes conservative variants thereof, which refers to a polypeptide in which up to 10, for example up to 8, for example up to 5, for example up to 3 amino acids are substituted with amino acids having similar or similar properties compared to the amino acid sequence of the antibody of the present application. These conservative variant polypeptides are preferably generated by making amino acid substitutions according to Table A.

[0212] [Table 1] In the present application, the term "IL-36R" generally refers to natural or recombinant IL-36R, and non-human homologues of IL-36R. For example, the IL-36R may be human IL-36R.

[0213] In the present application, the term "IL-17R" generally refers to natural or recombinant IL-17A and non-human homologues of IL-17A. For example, the IL-17A may be human IL-17A.

[0214] In this application, the term "nucleic acid molecule" generally refers to nucleotides of any length, either deoxyribonucleotides or ribonucleotides, in isolated form, or analogs either isolated from their natural environment or artificially synthesized.

[0215] As used herein, the term "pharmaceutically acceptable carrier" generally includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Physiologically acceptable carriers may include, for example, buffers, antioxidants, low molecular weight (fewer than about 10 residues) polypeptides, proteins, hydrophilic polymers, amino acids, monosaccharides, disaccharides and other carbohydrates, chelating agents, sugar alcohols such as sodium, salt-forming counterions, and / or nonionic surfactants.

[0216] As used herein, the terms "specific binding" or "specific" generally refer to a measurable and reproducible interaction, such as binding between a target and an antibody, that allows determination of the presence of a target in the presence of a heterogeneous population of molecules (including biomolecules). For example, an antibody that specifically binds a target (which may be an epitope) may bind to that target with higher affinity, avidity, more readily, and / or for a longer period of time than it binds to other targets. In certain embodiments, for epitopes on a protein that specifically bind to an antibody, the epitope is conserved across proteins of different species. In certain embodiments, specific binding includes, but is not required to be, exclusive binding.

[0217] In this application, the term "subject" generally refers to a human or non-human animal, including, but not limited to, a cat, dog, horse, pig, cow, sheep, rabbit, mouse, rat, or monkey.

[0218] In the present application, references to related proteins, polypeptides and / or amino acid sequences should also be understood to include at least the scope of variants or homologues with the same or similar functions as said proteins or polypeptides.

[0219] In the present application, the variant may be, for example, a protein or polypeptide having one or more amino acids substituted, deleted, or added to the amino acid sequence of the protein and / or polypeptide (e.g., an antibody or fragment thereof that specifically binds to a CD73 protein). For example, the functional variant may include a protein or polypeptide having amino acid changes due to at least one, e.g., 1 to 30, 1 to 20, or 1 to 10, e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, and / or insertions. The functional variant may substantially retain the biological properties of the protein or polypeptide prior to the change (e.g., substitution, deletion, or addition). For example, the functional variant may retain at least 60%, 70%, 80%, 90%, or 100% of the biological activity (e.g., antigen-binding ability) of the protein or polypeptide prior to the change. For example, the substitution may be a conservative substitution.

[0220] In the present application, the homologue may be a protein or polypeptide having at least about 85% (e.g., having at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or more) sequence homology with the amino acid sequence of the protein and / or polypeptide (e.g., an antibody or fragment thereof that specifically binds to a CD73 protein).

[0221] In this application, the term "homology" generally refers to the similarity, resemblance, or relationship between two or more sequences. The "percent sequence identity" can be calculated in the following manner: two sequences are compared within a comparison window, and the number of positions where the two sequences contain the same nucleic acid base (e.g., A, T, C, G, I) or the same amino acid residue (e.g., Ala, Pro, Ser, Thr, Gly, Val, Leu, Ile, Phe, Tyr, Trp, Lys, Arg, His, Asp, Glu, Asn, Gln, Cys, and Met) is determined to obtain the number of matching positions. The number of matching positions is then divided by the total number of positions within the comparison window (i.e., the window size), and the result is multiplied by 100 to generate the percentage sequence identity. Comparison to determine the percent sequence identity can be performed in various ways known in the art, for example, using computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software, as disclosed herein. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment within the full-length sequences or target sequence regions being compared. The homology may be measured using the FASTA and BLAST methods. For a description of the FASTA algorithm, see W.R. Pearson and D.J. Lipman, "Improved Tools for Biological Sequence Comparison," Proc. Natl. Acad. Sci., 85:2444-2448, 1988, and D.J. Lipman and W.R. Pearson, "Rapid and Sensitive Protein Similarity Searching," Science, 227:1435-1441, 1989. For a description of the BLAST algorithm, see S. Altschul, W. Gish, W. Miller, E.W. Myers, and D. Lipman, "Basic Local Alignment Search Tools," Journal of Molecular Biology, 215:403-410, 1990.

[0222] In this application, the term "comprise" generally means including, encompassing, containing, or including. In some cases, it also means "is" or "consisting of."

[0223] In this application, the term "about" generally refers to a variation within 0.5%-10% above or below a specified numerical value, for example, a variation within 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% above or below a specified numerical value. Detailed Description of the Invention

[0224] IL-36R antibody According to one aspect, the present application provides an antigen-binding protein that targets IL-36R. The antigen-binding protein that targets IL-36R can maintain a relatively high affinity for IL-36R and have superior IL-36R binding activity. The antigen-binding protein that targets IL-36R can be a surrogate antibody to another IL-36R antibody (the amino acid sequence of HCDR1 is set forth in SEQ ID NO:3, the amino acid sequence of HCDR2 is set forth in SEQ ID NO:2, the amino acid sequence of HCDR3 is set forth in SEQ ID NO:1, the amino acid sequence of VH is set forth in SEQ ID NO:4, the amino acid sequence of the heavy chain is set forth in SEQ ID NO:11, the amino acid sequence of LCDR1 is set forth in SEQ ID NO:7, the amino acid sequence of LCDR2 is set forth in SEQ ID NO:6 (STS), the amino acid sequence of LCDR3 is set forth in SEQ ID NO:5, the amino acid sequence of VL is set forth in SEQ ID NO:8, and the amino acid sequence of the light chain is set forth in SEQ ID NO:12), and is used in efficacy studies in a mouse model.

[0225] In the present application, the antigen binding protein targeting IL-36R comprises at least one CDR of a heavy chain variable region VH and a light chain variable region VL, wherein the VH may comprise the amino acid sequence shown in SEQ ID NO: 30 and the VL may comprise the amino acid sequence shown in SEQ ID NO: 34. In the present application, the antigen binding protein targeting IL-36R comprises HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the amino acid sequence of HCDR1 is shown in SEQ ID NO: 29, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 28, the amino acid sequence of HCDR3 is shown in SEQ ID NO: 27, the amino acid sequence of LCDR1 is shown in SEQ ID NO: 33, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 32 (AAS), and the amino acid sequence of LCDR3 is shown in SEQ ID NO: 31.

[0226] In the present application, the antigen binding protein targeting IL-36R may comprise a heavy chain variable region VH, and the VH may comprise the amino acid sequence shown in SEQ ID NO: 30. In the present application, the antigen binding protein targeting IL-36R may comprise a light chain variable region VL, and the VL may comprise the amino acid sequence shown in SEQ ID NO: 34. In the present application, the antigen binding protein targeting IL-36R may comprise a VH and a VL, and the VH may comprise the amino acid sequence shown in SEQ ID NO: 30, and the VL may comprise the amino acid sequence shown in SEQ ID NO: 34.

[0227] In the present application, the antigen-binding protein targeting IL-36R may comprise an antibody heavy chain constant region. For example, the antibody heavy chain constant region may be derived from an IgG constant region. For example, the antibody heavy chain constant region may comprise the amino acid sequence set forth in SEQ ID NO: 35.

[0228] In the present application, the antigen-binding protein targeting IL-3R may comprise an antibody light chain constant region. For example, the antibody light chain constant region may be derived from an Igκ constant region. For example, the antibody light chain constant region may comprise the amino acid sequence set forth in SEQ ID NO: 36.

[0229] In the present application, the antigen binding protein that targets IL-36R may comprise an antibody heavy chain, wherein the antibody heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 37. In the present application, the antigen binding protein that targets IL-36R may comprise an antibody light chain, wherein the antibody light chain may comprise the amino acid sequence set forth in SEQ ID NO: 38. In the present application, the antigen binding protein that targets IL-36R may comprise an antibody heavy chain and an antibody light chain, wherein the antibody heavy chain may comprise the amino acid sequence set forth in SEQ ID NO: 37, and the antibody light chain may comprise the amino acid sequence set forth in SEQ ID NO: 38.

[0230] In the present application, the antigen-binding protein targeting IL-36R may include an antibody or an antigen-binding fragment thereof. For example, the antibody includes a monoclonal antibody, a chimeric antibody, a humanized antibody, and / or a fully human antibody. For example, the antigen-binding fragment includes a Fab, a Fab', an Fv fragment, a F(ab')2, a F(ab)2<, a scFv, a dis-scFv, and / or a dAb.

[0231] Use, methods, and indications The present application provides methods for preventing and / or treating systemic lupus erythematosus by targeting the dual targets of IL-17A and IL-36R.

[0232] According to one aspect, the present application provides the use of a drug combination in the manufacture of a medicament, said medicament being for preventing and / or treating systemic lupus erythematosus, wherein said drug combination comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R.

[0233] On the other hand, the present application provides use of a drug combination in the manufacture of a medicament, wherein the medicament is used to prevent and / or treat systemic lupus erythematosus, and wherein the drug combination comprises a nucleic acid molecule encoding an antigen-binding protein that targets IL-17A and a nucleic acid molecule encoding an antigen-binding protein that targets IL-36R.

[0234] On the other hand, the present application further provides use of an isolated antigen-binding protein in the manufacture of a medicament, wherein the isolated antigen-binding protein comprises a first binding domain that targets IL-36R and a second binding domain that targets IL-17A, and the medicament is used for preventing and / or treating systemic lupus erythematosus. For example, the isolated antigen-binding protein may be a bispecific antibody and target both IL-36R and IL-17A.

[0235] On the other hand, the present application provides a method for preventing and / or treating systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

[0236] For example, the medicament may comprise an antigen-binding protein that targets IL-17A and an antigen-binding protein that targets IL-36R. For example, the medicament may comprise a bi / multispecific antibody that simultaneously targets IL-17A and IL-36R.

[0237] On the other hand, the present application further provides a drug combination, which is used to prevent and / or treat systemic lupus erythematosus, and the drug combination comprises an antigen-binding protein that targets IL-17A and an antigen-binding protein that targets IL-36R.

[0238] On the other hand, the present application further provides a drug combination, which is used to prevent and / or treat systemic lupus erythematosus, wherein the drug combination comprises a nucleic acid molecule encoding an antigen-binding protein that targets IL-17A and a nucleic acid molecule encoding an antigen-binding protein that targets IL-36R.

[0239] On the other hand, the present application further provides an isolated antigen-binding protein, which is used to prevent and / or treat systemic lupus erythematosus, wherein the isolated antigen-binding protein comprises a first binding domain that targets IL-36R and a second binding domain that targets IL-17A. For example, the isolated antigen-binding protein is a bi / multispecific antibody that targets IL-17A and IL-36R.

[0240] In the present application, the systemic lupus erythematosus may include any disease and / or condition associated with systemic lupus erythematosus known in the art, for example, the systemic lupus erythematosus may include lupus erythematosus nephritis.

[0241] In this application, the lupus erythematosus nephritis can be characterized by one or more of the following: (1) glomerular lesions; (2) tubulointerstitial lesions; (3) renal vascular lesions; (4) renal IgG, IgA, IgM, C3, C4, and / or C1q, fibroblast protein deposition; and (5) deposition in the membrane zones and capillary walls.

[0242] In the present application, simultaneous targeting of IL-17A and IL-36R can effectively increase the survival rate of subjects with systemic lupus erythematosus.

[0243] In the present application, by simultaneously targeting IL-17A and IL-36R, elevated urinary protein levels in a subject can be effectively alleviated.

[0244] In the present application, by simultaneously targeting IL-17A and IL-36R, the pathological damage to the kidney caused by systemic lupus erythematosus can be effectively alleviated.

[0245] In the present application, by simultaneously targeting IL-17A and IL-36R, renal fibrosis due to systemic lupus erythematosus can be effectively alleviated and / or inhibited.

[0246] CDR classification The CDR of an antibody, also known as the complementarity-determining region, is a part of the variable region. The amino acid residues in this region can contact the antigen or antigen epitope. Antibody CDRs can be determined using various coding systems, such as CCG, Kabat, Chothia, IMGT, and a comprehensive consideration of Kabat / Chothia. These coding systems are known in the art and may be found, for example, at http: / / www.bioinf.org.uk / abs / index.html#kabatnum. Those skilled in the art can determine CDR regions using different coding systems based on the antibody sequence and structure. The CDR regions may differ depending on the coding system. In the present application, the CDR may include a CDR sequence divided according to any CDR division method, or may include a variant thereof, where the variant includes the amino acid sequence of the CDR after one or more amino acid substitutions, deletions, and / or additions. For example, 1 to 30, 1 to 20, or 1 to 10, or for example, 1, 2, 3, 4, 5, 6, 7, 8, or 9 amino acid substitutions, deletions, and / or insertions, and homologs thereof are also included, and the homologs may be amino acid sequences having at least about 85% sequence identity (e.g., at least about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more) with the amino acid sequence of the CDR.

[0247] Antigen-binding proteins that target IL-17A In the present application, the antigen-binding protein targeting IL-17A may comprise at least one CDR in an antibody heavy chain variable region VH, for example, the VH may comprise the amino acid sequence shown in SEQ ID NO:16.

[0248] In the present application, the antigen binding protein that targets IL-17A may comprise an HCDR3, wherein the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 13. In the present application, the antigen binding protein that targets IL-17A may comprise an HCDR2, wherein the HCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 14. In the present application, the antigen binding protein that targets IL-17A may comprise an HCDR1, wherein the HCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 15.

[0249] In the present application, the antigen binding protein targeting IL-17A may comprise a VH, wherein the VH comprises the amino acid sequence shown in SEQ ID NO:16.

[0250] In the present application, the antigen-binding protein targeting IL-17A may comprise at least one CDR in an antibody heavy chain variable region VL, for example, the VL may comprise the amino acid sequence shown in SEQ ID NO:20.

[0251] In the present application, the antigen binding protein that targets IL-17A may comprise an LCDR3, wherein the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 17. In the present application, the antigen binding protein that targets IL-17A may comprise an LCDR2, wherein the LCDR2 may comprise the amino acid sequence set forth in SEQ ID NO: 18 (KVS). In the present application, the antigen binding protein that targets IL-17A may comprise an LCDR1, wherein the LCDR1 may comprise the amino acid sequence set forth in SEQ ID NO: 19.

[0252] In the present application, the antigen binding protein targeting IL-17A may comprise a VL, wherein the VL comprises the amino acid sequence shown in SEQ ID NO:20.

[0253] In the present application, the antigen-binding protein targeting IL-17A may comprise an antibody or an antigen-binding fragment thereof. For example, the antibody includes a monoclonal antibody, a chimeric antibody, a humanized antibody, and / or a fully human antibody. For example, the antigen-binding fragment includes a Fab, a Fab', an Fv fragment, a F(ab')2, a F(ab)2, a scFv, a dis-scFv, and / or a dAb.

[0254] In the present application, the antigen-binding protein targeting IL-17A may comprise a heavy chain constant region. For example, the heavy chain constant region may be derived from the heavy chain constant region of IgG. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG1. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG4. For example, the heavy chain constant region may comprise the amino acid sequence set forth in SEQ ID NO: 21.

[0255] In the present application, the antigen-binding protein targeting IL-17A may comprise a light chain constant region. For example, the light chain constant region may be derived from the light chain constant region of Igκ. For example, the light chain constant region may comprise the amino acid sequence set forth in SEQ ID NO: 10.

[0256] Antigen-binding proteins targeting IL-36R In the present application, the antigen-binding protein targeting IL-36R may comprise at least one CDR in an antibody heavy chain variable region VH, for example, the VH may comprise the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO: 30.

[0257] In the present application, the antigen binding protein that targets IL-36R may comprise an HCDR3, wherein the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO: 27. In the present application, the antigen binding protein that targets IL-36R may comprise an HCDR2, wherein the HCDR2 may comprise the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO: 28. In the present application, the antigen binding protein that targets IL-36R may comprise an HCDR1, wherein the HCDR1 may comprise the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 29.

[0258] In the present application, the antigen binding protein targeting IL-36R may comprise a VH, wherein the VH comprises the amino acid sequence shown in SEQ ID NO:4 or SEQ ID NO:30.

[0259] In the present application, the antigen-binding protein targeting IL-36R may comprise at least one CDR in an antibody heavy chain variable region VL, for example, the VL may comprise the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO: 34.

[0260] In the present application, the antigen binding protein that targets IL-36R may comprise an LCDR3, wherein the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:5 or SEQ ID NO:31. In the present application, the antigen binding protein that targets IL-36R may comprise an LCDR2, wherein the LCDR2 may comprise the amino acid sequence shown in SEQ ID NO:6 (STS) or SEQ ID NO:32 (AAS). In the present application, the antigen binding protein that targets IL-36R may comprise an LCDR1, wherein the LCDR1 may comprise the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:33.

[0261] In the present application, the antigen binding protein that targets IL-36R may comprise a VL, wherein the VL comprises the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:34.

[0262] In the present application, the antigen-binding protein targeting IL-36R may include an antibody or an antigen-binding fragment thereof. For example, the antibody includes a monoclonal antibody, a chimeric antibody, a humanized antibody, and / or a fully human antibody. For example, the antigen-binding fragment includes a Fab, a Fab', an Fv fragment, a F(ab')2, a F(ab)2, a scFv, a dis-scFv, and / or a dAb.

[0263] In the present application, the antigen-binding protein targeting IL-36R may comprise a heavy chain constant region. For example, the heavy chain constant region may be derived from the heavy chain constant region of IgG. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG1. For example, the heavy chain constant region may be derived from the heavy chain constant region of human IgG4. For example, the heavy chain constant region may comprise the amino acid sequence set forth in SEQ ID NO:9 or SEQ ID NO:35.

[0264] In the present application, the antigen-binding protein targeting IL-36R may comprise a light chain constant region. For example, the light chain constant region may be derived from the light chain constant region of Igκ. For example, the light chain constant region may comprise the amino acid sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 36.

[0265] Bi / multispecific antibodies In the present application, the multispecific antibody can simultaneously target IL-17A and IL-36R. For example, the multispecific antibody may be a bispecific antibody. For example, the IL-17A may be human IL-17A. For example, the IL-36R may be human IL-36R.

[0266] In the present application, the multispecific antibody may comprise a targeting portion for IL-17A (first binding domain) and a targeting portion for IL-36R (second binding domain). In the present application, the multispecific antibody may have one or more of the following properties: (1) binding to IL-36R with high affinity, (2) binding to IL-1Rrp2 with high affinity, (3) inhibiting the binding of IL-36α, IL-36β, and IL-36γ to IL-36R, and (4) inhibiting cytokine secretion via IL-36α, IL-36β, and IL-36γ.

[0267] In the present application, the IL-17A targeting portion may comprise at least one CDR in the antibody heavy chain variable region VH. For example, the VH may comprise the amino acid sequence shown in SEQ ID NO:16.

[0268] In the present application, the targeting portion of said IL-17A may comprise HCDR3, wherein said HCDR3 comprises the amino acid sequence shown in SEQ ID NO:13.

[0269] In the present application, the targeting portion of said IL-17A may comprise HCDR2, wherein said HCDR2 comprises the amino acid sequence shown in SEQ ID NO:14.

[0270] In the present application, the targeting portion of said IL-17A may comprise HCDR1, wherein said HCDR1 comprises the amino acid sequence shown in SEQ ID NO:15.

[0271] In the present application, the targeting portion of IL-17A may comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 15, the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 14, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 13.

[0272] In the present application, the targeting portion of IL-17A may comprise a VH, and the VH may comprise the amino acid sequence shown in SEQ ID NO:16.

[0273] For example, the IL-17A targeting portion may comprise at least one CDR in an antibody light chain variable region VL, for example, the VL may comprise the amino acid sequence set forth in SEQ ID NO:20.

[0274] In the present application, the targeting portion of said IL-17A may comprise LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:17.

[0275] In the present application, the targeting portion of said IL-17A may comprise LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 18 (KVS).

[0276] In the present application, the targeting portion of said IL-17A may comprise LCDR1, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO:19.

[0277] In the present application, the targeting portion of IL-17A may comprise LCDR1, LCDR2 and LCDR3, wherein LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 19, LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS), and LCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 17.

[0278] In the present application, the targeting portion of IL-17A may comprise a VL, and the VL may comprise the amino acid sequence shown in SEQ ID NO:20.

[0279] In the present application, the IL-17A targeting moiety may be an IL-17A antibody. For example, the IL-17A targeting moiety may further comprise an antibody heavy chain constant region. For example, the IL-17A targeting moiety may further comprise an antibody light chain constant region.

[0280] In the present application, the heavy chain constant region of the IL-17A antibody may comprise the amino acid sequence shown in SEQ ID NO: 21. In the present application, the light chain constant region of the IL-17A antibody may comprise the amino acid sequence shown in SEQ ID NO: 10.

[0281] For example, the IL-36R targeting portion may comprise at least one CDR in an antibody heavy chain variable region VH. For example, the VH may comprise the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO: 30.

[0282] In the present application, the targeting portion of IL-36R may comprise HCDR3, wherein said HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO:27.

[0283] In the present application, the targeting portion of IL-36R may comprise HCDR2, wherein said HCDR2 comprises the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:28.

[0284] In the present application, the targeting portion of IL-36R may comprise HCDR1, wherein said HCDR1 comprises the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:29.

[0285] In the present application, the targeting portion of IL-36R may comprise HCDR1, HCDR2 and HCDR3, wherein the HCDR1 comprises the amino acid sequence shown in SEQ ID NO:3 or SEQ ID NO:29, the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:2 or SEQ ID NO:28, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:1 or SEQ ID NO:27.

[0286] In the present application, the targeting portion of IL-36R may comprise a VH, and the VH may comprise the amino acid sequence shown in SEQ ID NO:4 or SEQ ID NO:30.

[0287] For example, the targeting portion of IL-36R may comprise at least one CDR in the antibody light chain variable region VL. For example, the VL may comprise the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:34.

[0288] In the present application, the targeting portion of said IL-36R may comprise LCDR3, wherein said LCDR3 comprises the amino acid sequence shown in SEQ ID NO:5 or SEQ ID NO:31.

[0289] In the present application, the targeting portion of IL-36R may comprise LCDR2, wherein said LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

[0290] In the present application, the targeting portion of said IL-36R may comprise LCDR1, wherein said LCDR1 comprises the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:33.

[0291] In the present application, the targeting portion of IL-36R may comprise LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:33, the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO:6 (STS) or SEQ ID NO:32 (AAS), and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:31.

[0292] In the present application, the targeting portion of IL-36R may comprise a VL, and the VL may comprise the amino acid sequence shown in SEQ ID NO:8 or SEQ ID NO:34.

[0293] In the present application, the IL-36R targeting portion may be an scFv. For example, the VH and VL may be linked by a connecting peptide. For example, the scFv may comprise the amino acid sequence set forth in SEQ ID NO: 24.

[0294] In a specific embodiment, the bispecific antibody is formed by fusing ScFvs of an anti-IL-17A antibody and an anti-IL-36R antibody, and has two pairs of symmetrical peptide chains, each pair of peptide chains comprising a light chain (L chain) and a heavy chain (H chain), all of the peptide chains being linked by disulfide bonds, and any pair of peptide chains has the H chain and L chain structure shown in Formula I from the N-terminus to the C-terminus, [ka] where: VH represents the heavy chain variable region of the anti-IL-17A antibody; VL represents the light chain variable region of the anti-IL-17A antibody; CH1, CH2, and CH3 represent the heavy chain constant regions CH1, CH2, and CH3 of the anti-IL-17A antibody, respectively. CL represents the light chain constant region of the anti-IL-17A antibody; ScFv represents the ScFv of the anti-IL-36R antibody; L represents a linker element, "~" represents a disulfide bond, "-" represents a peptide bond; Here, the bispecific antibody has the activity of simultaneously binding to IL-17A and IL-36R.

[0295] For example, the heavy chain of the bispecific antibody may have the amino acid sequence set forth in SEQ ID NO: 25, and the light chain of the bispecific antibody may have the amino acid sequence set forth in SEQ ID NO: 23.

[0296] The double antithesis of the present application includes not only complete antibodies, but also immunoreactive antibody fragments or fusion proteins formed by antibodies with other sequences, and therefore the present application also includes fragments, derivatives and analogs of said antibodies.

[0297] The term "double antithesis" as used herein refers to an antibody comprising two of the above Formula I structures and having anti-IL-17A and anti-IL-36R activity. This term also encompasses variants of antibodies comprising two of the above Formula I structures and having the same function as the double antithesis of the present application. These variants include, but are not limited to, deletion, insertion, and / or substitution of one or more amino acids (usually 1 to 50, for example, 1 to 30, for example, 1 to 20, for example, 1 to 10) and addition of one or more amino acids (usually 20 or less, for example, 10 or less, for example, 5 or less) to the C-terminus and / or N-terminus. For example, it is well known in the art that substitution with amino acids having similar or close properties generally does not alter the function of a protein. For example, addition of one or more amino acids to the C-terminus and / or N-terminus generally does not alter the function of a protein. This term also encompasses active fragments and active derivatives of the double antithesis of the present application.

[0298] drugs In the present application, the drug may include an active molecule and, optionally, a pharmaceutically acceptable carrier. Typically, these substances are formulated in a non-toxic, inert, and pharmaceutically acceptable aqueous medium, where the pH value may vary depending on the nature of the formulated substance and the condition being treated, but may usually be about 5-8, for example, about pH 6-8. The formulated drug may be administered by any conventional route, including, but not limited to, intraperitoneal, intravenous, or topical administration.

[0299] The drug of the present application contains a safe and effective amount (e.g., 0.001-99 wt%, e.g., 0.01-90 wt%, e.g., 0.1-80 wt%) of the active ingredient described herein and a pharmaceutically acceptable carrier or excipient. Such carriers include, but are not limited to, saline, buffer solutions, glucose, water, glycerol, ethanol, and combinations thereof. The drug formulation must be compatible with the route of administration. The pharmaceutical composition of the present application can be prepared in the form of an injection using a conventional method, for example, saline or an aqueous solution containing glucose and other adjuvants. Pharmaceutical compositions such as injections and solutions are preferably prepared under sterile conditions. The dosage of the active ingredient is a therapeutically effective amount, e.g., about 1 microgram / kilogram body weight to about 5 milligrams / kilogram body weight per day. The polypeptide of the present application can also be used in combination with other therapeutic agents.

[0300] When using a pharmaceutical composition, a safe and effective amount of the pharmaceutical composition is administered to a mammal, where the safe and effective amount is usually at least about 10 micrograms / kilogram body weight and in most cases does not exceed about 50 milligrams / kilogram body weight, for example, the dosage may be from about 10 micrograms / kilogram body weight to about 20 milligrams / kilogram body weight. The specific dosage must also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0301] The following examples are intended to merely illustrate the antigen-binding proteins, production methods and uses of the present application, without being bound by any theory, and are not intended to limit the scope of the present invention.

[0302] Example Example 1: Development of alternative antibodies for the mouse model of the IL-36R antibody of the present application The anti-human IL-36R antibody of the present application (HB0034: the amino acid sequence of HCDR1 is shown in SEQ ID NO: 3, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 2, the amino acid sequence of HCDR3 is shown in SEQ ID NO: 1, the amino acid sequence of VH is shown in SEQ ID NO: 4, the amino acid sequence of the heavy chain is shown in SEQ ID NO: 11, the amino acid sequence of LCDR1 is shown in SEQ ID NO: 7, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 6 (STS), the amino acid sequence of LCDR3 is shown in SEQ ID NO: 5, the amino acid sequence of VL is shown in SEQ ID NO: 8, and the amino acid sequence of the light chain is shown in SEQ ID NO: 12) does not bind to mice, and therefore will be used to develop surrogate antibodies to human IL-36R and to conduct drug efficacy detection experiments in mouse models.

[0303] 1.1 Production of hybridoma cells producing mouse monoclonal antibodies To produce mouse monoclonal antibodies, we employed the hybridoma production technology invented by Kohler and Milstein in 1975 (Nature, 1975, 256:495-497). First, we knocked out the IL-1Rrp2 gene in C57BL / 6 mice, and after confirming that the gene was not expressed, we selected five mice for immunization. Mouse IL-1Rrp2 protein (R&D, #2354-RP / CF) was emulsified with an immunoadjuvant and used to immunize five IL-1Rrp2 knockout mice. After four immunizations, serum was collected and titers were detected by ELISA. Splenocytes from each of the five mice were then fused with SP2 / 0 myeloma cells. Hybridoma cells were screened by HAT, and cell culture supernatants were subjected to detection of mouse IL-36R binding activity. High-affinity antibodies were selected by Biacore detection and screened for their inhibitory effect on BMDC secretion of IL-6 stimulated by mouse IL-36 β / γ. Finally, the best hybridoma monoclonal cell lines, including 44G8, were selected for sequence analysis (Table 1).

[0304] [Table 2] First, total cellular RNA (Qiagen, 74181) was extracted from antibody-positive hybridoma cells using a total cellular RNA extraction kit. cDNA was obtained by reverse transcription using a 5' rapid amplification of cDNA ends (5' RACE) kit (Takara, 634859). Primers specific to the antibody variable region genes were designed, and the antibody variable region genes were amplified in two PCR reactions using the cDNA as a template. The target gene was cloned into carriers containing mouse antibody constant region genes, 000005 (light chain mouse Igκ) and 000007 (heavy chain mouse IgG 2a, with the Fc having D265A N297A (EU numbering, abbreviated as DANA), which weakens antibody-FcγR binding and eliminates ADCC / CDC effects, while also removing the C-terminal ricin K), using In-Fusion Snap Assembly Master Mix (Takara, 638949) homologous recombination. The constructed plasmid was then transformed into E. coli Stellar TM The cells were transformed into a competent cell line (Takara, 636736), and monoclonal clones were selected and sent to Suzhou Anshengda Biotechnology Co., Ltd. (referred to as Anshengda) for Sanger sequencing. Based on the DNA sequencing results, the antibody variable region amino acid sequences were finally translated to obtain the antibody variable region amino acid sequences.

[0305] >VH (SEQ ID NO: 39) EVQLQQSGPELVKPGASVKMSCKASGYTFTDYNMHWVKQSHGKSLEWIGFFNPNNGGTRYNQKFKGKATLTVNKSSSTAYMDLRSLTSEDSAVYYCTRQEIYYSNYFDYWGQGTTLTVSS >VL (SEQ ID NO: 34) DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQKPGQPPKLLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYSCQQSYEDPYTFGGGAKLEIK 1.3 Production of HB0034SA antibody After the accurate heavy and light chain monoclonal sequence plasmids corresponding to the 44G8 sequence were returned from Anseongda, PCR primers were designed using the returned plasmid as a template to mutate asparagine N, a potential glycosylation site at position 73 in the heavy chain variable region, to glutamine Q. The full-length sequence of the mutated antibody gene (sequence shown below) was amplified and transferred to the mammalian cell expression vector pUKWO. The resulting light and heavy chain vectors were numbered 300700 and 300701, respectively. Plasmids were extracted using an endocrine-less plasmid mass extraction kit (Tiangen Biochemical Technology Co., Ltd., DP117). The heavy and light chain plasmids were mixed with polyetherimide PEI (Polysciences, 24765-1) at a mass concentration ratio of 1:2 to form liposome complexes. CHO-S cells (product number: R80007, Polysciences Technology (China) Co., Ltd.) were then transfected. After 7 days of low-temperature induction culture at 32°C, the cell culture supernatant was collected and analyzed for protein synthesis. The chimeric antibody HB0034SA was purified by affinity chromatography using HPLC. The amino acid sequence of HCDR1 is shown in SEQ ID NO: 29, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 28, the amino acid sequence of HCDR3 is shown in SEQ ID NO: 27, the amino acid sequence of VH is shown in SEQ ID NO: 30, the amino acid sequence of the heavy chain is shown in SEQ ID NO: 37, the amino acid sequence of LCDR1 is shown in SEQ ID NO: 33, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 32 (AAS), the amino acid sequence of LCDR3 is shown in SEQ ID NO: 31, the amino acid sequence of VL is shown in SEQ ID NO: 34, and the amino acid sequence of the light chain is shown in SEQ ID NO: 38.

[0306] Example 2: Study on the substitutability of HB0034SA The HB0034 antibody specifically binds to human IL-36R protein, but not to rabbit, rat, or mouse IL-36R protein. HB0034 is a monoclonal antibody capable of specifically binding to human IL-36R, obtained by screening human IL-36R-immunized mice, and is the antibody of choice for clinical administration.

[0307] HB0034SA is an anti-mouse IL-36R monoclonal antibody that was independently researched and developed by the applicant and obtained by screening mouse IL-36R immunized rats, and is intended to be an alternative antibody to HB0034.

[0308] 2.1 Comparison of the affinity of HB0034SA and HB0034 to mouse IL-36R (also known as IL-1 Rrp2) and human IL-36R, respectively The affinity measurement results showed that the affinity KD value between HB0034SA and mouse IL-36R was 5.68 × 10 -10 M, and the affinity KD value of HB0034 for human IL-36R is 3.25 × 10 -10 M, indicating that the affinity of HB0034 for human IL-36R is equivalent to the affinity of HB0034SA for mouse IL-36R.

[0309] 2.2 Comparison of the binding activity of HB0034SA and HB0034 to mouse IL-36R (also known as IL-1 Rrp2) and human IL-36R, respectively ELISA results showed that the binding EC of HB0034SA to mouse IL-36R was significantly higher at 1 μg / mL antigen coating. 50 The binding EC value of HB0034 to human IL-36R was 25.380 ng / mL, and the molecular weights of HB0034 and HB0034SA were both approximately 150 kDa. 50 12.120ng / mL (EC 50 Since the difference in the binding ability between HB0034SA and the corresponding target protein is approximately 1-fold, it is considered that the binding ability between HB0034SA and the corresponding target protein is equivalent to that of HB0034.

[0310] 2.3 Comparative study of in vitro biological activity of HB0034SA and HB0034 The biological activity of HB0034 and HB0034SA in inhibiting primary cell secreted cytokine (IL-6) was measured.

[0311] The experimental results showed that HB0034 inhibited the binding of recombinant human IL-36α to human IL-36R, and reduced the amount of IL-6 secreted by human monocyte-derived macrophages (MDMs) via IL-36α, demonstrating the IC of antibody inhibitory activity. 50 Similarly, HB0034SA inhibited the binding of recombinant mouse IL-36α to mouse IL-36R, reducing the amount of IL-6 secreted by mouse bone marrow-derived dendritic cells (BMDCs) via IL-36α, demonstrating the IC value of the antibody inhibitory effect. 50 The IC value of HB0034 was 0.0806 nM. Based on the above, under these experimental conditions, HB0034 has the biological activity of inhibiting human IL-36α and the human IL36R receptor, and HB0034SA has the biological activity of inhibiting mouse IL-36α and the mouse IL36R receptor, and the IC value of both is 50 There is no significant difference between the two (the difference in IC50 between the two is about two-fold), indicating that the biological functional activities of the two are equivalent.

[0312] From the above, the target affinity results show that the affinity of HB0034 to human IL-36R is slightly higher than that of HB0034SA to mouse IL-36R (approximately 47 times higher), but the binding activity results show that the binding ability of HB0034SA to the corresponding target protein is equivalent to that of HB0034. The biological function activity results show that HB0034 / HB0034SA inhibit the secretion of IL-6 in cells via the binding of human / mouse IL-36α to human / mouse IL-36R, and the IC 50The values ​​were 0.0413 nM and 0.0806 nM, respectively, indicating that the biological functional activities of both compounds were equivalent. Because Fc-terminal functional activity is an important mass attribute of non-HB0034, when assessing whether HB0034SA could be an alternative in non-clinical research pharmacology, we focused primarily on comparisons of biological activity, binding activity, and target protein affinity. Taking into account the alignment results of biological activity, binding activity, and target protein affinity, HB0034SA is considered a potential alternative.

[0313] Example 3: Functional inhibitory effect of combined stimulation with IL-17A antibody and IL-36R antibody HB0043 is a bispecific antibody targeting IL-17A and IL-36R, in which the IL-17A targeting portion of HB0043 uses the VH and VL of HB0017, and the IL-36R targeting portion of HB0043 uses the VH and VL of HB0034. The structural mode of HB0043 belongs to the Morrison mode (IgG-scFv), i.e., the C-terminus of each of the two heavy chains of a single IgG antibody is linked to an scFv fragment of another antibody, as shown in Figure 1. The amino acid sequence of the heavy chain of HB0043 is set forth in SEQ ID NO:25, and the amino acid sequence of the light chain is set forth in SEQ ID NO:23.

[0314] After digestion of healthy human dermal fibroblasts (NHDF), 3 × 10 5 The cells were suspended in medium (DMEM + 10% FBS + 1% P / S) at a concentration of 1000 ng / mL, seeded at 100 μL / well in a 96-well plate, and incubated overnight at 37°C, 5% CO2. The medium was replaced with basal medium, and the cells were starved for 16 hours. IL-17A was then diluted to nine concentrations in a 5-fold gradient starting from 1000 ng / mL, and IL-36α, β, and γ were diluted to nine concentrations in a 3-fold gradient starting from 1000 ng / mL in normal medium. The cells were then stimulated with NHDF for 24 hours. The supernatants were collected by centrifugation, and the protein concentrations of IL-6 and IL-8 in the supernatants were assayed by ELISA. The EC values ​​of IL-17A and IL-36 ligands were then determined. 50 was calculated. 4Cells were cultured overnight in a 96-well plate. Cells were stimulated with 15 ng / ml IL-36α, 1 ng / ml IL-36β, or 2 ng / ml IL-36γ plus 0.5 ng / ml IL-17A. Two-fold gradient dilutions of HB0034, HB0017, HB0043, and HB0017 + HB0034 antibodies were mixed in 200 μL of each plate to initial concentrations of 160, 160, 40, and 40 + 40 nM, respectively, and incubated overnight at 37°C, 5% CO2. Six-fold diluted supernatants were collected and used to detect IL-6 / 8 cytokine levels using a human IL-6 / 8 ELISA kit (Biolegend, Cat. #430515 / 431501). Concentration-response curves were generated for the antibodies.

[0315] As shown in Figures 2-7, the results indicate that the combination of HB0043 or HB0017 with HB0034, along with IL-36 ligand and IL-17A, effectively inhibited NHDF-induced IL-6 and IL-8 secretion. Antibody concentration-response curves showed that HB0043 significantly inhibited IL-6 and IL-8 secretion induced by these cytokines in a dose-dependent manner. Compared with HB0017 and HB0034, HB0043 exhibited a better inhibitory effect on IL-6 and IL-8 secretion at the same concentration, even achieving similar effects at lower concentrations. However, the combination of HB0017 and HB0034 showed effects similar to those of HB0043. Taken together, our data suggest that the HB0043 bispecific antibody and the combination of two monospecific antibodies (HB0017 and HB0034) can more effectively inhibit IL-6 and IL-8 secretion induced by IL-17A and IL-36 ligands than either monospecific antibody, and may therefore play a role in better dual inhibition of IL-17A and IL-36-mediated pathways in vitro.

[0316] Example 4: Evaluation of efficacy of IL-17A antibody, IL-36R antibody, and their combination in inhibiting UUO-induced mouse kidney fibrosis Thirty-six 12-week-old C57BL / 6 male mice were randomly divided into six groups according to their initial body weight. Six mice in each group underwent UUO surgery. The isotype control group received 900543 (an IgG1 (Fc silencer) negative control antibody targeting the small molecule TNP, 30 mg / kg, i.p.), the positive drug group received paricalcitol (0.1 μg / kg, i.p.), the combination group received HB0017 + HB0034SA (15 mg / kg, i.p. + 15 mg / kg, i.p.), the single drug group received HB0017 (30 mg / kg, i.p.), and the single drug group received HB0034SA (30 mg / kg, i.p.). A normal control group (no surgery) was administered one dose before UUO surgery. On the day of surgery, inhalation anesthesia was administered, and the left ureter of each mouse was ligated. After surgery, the drug was administered once every other day, three times a week for two weeks. Prior to harvest, the animals were weighed. Blood was collected, and serum was aliquoted and stored at -80°C. The kidney on the operated side was harvested, weighed, and preserved in formalin (for histological staining).

[0317] Serum creatinine (Cr) and serum urea nitrogen (BUN) were detected using commercially available kits. Renal tissue staining and immunohistochemistry were performed.

[0318] The results are shown in Figure 8. Compared to the normal control group, the renal index of the model group was improved by 29.8%. Compared to the 900543 model group, the renal index of the positive drug Pari group was decreased by 14.4%. The HB0017 + HB0034SA (14.3%) showed a tendency for a decrease compared to the single-dose group (HB0017: 13.2%, HB0034SA: 2.5%). Figure 9 shows that there was no statistical difference in blood Cr between the groups. Compared to the 900543 model group (17.9% increase, vs. normal control), the combination group HB0017 + HB0034SA (17.8%) showed a tendency for a decrease compared to the single-dose group (HB0017: 10.1%, 900971: 13.7%). Similarly, Figure 10 shows that there was no statistical difference in blood BUN between the groups. Among the drug treatment groups, the lowest blood BUN value was observed in the HB0017 + HB0034SA combination group, which showed a 14.1% decrease in blood BUN compared to the model group.

[0319] Next, the ameliorative effects of the test antibodies on renal fibrosis were evaluated using PAS staining and Masson staining, respectively. PAS staining and quantitative scores primarily reflected glomerular fibrosis. As shown in Figure 11, the dark blue-purple color within the glomerulus indicated positive fibrosis. The quantitative analysis results in Figure 12 show that UUO successfully induced significant fibrosis in the glomerulus (P<0.001). Compared with the model group, both the positive drug (P<0.001) and the test antibody significantly inhibited glomerular fibrosis. Furthermore, the combination of HB0017 and HB0034SA was more effective than either HB0017 or HB0034SA administered alone. Masson staining and quantification of fibrosis area reflected the progression of tubulointerstitial fibrosis. As shown in Figure 13, the blue-positive signal in the tubulointerstitium indicated the fibrotic matrix. The quantitative analysis results in Figure 14 show that UUO significantly induced tubulointerstitial fibrosis in mice (P<0.001). Compared with the model group, the positive control and different antibody interference strategies tested all significantly inhibited tubulointerstitial fibrosis (P<0.01). Similarly, the combined treatment group HB0017 + HB0034SA showed the best effect.

[0320] To further elucidate the anti-renal fibrosis effects of the test antibodies, immunohistochemistry was used to detect positive expression of renal fibronectin (FN). FN is an important component of the extracellular matrix, a fibrosis matrix protein, and is used to characterize the phenotype of tissue fibrosis. As shown in Figure 15, UUO induced the massive expression and aggregation of tubulointerstitial FN, again resulting in obvious fibrosis in the kidneys of UUO mice. Each treatment group contained Pari and the test antibody, which reduced the positive FN expression signal, suggesting that the drug inhibited and reduced FN expression, providing a more effective biological effect in preventing and treating UUO-induced renal fibrosis.

[0321] Example 5 Therapeutic effect of combined use of IL-17A antibody and IL-36R surrogate antibody on lupus nephritis in spontaneous lupus erythematosus mice (NZB / NZW F1) Fifty NZB / NZW F1 mice were randomly divided into five groups based on animal ANA levels, anti-dsDNA levels, urinary protein, and initial body weight. Each group consisted of 10 mice: HB0017 monotherapy (anti-human IL-17A monotherapy, 50 mg / kg, i.p.), HB0034SA monotherapy (anti-mouse IL-36R monotherapy, 50 mg / kg, i.p.), HB0017 + HB0034SA combination therapy (25 + 25 mg / kg, i.p.), positive drug group (prednisone, 9 mg / kg, po), and homozygous control group (IgG1, 50 mg / kg, i.p.). Additionally, 10 C57BL / 6 mice served as negative controls. Here, the amino acid sequence of HCDR1 of the HB0017 antibody is shown in SEQ ID NO: 15, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 14, the amino acid sequence of HCDR3 is shown in SEQ ID NO: 13, the amino acid sequence of LCDR1 is shown in SEQ ID NO: 19, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 18, the amino acid sequence of LCDR3 is shown in SEQ ID NO: 17, the amino acid sequence of VH is shown in SEQ ID NO: 16, the amino acid sequence of VL is shown in SEQ ID NO: 20, the heavy chain amino acids are shown in SEQ ID NO: 22, and the antibody light chain amino acids are shown in SEQ ID NO: 23. The HB0034SA antibody is the antibody described in Example 1.

[0322] Significant increases in ANA and anti-dsDNA levels were detected in NZB / NZW F1 mice at 30 weeks of age. Animals in the isotype, HB0017, HB0034SA, and HB0017+HB0034SA combination groups were administered intraperitoneally. The model group received intraperitoneal injections of saline twice weekly for 10 to 40 consecutive weeks. The positive control group received intragastric administration once daily.

[0323] Animals were weighed twice weekly, and random urine samples were collected once weekly to detect urinary protein concentrations. At the end of the experiment, the left kidneys of the animals were harvested, sectioned, and fixed for pathology scoring.

[0324] The results of the weight change of NZB / NZW F1 mice are shown in Figure 16, and the results show that combined intraperitoneal injection of HB0017+HB0034SA can effectively improve the weight loss of mice.

[0325] The results of detecting urinary protein levels in NZB / NZW F1 mice are shown in Figure 17, and the results show that intraperitoneal injection of HB0017+HB0034SA group can delay and inhibit the increase in urinary protein levels in NZB / NZW F1 mice.

[0326] The evaluation results of kidney pathological damage in NZB / NZW F1 mice are shown in Figure 18, and the results show that intraperitoneal administration of the HB0017+HB0034SA group can significantly improve kidney pathological damage in NZB / NZW F1 mice.

[0327] The evaluation results of renal fibrosis in NZB / NZW F1 mice are shown in Figure 19, and the results show that intraperitoneal injection of HB0017+HB0034SA group can significantly inhibit renal fibrosis in NZB / NZW F1 mice.

[0328] Example 6 Therapeutic effect of combined use of IL-17A antibody and IL-36R antibody on lupus nephritis in spontaneous lupus erythematosus mice (MRL / lpr) Thirty MRL / lpr mice were randomly divided into two groups based on their ANA and anti-dsDNA levels, with 15 mice in each group: the HB0017 + HB0034SA combination group (25 + 25 mg / kg, i.p.) and the isotype control group (IgG1 50 mg / kg, i.p.). At 10 weeks of age, MRL / lpr mice were administered intraperitoneally twice weekly for 10 to 20 consecutive weeks, with a 2-week observation period. They were weighed weekly, and random urine samples were collected weekly to measure urinary protein concentrations. Plasma ANA and anti-dsDNA IgG were measured monthly. At the end of the experiment, the left kidneys of the animals were harvested, sectioned, and fixed for Masson staining and fibrosis scoring.

[0329] The survival statistics of MRL / lpr mice are shown in Figure 20, and the results show that intraperitoneal administration of HB0017+HB0034SA group reduces the mortality rate of MRL / lpr mice.

[0330] The detection results of urinary protein level in MRL / lpr mice are shown in Figure 21, and the results show that intraperitoneal injection of HB0017+HB0034SA group inhibits urinary protein level in MRL / lpr mice.

[0331] The evaluation results of renal fibrosis in MRL / lpr mice are shown in Figure 22, and the results showed that intraperitoneal injection of HB0017+HB0034SA group could inhibit renal fibrosis in MRL / lpr mice.

Claims

1. 1. Use of a drug combination in the manufacture of a medicament for preventing and / or treating systemic lupus erythematosus, wherein the drug combination comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R.

2. The use according to claim 1, wherein the IL-17A is human IL-17A.

3. The use according to any one of claims 1 to 2, wherein the antigen-binding protein that targets IL-17A is capable of inhibiting the associated action of IL-17A and IL-17R.

4. The use according to any one of claims 1 to 3, wherein the antigen-binding protein targeting IL-17A comprises at least one CDR in an antibody heavy chain variable region VH, and the VH comprises the amino acid sequence shown in SEQ ID NO:

16.

5. The use according to any one of claims 1 to 4, wherein the antigen-binding protein that targets IL-17A comprises HCDR3, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO:

13.

6. The use according to any one of claims 1 to 5, wherein the antigen-binding protein that targets IL-17A comprises HCDR2, and the HCDR2 comprises the amino acid sequence shown in SEQ ID NO:

14.

7. The use according to any one of claims 1 to 6, wherein the antigen-binding protein that targets IL-17A comprises HCDR1, and the HCDR1 comprises the amino acid sequence shown in SEQ ID NO:

15.

8. The use according to any one of claims 1 to 7, wherein the antigen-binding protein targeting IL-17A comprises a VH, and the VH comprises the amino acid sequence shown in SEQ ID NO:

16.

9. The use according to any one of claims 1 to 8, wherein the antigen-binding protein that targets IL-17A comprises an antibody heavy chain constant region.

10. The use according to claim 9, wherein the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

11. The use according to any one of claims 9 to 10, wherein the antibody heavy chain constant region is derived from an IgG1 or IgG4 heavy chain constant region.

12. The use according to any one of claims 9 to 11, wherein the heavy chain constant region of the antigen-binding protein targeting IL-17A comprises the amino acid sequence shown in SEQ ID NO:

21.

13. The use according to any one of claims 1 to 12, wherein the antigen-binding protein targeting IL-17A comprises at least one CDR in an antibody light chain variable region, and the VL comprises the amino acid sequence shown in SEQ ID NO:

20.

14. The use according to any one of claims 1 to 13, wherein the antigen-binding protein that targets IL-17A comprises an LCDR3, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:

17.

15. The use of any one of claims 1 to 14, wherein the antigen-binding protein that targets IL-17A comprises an LCDR2, and the LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 18 (KVS).

16. The use according to any one of claims 1 to 15, wherein the antigen-binding protein that targets IL-17A comprises an LCDR1, and the LCDR1 comprises the amino acid sequence shown in SEQ ID NO:

19.

17. The use according to any one of claims 1 to 16, wherein the antigen-binding protein targeting IL-17A comprises a VL, and the VL comprises the amino acid sequence shown in SEQ ID NO:

20.

18. The use according to any one of claims 1 to 17, wherein the antigen-binding protein that targets IL-17A comprises a light chain constant region.

19. The use according to claim 18, wherein the light chain constant region is derived from Igκ.

20. The use according to any one of claims 18 to 19, wherein the light chain constant region of the antigen-binding protein targeting IL-17A comprises the amino acid sequence shown in SEQ ID NO:

10.

21. The use according to any one of claims 1 to 20, wherein the IL-36R is human IL-36R.

22. The use according to any one of claims 1 to 21, wherein the antigen-binding protein targeting IL-36R comprises at least one CDR in an antibody heavy chain variable region VH, and the VH comprises the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO:

30.

23. The use of any one of claims 1 to 22, wherein the antigen-binding protein that targets IL-36R comprises HCDR3, and the HCDR3 comprises the amino acid sequence shown in SEQ ID NO: 1 or SEQ ID NO:

27.

24. The use of any one of claims 1 to 23, wherein the antigen-binding protein that targets IL-36R comprises HCDR2, and the HCDR2 comprises the amino acid sequence shown in SEQ ID NO: 2 or SEQ ID NO:

28.

25. The use of any one of claims 1 to 24, wherein the antigen-binding protein that targets IL-36R comprises HCDR1, and the HCDR1 comprises the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO:

29.

26. The use according to any one of claims 1 to 25, wherein the antigen-binding protein targeting IL-36R comprises a VH, and the VH comprises the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO:

30.

27. The use according to any one of claims 1 to 26, wherein the antigen-binding protein that targets IL-36R comprises an antibody heavy chain constant region.

28. 28. The use of claim 27, wherein the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

29. The antibody heavy chain constant region is derived from the heavy chain constant region of IgG1. Use according to any one of claims 27 to 28.

30. The use according to any one of claims 27 to 29, wherein the heavy chain constant region of the antigen-binding protein that targets IL-36R comprises the amino acid sequence shown in SEQ ID NO: 9 or SEQ ID NO:

35.

31. The use according to any one of claims 1 to 30, wherein the antigen-binding protein targeting IL-36R comprises at least one CDR in an antibody light chain variable region, and the VL comprises the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO:

34.

32. The use of any one of claims 1 to 31, wherein the antigen-binding protein that targets IL-36R comprises an LCDR3, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:5 or SEQ ID NO:

31.

33. The use of any one of claims 1 to 32, wherein the antigen-binding protein that targets IL-36R comprises an LCDR2, and the LCDR2 comprises the amino acid sequence shown in SEQ ID NO: 6 or SEQ ID NO: 32 (AAS).

34. The use of any one of claims 1 to 33, wherein the antigen-binding protein that targets IL-36R comprises LCDR1, and the LCDR1 comprises the amino acid sequence shown in SEQ ID NO: 7 or SEQ ID NO:

33.

35. The use of any one of claims 1 to 34, wherein the antigen-binding protein that targets IL-36R comprises a VL, and the VL comprises the amino acid sequence shown in SEQ ID NO: 8 or SEQ ID NO:

34.

36. The use of any one of claims 1 to 35, wherein the antigen-binding protein that targets IL-36R comprises a light chain constant region.

37. 37. The use of claim 36, wherein the light chain constant region is derived from Igκ.

38. The use according to any one of claims 36 to 37, wherein the light chain constant region of the antigen-binding protein that targets IL-36R comprises the amino acid sequence shown in SEQ ID NO: 10 or SEQ ID NO:

36.

39. The use according to any one of claims 1 to 38, wherein the systemic lupus erythematosus includes systemic lupus erythematosus nephritis.

40. 1. Use of an isolated antigen binding protein in the manufacture of a medicament, wherein the isolated antigen binding protein comprises a first binding domain that targets IL-17A and a second binding domain that targets IL-36R, and the medicament is used to prevent and / or treat systemic lupus erythematosus.

41. The isolated antigen binding protein comprises: (1) binding to IL-36R with high affinity; (2) binding to IL-1Rrp2 with high affinity; (3) inhibiting the binding of IL-36α, IL-36β, and IL-36γ to IL-36R; and (4) inhibiting cytokine secretion mediated by IL-36α, IL-36β, and IL-36γ.

42. 42. The use of any one of claims 40 to 41, wherein the isolated antigen-binding protein is selected from a monoclonal antibody, a chimeric antibody, a humanized antibody, or a combination thereof.

43. The use according to any one of claims 40 to 42, wherein the first binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody heavy chain variable region VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO:

16.

44. The use of any one of claims 40 to 43, wherein the first binding domain of the isolated antigen-binding protein comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

13.

45. 45. The use of any one of claims 40 to 44, wherein the first binding domain of the isolated antigen-binding protein comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:

14.

46. 46. ​​The use of any one of claims 40 to 45, wherein the first binding domain of the isolated antigen-binding protein comprises HCDR1, and said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:

15.

47. The use of any one of claims 40 to 46, wherein the first binding domain of the isolated antigen-binding protein comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO:

16.

48. 48. The use according to any one of claims 40 to 47, wherein the first binding domain of the isolated antigen-binding protein comprises at least one CDR in a light chain variable region VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

49. 49. The use of any one of claims 40 to 48, wherein the first binding domain of the isolated antigen-binding protein comprises an LCDR3, and the LCDR3 comprises the amino acid sequence shown in SEQ ID NO:

17.

50. 50. The use of any one of claims 40 to 49, wherein the first binding domain of the isolated antigen-binding protein comprises LCDR2, and said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

51. 51. The use of any one of claims 40 to 50, wherein the first binding domain of the isolated antigen-binding protein comprises LCDR1, and said LCDR1 comprises the amino acid sequence shown in SEQ ID NO:

19.

52. 52. The use of any one of claims 40 to 51, wherein the first binding domain of the isolated antigen-binding protein comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

53. 53. The use of any one of claims 40 to 52, wherein the isolated antigen-binding protein comprises a heavy chain constant region.

54. 54. The use of any one of claims 40 to 53, wherein the isolated antigen-binding protein comprises a light chain constant region.

55. The use according to any one of claims 53 to 54, wherein the heavy chain constant region is derived from human IgG1 or human IgG4.

56. The use according to any one of claims 54 to 55, wherein the light chain constant region is derived from human IgG1 or human IgG4.

57. The use according to any one of claims 53 to 56, wherein the heavy chain constant region comprises the amino acid sequence shown in SEQ ID NO:

21.

58. The use according to any one of claims 54 to 57, wherein the light chain constant region comprises the amino acid sequence shown in SEQ ID NO:

10.

59. 59. The use according to any one of claims 40 to 58, wherein the second binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO:

30.

60. 60. The use of any one of claims 40 to 59, wherein the second binding domain of the isolated antigen-binding protein comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO:

27.

61. 61. The use of any one of claims 40 to 60, wherein the second binding domain of the isolated antigen-binding protein comprises HCDR2, and wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:

28.

62. 62. The use of any one of claims 40 to 61, wherein the second binding domain of the isolated antigen-binding protein comprises HCDR1, and said HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:

29.

63. 63. The use of any one of claims 40 to 62, wherein the second binding domain of the isolated antigen-binding protein comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO:

30.

64. 64. The use of any one of claims 40 to 63, wherein the second binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO:

34.

65. 65. The use of any one of claims 40 to 64, wherein the second binding domain of the isolated antigen binding protein comprises an LCDR3, and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:

31.

66. 66. The use of any one of claims 40 to 65, wherein the second binding domain of the isolated antigen binding protein comprises LCDR2, and said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 or SEQ ID NO: 32 (AAS).

67. 67. The use of any one of claims 40 to 66, wherein the second binding domain of the isolated antigen-binding protein comprises LCDR1, and wherein said LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:

33.

68. 68. The use of any one of claims 40 to 67, wherein the second binding domain of the isolated antigen-binding protein comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO:

34.

69. The use according to any one of claims 64 to 68, wherein the second binding domain of the isolated antigen-binding protein comprises a VH and a VL, and the VH and VL are connected by a connecting peptide.

70. 70. The use of claim 69, wherein the amino acid sequence of the connecting peptide is (GS)n, where n is a positive integer.

71. 71. The use according to any one of claims 40 to 70, wherein the second binding domain of the isolated antigen-binding protein is an scFv.

72. 72. The use of claim 71, wherein the scFv of the second binding domain of the isolated antigen-binding protein comprises the amino acid sequence set forth in SEQ ID NO:

24.

73. 73. The use of any one of claims 40 to 72, wherein the isolated antigen-binding protein comprises (a) a first binding domain of an anti-IL-17A antibody, and (b) a second binding domain that binds to the anti-IL-17A antibody.

74. The use of claim 73, wherein the second binding domain is a single-chain variable region (scFv) of an anti-IL-36R antibody.

75. 75. The use according to any one of claims 40 to 74, wherein the second binding domain is directly or indirectly linked to the first binding domain.

76. 76. The use of claim 75, wherein the second binding domain is connected to the first binding domain by a linker.

77. The use according to any one of claims 73 to 76, wherein the scFvs of the anti-IL-17A antibody and the anti-IL-36R antibody are linked by a linker sequence.

78. 78. The use of any one of claims 40 to 77, wherein the isolated antigen-binding protein is a homodimer.

79. 79. The use of any one of claims 40 to 78, wherein the isolated antigen-binding protein is a tetravalent antibody.

80. 80. The use of any one of claims 40 to 79, wherein the isolated antigen-binding protein is a bispecific antibody.

81. 81. The use of claim 80, wherein the bispecific antibody is a double-chain antibody or a single-chain antibody.

82. The bispecific antibody has the structure shown in Formula I from the N-terminus to the C-terminus: 【Chemistry 1】 where: VH represents the heavy chain variable region of the anti-IL-17A antibody; VL represents the light chain variable region of an anti-IL-17A antibody; CH1, CH2, and CH3 represent the heavy chain constant regions CH1, CH2, and CH3 of the anti-IL-17A antibody, respectively; CL represents the light chain constant region of an anti-IL-17A antibody; ScFv represents the ScFv of the anti-IL-36R antibody; L represents a linker element, "~" represents a disulfide bond, "-" represents a peptide bond; The use according to any one of claims 80 to 81, wherein the bispecific antibody has the activity of simultaneously binding to IL-17A and IL-36R.

83. The use according to any one of claims 80 to 82, wherein the bispecific antibody is formed by fusing ScFv of the anti-IL-17A antibody and the anti-IL-36R antibody, and comprises two pairs of mutually symmetric peptide chains, each pair of peptide chains comprising a light chain (L chain) and a heavy chain (H chain), all of the peptide chains being linked by disulfide bonds, and any pair of peptide chains having, from the N-terminus to the C-terminus, the structure of the H chain and L chain shown in Formula I.

84. 84. The use according to any one of claims 80 to 83, wherein the bispecific antibody is a homodimer of peptide chains of the structure shown in formula I.

85. The use according to any one of claims 82 to 84, wherein the linker element is a connecting peptide.

86. 86. The use of claim 85, wherein the amino acid sequence of the connecting peptide is (GS)n, where n is a positive integer.

87. 87. The use according to any one of claims 83 to 86, wherein the heavy chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO: 25 and the light chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO:

23.

88. 88. The use of any one of claims 1 to 87, wherein the isolated antigen binding protein further comprises a detectable marker, a target marker, a drug, a toxin, a cytokine, a radionuclide, or an enzyme.

89. The use according to any one of claims 1 to 88, wherein the systemic lupus erythematosus comprises lupus erythematosus nephritis.

90. The use according to any one of claims 1 to 89, wherein the medicament is capable of alleviating elevated urinary protein levels due to systemic lupus erythematosus.

91. The use according to any one of claims 1 to 90, wherein the drug is capable of alleviating the pathological damage of the kidney caused by systemic lupus erythematosus.

92. The use according to any one of claims 1 to 91, wherein the medicament is capable of alleviating and / or inhibiting renal fibrosis due to systemic lupus erythematosus.

93. A method for preventing and / or treating systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

94. 94. The method of claim 93, wherein the systemic lupus erythematosus comprises lupus erythematosus nephritis.

95. A method of alleviating elevated urinary protein levels due to systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

96. A method for alleviating pathological damage to the kidney due to systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

97. 1. A method of alleviating and / or inhibiting renal fibrosis due to systemic lupus erythematosus, comprising administering to a subject in need thereof a drug capable of targeting IL-17A and IL-36R.

98. The method of any one of claims 93 to 97, wherein the IL-17A is human IL-17A.

99. The method of any one of claims 93 to 98, wherein the IL-36R is human IL-36R.

100. The method of any one of claims 93 to 99, wherein the drug comprises an antigen binding protein that targets IL-17A and an antigen binding protein that targets IL-36R.

101. 101. The method of claim 100, wherein the antigen binding protein that targets IL-17A is capable of inhibiting the associated action of IL-17A and IL-17R.

102. The method of any one of claims 100 to 101, wherein the antigen-binding protein targeting IL-17A comprises at least one CDR in an antibody heavy chain variable region VH, and the VH comprises the amino acid sequence shown in SEQ ID NO:

16.

103. The method of any one of claims 100 to 102, wherein the antigen binding protein that targets IL-17A comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

13.

104. The method of any one of claims 100 to 103, wherein the antigen binding protein that targets IL-17A comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:

14.

105. The method of any one of claims 100 to 104, wherein the antigen binding protein that targets IL-17A comprises HCDR1, and the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:

15.

106. The method of any one of claims 100 to 105, wherein the antigen binding protein targeting IL-17A comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO:

16.

107. 107. The method of any one of claims 100 to 106, wherein the antigen binding protein that targets IL-17A comprises an antibody heavy chain constant region.

108. 108. The method of claim 107, wherein the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

109. The method of any one of claims 107 to 108, wherein the antibody heavy chain constant region is derived from the heavy chain constant region of IgG1.

110. The method of any one of claims 107 to 109, wherein the antibody heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:

21.

111. The method of any one of claims 100 to 110, wherein the antigen binding protein targeting IL-17A comprises at least one CDR in an antibody light chain variable region, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

112. The method of any one of claims 100 to 111, wherein the antigen binding protein that targets IL-17A comprises an LCDR3, and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

17.

113. 113. The method of any one of claims 100 to 112, wherein the antigen binding protein that targets IL-17A comprises an LCDR2, and the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

114. The method of any one of claims 100 to 113, wherein the antigen binding protein that targets IL-17A comprises an LCDR1, and the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:

19.

115. The method of any one of claims 100 to 114, wherein the antigen binding protein that targets IL-17A comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

116. 116. The method of any one of claims 100 to 115, wherein the antigen binding protein that targets IL-17A comprises a light chain constant region.

117. The method of claim 116, wherein the light chain constant region is derived from Igκ.

118. The method of any one of claims 116 to 117, wherein the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:

10.

119. The method of any one of claims 100 to 118, wherein the antigen-binding protein targeting IL-36R comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence shown in SEQ ID NO: 4 or SEQ ID NO:

30.

120. 120. The method of any one of claims 100 to 119, wherein the antigen binding protein that targets IL-36R comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO:

27.

121. 121. The method of any one of claims 100 to 120, wherein the antigen binding protein that targets IL-36R comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:

28.

122. The method of any one of claims 100 to 121, wherein the antigen binding protein that targets IL-36R comprises HCDR1, and the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:

29.

123. The method of any one of claims 100 to 122, wherein the antigen binding protein targeting IL-36R comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO:

30.

124. The method of any one of claims 100 to 123, wherein the antigen binding protein that targets IL-36R comprises an antibody heavy chain constant region.

125. 125. The method of claim 124, wherein the antibody heavy chain constant region is derived from an IgG heavy chain constant region.

126. The method of any one of claims 124 to 125, wherein the antibody heavy chain constant region is derived from the heavy chain constant region of IgG1.

127. The method of any one of claims 124 to 126, wherein the antibody heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 9 or SEQ ID NO:

35.

128. The method of any one of claims 100 to 127, wherein the antigen-binding protein targeting IL-36R comprises at least one CDR in an antibody light chain variable region, and the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:

34.

129. 129. The method of any one of claims 100 to 128, wherein the antigen binding protein that targets IL-36R comprises an LCDR3, and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:

31.

130. 130. The method of any one of claims 100 to 129, wherein the antigen binding protein that targets IL-36R comprises an LCDR2, and the LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

131. The method of any one of claims 100 to 130, wherein the antigen binding protein that targets IL-36R comprises LCDR1, and the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:7 or SEQ ID NO:

33.

132. The method of any one of claims 100 to 131, wherein the antigen binding protein that targets IL-36R comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:

34.

133. 133. The method of any one of claims 100 to 132, wherein the antigen binding protein that targets IL-36R comprises a light chain constant region.

134. The method of claim 133, wherein the light chain constant region is derived from Igκ.

135. The method of any one of claims 133 to 134, wherein the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO: 10 or SEQ ID NO:

36.

136. 136. The method of any one of claims 93-135, wherein the medicament comprises an isolated antigen binding protein, the isolated antigen binding protein comprising a first binding domain that targets IL-17A and a second binding domain that targets IL-36R.

137. The isolated antigen binding protein comprises: (1) binding to IL-36R with high affinity; (2) binding to IL-1Rrp2 with high affinity; (3) inhibiting the binding of IL-36α, IL-36β, and IL-36γ to IL-36R; and (4) inhibiting cytokine secretion mediated by IL-36α, IL-36β, and IL-36γ.

138. 138. The method of any one of claims 136-137, wherein the isolated antigen binding protein is selected from a monoclonal antibody, a chimeric antibody, a humanized antibody, or a combination thereof.

139. The method of any one of claims 136 to 138, wherein the first binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO:

16.

140. 140. The method of any one of claims 136 to 139, wherein the first binding domain of the isolated antigen binding protein comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

13.

141. 141. The method of any one of claims 136 to 140, wherein the first binding domain of the isolated antigen binding protein comprises HCDR2, and the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO:

14.

142. 142. The method of any one of claims 136 to 141, wherein the first binding domain of the isolated antigen binding protein comprises HCDR1, and the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO:

15.

143. 143. The method of any one of claims 136 to 142, wherein the first binding domain of the isolated antigen-binding protein comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO:

16.

144. The method of any one of claims 136 to 143, wherein the first binding domain of the isolated antigen-binding protein comprises at least one CDR in a light chain variable region VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

145. 145. The method of any one of claims 136 to 144, wherein the first binding domain of the isolated antigen binding protein comprises an LCDR3, and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:

17.

146. 146. The method of any one of claims 136 to 145, wherein the first binding domain of the isolated antigen binding protein comprises LCDR2, and wherein said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 18 (KVS).

147. 147. The method of any one of claims 136 to 146, wherein the first binding domain of the isolated antigen binding protein comprises LCDR1, and wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO:

19.

148. 148. The method of any one of claims 136 to 147, wherein the first binding domain of the isolated antigen binding protein comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO:

20.

149. 149. The method of any one of claims 136-148, wherein the isolated antigen binding protein comprises a heavy chain constant region.

150. 150. The method of any one of claims 136-149, wherein the isolated antigen binding protein comprises a light chain constant region.

151. The method of any one of claims 149 to 150, wherein the heavy chain constant region is derived from human IgG1 or human IgG4.

152. The method of any one of claims 150 to 151, wherein the light chain constant region is derived from human IgG1 or human IgG4.

153. The method of any one of claims 149 to 152, wherein the heavy chain constant region comprises the amino acid sequence set forth in SEQ ID NO:

21.

154. The method of any one of claims 150 to 153, wherein the light chain constant region comprises the amino acid sequence set forth in SEQ ID NO:

10.

155. 155. The method of any one of claims 136 to 154, wherein the second binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody heavy chain variable region VH, wherein the VH comprises the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO:

30.

156. 156. The method of any one of claims 136 to 155, wherein the second binding domain of the isolated antigen binding protein comprises HCDR3, and the HCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO:

27.

157. 157. The method of any one of claims 136 to 156, wherein the second binding domain of the isolated antigen binding protein comprises HCDR2, and wherein the HCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 2 or SEQ ID NO:

28.

158. 158. The method of any one of claims 136 to 157, wherein the second binding domain of the isolated antigen binding protein comprises HCDR1, and wherein the HCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 3 or SEQ ID NO:

29.

159. 159. The method of any one of claims 136 to 158, wherein the second binding domain of the isolated antigen binding protein comprises a VH, and the VH comprises the amino acid sequence set forth in SEQ ID NO: 4 or SEQ ID NO:

30.

160. 160. The method of any one of claims 136 to 159, wherein the second binding domain of the isolated antigen-binding protein comprises at least one CDR in an antibody light chain variable region VL, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:8 or SEQ ID NO:

34.

161. 161. The method of any one of claims 136 to 160, wherein the second binding domain of the isolated antigen binding protein comprises an LCDR3, and the LCDR3 comprises the amino acid sequence set forth in SEQ ID NO:5 or SEQ ID NO:

31.

162. 162. The method of any one of claims 136 to 161, wherein the second binding domain of the isolated antigen binding protein comprises LCDR2, and wherein said LCDR2 comprises the amino acid sequence set forth in SEQ ID NO: 6 (STS) or SEQ ID NO: 32 (AAS).

163. 163. The method of any one of claims 136 to 162, wherein the second binding domain of the isolated antigen binding protein comprises LCDR1, and wherein the LCDR1 comprises the amino acid sequence set forth in SEQ ID NO: 7 or SEQ ID NO:

33.

164. 164. The method of any one of claims 136 to 163, wherein the second binding domain of the isolated antigen binding protein comprises a VL, and the VL comprises the amino acid sequence set forth in SEQ ID NO: 8 or SEQ ID NO:

34.

165. The method of any one of claims 136 to 164, wherein the second binding domain of the isolated antigen-binding protein comprises a VH and a VL, and the VH and VL are connected by a connecting peptide.

166. 166. The method of claim 165, wherein the amino acid sequence of the connecting peptide is (GS)n, where n is a positive integer.

167. 167. The method of any one of claims 136 to 166, wherein the second binding domain of the isolated antigen binding protein is an scFv.

168. 168. The method of claim 167, wherein the scFv of the second binding domain of the isolated antigen binding protein comprises the amino acid sequence set forth in SEQ ID NO:

24.

169. 169. The method of any one of claims 136-168, wherein the isolated antigen binding protein comprises (a) a first binding domain of an anti-IL-17A antibody, and (b) a second binding domain that binds to the anti-IL-17A antibody.

170. 170. The method of claim 169, wherein the second binding domain is a single chain variable region (scFv) of an anti-IL-36R antibody.

171. 171. The method of any one of claims 136 to 170, wherein the second binding domain is directly or indirectly linked to the first binding domain.

172. 172. The method of claim 171, wherein the second binding domain is connected to the first binding domain by a linker.

173. The method of any one of claims 170 to 172, wherein the scFvs of the anti-IL-17A antibody and the anti-IL-36R antibody are linked by a linker sequence.

174. 174. The method of any one of claims 136-173, wherein the isolated antigen binding protein is a homodimer.

175. 175. The method of any one of claims 136-174, wherein the isolated antigen binding protein is a tetravalent antibody.

176. 176. The method of any one of claims 136 to 175, wherein the isolated antigen binding protein is a bispecific antibody.

177. 177. The method of claim 176, wherein the bispecific antibody is a double-chain antibody or a single-chain antibody.

178. The bispecific antibody has the structure shown in Formula I from the N-terminus to the C-terminus: 【Chemistry 2】 where: VH represents the heavy chain variable region of the anti-IL-17A antibody; VL represents the light chain variable region of an anti-IL-17A antibody; CH1, CH2, and CH3 represent the heavy chain constant regions CH1, CH2, and CH3 of the anti-IL-17A antibody, respectively; CL represents the light chain constant region of an anti-IL-17A antibody; ScFv represents the ScFv of the anti-IL-36R antibody; L represents a linker element, "~" represents a disulfide bond, "-" represents a peptide bond; The method of any one of claims 176 to 177, wherein the bispecific antibody has the activity of simultaneously binding to IL-17A and IL-36R.

179. The method according to any one of claims 176 to 178, wherein the bispecific antibody is formed by fusing ScFv of the anti-IL-17A antibody and the anti-IL-36R antibody, and comprises two pairs of mutually symmetric peptide chains, each pair of peptide chains comprising a light chain (L chain) and a heavy chain (H chain), all of the peptide chains being linked by disulfide bonds, and any pair of peptide chains having, from the N-terminus to the C-terminus, the structure of the H chain and L chain shown in Formula I.

180. 180. The method of any one of claims 178 to 179, wherein the bispecific antibody is a homodimer of peptide chains of the structure shown in Formula I.

181. 181. The method of any one of claims 178 to 180, wherein the linker element is a connecting peptide.

182. 182. The method of claim 181, wherein the amino acid sequence of the connecting peptide is (GS)n, where n is a positive integer.

183. 183. The method of any one of claims 179 to 182, wherein the heavy chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO: 25, and the light chain of the bispecific antibody has the amino acid sequence set forth in SEQ ID NO:

23.

184. 184. The method of any one of claims 100-183, wherein the isolated antigen binding protein further comprises a detectable marker, a target marker, a drug, a toxin, a cytokine, a radionuclide, or an enzyme.

185. 185. The method of any one of claims 93 to 184, wherein the medicament optionally further comprises a pharmaceutically acceptable carrier.

186. The drug comprises a nucleic acid molecule encoding the antigen-binding protein.

186. The method of any one of claims 93 to 185.

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